Publications by Year: 2026

BACKGROUND: NUT carcinoma is a rare but highly lethal solid tumor without an effective standard of care. NUT carcinoma is caused by bromodomain-containing NUTM1 fusion oncogenes, most commonly BRD4::NUTM1. BRD4::NUTM1 recruits p300 to acetylate H3K27 forming expansive stretches of hyperacetylated chromatin called "megadomains" with the overexpression of corresponding oncogenes, including MYC. We hypothesized that transcriptional dysregulation caused by BRD4::NUTM1 would lead to the generation of cancer-specific antigens that could be therapeutically actionable.

METHODS: We integrated genomics, computational antigen prediction software, targeted immunopeptidomics using single-labeled and double-labeled peptide standards, and gain/loss-of-function genetic experiments on a panel of cell lines (N=5), a patient-derived xenograft, a tissue microarray (N=77), and patient samples from the Tempus AI Sequencing Database harboring evidence of NUTM1 fusions (N=165). We created an αPRAME425 T-cell receptor (TCR) × SP34 αCD3 bispecific molecule modeled after brenetafusp, an αPRAME425 TCR bispecific T-cell engager, as well as αPRAME425 TCR T-cells based on anzutresgene autoleucel and we applied these products to NUT carcinoma cells in vitro.

RESULTS: We identified PRAME as the most commonly expressed cancer/testis antigen in patient samples harboring the three canonical NUT carcinoma fusions (BRD4::NUTM1, BRD3::NUTM1, and NSD3::NUTM1). Additionally, 56% (43/77) of NUT carcinoma tissue microarray samples stained positive for PRAME. BRD4::NUTM1 expression in HEK 293T cells enhanced PRAME levels and BRD4::NUTM1 knockout in NUT carcinoma cells reduced PRAME levels. Immunopeptidomics detected more PRAME-derived human leukocyte antigen (HLA) ligands (N=9) than all other cancer/testis antigens combined (N=5). Targeted mass spectrometry detected the HLA-A*02:01/SLLQHLIGL (PRAME425) epitope in 100% (4/4) of HLA-A*02+, PRAME+ NUT carcinoma samples at higher levels (>0.01 fM) than HLA-A*02:01/RLDQLLRHV (PRAME312) or HLA-A*02:01/YLHARLREL (PRAME462). The αPRAME425 TCR × SP34 αCD3 bispecific molecule and αPRAME425 TCR T-cells each exhibited potent, T-cell mediated cytotoxicity against PRAME+ NUT carcinoma cells.

CONCLUSIONS: PRAME is highly and frequently expressed in NUT carcinoma, and the most common oncoprotein causing NUT carcinoma, BRD4::NUTM1, contributes to these high PRAME levels. PRAME epitopes presented by HLA class I are a previously unrecognized therapeutic vulnerability for NUT carcinoma that warrants clinical trials testing PRAME-targeted immunotherapies in this neglected patient population.

Pancreatic ductal adenocarcinoma (PDAC) has a relatively low incidence but a high mortality rate, primarily due to difficulties in early detection. Current state-of-the-art methods for diagnosing early-stage PDAC tend to be invasive, time-consuming, and unreliable, primarily due to the difficulties associated with the early detection of pancreatic cancers. Here we show a quick and sensitive method for the early diagnosis of PDAC using a signal-enhanced lateral flow immunoassay called SELFI. We develop SELFI, which generates a strong colorimetric signal through multiple hotspots formed by plasmonic gold nanoparticles (AuNPs) assembled on a silica nanoparticle. Our SELFI assay achieves a 10,123-fold increase in the limit of detection compared to conventional lateral flow immunoassays using 20 nm AuNPs, providing results within 15 min. We demonstrate that SELFI enables early diagnosis of PDAC, as indicated by a receiver operating characteristic curve and a larger area under the curve compared to the enzyme-linked immunosorbent assay. SELFI's effective diagnostic features can enhance the timely identification of PDAC and may also serve in the early diagnosis of a range of other diseases.

Longitudinal studies are required to measure individual differences in human brain aging, but are challenging over short intervals due to measurement error. Using cluster scanning, an approach that reduces error by densely repeating rapid structural scans, we assess brain aging in individuals across three timepoints in one year. Cluster scanning substantially improves the precision of individualized estimates, revealing previously undetectable individual differences in brain change. In just one year, we detect expected differences in the rates of brain aging between younger and older individuals, as well as differences between cognitively unimpaired and impaired individuals. Cognitively unimpaired older individuals variably reveal relative brain maintenance, unexpectedly rapid decline, and asymmetrical changes. We observe these atypical brain aging trajectories across structures and verify them in independent within-individual test-retest data. Cluster scanning promises to advance our understanding of the marked heterogeneity in brain aging by affording better short-term tracking of individual variability in structural change.

Sex differences in spatial abilities, such as the capacity to mentally rotate objects and manipulate them in space, are well-documented, typically emerging around age 13, with males consistently showing an advantage in response speed over females. However, little is known about the sex differences in the development of object imagery ability—the ability to mentally visualize the appearance of objects in terms of color and shape. Given neuroscience evidence that the ventral pathway, associated with object imagery, develops differently from the dorsal pathway involved in spatial processing, we hypothesized that the development of sex differences would vary between these two domains. In this study, we examined the development of three components of object imagery ability (shape, color, and texture) across four different age groups (13, 14, 15, and adults aged 18–35). A sample of 514 secondary school students from Singapore and 323 adults from the National University of Singapore were administered a series of spatial and object imagery tests. Females outperformed males in texture and shape imagery, and these differences remained consistent across all age groups and in adults, independent of specialization, suggesting a developmental pattern distinct from spatial ability.

Since 1991, the CDC has recommended screening for hepatitis B virus (HBV) infection in pregnancy and universal hepatitis B vaccination of all medically stable infants at birth, serving as a core strategy to prevent perinatal and postnatal infection and eliminate HBV transmission nationwide. On December 5, 2025, the Advisory Committee on Immunization Practices (ACIP) voted (1) among women who screen negative in pregnancy, parents decide, in consultation with providers, when or if to vaccinate their child for hepatitis B, and if not at birth, then no earlier than 2 months of age, and (2) consider collection of infant immune titers to guide decision-making for completing the vaccine series. We conducted a comprehensive review of the evidence of the safety, immunogenicity, efficacy, and effectiveness of the birth dose and a delayed first dose, and of the potential role of serology for clinical decision making. We analyzed studies of the epidemiology of HBV infection, clinical trials, systematic reviews, vaccine safety from surveillance and clinical studies, and potential impact of revised guidelines on individual and public health. We synthesized the history of ACIP recommendations and resulting trends in HBV incidence. The review found strong evidence for the safety and effectiveness of the birth dose, and no improved safety or effectiveness with a delayed first dose. We found no evidence to support use of post-vaccination serology. Infant vaccination has resulted in a 99% reduction in pediatric HBV infections; we found no evidence to support a change in vaccine recommendations but identified potential health consequences.

BACKGROUND: Physical activity is an established protective factor for colorectal cancer (CRC), but it is unclear if genetic variants modify this effect. To investigate this possibility, we conducted a genome-wide gene-physical activity interaction analysis.

METHODS: Using logistic regression (1-d.f), two-step screening and testing method (EDGE), and joint tests (3-d.f), we analyzed interactions between common genetic variants across the genome and physical activity in relation to CRC risk. Self-reported physical activity levels were categorized as active (≥ 8.75 MET-h/wk) vs. inactive (< 8.75 MET-h/wk; 39,992 participants) and as study- and sex-specific quartiles of activity (42,602 participants).

RESULTS: Physical activity was inversely associated with CRC risk overall (OR [active vs. inactive] = 0.85; 95% CI = 0.81-0.90). The two-step EDGE method identified an interaction between rs4779584, an intergenic variant near the GREM1 and SCG5 genes, and physical activity for CRC risk (p-interaction = 2.6 × 10-8). Stratification by genotype at this locus showed a significant reduction in CRC risk by 20% in active vs. inactive participants with the CC genotype (OR = 0.80; 95% CI = 0.75-0.85), but no significant physical activity-CRC associations among CT or TT carriers. When physical activity was modeled as quartiles, the 1-d.f. test identified that rs56906466, an intergenic variant near the KCNG1 gene, modified the association between physical activity and CRC (p-interaction = 3.5 × 10-8). Stratification at this locus showed that an increase in physical activity (highest vs. lowest quartile) was associated with a lower CRC risk solely among TT carriers (OR = 0.77; 95% CI = 0.72-0.82).

CONCLUSIONS: In summary, we identified two genetic variants that modified the association between physical activity and CRC risk. One of them, related to GREM1 and SCG5, suggests that the bone morphogenetic protein (BMP)-related, inflammatory, and/or insulin signaling pathways may be involved in the protective association between physical activity and colorectal carcinogenesis.

Few evidence-based programs exist to help women with a history of gestational diabetes reduce their risk of developing type 2 diabetes. In secondary analyses from a randomized clinical trial of a web-based lifestyle intervention program for postpartum women with recent gestational diabetes, we studied changes in self-efficacy for diet and physical activity and readiness to change health behaviors. Women were randomized at ∼6 weeks postpartum and completed questionnaires at 6 weeks and 6, 12, 18, and 24 months. Our study included 181 women (mean age 32.4 ± 5.2 years; 48% White, 19% Asian, 14% Black or African American, 17% other/mixed race; 34% Hispanic). In a linear mixed effects model, women in the intervention had significantly greater improvement in overall self-efficacy scores for physical activity compared with the control group at 24 months (difference in change scores between groups .35, 95% CI: .03 to .67, P = .03). The intervention group also demonstrated significantly greater improvement in self-efficacy scores for both physical activity subdomains, specifically "sticking to it" at 24 months and "making time" at 12 months. Participants in the intervention did not experience a significant difference in change in self-efficacy for diet or readiness to change compared with those in the control arm.

STUDY QUESTION: What is the impact of endometrial fluid (EF) on single, euploid frozen embryo transfer (FET) cycles on live birth rate (LBR) and is cycle cancellation for EF a worthwhile intervention?

SUMMARY ANSWER: The LBR of single euploid FETs was significantly lower by 20.2 percentage points when EF was persistent on the day of decision for progesterone start/trigger, but despite the lower LBR, cycle cancellation may not confer an improved chance at live birth.

WHAT IS KNOWN ALREADY: The incidence of EF in cycles ranges from 3% to 8%, thus, only a few small studies have been performed to evaluate its impact. Existing literature generally concludes that the presence of EF leading up to an embryo transfer is detrimental to successful implantation, however, these studies examined untested embryos.

STUDY DESIGN, SIZE, DURATION: A retrospective cohort study was performed at a single, academically affiliated infertility center in the USA from January 2014 to December 2022. Inclusion criteria comprised patients who underwent their first IVF cycle, had pre-implantation genetic testing for aneuploidy performed by trophectoderm biopsy, had at least one euploid embryo, and were undergoing their first FET. Cycles were subdivided into three groups: no EF present in the cycle (no EF group), EF present but resolved prior to the day of decision for progesterone start/trigger (EF resolved group), and lastly, EF persistent on the day of decision for progesterone start/trigger (EF persistent group). Clinical outcomes were compared between the groups. In a secondary analysis, all single, euploid FET cycles that were cancelled due to EF were identified. The first subsequent completed single, euploid FET during the same study period was identified and analyzed.

PARTICIPANTS/MATERIALS, SETTING, METHODS: Four thousand three hundred eight FET cycles met inclusion criteria. Four thousand one hundred forty documented no EF, 108 documented EF that resolved, and 60 documented EF that persisted. The primary outcome was LBR per ET. A logistic regression analysis was performed adjusting for baseline characteristics (age, BMI, gravidity, parity, reason for infertility) and cycle characteristics (method of fertilization, protocol, endometrial thickness achieved during FET, embryo grade/day cryopreserved). In our secondary analysis, 90 single, euploid FET cycles were identified as cancelled specifically due to the presence of EF. Following these 90 cancelled cycles, there were 58 cycles that were identified as the first subsequent completed FET after cancellation. For the first subsequent completed single, euploid FET after index cycle cancellation, the presence of EF and overall LBR were recorded.

MAIN RESULTS AND THE ROLE OF CHANCE: When EF was present, but resolved prior to decision for progesterone start/trigger, the LBR was 9.4 percentage points lower compared to the no EF group, however, this did not reach statistical significance (49.1% vs 58.5%, aOR 0.71 (95% CI 0.47, 1.05)). When EF was persistent on ultrasound on day of decision for progesterone start/trigger, the LBR was significantly lower by 20.2 percentage points when compared to the no EF group (38.3% vs 58.5%, aOR 0.50 (95% CI 0.28, 0.88)). Of 58 subsequent FET cycles identified after initial FET cancellation, 23 demonstrated EF recurrence (but were not cancelled). The overall LBR for all 58 subsequent cycles was 39.7% which was not significantly different from the EF persistent group (aOR 0.99 (95% CI 0.38, 2.64)).

LIMITATIONS, REASONS FOR CAUTION: The retrospective, single center design may limit generalizability. Analysis of only euploid embryos introduces selection bias. Challenges of studying EF include the variable and unknown etiology of EF and non-uniform documentation of quantity/measurement of EF. Given the low incidence of EF, the sample sizes are small in the EF groups but are similar in size to previous studies. Power analysis was conducted and to achieve an 80% chance of finding a 10% difference in LBR, 385 patients would be needed in each group. In light of the actual LBR difference of 20.2 percentage points (58.5% vs 38.3%), our sample size of 60 patients in the EF group provided an 88% chance of finding a statistically significant difference.

WIDER IMPLICATIONS OF THE FINDINGS: The LBR was 9.4 percentage points lower when EF resolved and 20.2 percentage points lower when EF was persistent. We identified a small cohort of subsequent cycles after initial cycle cancellation and the LBR achieved in these cycles was similar to the LBR in the index transfer cycle if the transfer was performed even in the setting of persistent EF at time of progesterone start/trigger; perhaps if EF is persistent, cycle cancellation may not confer an improved LBR. Overall, many cases of EF likely result from underlying endometrial pathology. Patients should be counseled accordingly.

STUDY FUNDING/COMPETING INTEREST(S): No funding was used for this study. The authors have no conflicts of interest.

TRIAL REGISTRATION NUMBER: N/A.

AIMS: To assess whether baseline functional performance assessed by exercise treadmill stress testing (EST) has additive value to coronary computed tomography angiography (CCTA) for risk stratification among patients with chronic coronary disease (CCD) and moderate or severe ischemia.

METHODS AND RESULTS: We performed a subgroup analysis of the ISCHEMIA trial including participants who underwent EST and CCTA. EST data and severity of coronary artery disease (CAD) on CCTA were evaluated by core laboratories, blinded to clinical data and results of the other test. The primary outcome for this analysis was all-cause death. Secondary outcomes were cardiovascular death, cardiovascular death or myocardial infarction (MI), MI and a composite of cardiovascular death, MI, or hospitalization for heart failure, unstable angina, or resuscitated cardiac arrest. EST and number of vessels diseased on CCTA were both interpretable in 1864 patients (median age 62 years, IQR 55-68, 83% males). During a median follow-up of 3.1 years, 69 patients died. Higher peak metabolic equivalents (METs) achieved on the qualifying stress test was associated with lower all-cause death (HR 0.86, CI 0.76-0.98; p=0.025). The addition of peak METs to CAD severity improved the predictive ability of the all-cause death and CV death models by 10-20% and 8-13% respectively, depending on the metrics used for CCTA. Adding peak METs to CCTA anatomical models resulted in better prediction of MI by 11-17%, cardiovascular death or MI by 10-14%, and 5-component composite outcome by 12-16%.

CONCLUSION: Peak METs on EST, a marker of functional performance, added prognostic value to models including CCTA anatomical findings in patients with CCD and moderate or severe ischemia.

Recent reductions in U.S. global health funding have disrupted essential programs in sub-Saharan Africa (SSA), highlighting the region's vulnerability to external financing shocks. The suspension of USAID initiatives has affected disease control, maternal care, and health system operations across 47 countries, raising urgent questions about how to sustain progress without reliable donor support. This commentary examines the potential of Public-Private Partnerships (PPPs)-structured collaborations in which governments and private actors share financing, risk, and managerial responsibility-to strengthen domestic capacity. Drawing on examples from Senegal, Nigeria, and Kenya, we explore how service, concession, financing, and technology-focused PPPs can mobilize additional resources, expand access, and improve service delivery. We also address key challenges, including governance risks, fiscal constraints, and shifting global power dynamics. While not a substitute for aid, well-designed PPPs aligned with national priorities can support more resilient, equitable, and self-reliant health systems in SSA.