Memphis Zoo

11164 Background: tMNs are rare, albeit serious complication in cancer survivors. A tMN risk prediction model is currently not available, therefore we leveraged clinical information and history in a large population-claims database to devise the first tMN risk prediction model in adult cancer survivors. Methods: SEER-Medicare was used to analyze 970,390 adults aged 66-84 diagnosed with first primary cancer (FPC) from 2000-2011 (with follow-up through 2015), who survived ≥1 year. Medicare claims data classified individuals with a priori identified conditions. We focused on prostate, GI, breast, lung, and bladder (n=830,468) FPCs to develop a tMN risk prediction model. The population was divided into training and validation cohorts. Χ ² test identified risk factors associated with tMN. The tMN risk score (TMNRS) was created as a simple arithmetic sum of independent predictors of tMN weighted according to the adjusted odds ratio from logistic regression analysis. Pts were categorized into risk groups (Table) based on their TMNRS, which were tested in the validation cohort. Model performance was evaluated using ROC and c-statistics. Results: 87-96% of tMN developed within the first 10 years of FPC. Predictors of tMN included history of autoimmunity, infections, cardiovascular disease, granulocyte-colony stimulating factor, FPC stage, chemoradiotherapy exposure, age at FPC diagnosis, and sex. Training analysis distinguished survivors into distinct risk groups (table) with 10-year incidence of tMN ranging from 0.3% to 1.5% (prostate), 0.04% to 1.1% (GI), 0.2% to 1.4% (breast), 0.1% to 1.2% (lung) and 0.1% to 1.4% (bladder). The table summarizes the incidence of tMN and by risk category for each of the FPCs. After validation, the c-statistic ranged from 0.62-0.68. Conclusions: We utilized the largest SEER-Medicare cohort to date to develop a tMN risk model. The TMNRS captures several novel predictors and can be readily used in the clinic. This easy-to-use tool distinguishes cancer survivors into clinically relevant groups at risk of tMN development. This study lays the framework for screening and monitoring of pts at high risk of tMN. In future, we will leverage increasingly available molecular data to improve prediction performance of the model. Web-based calculator to be published with the manuscript/available at time of presentation. [Table: see text]

Objective: To validate the design of a scale to measure the workload of the midwives based on Classification of Nursing Interventions (NIC), through their multicentric application in different delivery units. Methods: Quantitative, longitudinal, study multicentric character, conducted in three general university hospitals of the public system of health. The sample consisted of fifty midwives, who examined the validity of the construct of the designed scale, for a total of 370 births. Data collection began through the scale designed ad hoc by the research team, accounting for the time and average number of NIC interventions, performed at each birth. Results: The midwives of the study, are subject to an increase in their workload regarding the number and average time spent conducting interventions NIC in each attended delivery. In their working day (12-hour shift) they allocate 960.61 minutes (16 hours in day shift) and 840.29 minutes (14 hours in night shift), to execute their roles in childbirth attendance. Conclusion: The data indicate the validity of the scale designed ad hoc, as this instrument reflects the actual workload experienced by the midwives of the study.

Understanding children in the context of relationships is central to the Infant Mental Health (IMH) assessment. This chapter will review core components of caregiver-child relationship assessments, highlighting the impact of social, economic, cultural, historical, and political contexts on these relationships, the family-assessor relationship, and the assessor’s interpretation of the relationship. Paradigms, including DC:0–5™’s Cultural Formulation (ZERO TO THREE, Diagnostic classification of mental health and developmental disorders of infancy and early childhood. Revised edition (DC:0–5). Author, 2016) and the Irving Harris Foundation Diversity-Informed Tenets (St. John MS, Thomas K, Noroña CR, ZERO TO THREE J 33(2):13–22, 2012), will be used to support the assessor cultivating cultural humility and critical self-reflection and to increase the assessor’s appreciation of complexities within the caregiver–child relationship while decreasing bias.

Introduction: Mutations in myopalladin ( MYPN) gene are associated with cardiomyopathies (CM) and skeletal myopathies (SM). This study is aimed to identify Mypn -induced cardioskeletal phenotypes in a murine genetic reference population (GRP) and uncover common genetic mechanisms underlying the development of CM and SM. Hypothesis: Mypn induces common molecular signaling in cardiac and skeletal muscles. Methods: Pearson correlation between cardiac function and expression of Mypn in gastrocnemius muscles was performed in 40 mouse BXD recombinant inbred strains derived from C57BL/6J and DBA/2J parental mice. A causal Mypn-Q526X mutation was introduced to BXDs by crossing with MypnWT/Q526X knock-in mice and this generated F1 hybrid mutant (BXDQ526X) and wild type (BXDWT) strains. Cardiac (morphology, function by echo) and skeletal muscle (muscle mass, strength) phenotypes and transcriptomics (RNA-seq) were assessed in 3- and 6-month-old hybrid mice (N=5). Results: Skeletal muscle expression of Mypn was significantly associated with heart rate (HR) and heart mass (HM) in BXDs, while it was negatively associated with interventricular septum (IVS) thickness, indicating BXD strains with higher skeletal muscle Mypn expression had faster HR, higher HM but thinner IVS. Varied phenotypes in ejection fraction (EF%), ventricular volume and hypertrophy were found among BXD Q526X mice; BXD51 Q526X , BXD48 Q526X and BXD69 Q526X strains had significantly higher EF%, while some mutant mice showed EF% decrease compared to their respective BXD WT littermates. Many mutant lines displayed significantly reduced skeletal muscle strength or mass. Overt SM-related signs (rear limb deformity, restricted movement, waddling) were seen in BXD78 Q526X , while we found overlapping CM/SM traits in BXD51 Q526X mice. Conclusions: In this study, common Mypn -induced molecular signaling in cardiac and skeletal muscles is identified. Introduction of the Mypn -Q526X mutation into the diverse genetic background of BXD GRP exposed CM- and SM-related phenotypes in hybrid lines. The most susceptible lines with overt and overlapping CM/SM phenotypes will be useful to identify common genes, networks and pathways involved in CM and SM using systems genetics methods.

Coronavirus Disease 2019 (COVID-19) is an infectious disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The emergence of this virus has led to millions of deaths and the long-term cardiovascular and respiratory consequences of COVID-19 continue to pose a massive threat to public health. While recent studies have demonstrated that SARS-CoV-2 may enter kidney epithelial cells via angiotensin converting enzyme 2 (ACE2)-independent mechanisms by inducing receptor-independent macropinocytosis, it is currently unknown whether this process also occurs in cell types directly relevant to SARS-CoV-2-associated cardiovascular disease or pneumonia. Here, we investigated the ability of SARS-CoV-2 spike protein subunits to stimulate macropinocytosis in alveolar epithelial cells and macrophages. Flow cytometry analysis of fluid-phase marker internalization demonstrated that SARS-CoV-2 spike protein subunits S1, the receptor binding domain (RBD) of S1, and S2 stimulate macropinocytosis in both human and murine macrophages, but not in human lung epithelial cells. Pharmacological and genetic inhibition of macropinocytosis substantially decreased spike protein-induced macropinocytosis in macrophages both in vitro and in vivo . High resolution scanning electron microscopy (SEM) imaging confirmed spike protein-induced plasma membrane activities characteristic of macropinocytosis. Mechanistic studies demonstrated that inhibition of protein kinase C and phosphoinositide 3-kinase in macrophages blocks SARS-CoV-2 spike protein-induced macropinocytosis. Further, pharmacological blockade of ACE2 did not inhibit macropinocytosis in SARS-CoV-2 spike protein-treated cells. To our knowledge, these results demonstrate for the first time that SARS-CoV-2 spike protein subunits stimulate macropinocytosis in macrophages. These results may contribute to a better understanding of SARS-CoV-2 infection and its cardiovascular and respiratory complications.

126 Background: Lung cancer (LC) causes the most cancer deaths in the US, but early detection improves outcomes. Uptake of Low-Dose CT screening (LDCT) has been low, contributing to race-based disparities. Programmatic management of incidentally detected pulmonary nodules (PN) provides a complementary avenue for early detection which could address disparities. In our PN cohort, Detecting Early LC in the Mississippi Delta (DELUGE), we provide broad access to early detection across a region fraught with geographic, socioeconomic, and race-based disparities. However, many detected PN will not result in LC. After successful implementation at the program level, we seek to evaluate individual-level factors important for early-detection. We evaluated how individuals with small PN identified in DELUGE differ between those who were and were not diagnosed with LC. Methods: DELUGE is a prospective cohort study where we systematically manage incidentally detected PN with trained navigators and evidence-based risk stratification. We constructed DELUGE in a community-based healthcare system across the mid-south with some of the highest per-capita LC incidence and mortality rates in the US. We evaluated all PN ≤30mm in DELUGE from 2015-2022. We compared clinical and demographic characteristics between individuals who were or were not diagnosed with LC within 24 months. Primary analysis used logistic regression, reporting odds ratios (OR) with 95% confidence intervals. Results: From 2015-2022, 17,945 individuals with PN ≤30 mm (71% of the total cohort of 25,339) were identified and enrolled in DELUGE. They had median age of 65 years, were 56% female, and 27% Black / 69% White. 853 (4.8%) patients were diagnosed with LC within two years. PN size significantly predicted LC diagnosis. For every 1 mm increase in nodule size the odds of LC increased by 15% (OR: 1.15 [1.14-1.16]); PN in an upper lobe (OR: 2.0 [1.7-2.2]) and those with cavitation also increased the odds of LC (OR: 2.9[1.9-4.2]). Sex, rural/urban residence, and number of PN were not associated with LC. The most predictive individual level characteristics were age, prior cancer history (OR: 1.3 [1.1-1.5], family cancer history (OR: 1.7 [1.5-2.0], COPD (OR: 3.3 [2.9-3.8]), and smoking history (OR: 6.6 [5.3-8.4]). In the multiple variable model, the most significant associations with LC diagnosis included PN size, age, insurance, family cancer history, COPD, and smoking history (all p<0.0001). This model could provide estimated sensitivity 0.81 and specificity 0.81 for predicting LC (AUC= 0.88). Conclusions: Factors measurable at baseline have predictive ability, and predictive modeling may be useful in management of small PN. More focused follow-up could improve programmatic efficiency, targeting the alleviation of geographic, socioeconomic, and race-based health disparities in this high poverty region of the US.

Thanks to substantial support for biodiversity data mobilization in recent decades, billions of occurrence records are openly available, documenting life on Earth and enabling timely research, awareness raising, and policy-making. Initiatives across local to global scales have been separately funded to serve different, yet often overlapping audiences of data users, and have developed a variety of platforms and infrastructures to meet the needs of these audiences. The independent progress of biodiversity data providers has led to innovations as well as challenges for the community at large as we move towards connecting and linking a diversity of information from disparate sources as Digital Extended Specimens (DES). Recognizing a need for deeper and more frequent opportunities for communication and collaboration across the globe, an ad-hoc group of representatives of various international, national, and regional organizations have been meeting virtually since 2020 to provide a forum for updates, announcements, and shared progress. This group is provisionally named International Partners for the Digital Extended Specimen (IPDES), and is guided by these four concepts: Biodiversity, Connection, Knowledge and Agency. Participants in IPDES include representatives of the Global Biodiversity Information Facility (GBIF), Integrated Digitized Biocollections (iDigBio), American Institute of Biological Sciences (AIBS), Biodiversity Collections Network (BCoN), Natural Science Collections Alliance (NSCA), Distributed System of Scientific Collections (DiSSCo), Atlas of Living Australia (ALA), Biodiversity Information Standards (TDWG), Society for the Preservation of Natural History Collections (SPNHC), National Specimen Information Infrastructure of China (NSII), and South African National Biodiversity Institute (SANBI), as well as individuals involved with biodiversity informatics initiatives, natural science collections, museums, herbaria, and universities. Our global partners group strives to increase representation from around the globe as we aim to enable research that contributes to novel discoveries and addresses the societal challenges leading to the biodiversity crisis. Our overarching mission is to expand on the community-driven successes to connect biodiversity data and knowledge through coordination of a globally integrated network of stakeholders to enable an extensible technical and social infrastructure of data, tools, and working practices in support of our vision. The main work of our group thus far includes publishing a paper on the Digital Extended Specimen (Hardisty et al. 2022), organizing and hosting an array of activities at conferences, and asynchronous online work and forum-based exchanges. We aim to advance discussion on topics of broad interest to our community such as social and technical capacity building, broadening participation, expanding social and data networks, improving data models and building a backbone for the DES, and identifying international funding solutions. This presentation will highlight some of these activities and detail progress towards a roadmap for the development of the human network and technical infrastructure necessary to support the DES. It provides an opportunity for feedback from and engagement by stakeholder communities such as TDWG and other initiatives with a focus on data standards and biodiversity informatics, as we solidify our plans for the future in support of integrated and interconnected biodiversity data and credit for those doing the work.

Background: Exosomes have significant therapeutic promise; however, a key problem prohibiting and exploring exosomes in clinical therapy is the availability of disease-specific exosomes. Our recent in vitro and in vivo studies identified that combined treatment with Procainamide (P, DNMT1 inhibitor) and Tubastatin A (T, HDAC6 inhibitor) reduces inflammation upon lipopolysaccharide (LPS) stimuli. Here, we elucidate the therapeutic potential of exosomes derived from the macrophages treated with P+T during the inflammatory condition. Hypothesis: We hypothesize that exosomes derived from LPS-challenged macrophages (THP1) treated with P+T will provide a better anti-inflammatory response than direct drug treatment. Methods and Results: Macrophages were grown in exosome-depleted media for 72 hrs and stimulated once with LPS, P+T, or L+P+T for exosome collection. These exosomes were used for treating LPS-challenged macrophages. qRT-PCR analysis was performed to check for the expression of pro-inflammatory genes after exosome treatment. Our results show that LPS-challenged macrophages treated with exosome from L+P+T showed significantly reduced expression of TNFα and IL1β when compared to the direct drug treatments (Fig. A, B) . We also observed that the pro-inflammatory microRNAs such as miR-21 and miR181-a were significantly reduced in the L+P+T stimulated exosome group (Fig. C, D) . Conclusions: We show for the first time that drug-stimulated exosomes are more effective in reducing inflammation than direct drug treatment. These specific exosomes could be used for infection-related therapy.

Background: Cardiomyopathies are responsible for nearly 10% of cardiac deaths in neonates. Recently, biallelic variants in ribosomal protein L3-like ( RPL3L , NM_005061.2) have been reported in neonates with dilated cardiomyopathy (DCM) and heart failure (HF). This study is aimed to study RPL3L induced genetic pathways and mechanisms involved in the development of DCM. Methods: Whole exome and RNA sequencing, histology, immunohistochemistry, and Western blotting were performed in a human explanted heart. Genetic correlation, expression quantitative trait loci (eQTL) mapping and functional analysis were performed using cardiac gene expression data from the patient as well as human and murine genetic reference populations (GRPs). Results: Two-month-old patient with DCM and HF carrying compound heterozygous RPL3L variants, p.A51T and p.V231F, has been managed on an INTERMACS profile 2 with continuous-flow ventricular assist device and successfully bridged to heart transplantation at the age of 4 months. Morphology of the explanted heart displayed apical deep intertrabecular recesses consistent with left ventricular noncompaction (LVNC). Histology revealed interstitial fibrosis and myocardial hypertrophy. No signs of myocarditis and glycogen or mucopolysaccharides deposits were detected. Immunohistochemistry revealed abnormal clusters of RPL3L protein in the cytosol of cardiomyocytes and disruption of F-actin, Z-disk proteins, MYL4 and dystrophin was evident. In a mouse heart, the Rpl3l level was of 33.45 RPKM, while levels of RPL3L appeared to be 32 RPKM in a human heart compared to its mean expression in other adult tissues of 2.54 (mouse) and 2.36 (human). Systems genetics analysis identified high expression values ranged from 11.31 to 12.16 across murine GRPs of BXD mice with the ~1.8-fold difference. Pathways such as “thermogenesis”, “diabetic cardiomyopathy” and “DCM” significantly associated with RPL3L. e QTL mapping suggested Myl4 (Chr 11) and Sdha (Chr 13) as the upstream regulators of Rpl3l . Conclusions: Compound RPL3L heterozygosity is causal for neonatal DCM and LVNC. The RPL3L is highly expressed in the heart tissue of humans and mice. Genes, Myl4 and Sdha, are strong candidates that regulate expression of Rpl3l in murine heart.

Background: Macrophage polarization plays a key role in the inflammatory process. M1 pro-inflammatory and M2 anti-inflammatory phenotypes can down-regulate each other and may contribute to the pathogenesis of various diseases. Small Cajal Body Associated RNAs (SCARNAs) play a key role in alternative splicing and maturation of mRNAs. Our recent studies found that a combination of Procainamide (P, DNMT1 inhibitor) and Tubastatin A (T, HDAC6 inhibitor) reduces inflammation upon lipopolysaccharide (LPS) stimuli. Hypothesis: We hypothesize that the P+T treatment increases the expression of SCARNA20 hence reducing the proinflammatory response and promoting M2 macrophage polarization after LPS challenge. Methods and Results: To elucidate SCARNAs of interest during the inflammatory response, we treated macrophages with LPS (1μg/mL) and P (400nM/mL) + T (2.5μM/mL) for 1hr and performed RNA sequencing. Based on the sequencing results and qRT-PCR validation, SCARNA20 was the most significantly differentially expressed SCARNA between conditions (Fig. A) . The expression of TNFα was significantly reduced with the P+T treatment (Fig. B) . SCARNA20 overexpression (OE) showed an increase in the expression of the M2 marker CD163 and a reduction in the expression of the M1 marker CD80 (Fig. C) . Additionally, TNFα expression was significantly reduced in the SCARNA20 OE samples after the LPS challenge without treatment with P+T (Fig. D) . Finally, SCARNA20 knockdown macrophages (Fig. E) treated with P+T did not suppress TNFα expression (Fig. F) . Conclusions: We report for the first time that SCARNA20 is an important regulator of M2 macrophage polarization and pro-inflammatory response.

Background: Long non-coding RNAs (lncRNAs) have been linked to a wide range of pathologic diseases despite having a limited capacity for protein coding. MIR17HG is the host gene for the miR17-92a-1 cluster, a group of six microRNAs involved in several cellular functions. Dysregulation of MIR17HG has been associated with multiple diseases such as Feingold Syndrome, osteoarthritis, Parkinson’s disease, and cancer. Treatment with histone deacetylase-6 inhibitor (Tubastatin A -TBA) reduces inflammatory response on macrophages after LPS challenge. Here, we analyze the role of MIR17HG as an epigenetic regulator of inflammation in LPS-induced THP1 cells. Hypothesis: We hypothesize that TBA suppresses the effect of MIR17HG and promotes protection in macrophages under LPS-induced inflammation. Methods and Results: To elucidate potential lncRNAs of interest during macrophage inflammatory response, we treated macrophages with LPS (1 μg/mL) and TBA (2.5 μM) for 1hr and performed RNA sequencing. We selected MIR17HG for further investigation based on the sequencing data (Fig. A) and bioinformatic analysis. The expression of MIR17HG in LPS and TBA treatment conditions was validated by qRT-PCR. MIR17HG expression was significantly higher in LPS and treatment with TBA suppressed the LPS-stimulated MIR17HG expression (Fig. B, C) . We also observed the IL1β behaved in a similar manner (Fig. D) . Further overexpression and knockdown experiments will be performed to identify the link between MIR17HG and ILβ. Conclusion: We report for the first time that MIR17HG is an important mediator of the pro-inflammatory response of macrophages.