Childhood maltreatment, psychological resources, and depressive symptoms in women with breast cancer.

Childhood maltreatment is associated with elevated risk for depression across the human lifespan. Identifying the pathways through which childhood maltreatment relates to depressive symptoms may elucidate intervention targets that have the potential to reduce the lifelong negative health sequelae of maltreatment exposure. In this cross-sectional study, 271 women with early-stage breast cancer were assessed after their diagnosis but before the start of adjuvant treatment (chemotherapy, radiation, endocrine therapy). Participants completed measures of childhood maltreatment exposure, psychological resources (optimism, mastery, self-esteem, mindfulness), and depressive symptoms. Using multiple mediation analyses, we examined which psychological resources uniquely mediated the relationship between childhood maltreatment and depressive symptoms. Exposure to maltreatment during childhood was robustly associated with lower psychological resources and elevated depressive symptoms. Further, lower optimism and mindfulness mediated the association between childhood maltreatment and elevated depressive symptoms. These results support existing theory that childhood maltreatment is associated with lower psychological resources, which partially explains elevated depressive symptoms in a sample of women facing breast cancer diagnosis and treatment. These findings warrant replication in populations facing other major life events and highlight the need for additional studies examining childhood maltreatment as a moderator of treatment outcomes

Predicting the Tolerated Sequences for Proteins and Protein Interfaces Using RosettaBackrub Flexible Backbone Design

Predicting the set of sequences that are tolerated by a protein or protein interface, while maintaining a desired function, is useful for characterizing protein interaction specificity and for computationally designing sequence libraries to engineer proteins with new functions. Here we provide a general method, a detailed set of protocols, and several benchmarks and analyses for estimating tolerated sequences using flexible backbone protein design implemented in the Rosetta molecular modeling software suite. The input to the method is at least one experimentally determined three-dimensional protein structure or high-quality model. The starting structure(s) are expanded or refined into a conformational ensemble using Monte Carlo simulations consisting of backrub backbone and side chain moves in Rosetta. The method then uses a combination of simulated annealing and genetic algorithm optimization methods to enrich for low-energy sequences for the individual members of the ensemble. To emphasize certain functional requirements (e.g. forming a binding interface), interactions between and within parts of the structure (e.g. domains) can be reweighted in the scoring function. Results from each backbone structure are merged together to create a single estimate for the tolerated sequence space. We provide an extensive description of the protocol and its parameters, all source code, example analysis scripts and three tests applying this method to finding sequences predicted to stabilize proteins or protein interfaces. The generality of this method makes many other applications possible, for example stabilizing interactions with small molecules, DNA, or RNA. Through the use of within-domain reweighting and/or multistate design, it may also be possible to use this method to find sequences that stabilize particular protein conformations or binding interactions over others

Elevated cortisol awakening response associated with early life stress and impaired executive function in healthy adult males

Experiencing early life stress (ELS) and subsequent dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis may play a role in the aetiology of mental health disorders. However, the exact mechanisms linking HPAaxis dysregulation with the development of psychopathology have not been fully delineated. Progress in this area is hampered by the complex and often conflicting associations found between markers of HPA-axis function and risk factors for mental health disorders such as impaired executive function (EF) and ELS. This study investigated the association of the cortisol awakening response (CAR) with ELS and EF in a healthy adult male population (n =109, aged 21–63). As previous inconsistencies in CAR and ELS association studies may be the result of not considering ELS-related factors such as cumulative exposure, type of stressor and developmental timing of ELS, these were also investigated. The main findings were that the CAR was significantly elevated in individuals reporting ELS compared to those reporting no ELS (p =0.007) and that an elevated CAR predicted poorer problem solving/planning (p=0.046). Cumulative exposure, type of stressor and developmental timing of ELS were also found to impact significantly on the CAR. These results suggest that ELS is associated with chronic changes in HPA-axis function and that these changes may be associated with impairments in problem solving/ planning. Future work should investigate further the neurobiological mechanisms linking ELS, the CAR and EF and their role in conferring risk for the development of mental health disorders

Tumor Biology and Immune Infiltration Define Primary Liver Cancer Subsets Linked to Overall Survival After Immunotherapy

Primary liver cancer is a rising cause of cancer deaths in the US. Although immunotherapy with immune checkpoint inhibitors induces a potent response in a subset of patients, response rates vary among individuals. Predicting which patients will respond to immune checkpoint inhibitors is of great interest in the field. In a retrospective arm of the National Cancer Institute Cancers of the Liver: Accelerating Research of Immunotherapy by a Transdisciplinary Network (NCI-CLARITY) study, we use archived formalin-fixed, paraffin-embedded samples to profile the transcriptome and genomic alterations among 86 hepatocellular carcinoma and cholangiocarcinoma patients prior to and following immune checkpoint inhibitor treatment. Using supervised and unsupervised approaches, we identify stable molecular subtypes linked to overall survival and distinguished by two axes of aggressive tumor biology and microenvironmental features. Moreover, molecular responses to immune checkpoint inhibitor treatment differ between subtypes. Thus, patients with heterogeneous liver cancer may be stratified by molecular status indicative of treatment response to immune checkpoint inhibitors

Targeted insertion of large genetic payloads using cas directed LINE-1 reverse transcriptase

A difficult genome editing goal is the site-specific insertion of large genetic constructs. Here we describe the GENEWRITE system, where site-specific targetable activity of Cas endonucleases is coupled with the reverse transcriptase activity of the ORF2p protein of the human retrotransposon LINE-1. This is accomplished by providing two RNAs: a guide RNA targeting Cas endonuclease activity and an appropriately designed payload RNA encoding the desired insertion. Using E. coli as a simple platform for development and deployment, we show that with proper payload design and co-expression of helper proteins, GENEWRITE can enable insertion of large genetic payloads to precise locations, although with off-target effects, using the described approach. Based upon these results, we describe a potential strategy for implementation of GENEWRITE in more complex systems

Our Collective Expressions of 2020

Tiger King, Cicadas, sourdough, wildfires, RBG, the election, and COVID. As the year ends, celebrate, grieve, and question all the craziness that 2020 threw at us by contributing to Bryant’s first ever zine.https://digitalcommons.bryant.edu/zine/1000/thumbnail.jp

Cortisol Awakening Response as a Prospective Risk Factor for Depressive Symptoms in Women After Treatment for Breast Cancer.

ObjectiveThe aim of the study was to investigate hypothalamic-pituitary-adrenal axis (HPA axis) functioning as a neurobiological risk factor for depressive symptoms in an ongoing longitudinal, observational study of women undergoing treatment and recovery from breast cancer. Many women with breast cancer experience depressive symptoms that interfere with their treatment, recovery, and quality of life. Psychosocial risk factors for depression among patients with cancer and survivors have been identified, yet neurobiological risk factors in this population remain largely unexamined.MethodsWomen recently diagnosed with early-stage breast cancer (N = 135) were enrolled before starting neoadjuvant/adjuvant treatment (radiation, chemotherapy, endocrine therapy). At baseline, participants collected saliva samples to measure diurnal HPA axis functioning for 3 days: at waking, 30 minutes after waking, 8 hours after waking, and bedtime. Participants also completed a standardized measure of depressive symptoms (Center for Epidemiological Studies-Depression Scale) at baseline and 6 months after completion of primary treatment. Multivariate regression was used to predict continuous depressive symptoms at 6-month posttreatment from continuous depressive symptoms at baseline, cortisol awakening response (CAR), and other measures of diurnal HPA axis functioning.ResultsThe magnitude of CAR predicted changes in depressive symptoms over time, such that women with a higher CAR showed a greater increase from baseline to 6-month posttreatment (b = 5.67, p = .023). Diurnal slope and total cortisol output were not associated with concurrent depressive symptoms or their change over time.ConclusionsElevated CAR may be a neurobiological risk factor for increases in depressive symptoms in the months after breast cancer treatment and warrants further investigation