The FAM13A Long Isoform Regulates Cilia Movement and Co-ordination in Airway Mucociliary Transport.

SNPs in the FAM13A locus are amongst the most commonly reported risk alleles associated with chronic obstructive pulmonary disease (COPD) and other respiratory diseases, however the physiological role of FAM13A is unclear. In humans, two major protein isoforms are expressed at the FAM13A locus: 'long' and 'short', but their functions remain unknown, partly due to a lack of isoform conservation in mice. We performed in-depth characterisation of organotypic primary human airway epithelial cell subsets and show that multiciliated cells predominantly express the FAM13A long isoform containing a putative N-terminal Rho GTPase activating protein (RhoGAP) domain. Using purified proteins, we directly demonstrate RhoGAP activity of this domain. In Xenopus laevis, which conserve the long isoform, Fam13a-deficiency impaired cilia-dependent embryo motility. In human primary epithelial cells, long isoform deficiency did not affect multiciliogenesis but reduced cilia co-ordination in mucociliary transport assays. This is the first demonstration that FAM13A isoforms are differentially expressed within the airway epithelium, with implications for the assessment and interpretation of SNP effects on FAM13A expression levels. We also show that the long FAM13A isoform co-ordinates cilia-driven movement, suggesting that FAM13A risk alleles may affect susceptibility to respiratory diseases through deficiencies in mucociliary clearance. This article is open access and distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).

Intolerance of uncertainty, experiential avoidance, and trust in physician: a moderated mediation analysis of emotional distress in advanced cancer.

We tested whether patients' trust in physician moderated the hypothesized indirect association between intolerance of uncertainty (IU; inability to tolerate the unknown) and emotional distress through the mediator, experiential avoidance (EA; efforts to avoid negative emotions, thoughts, or memories), in patients with advanced cancer. The sample included 108 adults with Stage III or IV cancer (53% female; Mage = 63 years) recruited from a metropolitan cancer center. All constructs were measured by standardized self-report instruments. The PROCESS macro for SPSS tested the moderated mediation model. IU evidenced significant direct and indirect relationships with anxiety and depressive symptoms. Trust in physician moderated the indirect relationship between IU and anxiety (not depressive symptoms), albeit in an unexpected direction. Specifically, the indirect relationship between IU and anxiety symptoms through EA was significant for those with moderate to high physician trust but not low trust. Controlling for gender or income did not change the pattern of findings. IU and EA may be key intervention targets, particularly in acceptance-or meaning-based interventions for patients with advanced cancer.

The indirect influence of 'invisible' support on pulmonary function among adults with chronic obstructive pulmonary disease.

Individuals living with chronic obstructive pulmonary disease (COPD) often require support from family or friends. We examined whether invisible support - support that is provided but goes unnoticed - is related to pulmonary function, and whether this association is mediated by depressive symptoms and illness perceptions. Sixty-six dyads of individuals with COPD and their informal caregivers reported on receipt and provision of support, respectively. Those with COPD completed measures of depressive symptoms, illness perceptions and pulmonary function. Although invisible support was not directly related to pulmonary function, mediation analyses revealed a combined indirect effect through lower depressive symptoms and less negative illness perceptions. Interventions teaching skillful delivery of support to caregivers may reduce depressive symptoms and threatening illness cognitions, which may contribute to improvements in symptom burden among patients with COPD.

Relationships between Intolerance of Uncertainty, Worry, Rumination, and Distress in College Students During the Coronavirus Pandemic: the Role of COVID-19 Threat Appraisals.

BACKGROUND: In two conditional process models, we examined whether intolerance of uncertainty (IU) had both direct and indirect effects on coronavirus anxiety (through worry) and depressive symptoms (through rumination) among college students; these associations were hypothesized to be more likely among students who appraised COVID-19 as highly threatening. METHOD: Data were collected during the COVID-19 pandemic from September 2020 to November 2020 in the USA. Participants (n = 134) completed measures of IU, COVID-19 specific threat appraisal, rumination, worry, coronavirus anxiety, and depressive symptoms. The PROCESS macro (Model 8) was used for analyses with gender as a covariate. RESULTS: IU had a direct positive effect on coronavirus anxiety and the effect was strongest among students who perceived COVID-19 as more threatening. Threat appraisal did not moderate the IU-depressive symptoms relationship. IU had an indirect effect on depressive symptoms through rumination at all levels of threat appraisal. Unexpectedly, this indirect effect was strongest among students who perceived the pandemic as less threatening. CONCLUSION: Results may inform interventions that address IU, threat appraisals, and repetitive negative thinking to mitigate symptoms of coronavirus anxiety and depression.

Biomarker opportunities in the treatment of cancer-related depression.

Depression comorbid with cancer is common and associated with a host of negative health outcomes. The inflammatory basis of depression is a growing area of research in cancer, focused on how stressors transduce into inflammation and contribute to the emergence of depression. In this review, we synthesize inflammatory biomarker associations with both depression and the currently available pharmacotherapies and psychotherapies in cancer, underscoring the need for expanding research on anti-inflammatory agents with antidepressant effects. Modulation of inflammatory neuroimmune pathways can slow tumor progression and reduce metastases. Biomarkers associated with depression in cancer may help with diagnosis and treatment monitoring, as well as inform research on novel drug targets to potentially improve cancer survival.

Coping self-efficacy, perceived helpfulness of coping, and distress: a longitudinal investigation of breast and gynecologic cancer patients undergoing chemotherapy.

We examined changes in coping self-efficacy (CSE) pre- and post-chemotherapy and whether these changes predicted depressive symptoms and perceived stress after chemotherapy among women breast and gynecological cancers. We further tested whether perceived helpfulness of coping strategies used during chemotherapy influenced these effects. In a longitudinal design, participants (n = 79) provided data on CSE, depressive symptoms, and perceived stress pre-chemotherapy, post-chemotherapy (~ 4 months later), and at 8 and 12-month follow-up. During chemotherapy, participants completed a one-week daily diary on use and helpfulness of coping strategies in managing side effects. CSE decreased during chemotherapy, returning to baseline levels at follow-up. Higher problem-focused CSE pre- and post-chemotherapy predicted increases in distress among women who appraised their coping strategies as low or average in helpfulness during chemotherapy; problem-focused CSE was unrelated to changes in distress at high levels of perceived helpfulness. Increases in coping self-efficacy without concomitant helpful coping strategies may be markers for poor adjustment post-chemotherapy and identify patients who could benefit from psychosocial services. Combined education and skills-based interventions to align self-efficacy beliefs with coping strategies may reduce psychological burden.

Screening for Distress and Health Outcomes in Head and Neck Cancer.

Head and neck cancers (HNC) have higher rates of emotional distress than other cancer types and the general population. This paper compares the prevalence of emotional distress in HNC across various distress screening measures and examines whether significant distress or distress screening are associated with cancer-related survival. A retrospective observational cohort design was employed, with data collected from the Distress Assessment and Response Tool (DART) and linkages to administrative databases from 2010 to 2016. Descriptive and prevalence data were reported using multiple concurrently administered distress tools, including the Patient Health Questionaire-9 (PHQ-9), Generalized Anxiety Disorders-7 (GAD-7), Edmonton Symptom Assessment Scale-revised (ESAS-r), and MD Anderson Symptom Index-Head and Neck module (MDASI-HN). Across measures, 7.8 to 28.1% of the sample reported clinically significant emotional distress, with PHQ-9 and GAD-7 identifying lowest prevalence of moderate/severe distress, and the ultrashort distress screens within ESAS-r and MDASI-HN performing equivalently. Cox hazards models were used in univariate and multivariate survival analyses. ESAS depression (≥4), but not anxiety, was associated with increased risk of cancer-related mortality and patient completion of DART was associated with greater cancer-related survival. The findings underscore the importance of implementing routine distress screening for HNC populations and the utility of ultra-brief screening measures.

Recent trends in the management of depression in persons with cancer.

PURPOSE OF REVIEW: Depression is a prevalent comorbidity in cancer that significantly increases the risk for numerous negative health outcomes. This review updates the current evidence base for management of depression in cancer, highlighting new research directions based on the inflammatory hypothesis of depression. RECENT FINDINGS: Research on pharmacotherapy and psychotherapy for depression in cancer has shown mixed efficacy partly because of methodological issues arising from the phenomenology of depression in cancer. After decades of stagnancy, more recent high-quality clinical trials are beginning to provide an evidence base to guide treatment. Inflammatory cytokine-associated depression is a subtype of depression that may have particular relevance in cancer, opening new avenues to explore therapeutic targets and biobehavioral impacts of interventions, which may improve cancer outcomes. SUMMARY: The continuum of severity in cancer-related depression is important to consider in management approaches. Choice of treatment should be personalized to the patient and their symptom profile as there is currently insufficient evidence to recommend any particular medication or psychotherapy over another. Psychological interventions should be considered first line for mild-to-moderate depression, and pharmacological treatment added for more severe depression, which can be optimally delivered within a collaborative care model. VIDEO ABSTRACT: http://links.lww.com/YCO/A62.

Tolerating Uncertainty in the Dark: Insomnia Symptoms, Distress, and Well-Being Among Parents of Adolescents and Young Adults with Cancer.

BACKGROUND: Given the need to better understand mechanisms linking poor sleep and psychological distress in the context of chronic illness, we explored a novel factor, intolerance of uncertainty (IU), in relation to insomnia among parents of adolescents and young adults (AYAs) with cancer. We hypothesized that parents with higher IU would report greater insomnia symptoms, which would be associated with higher anxiety and depressive symptoms. These greater levels of anxiety and depressive symptoms are hypothesized to mediate the relationship between insomnia symptoms and subjective well-being (SWB). METHOD: Surveying 59 parents of AYAs with cancer, we computed a parallel-serial mediational analysis using bootstrapping techniques for ordinary least squares regression to test two pathways (adjusting for whether the AYA currently resided with the parent). The first serial pathway was IU→insomnia symptoms→anxiety symptoms→SWB. The second pathway was IU→insomnia symptoms→depressive symptoms→SWB. RESULTS: Although the first pathway involving sleep and anxiety as serial mediators was nonsignificant, the second pathway with sleep and depressive symptoms was significant. The relationship between IU and SWB was mediated through insomnia and depressive symptoms. An alternative serial mediation analysis wherein depressive symptoms preceded sleep was not significant, lending support to study findings. CONCLUSION: This study provides preliminary evidence that IU's detrimental influence on depression and SWB may operate through its influence on insomnia symptoms. Given implications for parents' well-being and, likely, their subsequent capacity to care for the AYA with cancer, interventions addressing IU and disturbed sleep among this underserved population deserve attention.

Emotional adjustment among parents of adolescents and young adults with cancer: the influence of social constraints on cognitive processing and fear of recurrence.

Parents of adolescents and young adults (AYAs) with cancer experience distress comparable to other caregiver populations, but remain understudied. This study tested the social cognitive processing model of emotional adjustment to cancer. We hypothesized that social constraints on emotional disclosure would inhibit cognitive processing and be related to greater fear of cancer recurrence (FCR), potentially negatively influencing psychological adjustment. Data were collected through an online cross-sectional survey study of 66 parents of AYAs with cancer (aged 15-39) and analyzed using bootstrapping techniques for ordinary least squares regression. One-third of the parents reported moderate to severe depressive symptoms. Serial mediation analyses indicated that greater social constraints were related to poorer cognitive processing and higher FCR, and, ultimately, greater depressive symptoms. Alternative models were tested and were not significant. Future psychosocial interventions for parents of AYAs with cancer should include improving cancer-related communication between parents and their social network.

Emotion regulation therapy for cancer caregivers-an open trial of a mechanism-targeted approach to addressing caregiver distress.

Informal caregivers (ICs) are integral to care provided to patients facing life-threatening or incurable illnesses. This responsibility causes considerable burden, as approximately one half of ICs report clinically significant symptoms of depression and/or anxiety that persist when left untreated. Psychosocial interventions containing efficacious treatment principles (e.g., cognitive behavior therapy [CBT]) show disappointing results in reducing anxiety and depression in ICs. This may reflect failure of these interventions to specifically target crucial mechanisms underlying the central feature of distress caused by the patient's illness-notably, perseverative negative thinking (PNT). Emotion Regulation Therapy (ERT) is an efficacious CBT developed to explicitly target mechanisms underlying PNT and the emotional concomitants that arise in response to stressful situations. This open trial was conducted to evaluate the acceptability and initial efficacy of ERT adapted to the experience of cancer ICs (ERT-C). Thirty-one ICs provided informed consent and completed eight weekly individual sessions of ERT-C. Participants completed self-report measures of depression and anxiety symptoms, PNT, emotion regulation deficits, and caregiver burden before and after treatment. ERT-C was well tolerated as indicated by 22 treatment completers and feedback provided in exit interviews. ICs demonstrated reduced depression and anxiety symptoms, PNT, and emotion regulation deficits with moderate to large effect sizes (Hedge's g range: 0.36-0.92). Notably, caregiver burden was not reduced but ICs expressed more ability to confront caregiving-related challenges. Findings offer promising but preliminary support for ERT-C as a conceptual model and treatment modality for distressed cancer ICs.

Illness Uncertainties Tied to Developmental Tasks Among Young Adult Survivors of Hematologic Cancers.

PURPOSE: Young adulthood is a period of building autonomy, relationships, and careers. Experiencing cancer as a young adult (YA) is an "off-time" event in the normative adult life cycle and may interrupt age-specific goals. The majority of prior research on illness uncertainty centers on medical concerns about recurrence or mortality. The current study identifies how YA survivors of hematologic cancers, an understudied group, experience illness uncertainties related to the developmental tasks of young adulthood. METHODS: This is a qualitative study of 53 YA hematologic cancer survivors, ages 20-39. Participants completed hour-long semistructured interviews about psychological, social, and treatment-related aspects of their cancer experience. Interviews were transcribed and coded using an abductive approach to qualitative analysis. RESULTS: Most participants (80%) spontaneously described at least one illness uncertainty tied to developmental tasks. Fertility was the most commonly reported type of uncertainty (55%), with more women than men reporting it, followed by family and intimate relationships (43%), peers and social life (36%), and academic or career goals (26%). These uncertainties were described with reference to the off-time nature of illness. Example excerpts are provided and interpreted. CONCLUSIONS: These findings have the potential to advance our understanding of the cancer experience of YA survivors by expanding on the notion of illness uncertainty in this population. Given the extent to which uncertainties related to developmental tasks were reported, tailored interventions targeting these concerns may improve quality of life among YAs with hematologic cancers.

In silico and in vitro evaluation of exonic and intronic off-target effects form a critical element of therapeutic ASO gapmer optimization.

With many safety and technical limitations partly mitigated through chemical modifications, antisense oligonucleotides (ASOs) are gaining recognition as therapeutic entities. The increase in potency realized by 'third generation chemistries' may, however, simultaneously increase affinity to unintended targets with partial sequence complementarity. However, putative hybridization-dependent off-target effects (OTEs), a risk historically regarded as low, are not being adequately investigated. Here we show an unexpectedly high OTEs confirmation rate during screening of fully phosphorothioated (PS)-LNA gapmer ASOs designed against the BACH1 transcript. We demonstrate in vitro mRNA and protein knockdown of off-targets with a wide range of mismatch (MM) and gap patterns. Furthermore, with RNase H1 activity residing within the nucleus, hybridization predicted against intronic regions of pre-mRNAs was tested and confirmed. This dramatically increased ASO-binding landscape together with relatively high potency of such interactions translates into a considerable safety concern. We show here that with base pairing-driven target recognition it is possible to predict the putative off-targets and address the liability during lead design and optimization phases. Moreover, in silico analysis performed against both primary as well as spliced transcripts will be invaluable in elucidating the mechanism behind the hepatoxicity observed with some LNA-modified gapmers.

Development of multimedia informational tools for breast cancer patients with low levels of health literacy.

OBJECTIVE: To create informational tools for breast cancer patients with low levels of health literacy. METHODS: Tools were developed through a three-stage process. (1) Focus groups were conducted with breast cancer survivors and interviews were held with health educators to determine content, source of information, format and medium of the tools. (2) Based on this feedback, a suite of tools was developed. (3) Focus groups were reconvened and health educators re-interviewed to obtain feedback and determine satisfaction. RESULTS: We developed a suite of five informational tools using low health literacy principles, which focused on learning about breast cancer resources and learning about the members of one's healthcare team, understanding the "journey" or trajectory of care beginning at diagnosis, hearing from other breast cancer patients about their own journey, and becoming informed about what to expect pre-and post-surgery for breast cancer. The final products were rated highly by breast cancer survivors. CONCLUSION: The developed materials, designed for patients who read below an 8th grade level, reflect the informational needs reported by breast cancer patients. PRACTICE IMPLICATIONS: Healthcare providers must consider utilizing design principles and theories of adult learning appropriate for those with low health literacy.

Randomized trial of functional electrical stimulation therapy for walking in incomplete spinal cord injury: effects on quality of life and community participation.

BACKGROUND: Functional electrical stimulation (FES) therapy has been applied to achieve functional benefits post spinal cord injury (SCI), but little is known about its effects on well-being. OBJECTIVE: Using a parallel-group randomized controlled trial (RCT) design (NCT00201968), the effects of a FES-assisted walking intervention on quality of life and participation post SCI were compared to a non-FES exercise program. METHODS: Individuals with chronic (≥18 months) incomplete SCI (level C2 to T12, AIS C or D) were randomized to a FES-assisted walking (intervention) or aerobic/resistance training (control) sessions 3 times a week for 16 weeks. The Spinal Cord Independence Measure (SCIM), Satisfaction With Life Scale, Lawton Instrumental Activities of Daily Living, Craig Handicap and Assessment Reporting Technique, Reintegration to Normal Living Index, and perceptions of intervention(s) outcomes were completed at baseline, 4, 6, and 12 months. Repeated measures general linear models were used to assess between-group differences. Perceptions of intervention(s) were analyzed using qualitative content analysis. RESULTS: Thirty-four individuals were randomized (17 per group); 27 remained at 12 months. The FES group had a significant increase (P < .01) on SCIM mobility subscores (mean [SD] = 17.27 [7.2] to 21.33 [7.6]) compared to the exercise group (mean [SD] = 19.9 [17.1] to 17.36 [5.5]). Although no significant between-group differences were detected for other outcomes, both groups reported positive gains in well-being from trial participation. CONCLUSIONS: The present study provides insight into the perceived benefits acquired by participating in an RCT comparing exercise to FES therapy and serves as a model for pinpointing domains of well-being that could be targeted for assessment in future SCI trials.

Enhancement of axonal regeneration by in vitro conditioning and its inhibition by cyclopentenone prostaglandins.

Axonal regeneration is enhanced by the prior ;conditioning' of peripheral nerve lesions. Here we show that Xenopus dorsal root ganglia (DRG) with attached peripheral nerves (PN-DRG) can be conditioned in vitro, thereafter showing enhanced neurotrophin-induced axonal growth similar to preparations conditioned by axotomy in vivo. Actinomycin D inhibits axonal outgrowth from freshly dissected PN-DRG, but not from conditioned preparations. Synthesis of mRNAs that encode proteins necessary for axonal elongation might therefore occur during the conditioning period, a suggestion that was confirmed by oligonucleotide microarray analysis. Culturing PN-DRG in a compartmentalized system showed that inhibition of protein synthesis (but not RNA synthesis) in the distal nerve impaired the conditioning response, suggesting that changes in gene expression in cultured DRG depend on the synthesis and retrograde transport of protein(s) in peripheral nerves. The culture system was also used to demonstrate retrograde axonal transport of several proteins, including thioredoxin (Trx). Cyclopentenone prostaglandins, which react with Trx, blocked the in vitro conditioning effect, whereas inhibition of other signalling pathways thought to be involved in axonal regeneration did not. This suggests that Trx and/or other targets of these electrophilic prostaglandins regulate axonal regeneration. Consistent with this hypothesis, morpholino-induced suppression of Trx expression in dissociated DRG neurons was associated with reduced neurite outgrowth.

Effective gene delivery to adult neurons by a modified form of electroporation.

Non-viral methods of transfection of cDNAs into adult neurons and other post-mitotic cells are generally very inefficient. However, the recent development of Nucleofector technology developed by Amaxa Biosystems allows direct delivery of cDNAs into the nucleus, enabling transfection of non-dividing cells. In this study, we describe a reliable method for culturing large numbers of retinal cells from adult rats and using Nucleofection, we were able to transfect cDNA-encoding GFP (jellyfish green fluorescent protein) into retinal ganglion cells (RGCs) with relatively high efficiency (up to 28%). Neuronal GFP expression was observed within 18 h and continued for up to 14 days. This compares with values up to 60% of RGCs expressing GFP following infection with an HSV-1 vector. Adult rat dorsal root ganglion (DRG) neurons were also successfully transfected. Thus, in summary, Nucleofection provides the possibility for a fast and efficient method for cDNA delivery and study of gene function in adult mammalian neurons.

Involvement of alpha7beta1 integrin in the conditioning-lesion effect on sensory axon regeneration.

Conditioning lesions of peripheral nerves improve axonal regeneration after injury and involve changes in expression of proteins required for axonal growth. Integrin alpha7beta1 expression in motor and sensory neurons increases following nerve lesions and motor axon regeneration is impaired in alpha7 integrin KO mice (J. Neurosci. 20, 1822-1830). To investigate the role of alpha7beta1 integrin in sensory axon regeneration, dorsal root ganglia of adult mice were cultured in gels of laminin-rich extracellular matrix (Matrigel) or collagen. Normal dorsal root ganglia in Matrigel or collagen supplemented with laminin showed spontaneous axonal outgrowth, which was greatly increased in conditioned preparations, but only in the presence of laminin. Conditioned dorsal root ganglia from normal mice cultured with a blocking antibody to beta1 integrin and from alpha7 integrin KO mice showed reduced axonal growth in both Matrigel- and laminin-supplemented collagen gels. Enhanced axonal regeneration after conditioning lesions therefore involves increased responsiveness to laminin and integrin alpha7beta1 expression.