Sanford Research

Small-cell lung carcinoma (SCLC) tumors are heterogeneous, with a subpopulation of cells primed for tumor initiation. Here, we show that Kinase Suppressor of Ras 2 (KSR2) promotes the self-renewal and clonogenicity of SCLC cells. KSR2 is a molecular scaffold that promotes Raf/MEK/ERK signaling. KSR2 is preferentially expressed in the ASCL1 subtype of SCLC (SCLC-A) tumors and is expressed in pulmonary neuroendocrine cells, one of the identified cells of origin for SCLC-A tumors. The expression of KSR2 in SCLC and pulmonary neuroendocrine cells (PNECs) was previously unrecognized and serves as a novel model for understanding the role of KSR2-dependent signaling in normal and malignant tissues. Disruption of KSR2 in SCLC-A cell lines inhibits the colony forming ability of tumor propagating cells (TPCs) in vitro and their tumor initiating capacity in vivo. The effect of KSR2 depletion on self-renewal and clonogenicity is dependent on the interaction of KSR2 with ERK. These data indicate that the expression of KSR2 is an essential driver of SCLC-A tumor propagating cell function, and therefore may play a role in SCLC tumor initiation. These findings shed light on a novel effector promoting initiation of ASCL1-subtype SCLC tumors, and a potential subtype-specific therapeutic target. Implications: Manipulation of the molecular scaffold KSR2 in ASCL1-subtype small-cell lung cancer cells reveals its contribution to self-renewal, clonogenicity, and tumor initiation.

This study examined associations between food insecurity (FI) severity, anxiety symptoms, and sleep duration among young adults in food-insecure households. We hypothesized that more severe FI and higher anxiety would independently predict shorter sleep duration, and that anxiety would amplify the FI-sleep duration relationship. Analysis was conducted on a subsample (n = 96) of the EAT 2010–2018 young adult cohort. Participants completed the U.S. Household Food Security Survey Module, Generalized Anxiety Disorder-7, and sleep assessment items. Linear regression models, controlling for demographics, showed that increased anxiety symptoms were associated with decreased sleep duration (p < .001), while FI severity was not significantly associated. A synergistic interaction between FI severity and anxiety (p = .04) revealed that individuals with severe FI and high anxiety had the shortest sleep duration. Results suggest that people struggling with both FI and anxiety may be at high risk of short sleep. Future interventions for individuals with FI should consider anxiety’s role in influencing sleep disturbance.

Drugs targeting the ghrelin receptor hold therapeutic potential in anorexia, obesity and diabetes. However, developing effective drugs is challenging. To tackle this common issue across a broad drug target, this study aims to understand how anamorelin, the only approved drug targeting the ghrelin receptor, operates compared to other synthetic drugs. Our research elucidated the receptor’s structure with anamorelin and miniGq, unveiling anamorelin’s superagonistic activity. We demonstrated that ligands with distinct chemical structures uniquely bind to the receptor, resulting in diverse conformations and biasing signal transduction. Moreover, our study showcased the utility of structural information in effectively identifying natural genetic variations altering drug action and causing severe functional deficiencies, offering a basis for selecting the right medication on the basis of the individual’s genomic sequence. Thus, by building on structural analysis, this study enhances the foundational framework for selecting therapeutic agents targeting the ghrelin receptor, by effectively leveraging signaling bias and genetic variations.

Objective Outcomes for low‐weight restrictive eating disorders, including anorexia nervosa, restricting type (AN‐R) and avoidant/restrictive food intake disorder (ARFID), are sub‐optimal. Reducing dietary restriction is a key treatment target. Understanding heterogeneity in patterns of change in dietary restriction may aid in improving outcomes. We examined latent trajectories of change in dietary restriction during treatment and follow‐up in AN‐R and ARFID. Methods Adolescents and adults with R‐EDs ( N = 276, 18% ARFID, 90% female, M age = 18) receiving intensive ED treatment completed assessments at five timepoints. Latent growth mixture modeling examined trajectories of change in dietary restriction, measured using the Eating Pathology Symptoms Inventory Restricting subscale. Classes were compared on clinical features at admission to determine characteristics prospectively associated with trajectory. Results A 3‐class solution emerged: Class 1 comprising individuals with “good response” ( n = 138; 33% of those with ARFID in the sample); Class 2 with “good response, rebounding” ( n = 81; 41% of ARFID); and Class 3 with “gradual response, low symptoms” ( n = 57; 26% of ARFID). Class 3 had lower anxiety and R‐ED symptoms than Classes 1 and 2. Class 2 presented with older age than Class 1. Discussion No ARFID‐specific classes emerged, underscoring similarities in response to intensive treatment between AN‐R and ARFID.

Study objectives: Reversal of warfarin-induced anticoagulation using prothrombin complex concentrate (PCC4) is more rapidly achieved than with traditional methods such as fresh frozen plasma (FFP). In many rural facilities the availability of both FFP and PCC4 has been limited. A tertiary hospital instituted a program to provide PCC4 to rural sites using an air transport team and pharmacy exchange. We hypothesized that increasing accessibility of PCC4 would shorten time to INR reversal. Methods: This was a retrospective study with the primary outcome being time to INR reversal (INR ≤1.6) and time to PCC4 administration from outside hospital admission. Active warfarin prescription, transfer to a tertiary facility, and administration of anticoagulation reversal between January 2013 and December 2020 were required for inclusion. Patients were grouped by dates before and after implementation of the program in August 2016. Linear regressions were performed to determine the effect of the variable and INR reversal methods on time to INR reversal as well as time to PCC4 administration. Time to event analysis was used to analyze the primary outcome between comparison groups. p values of less than 0.05 were considered significant. Results: Chart review identified 189 patients: 56 within the pre-implementation group and 133 in the post- implementation group. Statistics were compared between these two groups. The post-implementation group had a shorter time to INR reversal (median 9.97 hours) compared with the pre-implementation group (median 14.58 hours, p = 0.00004). Time to PCC4 administration was also significantly decreased (p = 0.023). No statistically significant differences were found for hospital survival or 30-day mortality. Conclusion: In rural hospitals, increasing availability of PCC4 using air medical transport along with a medication exchange program significantly reduces time to PCC4 administration in warfarin anticoagulated patients.

Feeding and eating disorders (FEDs) are a heterogeneous grouping of disorders at the mind‐body interface, with typical onset from childhood into emerging adulthood. They occur along a spectrum of disordered eating and compensatory weight management behaviors, and from low to high body weight. Psychiatric comorbidities are the norm. In contrast to other major psychiatric disorders, first‐line treatments for FEDs are mainly psychological and/or nutrition‐focused, with medications playing a minor adjunctive role. Patients, carers and clinicians all have identified personalization of treatment as a priority. Yet, for all FEDs, the evidence base supporting this personalization is limited. Importantly, disordered eating and related behaviors can have serious physical consequences and may put the patient's life at risk. In these cases, immediate safety and risk management considerations may at least for a period need to be prioritized over other efforts at personalization of care. This paper systematically reviews several key domains that may be relevant to the characterization of the individual patient with a FED aimed at personalization of management. These domains include symptom profile, clinical subtypes, severity, clinical staging, physical complications and consequences, antecedent and concomitant psychiatric conditions, social functioning and quality of life, neurocognition, social cognition and emotion, dysfunctional cognitive schemata, personality traits, family history, early environmental exposures, recent environmental exposures, stigma, and protective factors. Where possible, validated assessment measures for use in clinical practice are identified. The limitations of the current evidence are pointed out, and possible directions for future research are highlighted. These also include novel and emerging approaches aimed at providing more fine‐grained and sophisticated ways to personalize treatment of FEDs, such as those that utilize neurobiological markers. We additionally outline remote measurement technologies designed to delineate patients’ illness and recovery trajectories and facilitate development of novel intervention approaches.

Cell-free DNAs (cfDNAs) are DNA fragments found in blood. In healthy individuals, cfDNAs are primarily derived from immune cells, while in cancer patients, a significant fraction of cfDNAs originates from cancerous cells. These cancer-derived cfDNAs contain specific mutations, making cfDNA analysis a promising diagnostic biomarker. Recent studies have revealed that epigenetic information, such as DNA methylation and nucleosome positioning, is retained in cfDNAs, enhancing the accuracy of cell-of-origin predictions. This study aims to characterize the chromatin architecture preserved in cfDNAs by looking at nucleosomal DNA enrichment. Nucleosome fragments from both breast and pancreatic cancer patients are significantly enriched in open chromatin regions. A differential enrichment was observed between healthy donors and cancer patients at cell type-specific ATAC-seq peaks. Leveraging this pattern of open chromatin enrichment, we enhanced the prediction accuracy for identifying breast cancer-derived cfDNA through machine learning. Our analysis pipeline provides an interpretable machine learning platform that effectively detects cancer-specific nucleosome enrichment in cfDNAs.

Purpose of Review To highlight recent research on antidepressant use and weight change and explore best clinical practices for reducing weight gain and obesity risk in individuals with depression. Recent Findings Research on antidepressant use and weight gain suggests that genetic and biological factors including metabolizer phenotypes and inflammation can help to predict an individual’s threshold for weight change among specific agents. For individuals with increased susceptibility to metabolic complications, medications including bupropion, fluoxetine, and newer agents (e.g., gepirone) have shown to be efficacious in improving depressive symptoms while concurrently reducing metabolic risks. Additional areas of focus following antidepressant related weight gain include switching to a weight neutral drug alternative, integrated behavioral interventions, and/or pharmacotherapy including GLP-1 receptor agonists (e.g., metformin, liraglutide). Summary Individuals experiencing depression are at heightened risk of metabolic disorders and weight gain, which may be further exacerbated by antidepressant treatment. The increased support of weight neutral antidepressant agents in addition to innovative lifestyle interventions, breakthroughs in drug mechanisms, anti-obesity medications and overall familiarity with the side effects of each antidepressant class will help clinicians make appropriate decisions when treating patients with depression.

Introduction Studies have shown that early weight gain in family‐based treatment (FBT) predicts treatment response in adolescents with anorexia nervosa (AN); however, research examining factors associated with early weight gain in FBT is limited. This study tested the feasibility and acceptability of ecological momentary assessment (EMA) in early FBT, particularly to capture momentary data on family climate during mealtimes. Methods Using multiple methods, quantitative (EMA) and qualitative (interviews) data were collected in the first 4 weeks of FBT. Participants (11 families; 9 adolescents, 19 parents/caregivers) completed EMA assessments daily on the emotional climate during meals, parental strategies and confidence/agreement in renourishment. Qualitative interviews obtained technological and procedural data using EMA. Completion rates and markers of change were explored using repeated measures ANOVA. Interviews were analyzed using reflexive thematic analysis. Results The EMA completion rate for all family members was 78%: 84% for adolescents, 83% for mothers, 64% for fathers. Results demonstrated changes in caregivers' use of renourishment strategies and in the emotional climate (decreased anger) at mealtimes. No changes were observed in caregiver confidence/agreement in renourishment. Qualitative analyses revealed factors interfering with and facilitating the use of EMA. Discussion EMA is an acceptable and feasible tool for use with adolescents and their families in early FBT, particularly to capture momentary data on family climate during mealtimes. Future research is needed with larger sample sizes to examine the mechanisms of change in early FBT, and the utility of EMA as a clinical tool in FBT.

Psychological distress, including anxiety or mood disorders, emanates from the onset of chronic/unpredictable stressful events. Symptoms in the form of maladaptive behaviors are learned and difficult to treat. While the origin of stress-induced disorders seems to be where learning and stress intersect, this relationship and molecular pathways involved remain largely unresolved. The hippocampus, studied for its role in learning, is divided into regions that designate the passage of neuronal signaling during memory formation, including dentate gyrus (DG), CA3, CA2, and CA1. Inputs into these hippocampal subregions, like those from hypothalamic orexinergic neurons, may modify learning outcomes. We have previously shown the orexin system to balance stress states, where receptor subtypes prompt opposing actions on behavior. Here, we explore the connection between hippocampal orexin receptors and learning during stress. In a social stress/learning paradigm separating mice into stress resilient and vulnerable populations, hippocampal Orx1R and Orx2R transcription is regulated in a phenotype-dependent fashion. We further identified Orx1R as highly expressed in the hilus of DG, while Orx2R is abundant in CA2. Finally, we designed an experiment where mice were provided prior exposure to a stressful environment, which ultimately modified behavior, as well as transcription of hippocampal orexin receptors. Supplementary Information The online version contains supplementary material available at 10.1038/s41598-024-81590-w.

Background Accruing evidence suggests that personality-based approaches to eating disorder classification may offer several advantages over current diagnostic models, with prior research consistently identifying three personality-based groups characterized by either (1) high levels of impulsivity and dysregulation (termed the “undercontrolled” group), (2) high levels of rigidity and avoidance (termed the “overcontrolled” group), or (3) relatively normative levels of personality functioning (termed the “low psychopathology” group). Cognitive inflexibility (i.e., difficulty adjusting thoughts or behaviors) has theorized relevance to eating disorders. However, prior research has frequently failed to observe differences in cognitive inflexibility across eating disorder diagnostic groups. The present study aimed to identify personality-based groups in an eating disorder sample, and then to examine the relations between these groups and behavioral measures of cognitive inflexibility. Method 83 men and women who met DSM-5 criteria for anorexia nervosa or bulimia nervosa completed self-report questionnaires to assess trait-level approach/avoidance behaviors and impulsivity, as well as behavioral tasks assessing attentional set-shifting and reversal learning, two facets of cognitive inflexibility. Results Latent profile analysis of measures assessing approach/avoidance behaviors and impulsivity supported a three-class model replicating the undercontrolled, overcontrolled, and low psychopathology groups. Notably, the low psychopathology group was characterized by elevated reward responding. One-way ANOVAs indicated that the low psychopathology group demonstrated heightened perseverative errors (an indicator of impaired reversal learning) relative to the other groups. No group differences were observed for attentional set-shifting errors or probabilistic switch errors. Discussion Findings from the present study provide additional support for personality-based classification approaches identifying undercontrolled, overcontrolled, and low psychopathology eating disorder groups. Results also suggest that reward-related processes may contribute to disorder maintenance in the low psychopathology group, indicating potentially meaningful targets for intervention.

Objective Dysregulated eating is common among youth and is associated with trait‐level negative affect and emotion regulation difficulties. Despite the transient nature of affect, momentary associations among affect and eating behavior are unclear, which limits development of more impactful treatment tools, such as “just‐in‐time” intervention approaches (JITAI). The current study ( N = 62) drew from two ecological momentary assessment (EMA) studies involving children and adolescents who endorsed loss of control (LOC) eating symptoms during a two‐week assessment period. Method Intensive time series network analysis tested concurrent and prospective relationships across six specific affective states (i.e., upset, guilty, scared, tired, excited, attentive) and four eating‐related experiences (e.g., LOC, overeating, hunger, craving) in real time. Additionally, we repeated these models within demographic subgroups of the sample based on age, race, and sex. Results In the full‐sample models, contemporaneously assessed guilt was associated with craving and LOC eating, and tiredness was associated with LOC eating. In the prospective analysis, tiredness was negatively predicted by LOC eating and positively predicted by overeating at the previous timepoint, and attentiveness positively predicted craving. Differences in affect‐eating relationships were identified across teens and preteens as well as male and female participants. Discussion These results suggest that specific affective states are associated with dysregulated eating‐related experiences in real time among youth, and associations may differ depending on demographic characteristics. Findings may be used to inform the development and tailoring of momentary interventions.

Objective Avoidant/restrictive food intake disorder (ARFID) is a relatively new formal diagnosis for which empirical classification research (defined here as studies using latent class/latent profile analysis‐type methods) is still emerging. Such research focused on ARFID is an important gap to fill given questions about (1) the boundaries between ARFID and phenotypically similar presentations (e.g., eating disorders [EDs] such as anorexia nervosa [AN], and pediatric feeding disorder [PFD]), and (2) within‐ARFID heterogeneity. These questions have practical implications, including diagnostic reliability and treatment selection. Method This forum synthesizes the limited empirical classification literature seeking to quantitatively distinguish ARFID from non‐ARFID EDs or from PFD, and/or characterize within‐ARFID heterogeneity. Results To our knowledge, only five studies in clinical samples have used empirical classification methods to delineate ARFID from non‐ARFID EDs and/or characterize within‐ARFID heterogeneity; no studies have used such methods to delineate ARFID from PFD. Existing studies are mixed in determining how well ARFID can be distinguished from other EDs (particularly AN), but converge in identifying several potential ARFID subclasses (i.e., sensory sensitivity, low appetite, feared eating‐related consequences, and subclass representing a combination of these) with some overlapping features. Discussion The existing ARFID empirical classification literature should guide future ARFID classification research priorities (e.g., incorporating mechanistic variables as classification indicators, incorporating longitudinal variables as classification validators) to inform differences between ARFID and other disorders and between ARFID presentations. Dimensional approaches to conceptualizing, studying, and modeling psychopathology (namely, the Hierarchical Taxonomy of Psychopathology [HiTOP] and the Research Domain Criteria [RDoC]) may offer useful insights.

Emerging evidence from neurophysiological brain vital sign studies show repeatable sensitivity to cumulative subconcussive impairments over a season of contact sports. The current study addressed the need for research comparing a low-contact control group to high-contact group. Importantly, the study also expanded the scope of neurophysiological changes related to repetitive head impacts to include female athletes in addition to male athletes. In total, 89 high school student athletes underwent 231 brain vital sign scans over a full calendar year. The results replicated prior subconcussive cognitive impairments (N400 delays) and sensory impairments (N100 amplitude reductions) in male athletes and demonstrated similar subconcussive impairments for the first time in female athletes. While there was no significant subconcussive difference between female and male athletes, female athletes show overall larger responses in general. The findings demonstrated that subconcussive impairments are detectable in a controlled experimental comparison for both female and male high school athletes. The study highlights the opportunity to monitor subconcussive changes in cognitive processing for both female and male athletes to help advance prevention, mitigation and management efforts aimed at reducing athletes’ risk of potential long-term negative health outcomes related to cumulative exposure to repetitive head impacts.

Dysfunction of motile cilia can impair mucociliary clearance in the airway and result in primary ciliary dyskinesia (PCD). We previously showed that mutations in central pair apparatus (CPA) genes perturb ciliary motility and result in PCD in mouse models. However, little is known about how epithelial cell types in the ciliary microenvironment of the upper airway respond to defects in ciliary motility and mucociliary clearance. Here, we have used single-cell RNA sequencing to investigate responses in tracheal epithelial cells from mice with mutations in CPA genes Cfap221/ Pcdp1, Cfap54, and Spef2. Expected cell types were identified, along with an unidentified cell type not expressing markers of typical airway cells. Deuterosomal cells were found to exist in two states that differ largely in expression of genes involved in differentiation into ciliated cells. Functional enrichment analysis of differentially expressed genes (DEGs) revealed important cellular functions and molecular pathways for each cell type that are altered in mutant mice. Overlapping DEGs shed light on general responses to cilia dysfunction, while unique DEGs indicate that some responses may be specific to the individual mutation and ciliary defect.

Clinical research is an essential component to advance diagnosis and therapeutic development. In 2022, the International Rare Diseases Research Consortium (IRDiRC) and the European Joint Programme on Rare Diseases (EJP RD) brought together key stakeholders from across the globe to discuss common themes in clinical research networks (CRNs) for rare diseases. Various topics were raised during discussions including current state of CRNs, the need for new CRNs, multi-stakeholder perspectives on value of CRNs, and ways to collaborate on a global scale. Communication and coordination between various groups, taking advantage of existing experiences, can expedite establishment and execution of complex collaborations that will be necessary for CRNs. In this perspective, we discuss opportunities and highlight key considerations for developing successful collaborative CRNs across the globe.

Objective Metabolic and bariatric surgery (MBS) is associated with substantial, but variable, weight outcomes. The gut microbiome may be a factor in determining weight trajectory, but examination has been limited by a lack of longitudinal studies with robust microbiome sequencing. This study aimed to describe changes in the microbiome and associations with weight outcomes more than 2 years post surgery. Methods Data were collected at two Midwestern U.S. centers. Adults undergoing primary MBS were assessed before and 1, 6, 12, 18, and 24 months after surgery. BMI and metagenomic sequencing occurred at each assessment. A linear growth mixture model determined class structure for weight trajectory. Results A linear growth mixture model of participants ( N = 124) revealed a two‐class structure; one class had greater sustained weight loss relative to the other. Greater genus‐level taxonomic changes in the microbiome composition at each time point were associated with being in the more favorable weight trajectory class, after controlling for surgery type. Higher Proteobacteria relative abundance at 1 month was predictive of percentage weight change at 6, 12, 18, and 24 months ( p < 0.05 for all). Conclusions Greater genus‐level taxonomic changes in the gut microbiota are associated with improved weight trajectory. Early changes in the gut microbiota may be an important indicator of MBS outcomes and durability.