The University of Texas System (UT System) is an American government entity of the state of Texas that includes 13 higher educational institutions throughout the state including eight universities and five independent health institutions. The UT System is headquartered in Downtown Austin, and has a total enrollment of nearly 240,000 students (largest university system in Texas) and employs 21,000 faculty and more than 83,000 health care professionals, researchers and support staff. The UT System's $30 billion endowment (as of the 2019 fiscal year) is the largest of any public university system in the United States. As of 2018, Reuters ranks the UT System among the top 10 most innovative academic institutions in the world.
Importance:The management of patent ductus arteriosus (PDA) in preterm infants is controversial. Objective:To determine whether expectant management compared with active treatment of a protocol-defined PDA in preterm infants decreases the incidence of death or bronchopulmonary dysplasia (BPD). Design, Setting, and Participants:A randomized clinical trial including infants born at 22 to 28 weeks' gestation and diagnosed with a protocol-defined PDA between the age of 48 hours and 21 days at screening. The trial was conducted from December 2018 to December 2024 at 33 hospitals within the National Institute of Child Health and Human Development Neonatal Research Network. The final date of follow-up was June 2025. Interventions:Infants with PDA were randomized to expectant management (n = 242) or active treatment (n = 240; acetaminophen, ibuprofen, or indomethacin) to close the PDA. Main Outcomes and Measures:The primary outcome was death or BPD at 36 weeks' postmenstrual age. The secondary outcomes included the components of the primary outcome and other morbidities of prematurity. Results:A total of 482 infants were randomized (median gestational age, 25 weeks [IQR, 24 to 27 weeks]; median birth weight, 760 g [IQR, 620 to 935 g]). The trial was stopped for futility and safety after the 50% interim analysis for the primary outcome due to higher survival in the expectant management group. The incidence of death or BPD was 80.9% (195/241) of infants in the expectant management group vs 79.6% (191/240) of infants in the active treatment group (adjusted risk difference, 1.2% [95% CI, -5.7% to 8.1%]; P = .73). The incidence of death before 36 weeks' postmenstrual age was 4.1% (10/241) of infants in the expectant management group vs 9.6% (23/240) of infants in the active treatment group (adjusted risk difference, -5.6% [95% CI, -10.1% to -1.2%]; P = .01). Infections resulting in death occurred in 0.8% (2/241) of infants in the expectant management group vs 3.8% (9/240) of infants in the active treatment group. Conclusions and Relevance:In extremely preterm infants with a protocol-defined PDA, death or BPD did not differ between the expectant management group and the active treatment group. Survival was substantially higher with expectant management. Trial Registration:ClinicalTrials.gov Identifier: NCT03456336.
Importance:The current ocular Common Terminology Criteria for Adverse Events (CTCAE) mix eye signs with symptoms and lack standardized clinical photographs and experimental oncology drug dose modification recommendations. Robust reporting of ocular adverse events (AEs) is important to maintain patient safety and to guide the development of novel efficacious drugs. Objective:To develop improved ocular AE grading scales to reliably evaluate and grade ocular AEs in patients on experimental oncology drug therapy and to provide clear drug dose modification recommendations. Design, Setting, and Participants:A collaborative multicenter interspecialty working group consisting of oncologists and academic ophthalmologists from 11 academic centers in the US and ophthalmologists from the US Food and Drug Administration was assembled in February 2023 to form a consensus on new experimental oncology drug-related ocular AE grading scales. The grading scales were released in June 2023. Main Outcomes and Measures:Expert consensus on novel experimental oncology drug-related ocular AE grading scales. Results:Six experimental oncology drug-related ocular AE grading scales were developed with agreement from ophthalmologists and oncologists for use in antibody-drug conjugate clinical trials: visual acuity, eye symptoms, cornea, conjunctiva/sclera, anterior chamber, and retina/posterior segment. Conclusions and Relevance:The new experimental oncology drug-related ocular AE grading scales developed by the consensus panel were developed to be more concise, containing photographs where applicable, and to provide clear drug dose modification recommendations compared with the previous CTCAE. Use of these ocular AE grading scales may allow for more objective and consistent incidence measurements of ocular AEs throughout clinical trials and postmarketing, potentially facilitating safe testing of novel agents that may cause eye toxicity.
Prostate cancer is one of the most common cancers among men in the United States and is a leading cause of cancer-related deaths and the second most common cancer in men worldwide. In this study, we used a Boolean network model to analyze prostate cancer signaling pathways and to identify optimal drug combinations for precision therapy. By integrating publicly available biological signaling pathway data with recent research findings, we developed a comprehensive model that represents protein-protein interactions, gene mutations, and pathway dysregulation. Faults induced by mutations were modeled using the “stuck at 0” or “stuck at 1” fault paradigms, capturing the impact of genetic alterations on pathway behavior. The model was simulated across various drug combinations to determine which therapies could most effectively alleviate the aberrant signaling caused by specific mutations. To quantify therapeutic efficacy, we calculated a Size Difference (SD) score, a metric analogous to Hamming distance, measuring the deviation from normal, for each drug combination and fault scenario. The results revealed that drug combinations involving Berberine, Docetaxel, Olaparib, and Enzalutamide showed promising prediction efficacy (more than 90%), indicating higher therapeutic potential. A distinguishing feature of this work is that, in addition to the standard prostate cancer drugs, we have included Berberine, a non-toxic natural compound with beneficial effects. These computational findings provide a framework for future experimental and clinical validation, which is necessary to confirm the therapeutic relevance of the predicted drug combinations.
INTRODUCTION:Asymptomatic moyamoya angiopathy (MMA) is increasingly detected through noninvasive imaging; however, its optimal management remains controversial. This multicenter retrospective cohort study compared outcomes in asymptomatic versus symptomatic MMA patients undergoing surgical revascularization. PATIENTS AND METHODS:A total of 475 patients treated with bypass surgery across multiple academic centers were included, with 56 (11.8%) classified as asymptomatic and 419 (88.2%) as symptomatic. Baseline demographics, surgical characteristics, and outcomes-including perioperative stroke, intraoperative complications, and follow-up stroke events-were collected. Asymptomatic MMA was defined as the absence of any prior ischemic or hemorrhagic stroke, seizures, or other neurological symptoms at the time of diagnosis. Both unadjusted analyses and propensity score weighting using inverse probability of treatment weighting (IPTW) were performed to adjust for potential confounders. RESULTS:In the unadjusted analysis, asymptomatic patients had significantly lower rates of all perioperative strokes (1.7% vs 11.4%; p = 0.05) and intraoperative complications (1.7% vs 11.2%; p = 0.05) compared to symptomatic patients. Additionally, follow-up stroke rates were lower in the asymptomatic group (1.7% vs 11.2%; p = 0.05). After IPTW adjustment, the reduction in intraoperative complications (OR: 0.08, 95% CI: 0.01-0.64; p = 0.01) and follow-up stroke rates (OR: 0.12, 95% CI: 0.01-0.91; p = 0.04) persisted, while differences in overall perioperative stroke were not statistically significant. CONCLUSION:Bypass surgery in selected asymptomatic MMA patients is associated with reduced intraoperative complications, and fewer follow-up stroke rates. These findings support the careful consideration of surgical intervention in asymptomatic patients, emphasizing the importance of patient selection for optimal outcomes.
Background Oncolytic herpes simplex virus (oHSV) therapy is a live virus-based immunotherapy that lyses tumor cells which release antigens and activate antitumor immunity. oHSV therapy has been shown to increase ATP production and release of extracellular ATP (eATP). In the extracellular tumor microenvironment, eATP functions as an immune-activating damage-associated molecular pattern but is hydrolyzed to extracellular adenosine (eADO), which can be immune-suppressive. eADO is generated by the sequential action of ectoenzymes CD39 and CD73 (NT5E). Here, we examined the role of immunosuppressive eADO signaling in regulating antitumor immune efficacy of oHSV.Methods We evaluated changes in eADO signaling in vitro and in patient specimens after virotherapy. A genetic CD73 knock-out mouse model and blocking antibodies were used to assess the impact of CD73 on virotherapy in two different solid tumor models. Single-cell RNA sequencing was employed to assess changes in immune cell infiltration and communication. Flow cytometric immunophenotyping and immunofluorescent imaging were utilized to confirm single-cell sequencing predicted changes in tumor microenvironment.Results Transcriptomic analysis of patient tumors pre-virotherapy and post-virotherapy with CAN-3110 revealed increased expression of the adenosine receptor gene ADORA2B after treatment. High NT5E gene expression, as well as gene signatures suggestive of adenosine signaling, correlated with a significantly worse prognosis for patients with solid tumors. Single-cell sequencing of immune cells recruited to tumor-bearing brain hemispheres in CD73 knockout mice revealed an increase in macrophage-mediated antigen presentation and CD4+ T cell cross-communication. Intracranial tumor-bearing CD73 knock-out mice treated with oHSV showed significant therapeutic improvement as the result of oHSV compared with wild-type mice. Combination of virotherapy with CD73 antibody blockade also resulted in enhanced antitumor efficacy.Conclusions Here, we identify that immunosuppressive eADO signaling in the TME is a major barrier to oHSV therapy and CD73 blockade prevents tumor immune escape. The combination of oHSV with CD73 blockade supports the development of an antitumor immune memory response in solid tumors. This study supports clinical development of this combination strategy.
