Publications by Year: 2026

We utilized the K14-Cre Brca1f/fTp53f/f mouse model to investigate whether a pulse of PARP inhibitor (PARPi) ± an AKT inhibitor (AKTi) can prevent Brca1-related breast cancer. PARPi alone did not intercept or prevent tumor development. PARPi+AKTi intercepted tumors but did not prevent new tumors. These data confirm the efficacy of a PARPi and an inhibitor of PI3K signaling in treating BRCA1/2-related tumors, but this combination is not sufficient to prevent carcinogenesis.

Evidence suggests that cancer-related accelerated aging contributes to an earlier onset of chronic diseases; persistent symptoms; and decrements in patients' quality of life. This review presents the Multifactorial Model of Cancer-related Accelerated Aging (MMCRAA), a conceptual framework that is grounded in Life Course Theory and supported by empiric evidence. The model includes six inter-related concepts: person, behavioral, biological, treatment, symptom, and life course factors. The MMCRAA can be used by clinicians and researchers to identify patients at increased risk for cancer-related accelerated aging; guide personalized treatment planning; and inform the development of interventions and research.

Bacterial biofilms, prevalent in human infections, present a major barrier to effective antibacterial therapy due to limited drug permeability and resistance. Here we introduce a 'trick-bacteria-with-bacteria' strategy that employs bacteria modified via calcium chloride treatment and antibiotic loading, followed by ultraviolet inactivation. These modified bacteria integrate selectively into biofilms of the same species, enabling targeted intra-biofilm drug release triggered by local pH and hydrogen peroxide. Species-specific integration is essential, as mismatched strains exhibit spatial segregation due to differences in surface adhesins and protein profiles. The strategy is effective against polymicrobial biofilms and demonstrated efficacy in treating biofilms formed by Staphylococcus aureus, Escherichia coli and Candida albicans. It also reinvigorates biofilm-associated macrophages by inducing the release of biofilm-derived l-arginine, enhancing immune responses. In vivo studies using subcutaneous and bone implant infection models showed stronger biofilm eradication and longer-term immunity in animals treated with modified bacteria compared with those treated with antibiotics, including resistance to re-infection. This approach could be adapted to modify infection-related bacteria from patients for personalized intra-biofilm drug delivery.

Aberrant activation of NF-κB transcription factors is a hallmark of human lymphomas. Most lymphoma-intrinsic as well as microenvironment-induced NF-κB activation occurs upstream of the key kinase IKK2, therefore affecting additional pathways. Here, we show that canonical NF-κB signaling in mouse B cells, induced through the expression of one or two copies of a constitutively active IKK2 variant, dose-dependently drives lymphomagenesis. The observed phenotype and stereotypic B cell receptor clonality resemble human small lymphocytic lymphoma (SLL) and chronic lymphocytic leukemia (CLL). Stronger IKK2 signaling drives early B1a cell expansion and uniform SLL/CLL-like lymphomagenesis, while intermediate signals cause more heterogeneous malignancies. Mechanistically, constitutive IKK2 signals provide a profound cell-intrinsic competitive advantage to B1a cells and dose-dependently synergize with TCL1 overexpression in driving aggressive CLL. Further, strong constitutive NF-κB activation overcomes critical microenvironmental dependencies of TCL1-driven lymphomas. Our findings establish canonical NF-κB as an oncogenic driver in lymphoma and reveal reduced microenvironment dependency as a key NF-κB-mediated mechanism, thus highlighting its therapeutic relevance.

DNA origami holds great potential for advancing therapeutics, but the lack of methods for the precise assessment of structural integrity in vivo prevents its translation. Here we introduce proximity ligation assay for structural tracking and integrity quantification (PLASTIQ) for resolving origami structural integrity with only 1 µl of blood sample and with a detection limit of 0.01 fM. Through PLASTIQ, we could observe and quantify the dynamics of DNA origami degradation during blood circulation and evaluate the effectiveness of PEGylation for slowing this process in a murine model. Additionally, by using a double-layered barrel-like origami structure, we found distinct degradation kinetics of DNA helices depending on their specific location, revealing the slower degradation of internal helices compared with the outer ones. Our results suggest that PLASTIQ offers a quantitative approach for assessing DNA origami integrity in vivo by longitudinal sampling, providing dynamic pharmaceutical-level insights for accelerating the development of DNA-nanostructure-based therapeutic molecules and drugs.

Chronic inflammation promotes aging and age-associated diseases. While metabolic interventions can modulate inflammation, how metabolism and inflammation are connected remains unclear. Cytoplasmic chromatin fragments (CCFs) drive chronic inflammation through the cGAS-STING pathway in senescence and aging. However, CCFs are larger than nuclear pores, and how they translocate from the nucleus to the cytoplasm remains uncharacterized. Here we report that chromatin fragments exit the nucleus via nuclear egress, a membrane trafficking process that shuttles large complexes across the nuclear envelope. Inactivating critical nuclear egress proteins, the ESCRT-III or Torsin complex, traps chromatin fragments at the nuclear membrane and suppresses cGAS-STING activation and senescence-associated inflammation. Glucose limitation or metformin inhibits CCF formation through AMPK-dependent phosphorylation and autophagic degradation of ALIX, an ESCRT-III component. In aged mice, metformin reduces ALIX, CCFs, and cGAS-mediated inflammation in the intestine. Our study identifies a mechanism linking metabolism and inflammation and suggests targeting the nuclear egress of chromatin fragments as a strategy to suppress age-associated inflammation.

Adult, symptomatic Chiari malformation Type I (CMI) is a painful, often debilitating, neurological condition which is defined by the herniation, or extension, of the cerebellar tonsils below the skull. Research has shown that Chiari patients on average exhibit a number of anatomical variations, or morphometric differences, from healthy controls in the cranio-vertebral region; however the potential contribution of these differences to CMI's pathophysiology is not clear. This case-control study looked at nine representative morphometric measures (MM) in 432 adult, female CMI subjects and 148 adult, female controls. Each measure was dichotomized at three increasing distances from the control mean to represent exposures in an odds ratio analysis with CMI as the outcome. In addition, logistic regression modeling was used to determine the overall predictive ability of the MMs. Finally, disease severity was compared across three CMI subgroups with varying degrees of morphometric severity. We found that a reduced fastigium height demonstrated the largest increase in both crude and adjusted odds ratios at every level with an exposure-response pattern. Logistic regression correctly identified 87% of the CMI subjects as CMI based on the MMs. On average, CMI subjects had more than 3 MMs that were at least one standard deviation from the control mean, but there was no association between morphological and disease severity. These results suggest that further studies into anatomical variations such as fastigium height in CMI patients are warranted.

Subdominant B-cell immune responses to conserved epitopes are major obstacles in eliciting broadly neutralizing antibodies (bnAbs) against HIV-1 through natural infection or vaccination. Although the sequence conserved membrane proximal external region (MPER) of HIV-1 gp41 is partially occluded on the virion surface, epitope-focused immunogens could mitigate access limitations. Here, we found that a MPER/liposome vaccine delivered with a single CD4 T cell helper epitope results in a post-priming response hierarchy, eliciting low-affinity MPER-specific B cells. Heterologous boosting, however, promotes MPER-specific B cell clonal expansion and enhances plasma antibody functionality. This improvement is associated with increased B-cell affinity for MPER and reduced competition from B cells targeting the helper epitope. While helper peptide co-delivery increases the affinity of serum antibodies, the outcome of subsequent MPER antibody responses is shaped by the priming antigen. Our results offer insights into heterologous immunization strategies to potentiate subdominant B cell responses against frequently mutating viruses.

South Asians experience disproportionately elevated cardiometabolic disease risk yet remain underrepresented in genomic research. The OurHealth Study builds a digital biobank of US South Asian adults, integrating remote surveys, mailed biospecimens for sequencing, and electronic health record sharing to identify genetic and non-genetic drivers of cardiometabolic disease. By pairing remote participation with culturally tailored outreach, OurHealth enhances accessibility, supports granular phenotyping, and addresses logistical barriers to genomic research inclusion.