Awards Program Research Articles

A multivariate blood metabolite algorithm stably predicts risk and resilience to major depressive disorder in the general population.

Socioeconomic pressures, sex, and physical health status strongly influence the development of major depressive disorder (MDD) and mask other contributing factors in small cohorts. Resilient individuals overcome adversity without the onset of psychological symptoms, but resilience, as for susceptibility, has a complex and multifaceted molecular basis. The scale and depth of the UK Biobank affords an opportunity to identify resilience biomarkers in rigorously matched, at-risk individuals. Here, we evaluated whether blood metabolites could prospectively classify and indicate a biological basis for susceptibility or resilience to MDD. Using the UK Biobank, we employed random forests, a supervised, interpretable machine learning statistical method to determine the relative importance of sociodemographic, psychosocial, anthropometric, and physiological factors that govern the risk of prospective MDD onset (total n=15,710). We then used propensity scores to rigorously match individuals with a history of MDD (n=491) against a resilient subset of individuals without an MDD diagnosis (retrospectively or during follow-up; n=491) using an array of key social, demographic, and disease-associated drivers of depression risk. 381 blood metabolites and clinical chemistry variables and 4 urine metabolites were integrated to generate a multivariate random forest-based algorithm using 10-fold cross-validation to predict prospective MDD risk and resilience. In unmatched individuals, a first case of MDD, with a median time-to-diagnosis of 72 years, can be predicted using random forest classification probabilities with an area under the receiver operator characteristic curve (ROC AUC) of 0.89. Prospective resilience/susceptibility to MDD was then predicted with a ROC AUC of 0.72 (x˜= 3.2 years follow-up) and 0.68 (x˜= 7.2 years follow-up). Increased pyruvate was identified as a key biomarker of resilience to MDD and was validated retrospectively in the TwinsUK cohort. Blood metabolites prospectively associate with substantially reduced MDD risk. Therapeutic targeting of these metabolites may provide a framework for MDD risk stratification and reduction. New York Academy of Sciences' Interstellar Programme Award; Novo Fonden; Lincoln Kingsgate award; Clarendon Fund; Newton-Abraham studentship (University of Oxford). The funders had no role in the development of the present study.

Implementing Promising Strategies to Reduce the Risk for Viral Hepatitis and Liver Cancer Among People Who Inject Drugs.

To describe a 3-year demonstration project with selected Centers for Disease Control and Prevention National Comprehensive Cancer Control Program (NCCCP) award recipients to build partnerships with local organizations to improve knowledge and awareness of the association between injecting drugs and the risk for viral hepatitis and liver cancer, improve delivery of viral hepatitis services, and implement comprehensive syringe services programs. A mixed-methods descriptive evaluation of selected evidence-based interventions or promising strategies that each award recipient implemented based on the needs of their population. Selected provider and patient populations served by NCCCP award recipients in Iowa, Minnesota (American Indian Cancer Foundation), Mississippi, and West Virginia. Four award recipients that implemented individually-tailored strategies and activities. Processes were assessed through monitoring and tracking tools. Challenges, lessons learned, and recommendations were collected via qualitative interviews. We used descriptive statistics to analyze quantitative data. We analyzed award recipient interviews using thematic analysis. Activities were implemented across four strategies. Strong public-private partnerships, ongoing technical assistance, a deep understanding of individual populations, and a shared commitment to remaining flexible were main factors. While challenges existed, award recipients implemented key strategies and activities in their populations. Findings contribute to the scaling of best practices to the larger cancer control community especially those whose populations are at higher risk for viral hepatitis.

Awards Program Summer 2023

The Summer 2023 Awards Program recognizes Society, Division, Section, and Student award winners and award opportunities.

Impediments to Greater Diversity in the Cancer Research Workforce: Do Patterns of NCI Funding of Training and Educational Awards to Institutions With Rich Research Resources but Low Student Diversity Indicate Structural Bias?

Purpose: To examine patterns of NCI training and educational awards (T32 & R25) by indicators of research capacity and student diversity. Methods: FY2019 data from the US Department of Education and NIH Exporter were used to examine student diversity and NCI funding by research capacity as defined by Carnegie Classification of Institutes of Higher Education. Results: In FY2019, the Carnegie Classification for Doctoral Universities (n = 412) included 131 “R1”_ and 135 “R2”_ research-intensive universities, and 146 other doctoral and professional universities ("DPU"_).At all Carnegie Institutions, >45% students were White. By Carnegie classes, compared to R2 and DPUs, R1s had the lowest proportions of African American, American Indian/Alaskan Native, Native Hawaiian and Other Pacific Islander, and female students, at both college and graduate levels. Proportions of Hispanic undergraduates were similar across Carnegie classes, and generally higher than those for Hispanic graduate students, which were lowest among R1s relative to R2s and DPUs. Asian American and nonresident alien students (undergraduate and graduate) comprised higher proportions of R1 students than those at R2s and DPUs.Schools varied by Minority Serving Institution status. For instance, numbers of Hispanic Serving Institutions were similar for R1s (16), R2s (16), and DPUs (18), but 11 R2s were Predominantly Black Institutions and only one R1 was and no DPUs. In contrast, 71 R1s were Asian American Serving Institutions, far higher than the 16 R2s and 19 DPUs with that status.Of >2,000 “NCI R01 and equivalent awards”_ in FY2019, >90% were awarded to R1s, with <10% at R2s and <1% at DPUs. Patterns by Carnegie class were similar for NCI Fellowship (F), Career Development (K), and Training Program awards (T). Conclusion: Both low student diversity at research resource-rich schools and higher diversity at schools with fewer research awards may contribute to and perpetuate few individuals from underrepresented racial and ethnic groups working in cancer research. To address this long-standing problem requires understanding how many factors and systems interact at multiple levels (e.g., individual, institutional, funding agency) to drive and block access to training and career advancement in cancer research.

0232 A mindfulness intervention to improve sleep in a diverse sample: results from a pilot feasibility study

Abstract Introduction Emerging data suggests that stress is a contributor to sleep health disparities. Mindfulness techniques are effective at reducing stress, yet limited studies have examined its effect on sleep among a diverse sample. We examined stress, sleep, and cardiovascular risk factors before and after participation in a pilot 30-day mindfulness intervention study. Methods Among a sample of Asian, Black, Hispanic, and White young adults (n=18), participants underwent 35-days of wrist actigraphy, completed questionnaires on stress (Perceived Stress Scale) and sleep patterns (Pittsburgh Sleep Quality Index) and provided blood pressure and weight measurements at baseline, midpoint, and endpoint. Following approximately 5-days of actigraphy, participants received 1-hour of sleep hygiene education and started a 30-day mindfulness meditation via a mobile application (Headspace™). We calculated means and standard deviations (SD) or frequencies for stress levels, sleep quality, and sleep duration, body mass index, and blood pressure before and after the intervention. Results Participants on average were 30 years of age (SD=10.2), 88.9% female, and identified as Asian (11.1%), Black/African American (44.4%), Hispanic (22.2%-not mutually exclusive), and White (33.3%). Most participants had a bachelor’s degree or higher (88.9%). After completing the intervention, participants decreased in stress levels [15.7 (SD=7.7) vs. 13.4 (SD=7.5)] and poor sleep quality [8.3 (SD=2.1) vs 5 (SD=2.2)]. The distribution of short sleepers decreased, 27.8% to 11%. There were no changes in actigraphy-measured sleep duration. The prevalence of obesity and elevated blood pressure decreased from 53% to 47% and 16.7% to 11.1%, respectively. Conclusion We found it feasible to conduct a 30-day app-based intervention among a predominately racial/ethnic minority population. There were modest decreases in stress, short sleep, obesity, and hypertension after the completion of the intervention. Our results suggest stress reduction may be an avenue to improve sleep and cardiovascular health among racial minorities. These results should be replicated in a larger sample to confirm. Support (if any) National Institutes of Health, National Institute for Heart Lung and Blood 1R01HL157954 and K01HL138211; Georgia Center for Diabetes Translation Research (GCDTR) Pilot & Feasibility Pilot Award Program

Clinical research resource support for off-site research coordinators in intensive and specialty care units.

Clinical Research Coordinators (CRCs) are vital collaborators in a clinical research project. They often are the primary liaisons between investigators and human participants in studies and are involved in every aspect of many protocols, including participant recruitment, care (both usual medical care and specific study-related monitoring and procedures), data collection, specimen processing, and follow-up. The Clinical Translational Science Award program, which was created by the National Institutes of Health in 2006, has significantly expanded the venues in which Clinical Research Resource (CRR) - based CRCs are embedded. CRCs functioning in these areas, outside of the research-focused in-patient environment of the CRR, are designated as "off-site" CRCs. Many of these locations, such as intensive care units and emergency departments, require that CRCs interact regularly with healthcare providers whose primary functions are focused on providing optimal patient care rather than research and often involving very complex patients. These off-site CRCs require additional training and support outside of the usual research-oriented environment of the CRR. They are required to function within the context of the patient-care team while fostering implementation of collaborative research. This is a description of such a program specifically geared to off-site CRCs with the goal of enhancing the quality of research and experiences of CRCs.

The role of awards in promoting educational leadership in nursing: A qualitative descriptive study in gerontological nursing

BackgroundAs the population ages, the need for high quality nursing education in the unique health and illness needs of older people is required at undergraduate and postgraduate levels. Gerontological nursing and gerontological nursing education are critically important in this new age of human longevity and chronic disease. To facilitate high quality and engaging educational practices in gerontology, the National Hartford Center for Gerontological Nursing Excellence offered a professional recognition award program, entitled the Distinguished Educator in Gerontological Nursing Award (the Award). ObjectivesDescribe participants’ perceptions of an awards program in gerontological nursing education. DesignQualitative descriptive research. SettingsNational Hartford Center for Gerontological Nursing Excellence, a professional body that aims to enhance and sustain the capacity and competency of nurses to provide quality care to older adults, opened the Award to international applications in 2018. ParticipantsNine awardees, residing in North America and Asia. MethodsSemi-structured individual interviews followed by inductive, thematic analysis. ResultsThe Award was valued for its prestige and recognition; the process of applying was affirming; and achievement of the Award strengthened awardee confidence to lead and advocate for gerontological nursing education. A model for understanding the Award, focused on value, application and confidence is proposed. ConclusionsThe use of award programs for gerontological education expertise may improve nurse educators’ confidence and performance within educational settings. How the Award impacts student learning remains unknown. Further research into the benefits and limitations of award programs for nurse educators specializing in gerontological nursing and other fields, their managers, and students is required to fully understand the role of educational award programs in nursing.

Weight cycling may induce lipid handling in mast cells

Abstract Weight cycling worsens diabetes risk in both humans and mice. We recently found that weight loss and weight cycling induce many immunological changes in the adipose tissue of mice by single cell RNA-sequencing. We also found a substantial increase in adipose mast cells with weight cycling, but not weight loss. The purpose of this study was to confirm and characterize the changes in mast cells with weight cycling. However, using flow cytometry (cKit+FcER1+) and Toluidine blue staining, we found that adipose mast cells are greatest in the weight loss group, in contrast to our prior study using single cell RNA-sequencing. Upon further analysis, we found two unique mast cell populations in our single cell sequencing dataset: one that we consider traditional mast cells and one with lower expression of mast cell surface and protease genes and elevated expression of lipid handling and antigen presentation genes. The second fraction appeared similar to lipid-associated macrophages and accounted for most of the mast cells in the weight cycled group. By flow cytometry, we confirmed the %CD9+, MHCII (I-A/I-E)+, and CD74+ mast cells were highest in weight cycled mice. We also found two mast cell populations in human subcutaneous adipose tissue that appear similar to the murine populations in our dataset, with one population significantly correlating with weight variability. Together, these data suggest that weight cycling may induce a population of lipid-associated mast cells. We next aim to to induce lipid handling in bone marrow derived mast cells by repeated exposure to adipose conditioned media in order to understand the mechanisms which induce lipid handling. This project was funded by a Veterans Affairs Merit Award 5I01BX002195 to AHH. AHH is also supported by a Career Scientist Award from the Veterans Affairs (IK6 BX005649). HLC was funded by an American Heart Association Postdoctoral Fellowship (20POST35120547), MAC was funded by an NIH F31 Predoctoral Fellowship (1F31DK123881), and both were previously supported by the Molecular Endocrinology Training Program (T32 DK07563). Additionally, the human mast cell work was funded by VICTR grants to HLC and MM. The Vanderbilt Institute for Clinical and Translational Research (VICTR) is funded by the National Center for Advancing Translational Sciences (NCATS) Clinical Translational Science Award (CTSA) Program, Award Number 5UL1TR002243-03.

Using synaptic connections to dissect neural microcircuitry

There are a number of methods used to study synapses through selective labeling and control. However, these techniques are often cytotoxic, difficult to implement, or lack the selectivity required to most effectively study microcircuits. We aim to create two novel techniques for studying how the brain is wired – a method for transsynaptic genetic labeling and a method for selectively destroying synapses. For synaptic labeling we are using the C. elegans orthologs for the Notch-Delta signaling system, Glp-1 and Lag-2. Glp-1 was modified by replacing the intracellular portion of the protein with cre recombinase, a site directed DNA recombination enzyme. It is hypothesized that when a cell expressing the chimeric Glp1-Cre protein comes in close contact with a cell expressing Lag-2, cre recombinase will be released allowing for the selective expression of a fluorescent molecule based on cell proximity. In vitro testing via confocal microscopy indicates that the labeling mechanism performs as expected, labeling cells based on contact in HEK 293T cells.To selectively destroy synapses, we have developed a chimeric protein, CadPlexin, that will activate repulsion signals through homophilic binding between two cells connected by a synapse. CadPlexin is composed of the extracellular domain of fruit fly DE-Cadherin and the transmembrane and intracellular domains of mouse plexin-B2. Cadherins bind to one another homophillically, acting to bind cells with one another. Plexins, when dimerized and activated by their usual ligand, Semaphorin, will cause a downstream signaling cascade that induces cell-cell repulsion. We hypothesize that, when two cells expressing CadPlexin are in close contact (i.e. at a synapse), CadPlexin will selectively destroy the synapse, as the extracellular domains from DE-Cadherin will bind together and mimic semaphorin binding and clustering required to activate plexin signaling. Preliminary results from in vitro experiments suggest that CadPlexin performs as expected, seen through stress fibers in the actin cytoskeleton of Cos7 cells transfected with CadPlexin – a characteristic cytoskeletal change induced through Plexin signaling. Together, these techniques will allow us to label synaptically connected neurons and destroy synapses with surgical precision. Funding Sources: Murchison Summer Research Fellowship, Trinity University Start-Up Funds, McNair Scholars Program, the Brain and Behavior Research Foundation NARSAD Young Investigator Award, Mary E. Groff Foundation, Women in STEM Program. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Hemisphere-specific characterization of projections from the Pedunculopontine Tegmental Nucleus to Substantia Nigra pars Compacta dopaminergic neurons

The neurotransmitter dopamine has been shown to be implicated in motivation and reward, notably in the nigrostriatal dopaminergic pathway. Within this pathway, our research focuses on the synapse between the midbrain regions pedunculopontine tegmental nucleus (PPN) and substantia nigra pars compacta (SNc). The PPN is unusual in that it sends projections to both ipsilateral and contralateral sides of the brain, unlike other brain structures that confine their innervations to either ipsilateral or contralateral. To understand the nature of these inputs, the current study focuses specifically on the glutamatergic excitatory projections as well as the GABAergic inhibitory projections within the PPN-SNc circuit using optogenetics in combination with electrophysiological and confocal microscopic methods. These projections have not been previously studied due to a lack of tools. The goal of this particular study is to investigate how hemisphere-specific inputs differ in their synaptic strength. Stereotaxic surgery is performed to unilaterally deliver virus that encodes expression for a depolarizing light-gated ion channel, Channelrhodopsin (ChR2), tagged with yellow fluorescent protein. Light-gated channels were activated to selectively depolarize PPN axons located in the input region that subsequently stimulates synapses onto dopamine neurons. Electrophysiological tests were then run to obtain electrical recordings that permit the quantification of excitatory and inhibitory responses within the PPN-SNc pathway. Finally, brain slices were immunostained with antibodies to tyrosine hydroxylase, a precursor to dopamine, glutamic acid decarboxylase, a GABA-synthesizing enzyme, and vesicular glutamate transporter to visualize dopaminergic neurons, GABAergic projections, and glutamatergic projections, respectively. Confocal images were collected in order to quantify the macroscopic distribution of ipsilateral and contralateral projections in the SNc. We are also using injections of retrograde beads into the SNc to label projecting neurons in the PPN to confirm the hemisphere specificity seen in anterograde labeling.Preliminary findings suggest GABAergic PPN efferents project only to ipsilateral SNc. However, glutamatergic PPN efferent project to both ipsilateral and contralateral SNc, with differing strengths. Our research will permit greater clarity for future studies which seek to understand the underlying neural network and synaptic-level processes of the nigrostriatal dopaminergic pathway. Acknowledgements: This research was supported by: Murchison Summer Research Fellowship, Biology Summer Research Fellowship, Trinity University Start-Up Funds, McNair Scholars Program, the Brain and Behavior Research Foundation NARSAD Young Investigator Award, and the Mary E. Groff Foundation. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

The Ikaros zinc finger transcription factor Eos promotes T H2 differentiation and function by propagating IL-2/STAT5 signaling.

Abstract The Ikaros zinc finger transcription factor Eos has largely been associated with chromatin regulation promoting immunosuppressive regulatory T cells. However, Eos’ role in the differentiation and function of pro-inflammatory T cells has remained unclear. Surprisingly, our work reveals that Eos is a positive regulator of CD4 +T helper 2 (T H2) cells—effector T cells that participate in anti-helminthic immunity but are also implicated in inducing allergic asthma. Using in vitro-generated T H2 cells and an in vivo allergic asthma mouse model, we found that Eos-deficient T cells had reduced gene and protein expression of critical T H2 transcription factors (including the lineage-defining transcription factor Gata3), effector cytokines, and differentiation receptors. Among the various T H2-polarizing pathways, the IL-2/STAT5 axis and its downstream T H2 gene targets emerged as one of the most significantly downregulated networks in Eos deficiency. Using in vitro-generated T H2 cells and overexpression of Eos zinc-finger-domain mutants, we discovered that Eos forms a novel complex with and promotes the tyrosine-phosphorylated activation of STAT5. Additionally, we showed that components of the IL-2/STAT5 pathway participate in a feed-forward loop to promote Eos expression in T H2 cells, further supporting Eos’ regulatory connection with the IL-2/STAT5 axis. Together, these data define a novel mechanism whereby Eos mediates IL-2/STAT5 activity to facilitate T H2 differentiation. This work is significant, as its findings reframe our understanding of Eos’ role in T cell differentiation. K.J.O. is supported by a grant from The National Institutes of Health (NIH) AI134972, as well as from The Ohio State University College of Medicine and The Ohio State University Comprehensive Cancer Center. J.A.T. is supported by funding through the Susan Huntington Dean’s Distinguished University Fellowship and the NIH T32 “Interdisciplinary Program in Microbe-Host Biology” pre-doctoral fellowship administered through the OSU Infectious Diseases Institute and OSU Department of Microbial Infection and Immunity. K.M.G. is supported by NIH grant 1R01ES028829-01A1. L.M.C. and K.J.O. were supported in part by the Jeffress Trust Awards Program in Interdisciplinary Research. K.A.R. is supported by funding through The Ohio State University College of Medicine Advancing Research in Infection and Immunity Fellowship Program.

Longitudinal analysis of the LA-SPARTA cohort of high-risk individuals after SARS-CoV-2 infection and vaccination

Abstract Questions remain regarding correlates of risk and immune protection against SARS-CoV-2 infection and vaccination response. Thus, we prospectively enrolled 200 participants with a high risk of SARS-CoV-2 occupational exposure. Longitudinal analysis of participant exposure risks, vaccination/infection status, and symptoms were assessed at 3, 6, and 12 months, with blood and saliva collection. Quantitative ELISA assay was used to assess the serological response to the SARS-CoV-2 spike holoprotein (S), S-receptor binding domain (RBD) and nucleocapsid protein (NP). 40 of 200 (20%) participants were found to be infected via serology. Equal incidence of infection was found in healthcare and non-healthcare occupations. In those infected, only 79.5% seroconverted for NP, and 11.5% were unaware they had been infected. The antibody response to S was greater than to RBD. Additionally, Hispanic ethnicity was associated with 2-fold greater incidence of infection despite vaccination. Booster vaccination significantly increased the avidity of RBD-specific responses to variant spike proteins. No differences in avidity were found if a participant was boosted via vaccination or natural infection. Collectively, our results indicate that antibody quality and holoprotein response may reveal meaningful determinants of protection beyond RBD antibody titer alone. Additionally, determinants of infection risk may include race/ethnicity, and remain independent of comorbidity and humoral response in this cohort. This study received funding from Center for Influenza Vaccine Research for High Risk Populations- CIVIC 75N93019C00052 (EFR), Lundquist Institute Institutional Funds (MRY), UCLA W. M. Keck Foundation COVID 19 Research Award Program (EFR), and the Community Engagement Alliance Against COVID-19 (CEAL) (MRY, EFR). The project described was supported by the National Center for Advancing Translational Sciences through the UCLA CTSI Grant UL1TR001881. The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or other funding sources. MMJ is supported by the NIH grants TL 1 DK132768 and U2C DK129496.

In silicooptimization of prenatal vaccine regimens to promote early-life immunity

Abstract Newborn children are vulnerable to infection due to their dampened humoral immune response. Maternal immunoglobulin G (IgG) transferred across the placenta provides passive immunity to newborns, and prenatal vaccination to boost pathogen-specific IgG transfer successfully reduced the incidence of neonatal tetanus, diphtheria, and acellular pertussis (Tdap) infections. Despite this, higher rates of infection among premature neonates signifies a deficiency in current immunization programs. To identify regulators of IgG transfer and refine prenatal vaccine regimens, we used a novel in silico approach. To disentangle the role of placental Fc gamma receptors (FcγRs) in IgG transfer, we conducted multiplexed immunofluorescence (mIF) to measure FcγR expression in paraffin-embedded placental tissue. A mechanistic model of placental IgG transfer informed by single cell RNA sequencing and the mIF data revealed FcγRIIb as a key driver of dynamic subclass-specific IgG transcytosis in placental endothelial cells (ECs). In model simulations and experiments in vitro with human umbilical vein ECs, we found the maternal IgG profile fine-tunes antigen- and subclass-specific IgG transfer dynamics. To identify immunization windows of opportunity for maximum IgG transfer, we simulated maternal vaccination by integrating a model of B cell activation and antibody production into the mechanistic model. This revealed first trimester vaccination as a potential strategy to maximize Tdap-induced IgG transport to premature newborns. We conclude that optimal prenatal vaccine regimens depend on gestational length and that novel prenatal vaccines can leverage these determinants of IgG transport to maximize neonatal immune protection. Supported by grants from NIH (T32 GM145443) the Jeffress Trust Awards Program.

The extracellular tail of IFITM3 promotes SARS-CoV-2 entry into cells and is diversifying in primates

Abstract The interferon-induced transmembrane (IFITM) proteins confer cells with resistance to diverse virus infections by altering membrane biomechanics and disfavoring virus-cell membrane fusion. Human IFITM3 strongly restricts SARS-CoV and MERS Spike-mediated infections in endosomes. However, work from our labs demonstrated that IFITM3 has opposing effects on SARS-CoV-2 (SCV2) infection: IFITM3 in endosomes restricts SCV2 infection, but IFITM3 at the cell surface enhances SCV2 infection. In the present study, we investigated the determinants governing the enhancement of SCV2 infection by human IFITM3. Using clinical isolates of SCV2 and pseudoviruses bearing SCV2 Spike, we found that the penultimate and ultimate amino acid residues of IFITM3, which are predicted to extend into the extracellular space, are essential for enhancement of SCV2 Spike-mediated infection. Deletion of these residues in human IFITM3 resulted in loss of SCV2 infection enhancement. On the other hand, we found that certain non-human IFITM3 proteins enhanced SCV2 infection to a greater extent than human IFITM3, and this mapped to sequence divergence in the penultimate and ultimate residues of the IFITM3 extracellular tail. Transferring the last two amino acids of macaque IFITM3 to human IFITM3 resulted in further enhancement of SCV2 infection. These results indicate that certain non-human primate IFITM3 proteins may be poised to act as potent enhancers of SCV2 infection in those species. Genomic analyses revealed that the IFITM3 extracellular tail is diversifying rapidly and recurrently in primates over evolutionary time, raising the possibility that variation at these sites is adaptive in nature and allows for escape from co-option by coronaviruses. NIH Intramural Research Program NIAID Intramural Targeted Anti-COVID19 Program Award

APSA MENA Program Awards $41,000 in Research Grants to MENA Scholars

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T cell functional phenotyping on a single cell scale using hydrogel microparticles.

Abstract Engineered cell therapies, especially chimeric antigen receptor (CAR) T cell therapies, have shown much promise in treating various cancers, most notably hematologic malignancies. However, the success of these therapies is highly variable between cancer types and across patient populations. A growing body of literature suggests that certain T cell functional properties are key drivers of response; thus, it is imperative to develop a more thorough understanding of the functional heterogeneity in T cell populations in order to inform the design of the next generation of cancer immunotherapies. Here, we used a new technology our team developed known as nanovials, which are microfluidically manufactured hydrogel microparticles, to enable the specific activation and capture of secreted products of T cells on a single-cell level. Leveraging this platform, we characterized the secretion of IFN-γ and TNF-α by individual CD8 +T cells harvested from OT-I mice. After initial expansion after isolation, T cells were loaded into functionalized nanovials and specifically activated with OVA peptide. The cells loaded in the nanovials were then separated based on cytokine secretion levels via fluorescence-activated cell sorting (FACS). Unlike traditional cytokine secretion assays which require fixation and permeabilization, cells remain viable throughout our process, allowing for sorted subpopulations to be dissociated from the microparticles, expanded, and further analyzed via cytotoxicity, co-culture, or phenotypic studies. Collectively, our efforts introduce a new paradigm for elucidating the functional properties of immune cells, providing critical insights that will guide the future design of engineered cell therapeutics. M.K. is a recipient of a National Science Foundation Graduate Research Fellowship Program award.

Disparities in care and outcomes for primary liver cancer in England during 2008-2018: a cohort study of 8.52 million primary care population using the QResearch database.

Liver cancer has one of the fastest rising incidence and mortality rates among all cancers in the UK, but it receives little attention. This study aims to understand the disparities in epidemiology and clinical pathways of primary liver cancer and identify the gaps for early detection and diagnosis of liver cancer in England. This study used a dynamic English primary care cohort of 8.52 million individuals aged ≥25 years in the QResearch database during 2008-2018, followed up to June 2021. The crude and age-standardised incidence rates, and the observed survival duration were calculated by sex and three liver cancer subtypes, including hepatocellular carcinoma (HCC), intrahepatic cholangiocarcinoma (CCA), and other specified/unspecified primary liver cancer. Regression models were used to investigate factors associated with an incident diagnosis of liver cancer, emergency presentation, late stage at diagnosis, receiving treatments, and survival duration after diagnosis by subtype. 7331 patients were diagnosed with primary liver cancer during follow-up. The age-standardised incidence rates increased over the study period, particularly for HCC in men (increased by 60%). Age, sex, socioeconomic deprivation, ethnicity, and geographical regions were all significantly associated with liver cancer incidence in the English primary care population. People aged ≥80 years were more likely to be diagnosed through emergency presentation and in late stages, less likely to receive treatments and had poorer survival than those aged <60 years. Men had a higher risk of being diagnosed with liver cancer than women, with a hazard ratio (HR) of 3.9 (95% confidence interval 3.6-4.2) for HCC, 1.2 (1.1-1.3) for CCA, and 1.7 (1.5-2.0) for other specified/unspecified liver cancer. Compared with white British, Asians and Black Africans were more likely to be diagnosed with HCC. Patients with higher socioeconomic deprivation were more likely to be diagnosed through the emergency route. Survival rates were poor overall. Patients diagnosed with HCC had better survival rates (14.5% at 10-year survival, 13.1%-16.0%) compared to CCA (4.4%, 3.4%-5.6%) and other specified/unspecified liver cancer (12.5%, 10.1%-15.2%). For 62.7% of patients with missing/unknown stage in liver cancer, their survival outcomes were between those diagnosed in Stages III and IV. This study provides an overview of the current epidemiology and the disparities in clinical pathways of primary liver cancer in England between 2008 and 2018. A complex public health approach is needed to tackle the rapid increase in incidence and the poor survival of liver cancer. Further studies are urgently needed to address the gaps in early detection and diagnosis of liver cancer in England. The Early Detection of Hepatocellular Liver Cancer (DeLIVER) project is funded by Cancer Research UK (Early Detection Programme Award, grant reference: C30358/A29725).

Unveiling the antiviral activity of interferon epsilon in respiratory infections

Abstract Type I interferons (IFN-I), including IFN-α and IFN-β, have demonstrated efficacy in treatments against some viral infections but with a considerable amount of undesirable side effects. IFN-ɛ, a recently discovered member of the IFN-I family, has been found to be expressed constitutively in several tissues, including the lung. However, the antiviral effect of IFN-ɛ against respiratory viral infections is largely unknown. Human respiratory syncytial virus (RSV) is the most important agent responsible for acute lower respiratory tract diseases in infants worldwide. Each year in the United States, RSV leads to approximately 2.1 million outpatient (non-hospitalization) visits among children younger than five years old, with a considerable number of hospitalizations among children younger than five years old and adults 65 years and older. Currently, no vaccine is available to prevent this respiratory tract infections, and new strategies are necessary to treat patients. Therefore, in this study, we aimed to investigate the antiviral effect of IFN-ɛ against respiratory viruses, such as RSV. Using a human epithelial cell line, we assessed the expression, susceptibility, and antiviral effect of IFN-ɛ on RSV infection. Our results demonstrate that RSV is capable of inducing IFN-ɛ. Moreover, RSV is susceptible to the antiviral activity of the rhIFN-ɛ, reducing the number of infected cells as well as the viral replication. That effect is due to the induction of the expression of ISGs with a low inflammatory profile. Overall, our findings demonstrate that RSV is susceptible to the effect of IFN-ɛ, suggesting a potential therapeutic effect of this novel member of the IFN-I family to treat respiratory viral infections. This work was funded in part by a Louisiana State University School of Veterinary Medicine Competitive Research Program Award

The impact of the complement receptors C3aR1 and C5aR1 on the progression of melanoma

Abstract Melanoma is an aggressive skin cancer that develops from the malignant transformation of pigment-producing skin cells, melanocytes. The incidence of cutaneous melanoma is remarkably high, with an estimated number of new cases in the United States in 2022 close to 100,000 patients. Several previous reports pointed out the effect of the complement system in the progression of melanoma, although the precise mechanism is largely unknown. The complement system is a crucial component of innate immunity, and it also has a significant role in adaptive immunity regulating the function of immune cells. The complement receptors C3aR1 and C5aR1 are present on the surface of various immune cells. Anaphylatoxins (C3a and C5a) generated by complement activation bind to their respective receptors, C3aR1 and C5aR1, suppress the antitumor function of immune cells and promote migration and activity of immunosuppressive cells in the tumor microenvironment. Hence, C3aR1 and C5aR1 act as immune checkpoint receptors. To identify the precise role of the complement receptors in melanoma, we challenged C3 −/−, C3aR1 −/−, and C5aR1 −/−mice with the B16F10 murine melanoma cells. We showed that the deficiency of these molecules substantially delayed tumor growth and promoted an antitumorigenic immune response. The results of this study indicate the distinct role of complement receptor signaling on melanoma growth and suggest a novel immunotherapeutic approach. Developmental Research Program Award from the MD Anderson Melanoma SPORE (P50CA221703-04)

CPR News

The CPR Institute's Annual Awards Program was led by an achievement award named in honor of CPR's founder for Ohio State University Moritz College of Law's Joseph B. Stulberg, and Diversity Award honorees—cited for their perseverance in improving equality and inclusion in conflict resolution practices—arbitrator Amanda Lee, of London, and academician and author Benjamin G. Davis, of Charlottesville, Va.