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BackgroundLarge medical centers in urban areas, like Los Angeles, care for a diverse patient population and offer the potential to study the interplay between genetic ancestry and social determinants of health. Here, we explore the implications of genetic ancestry within the University of California, Los Angeles (UCLA) ATLAS Community Health Initiative-an ancestrally diverse biobank of genomic data linked with de-identified electronic health records (EHRs) of UCLA Health patients (N=36,736).MethodsWe quantify the extensive continental and subcontinental genetic diversity within the ATLAS data through principal component analysis, identity-by-descent, and genetic admixture. We assess the relationship between genetically inferred ancestry (GIA) and >1500 EHR-derived phenotypes (phecodes). Finally, we demonstrate the utility of genetic data linked with EHR to perform ancestry-specific and multi-ancestry genome and phenome-wide scans across a broad set of disease phenotypes.ResultsWe identify 5 continental-scale GIA clusters including European American (EA), African American (AA), Hispanic Latino American (HL), South Asian American (SAA) and East Asian American (EAA) individuals and 7 subcontinental GIA clusters within the EAA GIA corresponding to Chinese American, Vietnamese American, and Japanese American individuals. Although we broadly find that self-identified race/ethnicity (SIRE) is highly correlated with GIA, we still observe marked differences between the two, emphasizing that the populations defined by these two criteria are not analogous. We find a total of 259 significant associations between continental GIA and phecodes even after accounting for individuals' SIRE, demonstrating that for some phenotypes, GIA provides information not already captured by SIRE. GWAS identifies significant associations for liver disease in the 22q13.31 locus across the HL and EAA GIA groups (HL p-value=2.32×10-16, EAA p-value=6.73×10-11). A subsequent PheWAS at the top SNP reveals significant associations with neurologic and neoplastic phenotypes specifically within the HL GIA group.ConclusionsOverall, our results explore the interplay between SIRE and GIA within a disease context and underscore the utility of studying the genomes of diverse individuals through biobank-scale genotyping linked with EHR-based phenotyping.

Patients with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can be diagnosed by PCR during acute infection or later in their clinical course by detection of virus-specific antibodies. While in theory complementary, both PCR and serologic tests have practical shortcomings. A retrospective study was performed in order to further define these limitations in a clinical context and to determine how to best utilize these tests in a coherent fashion. A total of 3,075 patients underwent both PCR and serology tests at University of California, Los Angeles (UCLA), in the study period. Among these, 2,731 (89%) had no positive tests at all, 73 (2%) had a positive PCR test and only negative serology tests, 144 (5%) had a positive serology test and only negative PCR tests, and 127 (4%) had positive PCR and serology tests. Approximately half of the patients with discordant results (i.e., PCR positive and serology negative or vice versa) had mistimed tests in reference to the course of their disease. PCR-positive patients who were asymptomatic or pregnant were less likely to generate a detectable humoral immune response to SARS-CoV-2. On a quantitative level, the log number of days between symptom onset and PCR test was positively correlated with cycle threshold (CT) values. However, there was no apparent relationship between PCR CT and serologic (arbitrary units per milliliter) results.

IntroductionCore facilities play crucial roles in carrying out the academic research mission by making available to researchers advanced technologies, facilities, or expertise that are unfeasible for most investigators to obtain on their own. To facilitate translational science through support of core services, the University of California, Los Angeles Clinical and Translational Science Institute (UCLA CTSI) created a Core Voucher program. The underlying premise is that by actively promoting interplay between researchers and core facilities, a dynamic feedback loop could be established that could enhance both groups, the productivity of the former and the relevance of the latter. Our primary goal was to give translational investigators what they need to pursue their immediate projects at hand.MethodsTo implement this system across four noncontiguous campuses, open-source web-accessible software applications were created that were scalable and could efficiently administer investigator submissions and subsequent reviews in a multicampus fashion.ResultsIn the past five years, we have processed over 1400 applications submitted by over 750 individual faculty members across both clinical and nonclinical departments. In total, 1926 core requests were made in conjunction with 1467 submitted proposals. The top 10 most popular cores accounted for 50% of all requests, and the top half of the most popular cores accounted for 90% of all requests.ConclusionTracking investigator demand provides a unique window into what are the high- and low-priority core services that best support translational research.

Osteosarcoma is the most common primary malignancy of bone in children, adolescents, and adults. Despite extensive surgery and adjuvant aggressive high-dose systemic chemotherapy with potentially severe bystander side effects, cure is attainable in about 70% of patients with localized disease and only 20%-30% of those patients with metastatic disease. Targeted therapies clearly are warranted in improving our treatment of this adolescent killer. However, a lack of osteosarcoma-associated/specific markers has hindered development of targeted therapeutics. We describe a novel osteosarcoma-associated cell surface antigen, ALCAM. We, then, create an engineered anti-ALCAM-hybrid polymerized liposomal nanoparticle immunoconjugate (α-AL-HPLN) to specifically target osteosarcoma cells and deliver a cytotoxic chemotherapeutic agent, doxorubicin. We have demonstrated that α-AL-HPLNs have significantly enhanced cytotoxicity over untargeted HPLNs and over a conventional liposomal doxorubicin formulation. In this way, α-AL-HPLNs are a promising new strategy to specifically deliver cytotoxic agents in osteosarcoma.

Analysis of chronic myelomonocytic leukemia suggests that subtle mutations within the ligand-binding or transmembrane domains can radically alter the phenotype. The Ras protein is a part of multicomponent signal necessary for the transformation. Mutations within Ras proteins are observed in patients with acute myeloid leukemia. A mutant platelet-derived growth factor receptor beta may inappropriately trigger Ras. These findings underline the possible use of anti-Ras therapy.