Publications by Year: 2026

Understanding the function of genetic variants associated with human traits and diseases remains a significant challenge. Here, we combined analyses based on natural genetic variation and genetic engineering to dissect the function of 94 non-coding variants associated with hematological traits. We describe 22 genetic variants impacting hematological variation through gene expression. Further, through in-depth functional analysis, we illustrate how a rare, non-coding variant near the CUX1 transcription factor impacts megakaryopoiesis through the modulation of the CUX1 transcriptional cascade. Collectively, our findings enhance the functional interpretation of genetic association studies and advance understanding of how non-coding variants contribute to blood and immune system variation.

BACKGROUND AND OBJECTIVES: Double seronegative NMOSD (DS-NMOSD) lacks approved disease-modifying treatments, and limited data exist on optimal relapse-prevention strategies. In this multicenter, international, retrospective cohort study, we sought to compare the real-world effectiveness of anti-CD20 agents vs nonspecific immunosuppressants as disease-modifying strategies for relapse prevention in DS-NMOSD.

METHODS: A retrospective cohort database was constructed using standardized data collection from medical records across collaborating centers in the United States, Brazil, the United Kingdom, Thailand, Turkiye, and China. Patients meeting IPND-2015 NMOSD criteria with negative serum aquaporin-4 and myelin oligodendrocyte glycoprotein antibody testing via cell-based assays and at least 12 months of follow-up were reviewed. The primary outcome was the incidence rate ratio (IRR) of relapses; secondary outcomes included the annualized relapse rate (ARR) and time to relapse.

RESULTS: A total of 103 patients with DS-NMOSD met study criteria, with a median follow-up of 6 years. Anti-CD20 therapy was associated with a significantly lower IRR (0.02, 95% CI 0.01-0.04) and ARR (0.17, 95% CI 0.07-0.40) compared with nonspecific immunosuppressants (0.76, 95% CI 0.40-1.43) after adjusting for covariates. Survival analysis demonstrated a prolonged relapse-free interval with anti-CD20 agents.

DISCUSSION: Our findings support the use of B-cell depletion as a potentially superior relapse-prevention strategy in DS-NMOSD, highlighting its potential as a first-line therapy.

CLASSIFICATION OF EVIDENCE: This study provides Class IV evidence that, in patients with DS-NMOSD, treatment with a DMT reduces relapse incidence rate ratio compared with no treatment and anti-CD20 DMTs are associated with a lower relapse incidence rate ratio compared with nonspecific immunosuppressants.

PURPOSE: We conducted the PediQUEST Response to the Pediatric Oncology Symptom Experience (PQ Response) randomized controlled trial (RCT) to assess whether combining feedback from an electronic patient-reported outcome (ePRO) system with specialized pediatric palliative care (SPPC) consultation improved health-related quality of life (HRQOL) in children with advanced cancer.

METHODS: This multicenter open-label RCT enrolled children 2 years and older with advanced cancer. The study was conducted between April 2018 and December 2021 at five US tertiary-level pediatric cancer centers. All parents and children 5 years and older answered weekly child HRQOL and symptom surveys over 18 weeks (2-week run-in). Child-parent dyads were assigned (1:1) to PQ Response (n = 74) or usual care (n = 80) for 16 weeks. Primary outcomes were the difference between average 16-week and baseline Pediatric Quality of Life Inventory (PedsQL-4.0) total scores reported by parents and children (range, 0-100; higher = better HRQOL; minimal clinically important difference [MCID], 4.5). Secondary outcomes were PedsQL subscales and symptom scores. Analyses followed an intention-to-treat approach.

RESULTS: Of 154 participants randomly assigned, 50% were girls, 78% were White, 17% were Hispanic, and 45% had brain tumors. The mean age was 11 years (standard deviation, 6.1). Parents assigned to PQ Response reported greater improvements in child HRQOL (PedsQL total mean difference 3.45 points [{95% CI, 0.48 to 6.43}; P = .023]; PedsQL physical 4.61 [{95% CI, 0.40 to 8.82}; P = .032]). Children reported similar improvements. Effects did not exceed MCIDs. No improvements were observed in PedsQL-psychosocial or symptom scores. Sensitivity analyses showed consistent effects, with most physical HRQOL scores and several child-reported symptom scores exceeding MCIDs. We observed site-specific variability. At the site with the largest adherence, all effects exceeded MCIDs. No adverse events reported.

CONCLUSION: Findings suggest benefits of integrating electronic patient-reported outcome feedback and SPPC into pediatric advanced cancer care. Enhanced implementation strategies are needed to optimize clinical impact.

PURPOSE: To characterize gastric cancer epidemiology in Latin America and the Caribbean, identify country-level predictors of the mortality-to-incidence ratio (MIR), and describe the clinical research landscape with emphasis on precision oncology (PO).

METHODS: We conducted a retrospective, country-level study integrating GLOBOCAN 2022 incidence and mortality data, ClinicalTrials.gov records (2004-2025), and socioeconomic indicators (United Nations Development Program Human Development Index [HDI] 2023 and current health expenditure). MIR was calculated per country. Precision-oncology studies were flagged by a curated drug dictionary applied to the Interventions field; country involvement was measured as country-study participations. Analyses included geospatial mapping, Spearman correlation, ordinary least squares regression, K-Means clustering (k = 3), and a Random Forest classifier for feature ranking and discrimination.

RESULTS: Across 24 countries, incidence ranged from 3.97 to 14.31 per 100,000 and mortality from 2.98 to 11.06 per 100,000. MIR was highest in Honduras (0.93), Belize (0.89), and Guatemala (0.88) and lowest in Cuba (0.65), Uruguay (0.66), and Costa Rica (0.68). The HDI correlated inversely with MIR (ρ = -0.71, P < .001); the association with number of trials was weak (ρ = -0.09). Three regional archetypes were identified. The Random Forest model achieved an AUC of 0.94 and ranked HDI as the top predictor. Of the 105 studies, 81 were interventional; phase III accounted for 40.7% and phase II for 30.9%. Country-study participations were concentrated in Brazil (23.4%), Chile (19.1%), and Argentina (15.2%). In PO, participation was dominated by Brazil, Chile, Argentina, and Mexico (72.2% of 140 participations), mostly involving trastuzumab, pembrolizumab, ramucirumab, and nivolumab.

CONCLUSION: Socioeconomic context was more associated with outcomes than research volume. Regional research remains concentrated and drug-limited, supporting policies to strengthen diagnostics, access, and equitable clinical investigation.

Chronic Graft versus Host Disease (cGVHD) remains a major hurdle to the success of hematopoietic stem cell transplantation (HSCT), directly impacting patient morbidity and mortality. Impaired Treg recovery in patients with cGVHD has led to clinical studies aiming to increase peripheral Treg numbers. We performed Phase I dose escalation clinical trials, testing the feasibility and safety of using freshly isolated donor-derived Treg infusions in steroid-refractory/dependent cGVHD. The Phase I was extended to a preliminary Phase II trial, resulting in a total of 33 treated patients. We report that Treg purification from donor leukapheresis using CliniMACS were feasible and that Treg infusions were safe. Importantly, Treg infusions resulted in improved symptoms, particularly at higher Treg doses. Global responses were observed in 71% of patients, and 52% of patients had at least a 2-point improvement in the cGVHD severity scale. Furthermore, improvement in cGVHD symptoms resulted in reductions in corticosteroids, ruxolitinib and mycophenolate (MMF) in 58%, 83% and 33% of patients, respectively, while calcineurin inhibitors were discontinued in 75% of patients. Exploratory analyses revealed the detection of infused Treg clonotypes up to 12 months post-infusion and suggest increased Treg numbers in circulation. We observed increases in serum levels of IL-7, IFN-g, and decreases in sCD13 and ST2 over time, which were not statistically significant following adjustment for multiple comparisons. Although these studies were not powered to assess efficacy, they suggest potential therapeutic benefits of donor-derived Treg in cGVHD treatment and highlight the need for larger Phase II clinical trials. NCT02385019 NCT03683498 (clinicaltrials.gov).

Systemic administration of influenza virus-specific monoclonal antibodies achieves low concentrations in the nasal mucosa, the portal of infection. Intranasal administration may be more relevant for preventing infection, but the pharmacokinetics of intranasal influenza antibodies is unknown. We present results of preclinical studies and first-in-human phase 1 trials of the intranasally administered CR9114, an anti-hemagglutinin stem antibody that protects against influenza A and B viruses. We tested safety and tolerability of different schedules and doses; pharmacokinetics in nasal mucosal lining fluid of the nose and nasopharynx, saliva, and serum; and ex vivo functionality. We evaluated in vivo efficacy of CR9114 in mice and nonhuman primates. Intranasal CR9114 was safe and well tolerated across all doses and schedules. The half-life of CR9114 in the nose was  3 hours. Steady-state concentrations were rapidly attained and sustained with multidosing. Trough concentrations were up to 92-fold higher with twice-daily administration compared with once-daily administration. Pharmacokinetics of intranasal CR9114 in nonhuman primates mirrored that of humans better than mice. Postdose nasal samples potently bound hemagglutinin from diverse strains of influenza A and B viruses and, particularly at the 10-milligram dose, neutralized A/H1N1, A/H5N1, and A/H3N2 more potently than baseline samples. Twice-daily administration of CR9114 protected nonhuman primates against influenza virus challenge with the same intranasal formulation and device as used in humans, providing evidence for the efficacy of intranasal multidosing. Together, these study findings characterize the pharmacokinetics of CR9114 after intranasal administration and provide proof of concept that intranasal antibodies can elicit efficacious passive immunity against influenza viruses.

Double-strand break (DSB) repair is highly mutagenic compared to normal replication. In budding yeast, repair of an HO (homothallism) endonuclease-induced DSB at the mating-type α locus (MATα) can be repaired by using an ectopic heterochromatic HMR::Kl-URA3 donor, producing MAT::Kl-URA3. Among MAT::Kl-Ura3- mutations arising during repair, 50% are base-pair substitutions. 30% are 1-bp indels in short homonucleotide runs, with -1 strongly favored over +1, whereas during replication, spontaneous -1 and +1 events are equal. Microhomology-bounded, repair-associated intragenic deletions (IDs) are recovered 12 times more frequently than tandem duplications (TDs). These data suggest a picture of the structure of the repair replication fork: IDs and TDs occur within the open structure of a migrating D-loop, where the 3' end of a partly copied new DNA strand can dissociate and anneal with a single-stranded region of microhomology either within  80 bp ahead or  40 bp behind the 3' end. Approximately  10% of repair-associated mutations are interchromosomal template switches (ICTS), even though the Kluyveromyces lactis URA3 sequence in HMR is only 72% identical (homeologous) with Saccharomyces cerevisiae ura3-52. ICTS events begin and end at regions of short ( 7.5 bp) microhomology; however, ICTS events are constrained to the middle of the copied sequence. Whereas microhomology usage in intragenic deletions is not influenced by adjacent homeology, we show that extensive pairing of adjacent homeology plays a critical role in ICTS. Thus, although by convention, structural variants are characterized by the precise base pairs at their junction, microhomology-mediated template switching actually requires alignment of extensive adjacent homeology.

Although mechanistic studies support a beneficial effect of several dietary flavonoids on telomere length (TL), to our knowledge no studies have examined associations between habitual flavonoid intakes and TL in population-based studies. We examined the associations between habitual intake of major flavonoid subclasses (flavonols, flavones, flavanones, flavan-3-ols and their polymers, and anthocyanins) and TL in a cross-sectional analysis of 4,944 disease-free females from the Nurses' Health Study (NHS). Flavonoid intakes were collected using food frequency questionnaire data, and TL was measured in peripheral blood leukocytes using quantitative real-time polymerase chain reaction. Multivariable-adjusted least squares mean leukocyte TL (z scores and corresponding standard error [SE]) for total and all flavonoid subclasses were calculated using generalized linear models. Although no individual flavonoid subclass was significantly associated with TL in the overall population, when we restricted analyses to younger and middle-aged participants (aged < 55 y), a higher anthocyanin intake associated with longer TL (least squares means ± SE: 0.06 ± 0.06 for the highest versus 0.24 ± 0.07 for the lowest quintile; P-trend = 0.042), corresponding to 6.6 (95% CI, 1.7-14.5) years of aging. In food-based analyses, participants aged < 55 y who consumed more berries had longer TL (Mean TL: 0.10 ± 0.04 for never/rarely; 0.21 ± 0.04 for ≤ 1 serving/week; 0.44 ± 0.26 for ≥ 2 servings/week; P = 0.033 for trend). Similarly, a higher anthocyanin intake was associated with longer TL among pre-menopausal females (0.46 ± 0.11 for the highest versus 0.02 ± 0.08 for the lowest quintile; P-trend = 0.001). Overall, habitual flavonoid intake was not associated with TL attrition in this cross-sectional analysis. However, in females aged < 55 y a higher anthocyanin intake was associated with longer TL, which raises the possibility that anthocyanin-rich foods may promote healthy aging and warrants further investigation with respect to age.