CRLF2 rearrangement in Ph-like acute lymphoblastic leukemia predicts relative glucocorticoid resistance that is overcome with MEK or Akt inhibition.

Philadelphia chromosome-like (Ph-like) acute lymphoblastic leukemia (ALL) is a genetically heterogeneous subtype of B-cell ALL characterized by chromosomal rearrangements and mutations that result in aberrant cytokine receptor and kinase signaling. In particular, chromosomal rearrangements resulting in the overexpression of cytokine receptor-like factor 2 (CRLF2) occur in 50% of Ph-like ALL cases. CRLF2 overexpression is associated with particularly poor clinical outcomes, though the molecular basis for this is currently unknown. Glucocorticoids (GCs) are integral to the treatment of ALL and GC resistance at diagnosis is an important negative prognostic factor. Given the importance of GCs in ALL therapy and the poor outcomes for patients with CRLF2 overexpression, we hypothesized that the aberrant signal transduction associated with CRLF2 overexpression might mediate intrinsic GC insensitivity. To test this hypothesis, we exposed Ph-like ALL cells from patient-derived xenografts to GCs and found that CRLF2 rearranged (CRLF2R) leukemias uniformly demonstrated reduced GC sensitivity in vitro. Furthermore, targeted inhibition of signal transduction with the MEK inhibitor trametinib and the Akt inhibitor MK2206, but not the JAK inhibitor ruxolitinib, was sufficient to augment GC sensitivity. These data suggest that suboptimal GC responses may in part underlie the poor clinical outcomes for patients with CRLF2 overexpression and provide rationale for combination therapy involving GCs and signal transduction inhibitors as a means of enhancing GC efficacy

Piloting an Oral History Approach to Investigate Cancer Perspectives Among Residents of Appalachian Kentucky

Introduction: Kentucky ranks first in the U.S. in overall cancer incidence and mortality rates. Areas of the state that fall within the Appalachian Region, along Kentucky’s eastern border, experience disproportionately high rates of cancer compared to non-Appalachian counties. Purpose: This pilot study investigates whether oral history interviews can be used to understand perspectives on cancer among residents of Appalachian Kentucky. Methods: In 2020, participants (n = 5) who identified as being from and/or having strong connections to Appalachian Kentucky were recruited to participate in this pilot study. Participants included individuals working in cancer-related fields, oncology professionals, and those with personal cancer experience. Using an oral history approach, subjects were asked about challenges within Appalachia that contribute to high rates of cancer regionally. Interviews were analyzed using qualitative content analysis, and data were condensed into themes, subthemes, and subtopics. Relational content analysis was then used to illustrate relationships between the problems being faced in Appalachia and their contributing factors, with potential solutions to those problems. Results: Six key themes emerged from analysis of the oral history interviews: (1) problems being faced in Appalachia; (2) contributing factors; (3) potential solutions; (4) Appalachian disposition; (5) experiences with and thoughts on cancer; and (6) defining success v. the future without changes (intervention). A further 25 subthemes were identified from within these themes. Taken together, these themes and subthemes point to potential areas for specific intervention to shift Appalachia’s cancer burden. Implications: This pilot study demonstrates potential benefit in using oral history interviews to elucidate Appalachian Kentuckians’ perspectives on cancer. From the nuanced insights gained through this method, a set of culturally appropriate interventions were identified that could address the disproportionate cancer burden in the region. Future studies using an oral history approach could aim to reveal other specific aspects of how cancer impacts individuals, families, and communities

Adhesion, Stiffness and Instability in Atomically Thin MoS2 Bubbles

We measured the work of separation of single and few-layer MoS2 membranes from a SiOx substrate using a mechanical blister test, and found a value of 220 +- 35 mJ/m^2. Our measurements were also used to determine the 2D Young's modulus of a single MoS2 layer to be 160 +- 40 N/m. We then studied the delamination mechanics of pressurized MoS2 bubles, demonstrating both stable and unstable transitions between the bubbles' laminated and delaminated states as the bubbles were inflated. When they were deflated, we observed edge pinning and a snap-in transition which are not accounted for by the previously reported models. We attribute this result to adhesion hysteresis and use our results to estimate the work of adhesion of our membranes to be 42 +- 20 mJ/m^2

#6 - Implications of Visual Social Access on the Welfare and Behavior of Shelter Dogs

Given the large number of dogs housed in animal shelters each year, it is important to consider how the shelter environment impacts dog welfare. The shelter environment is stressful due to factors such as excessive noise, lack of predictability and control, and social isolation. Social isolation in shelter dogs has been found to increase abnormal behavior and aggression and lead to poorer adoption outcomes. While social housing is ideal, it requires resources not available to all shelters. Providing visual access to other dogs is a relatively easy environmental modification that increases social opportunities and allows for more predictability and control over the environment, potentially improving welfare. To investigate the impact of visual access on the behavior of dogs, we used a within-subject design, conducting 5-min focal observations four times weekly before, during, and after visual access was provided by partially removing a barrier between crates at a suburban dog shelter. Our preliminary analysis of 17 subjects using non-parametric Friedman’s Tests (alpha = .05) found no significant difference between phases in regard to anxiety behaviors (χ2 (2) = .50, p = .78), frustration behaviors (χ2 (2) = .51, p = .77), time spent in the front of the crate (χ2 (2) = 4.50, p = .11), self-directed behaviors (χ2 (2) = 1.86, p = .40), resting behaviors (χ2 (2) = 4.59, p = .10), or vocalizations (χ2 (2) = 4.59, p= .10). The absence of an increase in vocalizations during visual access may encourage shelters to implement this change. However, the lack of a decrease in anxiety or frustration behaviors may indicate that visual access alone is insufficient for providing welfare benefits and that shelters should prioritize increasing social contact in dogs through playgroups or group housing. Keywords: shelter dog, animal welfare, barking, social housing, visual access, social contact, anxiety, environmental predictability, choic

Implications of Visual Social Access on the Welfare and Behavior of Shelter Dogs

Animal shelter environments have many stressful factors that impact the welfare of shelter dogs, such as lack of predictability and control, and social isolation. Social isolation has been found to increase abnormal behavior and lead to poorer adoption outcomes. Providing visual access to shelter dogs is a relatively easy environmental modification that increases social opportunities and allows for more predictability and control over the environment, potentially improving welfare. To investigate the impact of visual access on the behavior of dogs, we used a within-subject design, conducting 5-min focal observations four times weekly before, during, and after visual access was provided by partially removing a barrier between crates at a suburban dog shelter. Our preliminary analysis of 17 subjects using non-parametric Friedman’s Tests (alpha = .05) found no significant difference between phases in regard to anxiety behaviors (χ2 (2) = .50, p = .78), frustration behaviors (χ2 (2) = .51, p = .77), time spent in the front of the crate (χ2 (2) = 4.50, p = .11), self-directed behaviors (χ2 (2) = 1.86, p = .40), resting behaviors (χ2 (2) = 4.59, p = .10), or vocalizations (χ2 (2) = 4.59, p = .10). The absence of an increase in vocalizations during visual access may encourage shelters to implement this change. However, the lack of a decrease in anxiety or frustration behaviors may indicate that visual access alone is insufficient for providing welfare benefits and that shelters should prioritize increasing social contact in dogs through playgroups or group housing

The Effects of Olfactory Enrichment on Shelter Dog Behavior

Shelter environments are stressful for dogs due to loud noises and unfamiliar surroundings. Previous research showed that exposure to some scents resulted in reductions in activity and vocalizations in shelter dogs. We investigated the effects of two calming (lavender and vetiver) and two stimulating (lemon and rosemary) essential oils on crate position and active, resting, and stress behaviors. There were 8, 5-min observations conducted each week per dog, split between baseline and scent exposure. Our analysis using the Wilcoxon Signed-Rank test found that dogs exposed to lavender (n = 13), lemon (n = 10), rosemary (n = 13), and vetiver (n = 12) did not show a significant difference in crate position or amount of time they engaged in stress, resting, or active behaviors compared to baseline. The lack of behavioral improvement indicates that scent enrichment alone may not be enough to have a significant effect on shelter dog behavior

The Effects of Perspective Taking Implementing Intentions on Employee Evaluations and Hostile Sexism

The current research examined whether gender bias in the workplace could be reduced through perspective taking implementation intentions, which are if–then statements that specify how to accomplish goals (Gollwitzer, 1999). Amazon MTurk participants (N = 180, 53% male) learned they would complete a two-step performance review for a consulting company. Prior to receiving a male or female employee’s record, all participants were given a goal strategy to be fair in their review, with half also receiving an if–then strategy that encouraged perspective taking. Participants rated the employee on three work related dimensions (skillset, performance, and traits), provided an overall promotion recommendation, and completed the Ambivalent Sexism Inventory (Glick & Fiske, 1996). Although we did not find evidence of gender bias on the work measures, we found that the implementation intention strategy resulted in more positive employee evaluations overall and less hostile sexism than a simple goal strategy. We discuss the potential organizational benefits of employing perspective taking implementation intentions

Insistence on sameness relates to increased covariance of gray matter structure in autism spectrum disorder.

BACKGROUND: Autism spectrum disorder (ASD) is characterized by atypical development of cortical and subcortical gray matter volume. Subcortical structural changes have been associated with restricted and repetitive behavior (RRB), a core component of ASD. Behavioral studies have identified insistence on sameness (IS) as a separable RRB dimension prominent in high-functioning ASD, though no simple brain-behavior relationship has emerged. Structural covariance, a measure of morphological coupling among brain regions using magnetic resonance imaging (MRI), has proven an informative measure of anatomical relationships in typical development and neurodevelopmental disorders. In this study, we use this measure to characterize the relationship between brain structure and IS. METHODS: We quantified the structural covariance of cortical and subcortical gray matter volume in 55 individuals with high-functioning ASD using 3T MRI. We then related these structural metrics to individual IS scores, as assessed by the Repetitive Behavior Scale-Revised (RBS-R). RESULTS: We found that increased coupling among subcortical regions and between subcortical and cortical regions related to greater IS symptom severity. Most pronounced, the striatum and amygdala participated in a plurality of identified relationships, indicating a central role for these structures in IS symptomatology. These structural associations were specific to IS and did not relate to any of the other RRB subcomponents measured by the RBS-R. CONCLUSIONS: This study indicates that behavioral dimensions in ASD can relate to the coordination of development across multiple brain regions, which might be otherwise obscured using typical brain-behavior correlations. It also expands the structures traditionally related to RRB in ASD and provides neuroanatomical evidence supportive of IS as a separate RRB dimension. TRIAL REGISTRATION: ClinicalTrials.gov NCT01031407

Cross-genetic determination of maternal and neonatal immune mediators during pregnancy.

BACKGROUND:The immune system plays a fundamental role in development during pregnancy and early life. Alterations in circulating maternal and neonatal immune mediators have been associated with pregnancy complications as well as susceptibility to autoimmune and neurodevelopmental conditions in later life. Evidence suggests that the immune system in adults not only responds to environmental stimulation but is also under strong genetic control. METHODS:This is the first genetic study of > 700 mother-infant pairs to analyse the circulating levels of 22 maternal mid-gestational serum-derived and 42 neonatal bloodspot-derived immune mediators (cytokines/chemokines) in the context of maternal and fetal genotype. We first estimated the maternal and fetal genome-wide SNP-based heritability (h2g) for each immune molecule and then performed genome-wide association studies (GWAS) to identify specific loci contributing to individual immune mediators. Finally, we assessed the relationship between genetic immune determinants and ASD outcome. RESULTS:We show maternal and neonatal cytokines/chemokines displaying genetic regulation using independent methodologies. We demonstrate that novel fetal loci for immune function independently affect the physiological levels of maternal immune mediators and vice versa. The cross-associated loci are in distinct genomic regions compared with individual-specific immune mediator loci. Finally, we observed an interaction between increased IL-8 levels at birth, autism spectrum disorder (ASD) status, and a specific maternal genotype. CONCLUSIONS:Our results suggest that maternal and fetal genetic variation influences the immune system during pregnancy and at birth via distinct mechanisms and that a better understanding of immune factor determinants in early development may shed light on risk factors for developmental disorders

Resilience-Focused HIV Care to Promote Psychological Well-Being During COVID-19 and Other Catastrophes

The COVID-19 pandemic has adversely affected people with HIV due to disruptions in prevention and care services, economic impacts, and social isolation. These stressors have contributed to worse physical health, HIV treatment outcomes, and psychological wellness. Psychological sequelae associated with COVID-19 threaten the overall well-being of people with HIV and efforts to end the HIV epidemic. Resilience is a known mediator of health disparities and can improve psychological wellness and behavioral health outcomes along the HIV Continuum of Care. Though resilience is often organically developed in individuals as a result of overcoming adversity, it may be fostered through multi-level internal and external resourcing (at psychological, interpersonal, spiritual, and community/neighborhood levels). In this Perspective, resilience-focused HIV care is defined as a model of care in which providers promote optimum health for people with HIV by facilitating multi-level resourcing to buffer the effects of adversity and foster well-being. Adoption of resilience-focused HIV care may help providers better promote well-being among people living with HIV during this time of increased psychological stress and help prepare systems of care for future catastrophes. Informed by the literature, we constructed a set of core principles and considerations for successful adoption and sustainability of resilience-focused HIV care. Our definition of resilience-focused HIV care marks a novel contribution to the knowledge base and responds to the call for a multidimensional definition of resilience as part of HIV research