Chimeric Antigen Receptor (CAR) cells provide an effective new therapeutic approach to combating cancer and other diseases such as HIV. A limitation however is that CAR T cells are susceptible to functional decline over time due to the chronically inflammatory environment of HIV infection. Chronic HIV-1 infection contributes to immune exhaustion by inducing metabolic stress, leading to increased reactive oxygen species (ROS), mitochondrial dysfunction, and persistent immune activation. Urolithin A (UA), a gut microbiome-derived metabolite, is shown in many studies to enhance mitochondrial function through mitophagy, reduce oxidative stress, and limit chronic inflammation. We hypothesized that treatment with UA will improve the metabolic resilience and functionality of CAR cells, enabling them to maintain enhanced anti-HIV activity in the metabolically stressful environment associated with HIV infection. In this study, we treated our mScarlet+ CAR T cells with UA or with vehicle, coincubated with GFP+ Envelope-expressing cell lines, and assessed the impact of UA on CAR T. Our findings indicated that UA treatment reduced ROS levels, increased autophagy, and improved cytokine secretion during HIV infection in CAR T cells. Results from humanized mice models show that UA treatment improved viral suppression. These findings support the potential of UA as a novel therapeutic strategy to enhance CAR T cell efficacy in chronic HIV infection.

Advanced thyroid cancer patients have limited treatment options and poor survival (~10% at 10 years). Though checkpoint inhibitors (ICI) show benefit in many cancers, their use is limited in thyroid cancer as it is immunosuppressive. One potential mechanism of ICI resistance is the high circulation of myeloid-derived suppressor cells (MDSCs) in the peripheral blood of thyroid cancer patients, which inhibit anti-tumor immunity. In other tumor models, TLR9 agonist CpG activates immune cells by reducing suppressive activity and increasing immune tumor infiltration. We hypothesized that combining ICI with a CpG will reverse MDSC suppression, reversing ICI resistance in thyroid cancer. Mice bearing BRAFV600E+ thyroid tumors were randomized to control or ICI (anti-PD1 or anti-PDL1; 250 mg/dose i.p., twice weekly), with or without conjugated CpG. Immune populations in tumor and spleen were assessed by immunofluorescence, flow cytometry, functional assays, and tumor growth was measured. In vitro, MDSCs suppressed effector, antigen experienced CD44+, IFNγ+CD8+ T-cell; this effect was reversed by CpG. In vivo, PD1+ CD8+ T cells and PDL1+ MDSCs were enriched in the tumor, enabling targeted CpG delivery via ICI conjugates. Because systemic CpG is clinically toxic, conjugation allows localized delivery. Mice treated with ICI-CpG conjugates showed significantly reduced tumor growth and increased cytotoxic CD8+ T cells in the tumor. This identified CpG as a novel strategy to overcome resitance to ICI therapy in advanced thyroid cancer.

Metabolic syndrome (MetS), defined by central obesity, insulin resistance, hypertension, hypertriglyceridemia, and low high-density lipoprotein (HDL), is closely linked to metabolic dysfunction-associated steatotic liver disease (MASLD), which can progress to steatohepatitis and cirrhosis, key risk factors for hepatocellular carcinoma (HCC). While MetS is a distinct condition, its independent impact on outcomes after thermal ablation for early-stage HCC remains unclear. This retrospective study analyzed 126 patients treated with thermal ablation for early-stage HCC at UCLA (2005–2022). MetS was defined using National Cholesterol Education Program Adult Treatment Panel III criteria; 65 patients had MetS and 61 did not. Etiologies included viral hepatitis, alcohol-related liver disease, nonalcoholic steatohepatitis, cryptogenic, and autoimmune causes. Survival outcomes were evaluated using Kaplan–Meier and log-rank tests, with Cox regression identifying predictors of progression-free survival (PFS) and overall survival (OS). MetS was associated with worse outcomes, including shorter PFS (p=0.01) and intrahepatic distant PFS (p=0.009), and independently predicted increased intrahepatic distant recurrence (p=0.03). In contrast, higher HDL levels were linked to improved OS (p=0.002) and PFS (p=0.01). These findings suggest MetS increases recurrence risk after HCC ablation, while higher HDL may be protective.

Human genetic studies suggest that skipping exon 2 in the CD33 gene reduces Alzheimer’s disease susceptibility. As a target for developing therapeutics, antisense oligonucleotides (ASO) can bind to a splicing regulatory sequence on exon 2 to modulate exon 2 skipping. However, the regulatory sequence folds into a hairpin structure that complicates traditional ASO complementary binding. To circumvent this issue, we designed a unique “3D” ASO that binds in the major groove to stabilize the hairpin and prevent recognition by the spliceosome. We created a fluorescence reporter assay to measure various ASO constructs efficacy in exon 2 skipping, using flow cytometry and qPCR analysis. An increase in the skipped isoform is observed with ASOs increasing in residues interacting at the major groove, suggesting increased affinity for ASO binding. To characterize the best ASO design, we tested modifications including minimizing steric hindrance and implementing linkers. Through several rounds of cellular testing and refinement, we have identified two innovative 3D designs that efficaciously induce exon 2 skipping. Subsequent work will test these constructs in microglia. Overall, our studies have identified therapeutic candidates to mitigate the devastating impacts of Alzheimer’s disease.

Acute pancreatitis is an inflammatory disease characterized by a range of manifestations varying from mild self-limiting forms to severe cases of organ failure. Early detection of factors influencing severity is crucial for patients' management. In the current project, it is proposed to apply the results of proteomics for identifying molecular pathways and biomarkers related to acute pancreatitis and its development. To conduct the research, special software will be applied to conduct proteomic analysis of the patient samples and identify protein levels. To reveal the biological processes connected with the development of acute pancreatitis and pathways involved in its occurrence, pathway enrichment and gene ontology analysis are proposed to conduct in the course of the investigation. To detect differences between different proteomic profiles, the participants will be divided into groups by the following factors: organ failure, BMI, gender, age, and severity. It is supposed that the comparison of proteomics in the strata defined by the above clinical features will help to detect the pathways and biomarkers connected with increased risks. The authors predict that proteomic and ontology-pathway enrichments will be identified depending on organ failure and high BMI. Furthermore, it is supposed that differences in these parameters can be revealed according to patients' gender and age. This information can assist in better understanding the mechanisms of the disease.