# Sanford Research

• Sioux Falls, United States
Recent publications
Rare disease patients face many challenges including diagnostic delay, misdiagnosis and lack of therapies. However, early access to diagnosis and therapies can modify the management and the progression of diseases, which in return positively impacts patients, families and health care systems. The International Rare Diseases Research Consortium set up the multi-stakeholder Working Group on developing methodologies to assess the impact of diagnoses and therapies on rare disease patients. Using the patients’ journey on the diagnostic paradigm, the Working Group characterized a set of metrics, tools and needs required for appropriate data collection and establishment of a framework of methodologies to analyze the socio-economic burden of rare diseases on patients, families and health care systems. These recommendations are intended to facilitate the development of methodologies and to better assess the societal impact of rare diseases.
Solid tumours are innervated by nerve fibres that arise from the autonomic and sensory peripheral nervous systems1–5. Whether the neo-innervation of tumours by pain-initiating sensory neurons affects cancer immunosurveillance remains unclear. Here we show that melanoma cells interact with nociceptor neurons, leading to increases in their neurite outgrowth, responsiveness to noxious ligands and neuropeptide release. Calcitonin gene-related peptide (CGRP)—one such nociceptor-produced neuropeptide—directly increases the exhaustion of cytotoxic CD8⁺ T cells, which limits their capacity to eliminate melanoma. Genetic ablation of the TRPV1 lineage, local pharmacological silencing of nociceptors and antagonism of the CGRP receptor RAMP1 all reduced the exhaustion of tumour-infiltrating leukocytes and decreased the growth of tumours, nearly tripling the survival rate of mice that were inoculated with B16F10 melanoma cells. Conversely, CD8⁺ T cell exhaustion was rescued in sensory-neuron-depleted mice that were treated with local recombinant CGRP. As compared with wild-type CD8⁺ T cells, Ramp1−/⁻ CD8⁺ T cells were protected against exhaustion when co-transplanted into tumour-bearing Rag1-deficient mice. Single-cell RNA sequencing of biopsies from patients with melanoma revealed that intratumoral RAMP1-expressing CD8⁺ T cells were more exhausted than their RAMP1-negative counterparts, whereas overexpression of RAMP1 correlated with a poorer clinical prognosis. Overall, our results suggest that reducing the release of CGRP from tumour-innervating nociceptors could be a strategy to improve anti-tumour immunity by eliminating the immunomodulatory effects of CGRP on cytotoxic CD8⁺ T cells.
Background CLN8-Batten disease (CLN8 disease) is a rare neurodegenerative disorder characterized phenotypically by progressive deterioration of motor and cognitive abilities, visual symptoms, epileptic seizures, and premature death. Mutations in CLN8 results in characteristic Batten disease symptoms and brain-wide pathology including accumulation of lysosomal storage material, gliosis, and neurodegeneration. Recent investigations of other subforms of Batten disease (CLN1, CLN3, CLN6) have emphasized the influence of biological sex on disease and treatment outcomes; however, little is known about sex differences in the CLN8 subtype. To determine the impact of sex on CLN8 disease burden and progression, we utilized a Cln8 mnd mouse model to measure the impact and progression of histopathological and behavioral outcomes between sexes. Results Several notable sex differences were observed in the presentation of brain pathology, including Cln8 mnd female mice consistently presenting with greater GFAP ⁺ astrocytosis and CD68 ⁺ microgliosis in the somatosensory cortex, ventral posteromedial/ventral posterolateral nuclei of the thalamus, striatum, and hippocampus when compared to Cln8 mnd male mice. Furthermore, sex differences in motor-behavioral assessments revealed Cln8 mnd female mice experience poorer motor performance and earlier death than their male counterparts. Cln8 mnd mice treated with an AAV9-mediated gene therapy were also examined to assess sex differences on therapeutics outcomes, which revealed no appreciable differences between the sexes when responding to the therapy. Conclusions Taken together, our results provide further evidence of biologic sex as a modifier of Batten disease progression and outcome, thus warranting consideration when conducting investigations and monitoring therapeutic impact.
Loss-of-control eating (LOCE, the subjective inability to refrain from eating or cease eating), is highly mood-driven. Mood-related eating motives and eating expectancies have been identified as contributors to binge eating. However, little is known about how these factors relate to LOCE, much less their relationship with daily-level LOCE. This study assessed the impact of trait eating expectancies and daily eating motives on the relationship between daily affective states and LOCE. United States adults (n = 109) reporting recent LOCE participated in a ten-day diary study, completing two surveys per day regarding eating behaviors, mood, and motives. Data were analyzed at the within- and between-subject levels utilizing a Bayesian approach to examine pathways from mood to LOCE, mediated by eating motives and accounting for a moderating impact of baseline eating expectancies on the path leg between mood and motives. Negative mood was associated with LOCE at both the within- and between-subjects level by way of coping motives, and directly at the within-subjects level. Negative affect (NA) reduction expectancies did not moderate the indirect pathway. Positive mood was only associated with LOCE at the within-subjects level, via pleasure motives. This relationship was potentiated via reward expectancies. Therefore, although negative mood appears be a robust predictor of LOCE regardless of trait NA reduction expectancies, positive mood appears to have a specific set of conditions under which individuals are at increased likelihood of LOCE at the within-subjects level. These findings suggest that eating expectancies and motives for eating may be meaningful targets in LOCE interventions.
Background While bariatric surgery results in substantial weight loss, one negative side effect of surgery is that patients often experience more rapid and intense intoxication effects after consuming alcohol. Objectives Given that alcohol use has been associated with impaired cognitive functioning in the general population, this study examined whether acute alcohol consumption after bariatric surgery immediately led to impaired cognitive control, and whether this effect was impacted by baseline levels of cognitive control. Setting Nonprofit teaching hospital, United States. Methods Participants were 34 adults who attended a laboratory visit before and 1 year after Roux-en-Y gastric bypass surgery, wherein they consumed a weight-based dose of alcohol and completed cognitive testing over the course of 3 hours. Results A series of generalized mixed-effect models demonstrated that performance on the cognitive task generally improved over time, likely due to practice effects. However, following bariatric surgery, individuals with impaired cognitive control before consuming alcohol experienced greater commission errors immediately afterward. Conclusions These findings suggest that alcohol use after bariatric surgery may produce immediate deficits in inhibitory control among individuals who are already vulnerable to impaired cognitive control. Clinicians should seek to educate bariatric surgery candidates on this possible effect, as deficits in inhibitory control may ultimately lead to risky behaviors and poor adherence with postsurgical medical recommendations.
“Feeling fat” is a subjective state that theoretically contributes to the maintenance of binge eating (BE). However, feeling fat, and its relation to BE among individuals with higher-weight bodies, has been infrequently studied. This study proposes a momentary-level model in which negative moral emotion states (disgust, guilt, shame) mediate the association between feeling fat and binge eating. In this study, 50 adults with higher-weight bodies (MBMI=40.3 ± 8.5 kg/m²; 84% female) completed a two-week ecological momentary assessment protocol, which measured experiences of feeling fat, emotion states, and binge-eating behavior. Univariate generalized linear mixed models (GLMM) evaluated the momentary associations among levels of feeling fat at Time 1, emotion states at Time 2, and binge eating at Time 2, controlling for Time 1 emotion states. GLMM results suggest that increases in each emotion from Time 1 to Time 2 mediated the association between Time 1 feeling fat and Time 2 binge eating. When modeled simultaneously within one multivariate multilevel structured equation model, disgust appeared to drive the relation between feeling fat and binge eating, over and above guilt and shame. Although preliminary, findings suggest increases in negative moral emotions, particularly disgust, mediate the feeling fat-binge eating association in adults with higher-weight bodies.
We explored the potential of cellulose nanofiber (CNF) for designing prolonged-release, thin-film drug delivery systems (TF-DDS). These delivery systems can be used as locally deployable drug-releasing scaffolds for achieving spatial and temporal control over therapeutic concentration in target tissues. Using doxorubicin (DOX) as a model anticancer drug, CNF-based TF-DDS were prepared using different film-formation processes, such as solvent casting and lyophilization. Formulations were prepared with or without the incorporation of additional macromolecular additives, such as gelatin, to include further biomechanical functionality. We studied the films for their mechanical properties, thermal stability, wettability, porosity and in vitro drug release properties. Our experimental results showed that CNF-based films, when prepared via solvent casting method, showed optimized performance in terms of DOX loading, and prolonged-release than those prepared via lyophilization-based fabrication processes. Scanning electron microscopy (SEM) analysis of the CNF-based films showed uniform distribution of fiber entanglement, which provided the scaffolds with sufficient porosity and tortuosity contributing to the sustained release of the drug from the delivery system. We also observed that surface layering of gelatin on CNF films via dip-coating significantly increased the mechanical strength and reduced the wettability of the films, and as such, affected drug release kinetics. The performance of the TF-DDS was evaluated in-vitro against two pancreatic cancer cell lines, i.e. MIA PaCa-2 and PANC-1. We observed that, along with the enhancement of mean dissolution time (MDT) of DOX, CNF-based TF-DDS were able to suppress the proliferation of pancreatic cancer cells in a time-dependent fashion, indicating that the drug liberated from the films were therapeutically active against cancer cells. Additionally, TF-DDS were also tested ex-vivo on patient-derived xenograft (PDX) model of pancreatic ductal adenocarcinoma (PDAC). We observed that DOX released from the TF-DDS was able to reduce Ki-67 positive, pancreatic cancer cells in these models.
Food insecurity (FI) may increase risk for binge eating through a “feast-or-famine” cycle, where fluctuations in food availability correspond to alternating periods of food restriction and opportunities for binge eating, but research on this topic is limited. To clarify the relationship between food availability and binge eating in the context of FI, this study examined the association between momentary food security level and subsequent binge-eating symptoms among individuals in food-insecure households and investigated how this association differs by factors that may modify the extent to which food availability fluctuates. Ecological momentary assessment data were collected in 2020–2021 from 75 young adults (Mage = 25.3 ± 1.8 years; 72% female; 72% Black, Indigenous, or a Person of Color) in the United States who had experienced past-month household FI. For 14 days, participants reported four times per day on food security and eating episodes, and binge-eating symptoms were assessed for each reported eating episode. About 35% of the variance in momentary food security ratings was accounted for by within-person variability over time. A significant within-person association was observed in multilevel analyses, indicating that instances of greater food security relative to one's average level predicted greater subsequent binge-eating symptoms. Moderation analyses revealed that this association was significant only among individuals reporting use of food assistance programs, high engagement in resource trade-off coping strategies (e.g., skipping bill payments to buy food), or low food security-related self-efficacy. Overall, findings offer support for the “feast-or-famine” cycle hypothesis as an explanation for the link between FI and binge eating, emphasize the importance of identifying approaches to promote more stable access to adequate food, and suggest potential intervention targets to reduce risk for binge eating in populations experiencing FI.
In developing tissues, knowing the localization and interactors of proteins of interest is key to understanding their function. Here, we describe the Breasi-CRISPR approach (Brain Easi-CRISPR), combining Easi-CRISPR with in utero electroporation to tag endogenous proteins within embryonic mouse brains. Breasi-CRISPR enables knock-in of both short and long epitope tag sequences with high efficiency. We visualized epitope tagged proteins with varied expression levels, such as ACTB, LMNB1, EMD, FMRP, NOTCH1, and RPL22. Detection was possible by immunohistochemistry as soon as one day after electroporation and we observed efficient gene editing in up to 50% of electroporated cells. Moreover, tagged proteins could be detected by immunoblotting in lysates from individual cortices. Next, we demonstrated that Breasi-CRISPR enables the tagging of proteins with fluorophores, allowing the visualization of endogenous sproteins via live-imaging in organotypic brain slices. Finally, we used Breasi-CRISPR to perform co-IP mass-spectrometry analyses of autism-related protein FMRP to discover its interactome in the embryonic cortex. Together, these data show Breasi-CRISPR is a powerful tool with diverse applications that will propel the understanding of protein function in neurodevelopment.
Background Loss-of-control (LOC) eating commonly develops during adolescence, and it predicts full-syndrome eating disorders and excess weight gain. Although negative emotions and emotion dysregulation are hypothesized to precede and predict LOC eating, they are rarely examined outside the self-report domain. Autonomic indices, including heart rate (HR) and heart rate variability (HRV), may provide information about stress and capacity for emotion regulation in response to stress. Methods We studied whether autonomic indices predict LOC eating in real-time in adolescents with LOC eating and body mass index (BMI) ⩾70th percentile. Twenty-four adolescents aged 12–18 (67% female; BMI percentile mean ± standard deviation = 92.6 ± 9.4) who reported at least twice-monthly LOC episodes wore biosensors to monitor HR, HRV, and physical activity for 1 week. They reported their degree of LOC after all eating episodes on a visual analog scale (0–100) using a smartphone. Results Adjusting for physical activity and time of day, higher HR and lower HRV predicted higher self-reported LOC after eating. Parsing between- and within-subjects effects, there was a significant, positive, within-subjects association between pre-meal HR and post-meal LOC rating. However, there was no significant within-subjects effect for HRV, nor were there between-subjects effects for either electrophysiologic variable. Conclusions Findings suggest that autonomic indices may either be a marker of risk for subsequent LOC eating or contribute to LOC eating. Linking physiological markers with behavior in the natural environment can improve knowledge of illness mechanisms and provide new avenues for intervention.
Purpose This study was designed to examine (1) the types of technologies or other applications (apps) emerging adults use to track their eating, physical activity, or weight; (2) who uses these apps and (3) whether eating and weight-related concerns during adolescence predict app use in emerging adulthood. Methods Longitudinal survey data were obtained from EAT 2010–2018 (Eating and Activity over Time study, N = 1428), a population-based sample of ethnically/racially and socioeconomically diverse adolescents (mean age: 14.5 ± 2.0 years), who were followed into emerging adulthood (mean age: 22.0 ± 2.0 years). Data were used to examine sociodemographic correlates of physical activity- and dietary-focused app use. Adjusted, gender-stratified logistic regressions were used to investigate longitudinal relationships between eating and weight-related concerns in adolescence and app use in emerging adulthood. Results Compared to men, women were more likely to use physical activity- (23.2 versus 12.5%, p < 0.001) and dietary-focused apps (16.1 versus 5.5%, p < 0.001). Among women, eating and weight-related concerns in adolescence, particularly unhealthy muscle-building behaviors (OR = 1.73, 95% CI 1.03–2.92), were associated with later dietary-focused app use. Among men, use of other muscle-building behaviors and body dissatisfaction in adolescence predicted use of physical activity- (ORother muscle-building = 1.60, 95% CI 1.03–2.49 and ORbody dissatisfaction = 1.67, 95% CI 1.06–2.65) and dietary-focused (ORother muscle-building = 2.18, 95% CI 1.07–4.47 and ORbody dissatisfaction = 2.35, 95% CI 1.12–4.92) apps 8 years later. Conclusions Eating and weight-related concerns may predict later use of physical activity- and dietary-focused apps; future research is needed to understand whether use of such apps further increases eating and weight-related concerns. Level of evidence III, well-designed longitudinal cohort study.
The aim of this study is to estimate heterogeneous patterns of multiple past-month substance use behaviors and examine associated medico-socio-demographic factors among a nationally representative sample of pregnant women. A total of 2215 currently pregnant women were identified from 2016, 2017, and 2018 National Survey of Drug Use and Health study. Latent class analysis was conducted to characterize the heterogeneous patterns of past-month substance use behaviors based on the use of tobacco, alcohol, marijuana, cocaine/crack, and the misuse of opioid/prescription pain relievers and methamphetamine/prescription stimulants. Risk profiles for prenatal substance use were compared between nonusers and latent subclasses using regression analyses and propensity score methods. Among the 22.3% of pregnant women who reported past-month use of at least one substance, the following five latent classes were defined: Alcohol Only Users (34.56%), Marijuana Only Users (9.64%), Tobacco Only Users (45.84%), Tobacco/Opioid Dual-Users (4.53%), and Polysubstance Users (5.43%). Of these subclasses, Alcohol Only Users and Marijuana Only Users had a risk profile for prenatal substance use similar to that of nonusers, indicating possible challenges in identifying exclusively alcohol-using or marijuana-using pregnant women. Considerable heterogeneity in substance use behaviors exists among pregnant women in the USA. Public health intervention strategies should recognize these diverse patterns of prenatal substance use, as well as the psychological and legal challenges these women face, to improve the health of pregnant women and their infants.
PurposeTo examine cross-sectional associations between food insecurity and 12-month eating disorders, mood disorders, and anxiety disorders among U.S. adults.Methods This study used data collected between 2001 and 2003 from 2914 participants in the National Comorbidity Survey-Replication, a nationally representative sample of U.S. adults (mean age = 44.9 years; 53.4% female). Twelve-month food insecurity was assessed with a modified version of the Short Form U.S. Household Food Security Scale. Twelve-month DSM-IV diagnoses of mental disorders were based on the World Health Organization Composite International Diagnostic Interview. Modified Poisson regression models were conducted, adjusting for age, sex, race/ethnicity, education, and income-to-poverty ratio.ResultsFood insecurity was experienced by 11.1% of participants. Food insecurity was associated with greater prevalence of bulimic-spectrum eating disorders (prevalence ratio [PR] = 3.81; 95% confidence interval [CI] 2.26–6.42), mood disorders (PR = 2.53; 95% CI 1.96–3.29), and anxiety disorders (PR = 1.69; 95% CI 1.39–2.07).Conclusion Results indicate that food insecurity is associated with a range of internalizing mental disorders, though these findings should be confirmed with contemporary data to reflect DSM-5 diagnostic updates and the economic effects of the COVID-19 pandemic. Findings from this study emphasize the need to expand food insecurity interventions and improve access to mental health services for food-insecure populations.
DUNE is a dual-site experiment for long-baseline neutrino oscillation studies, neutrino astrophysics and nucleon decay searches. ProtoDUNE Dual Phase (DP) is a 6 $$\times$$ × 6 $$\times$$ × 6 m $$^3$$ 3 liquid argon time-projection-chamber (LArTPC) that recorded cosmic-muon data at the CERN Neutrino Platform in 2019–2020 as a prototype of the DUNE Far Detector. Charged particles propagating through the LArTPC produce ionization and scintillation light. The scintillation light signal in these detectors can provide the trigger for non-beam events. In addition, it adds precise timing capabilities and improves the calorimetry measurements. In ProtoDUNE-DP, scintillation and electroluminescence light produced by cosmic muons in the LArTPC is collected by photomultiplier tubes placed up to 7 m away from the ionizing track. In this paper, the ProtoDUNE-DP photon detection system performance is evaluated with a particular focus on the different wavelength shifters, such as PEN and TPB, and the use of Xe-doped LAr, considering its future use in giant LArTPCs. The scintillation light production and propagation processes are analyzed and a comparison of simulation to data is performed, improving understanding of the liquid argon properties.
Migrating cells must deform their stiff cell nucleus to move through pores and fibers in tissue. Lamin A/C is known to hinder cell migration by limiting nuclear deformation and passage through confining channels, but its role in nuclear deformation and passage through fibrous environments is less clear. Cell and nuclear migration through discrete, closely spaced, slender obstacles which mimic the mechanical properties of collagen fibers are studied. Nuclei bypassed slender obstacles while preserving their overall morphology by deforming around them with deep local invaginations of little resisting force. The obstacles is not impeded the nuclear trajectory or cause a rupture of the nuclear envelope. Nuclei likewise deforms around single collagen fibers in cells migrating in 3D collagen gels. In contrast to its limiting role in nuclear passage through confining channels, lamin A/C facilitates nuclear deformation and passage through fibrous environments; nuclei in lamin‐null (Lmna−/−) cells loses their overall morphology and becomes entangled on the obstacles. Analogous to surface tension‐mediated deformation of a liquid drop, lamin A/C imparts a surface tension on the nucleus that allows nuclear invaginations with little mechanical resistance, preventing nuclear entanglement and allowing nuclear passage through fibrous environments.
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• Sanford Children's Health Research Center
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