Publications by Year: 2026

The rapid expansion of molecularly informed therapies in oncology, coupled with evolving regulatory food and drug administration (FDA) approvals, poses a challenge for oncologists seeking to integrate precision oncology medicine into patient care. Large language models (LLMs) have clinical potential, but their reliance on general knowledge limits their ability to provide up-to-date and niche treatment recommendations. Here, we developed a retrieval-augmented generation (RAG)-LLM workflow using the molecular oncology almanac (MOAlmanac) and benchmarked it against an LLM-only approach for biomarker-driven treatment recommendations. Our RAG-LLM achieved up to 95% accuracy on synthetic queries and 93% on real-world queries collected from practicing oncologists. Finally, our study explored several prompting and retrieval strategies to enhance performance. Taken together, this approach may serve as valuable guidance for deploying LLMs to support cancer patients' treatment decisions in precision oncology clinical settings.

Obesity is a non-communicable, multifactorial disorder that has steadily emerged as one of the major global health concerns. It significantly increases the risk of diabetes, cardiovascular diseases and cancer. In obesity, the accumulation of excess fat causes increase in the circulatory levels of adipose tissue-specific hormones (adipokines) and exacerbates carbohydrate-fuelled metabolic stress. These factors promote oxidative and genotoxic stress, resulting in chronic inflammation. Moreover, obesity-related factors contribute to increase in DNA damage and disrupt the DNA Damage Response (DDR), thereby promoting genomic instability. Consequently, obesity may facilitate a complex, multi-step process of cellular transformation and cancer progression. However, the mechanisms linking obesity-associated DDR alterations to cancer progression are active areas of investigation. Therefore, elucidating these aspects of DDR in obesity could enhance our understanding of the risk assessment and facilitate advancement in treatment strategies for patients with cancers and obesity.

INTRODUCTION: Delayed diagnosis (DDx) of Venous thromboembolism (VTE) contributes to preventable mortality. Our prior work resulted in an electronic Clinical Quality Measure (eCQM) for Diagnostic Delay of VTE (DOVE) [1] and a phenotyping algorithm to identify cases of VTE [2]. Current work incorporates voices of VTE survivors to extend that research.

METHODS: We interviewed 8 and surveyed 68 VTE survivors, coded and categorized text, and uploaded data into the DOVE qualitative database. Drawing on this database and patient self-management literature, notably the concepts: patient engagement [3,4] and patient activation [5,6] we developed a model to guide "Successful Living with VTE."

RESULTS: The 76 VTE survivors provided rich descriptions of their journeys from questioning that something may be wrong to making recommendations to help others. Participants were articulate, highly educated, mostly female and white, and geographically diverse. Recommendations were defined as "Recommendations for patients, providers and health care sites targeted to achieve timely VTE diagnosis and treatment across the trajectory from first concern through follow-up care." Patients are advised to be assertive, obtain education and bring a support person. Providers are advised to listen, be knowledgeable and consider genetic testing.

CONCLUSIONS: The recommendations make common sense, do not require expensive equipment or intensive training or extra staff. VTE survivors' recommendations merged with the science of patient self-management provided the model's structure. The model will inform a VTE curriculum and clinical decision support application, and guide research to promote successful living with VTE.

AIMS: Among statin-treated participants with elevated triglycerides and known cardiovascular disease or with diabetes and other risk factors, icosapent ethyl reduced the risk of cardiovascular events in the REDUCE-IT study. In this post hoc analysis of REDUCE-IT, we quantified the effects of icosapent ethyl on total hospitalizations and days lost to hospitalization and death.

METHODS: Randomization to treatment with 2 g twice daily of icosapent ethyl or matching placebo was performed among 8179 participants receiving statin therapy with established cardiovascular disease or age ≥50 years with diabetes and ≥1 additional risk factor, fasting triglyceride 1.69-5.63 mmol/L, and low-density lipoprotein cholesterol 1.06-2.59 mmol/L. Total hospitalizations were analyzed with a competing risks marginal model for total events. The likelihood of no days lost to hospitalization and death and the rate of days lost among those who were hospitalized or died during the study were analyzed with a zero-inflated Poisson regression model.

RESULTS: During a median 5.0 years of follow-up, icosapent ethyl treatment was associated with fewer total hospitalizations (HR (95% CI) = 0.91 (0.84, 0.98), P=0.017). Participants randomized to icosapent ethyl were more likely to survive until the end of the study without hospitalization (OR (95% CI) = 1.12 (1.02, 1.22), p=0.016) and had fewer days lost among those who were hospitalized or died (RR (95% CI) = 0.93 (0.93, 0.94), p<0.001).

CONCLUSION: Icosapent ethyl was associated with fewer total hospitalizations and fewer days lost due to hospitalization and death, providing additional insights on the effects of icosapent ethyl on patient-centered measures of total disease burden.

RATIONALE: Newborns who live at high altitudes are chronically exposed to low oxygen levels, which may impair lung development and induce vascular remodeling, often resulting in pulmonary hypertension, right ventricular hypertrophy, and right heart failure. Nitric oxide (NO) has a critical role in mediating pulmonary vasodilation and supporting healthy lung development. The potential therapeutic role of long-term inhaled NO in hypoxia-induced pulmonary hypertension and right ventricular disease has not been determined.

OBJECTIVE: To investigate the therapeutic effects of long-term inhaled NO in a mouse model of pulmonary hypertension in the context of impaired lung development.

METHODS: Beginning on post-natal day 3-4, mice were exposed to either 21% or 11% FiO 2 , with or without continuous inhaled NO at 10 ppm. We assessed exhaled NO levels and plasma nitrite and nitrate concentrations on mice at age 2-3 months. Pulmonary hypertension, right ventricular hypertrophy and cardiac function were evaluated using echocardiography and invasive hemodynamic measurements. Vascular and alveolar structure was analyzed by histology.

RESULTS: Chronic hypoxia impaired lung development and caused pulmonary hypertension. Levels of exhaled NO and plasma nitrite and nitrate concentrations were reduced by chronic hypoxia. Long-term inhaled NO therapy restored NO biomarkers and improved pulmonary hypertension, right ventricular hypertrophy, and right ventricular function. However, hypoxia-induced alveolar and vascular rarefaction were unaffected by inhaled NO.

CONCLUSION: These findings support further investigation of prolonged inhaled NO as a potential therapeutic strategy for conditions associated with chronic hypoxia, such as those experienced at high altitude.

Herein, we describe a synthetic route toward privileged 4-indolyl-3,5-diaryl-3-pyrrolin-2-ones based on a previously reported Friedel-Crafts reaction of 5-hydroxy-3,5-diaryl-3-pyrrolin-2-ones with indole. The intermediate 5-indolyl-3,5-diaryl-3-pyrrolin-2-ones are not isolated but further reacted under one-pot conditions, leading to the indole moiety migration from position C5 to position C4 of the 3-pyrrolin-2-one ring. The optimal reaction conditions found involved stirring with 2 equiv of aluminum chloride in 1,4-dioxane to complete the Friedel-Crafts step and then heating at 130 °C for 40 min in a microwave reactor to achieve the rearrangement step. Using the developed chemistry, a variety of compounds were prepared for biological testing, including those oxidized at C5 because 5-hydroxy-3-pyrrolin-2-ones have been reported to possess diverse biological properties as well. The synthesized compounds were tested for antiproliferative activities against MDA-MB-231 triple-negative breast cancer cells under normoxic and hypoxic conditions at a single concentration of 10 μM, and a number of compounds belonging to each of the series were identified to have noteworthy antiproliferative action under both normoxia and hypoxia. Several compounds from each series were further tested against ovarian cancer cells, and compounds from each series were capable of reducing cell viability of chemotherapy-resistant OVCAR-5 cells by as much as 75-80% at a concentration of 5 μM.

Precision neurotherapeutics represents a transformative paradigm shift from standardized "one-size-fits-all" treatments of neurological, neurodegenerative, and/or psychiatric disorders toward individualized interventions that leverage patient-specific biological, behavioral, and physiological characteristics. Traditional neurotherapeutic approaches achieve modest response rates of 30-60% for first-line treatments, necessitating personalized strategies that account for individual differences in genetics, brain structure and function, and treatment response profiles. This review examines advances across three core domains: pharmaceutical approaches utilizing fragment-based drug discovery, pharmacokinetic modeling, and quantitative systems pharmacology; neuromodulation technologies evolving from open-loop to adaptive closed-loop systems with real-time biomarker feedback; and biomarker development spanning neuroimaging, pharmacogenomics, and digital health applications. Critical challenges include developing robust methodological frameworks for single-subject parameter estimation, addressing signal-to-noise ratio limitations in neuroimaging, and navigating complex regulatory landscapes. The convergence of artificial intelligence, computational modeling, and US Food and Drug Administration policy shifts toward in silico approaches creates unprecedented opportunities for mechanistically informed biomarkers that can guide truly personalized mental health care.

Bacterial RNA-binding proteins (RBPs) that control the translation of multiple transcripts act largely as negative regulators. Here, we report the identification and characterization of a positive regulator of translation (called PhaF) in the opportunistic pathogen Pseudomonas aeruginosa. Using CLIP-seq and CLAP-seq we identify upward of 50 transcripts targeted by PhaF. We demonstrate that PhaF acts to stimulate the translation of target mRNAs by binding upstream of the Shine-Dalgarno sequence using one or more of the multiple KPAA motifs located in an intrinsically disordered region of the protein. Importantly, we show that PhaF plays a key physiological role in P. aeruginosa through its translational control of the pslA transcript required for exopolysaccharide synthesis and biofilm formation. Our findings uncover an activator of translation in bacteria that binds target transcripts using an RNA-binding region reminiscent of those that are prominent in eukaryotic RBPs.