Citations

Abstract INTRODUCTION Risk factors associated with sporadic non‐amnestic and early‐onset Alzheimer's disease (AD) remain underexamined. METHODS We investigated a large, clinically heterogeneous, AD cohort for frequencies of established risk factors (hypertension, hypercholesterolemia, diabetes mellitus) alongside novel factors (non–right‐handedness, learning disability, seizures, autoimmune disease). RESULTS Early‐onset AD possessed lower frequencies of established risk factors (hypertension, hypercholesterolemia, diabetes mellitus, all p < 0.001) and higher frequencies of novel factors (non–right‐handedness, learning disability, active seizure, all p < 0.001; remote seizure, p = 0.002; and autoimmune disease, p = 0.007). An age at onset < 70 maximally distinguished novel from typical factors. Principal component analysis loaded novel factors into two components, non–right‐handedness and learning disability versus seizure and autoimmune disease, which combined, resulted in an exponential decrease in age at onset from one factor alone. DISCUSSION Identifying novel factors enriched in early‐onset and non‐amnestic AD introduces new theories of AD susceptibility and phenotypic heterogeneity, with significant implications for disease prediction and treatment. Highlights We identified a suite of novel factors overrepresented in early‐onset and non‐amnestic AD. These factors can be broadly conceptualized as neurodevelopmental (non–right‐handedness and learning disability) and neural environmental (seizure and autoimmunity). The combination of these factors produced exponential decreases in AD age at onset, compared to each alone, supporting a new theoretical framework for understanding AD risk with implications for disease prediction, prevention, and therapeutic intervention.

Abstract Obesity has been associated with non‐Hodgkin lymphoma (NHL), but the evidence is inconclusive. We examined the association between genetically determined adiposity and four common NHL subtypes: diffuse large B‐cell lymphoma (DLBCL), follicular lymphoma, chronic lymphocytic leukemia, and marginal zone lymphoma, using eight genome‐wide association studies of European ancestry ( N = 10,629 cases, 9505 controls) and constructing polygenic scores for body mass index (BMI), waist‐to‐hip ratio (WHR), and waist‐to‐hip ratio adjusted for BMI (WHRadjBMI). Higher genetically determined BMI was associated with an increased risk of DLBCL [odds ratio (OR) per standard deviation (SD) = 1.18, 95% confidence interval (95% CI): 1.05–1.33, p = .005]. This finding was consistent with Mendelian randomization analyses, which demonstrated a similar increased risk of DLBCL with higher genetically determined BMI (OR per SD = 1.12, 95% CI: 1.02–1.23, p = .03). No significant associations were observed with other NHL subtypes. Our study demonstrates a positive link between a genetically determined BMI and an increased risk of DLBCL, providing additional support for increased adiposity as a risk factor for DLBCL.

Abstract Background Breast cancer genome-wide association studies (GWAS) have identified more than 200 susceptibility loci, but most studies are dominated by European and East Asian populations. Methods We analyzed breast cancer GWAS summary statistics from African (AFR), East Asian (EAS), European (EUR), and Hispanic/Latina (H/L) samples (159,297 cases and 212,102 controls). We estimated logit-scale SNP-based heritability, polygenicity, and cross-ancestry genetic correlation, partitioned heritability across functional annotations, and integrated GWAS results with the Tabula Sapiens single-cell atlas using scDRS+. Results The logit-scale heritability of breast cancer ranged from ℎ 2 =0.47 (SE = 0.07) in EAS to AFR ℎ 2 =0.61 (SE = 0.10), with no significant differences across ancestries (p=0.63). The estimated number of susceptibility markers in a sparse normal-mixture effects model also varied from 4,446 (SE = 3,100) in EAS to 8,308 (SE = 2,751) in AFR, but differences were not significant across ancestries (p=0.55). Cross-sample genetic correlations varied, with the strongest correlation between EUR and EAS (𝜌 = 0.79, SE = 0.08) and weakest between AFR and H/L (𝜌 = 0.26, SE = 0.24). Regulatory annotations were enriched for breast cancer heritability across samples. Integration with single-cell expression profiles implicated ancestry-shared associations with innate immune, secretory epithelial, and stromal cell types. Conclusion These results indicate substantial cross-ancestry sharing of breast cancer polygenic architecture, highlight a consistent contribution of regulatory variation, and identify convergent cellular contexts that motivate functional follow-up and inform expectations for the transferability and attainable performance of common-variant risk prediction across populations.

This cross-sectional study analyzes patient-reported outcome findings from the Enhanced, Electronic Health Record–Facilitated Cancer Symptom Control (E2C2) trial to investigate level of symptom burden in adolescents and young adults with cancer.

BACKGROUND: The performance of estimated glomerular filtration rate (eGFR) among patients with heart failure (HF) may be worse than in the general population due to a higher prevalence of confounding factors affecting creatinine and cystatin C. Studies in this area are scarce and not stratified by type of HF. We evaluated the performance of current creatinine and cystatin C equations (eGFRcr, eGFRcys, and eGFRcrcys) compared with measured GFR (mGFR) among patients with HF stratified by ejection fraction. METHODS: We pulled data on Mayo Clinic patients with an mGFR performed for clinical indications from 2011 to 2023, with serum creatinine and cystatin C measured within 7 days and an echocardiogram performed up to 1 year before the mGFR date. HF was identified by the presence of International Classification of Diseases codes within 1 year before the mGFR and subgrouped into ejection fraction (EF) ≥50% (HFEF≥50%, n=182) or <50% (HFEF<50%, n=115) and compared with no-HF controls (n=1871). CKD-EPI (and EKFC) eGFRcr, eGFRcys, and eGFRcrcys equations were calculated and compared for bias (mGFR minus eGFR) and accuracy (1-P30, proportion of people with ≥30% difference between eGFR and mGFR). CIs were generated by bootstrapping. RESULTS: The HF groups were characterized by older age, higher proportion of males, more diabetes, higher creatinine, and higher cystatin C than controls. In terms of bias, eGFRcr overestimated mGFR to a greater extent in both HF groups compared with controls, whereas eGFRcys and eGFRcrcys showed similar bias in both HF groups and controls. In the HF groups, cystatin C-based equations were more accurate than eGFRcr, particularly within HFEF<50% (1-P30 of 28% and 34% for CKD-EPI eGFRcys and eGFRcrcys, respectively, versus 60% for eGFRcr), whereas eGFRcrcys was more accurate in controls. The CKD-EPI and EKFC equations were overall convergent, showing similar results. CONCLUSIONS: Among patients with HF, eGFRcr demonstrates inferior performance (more bias and less accuracy) compared with cystatin C-based eGFRs, with this effect being more pronounced in those with HFEF<50%.

Abstract Sex differences in cancer outcome, including that of glioblastoma (GBM), are shaped by biological, hormonal, and immunological factors and impact disease progression, treatment responses, survival, and tumor microenvironment (TME) interactions. Platelets regulate the immune responses and tumor progression in many cancers, but it is not clear how they contribute to these sex-based differences by affecting the dynamics of the TME. Here, we show that GBM patients exhibit heightened platelet reactivity driven by PAR4 signaling. In murine GBM models, both pharmacological inhibition of PAR4 using BMS986120 and genetic deletion of PAR4 significantly prolong survival in females but not males. This survival advantage is estrogen dependent: it is preserved in chromosomal male-hormonal female mice within the four-core genotype model and is rescued in ovariectomized mice treated with estrogen. The survival benefit is TME specific and is mediated by platelet-driven enhancement of CD8⁺ T cell infiltration into the tumor. Inhibition of platelet PAR4 signaling increases calcium signaling through an estrogen-dependent interaction between PAR4 and estrogen receptor β (ERβ)—a receptor interaction not previously described. PAR4-activated platelets within the TME suppress CD8⁺ T cell function, and depletion of CD8⁺ T cells abolishes both the tumor-induced platelet reactivity and the survival benefit conferred by PAR4 inhibition. These findings establish platelet-mediated PAR4 signaling as a critical driver of tumor progression and identify sex-specific immune responses as key to therapeutic efficacy.

ABSTRACTBackgroundThe Pediatric Oncology Group P9262 Phase 2 study of single‐agent paclitaxel demonstrated one complete response (CR), one partial response (PR), and four with stable disease (SD) among 15 patients with recurrent Wilms tumor (WT). Based on this activity, paclitaxel‐containing regimens have been used as salvage therapy for treatment‐refractory WT. We conducted a multi‐institutional retrospective study to further characterize the clinical activity of paclitaxel‐containing regimens in recurrent WT.MethodsTwelve institutions submitted anonymized data from patients with relapsed WT treated with paclitaxel. Response after one or two cycles of a paclitaxel‐containing regimen was reported according to Response Evaluation Criteria in Solid Tumors.ResultsTwenty‐eight patients with a median age at diagnosis of 5.5 years (range: 3 months to 31.9 years) were reported. Twenty had non‐anaplastic WT; eight had diffuse anaplasia (DA). Stage at diagnosis was I (n = 1), II (n = 1), III (n = 11), IV (n = 14), and V (n = 1). Patients received a mean of 8.5 anticancer drugs (range: 6–12) before paclitaxel, including eight who received high‐dose therapy/stem cell transplant. Paclitaxel (n = 13) or nab‐paclitaxel (n = 15) were predominantly administered in combination with other agents, most commonly doxorubicin and/or gemcitabine. Eleven of 26 patients with measurable disease had a partial response (7 = non‐anaplastic; 4 = DA), four had stable disease, and 11 had progressive disease. Two patients without measurable disease maintained a complete response for 12 and 16 months. The mean duration without progression was 7.6 months (range: 1–35 months).ConclusionsPaclitaxel‐containing regimens appear to be active against heavily pretreated WT with either non‐anaplastic or DA histology. Prospective studies are warranted to formally evaluate the efficacy of paclitaxel‐based therapies.

Background We aimed to assess the longitudinal changes of glycocalyx, a proteoglycan/glycoprotein layer that lines and protects endothelial cells in normotensive pregnancies (NPs); to correlate glycocalyx parameters with kidney injury markers (podocin‐positive to nephrin‐positive [P/N] ratio); and to explore changes in P/N ratio in preeclampsia. Methods Plasma and urine samples and glycocalyx measurements using side‐stream darkfield imaging were collected at each trimester from pregnant women (n=31). Plasma glycocalyx components were measured by ELISA, and urinary P/N‐positive extracellular vesicles by flow cytometry. Results In NPs (n=26), glycocalyx degradation increased from the first to the second trimester ( P =0.008) and returned to first‐trimester values in the third trimester ( P =0.008). Microvascular perfusion decreased from the first to the second trimester ( P =0.006) and increased back to first‐trimester values by the third trimester ( P =0.039). Plasma syndecan 1 level showed a steady increase from the first to the second trimester ( P <0.001) and further in the third trimester ( P <0.001); hyaluronic acid increased from the first to the second trimester ( P =0.016) without further changes. Glycocalyx degradation was associated with an increase in P/N ratio from the first to the second trimester of NPs and remained stable through the third trimester. P/N ratio strongly correlated with elevated syndecan 1 and hyaluronic acid levels in the third trimester. Comparison of P/N ratios between NP and preeclampsia (n=5) showed higher values in preeclampsia across all trimesters ( P =0.028). Conclusions Glycocalyx changes during NPs are associated with elevated urinary podocyte markers. Increase in P/N ratio across NPs, and further in preeclampsia, suggests that podocyte injury in preeclampsia is extension of physiological changes in pregnancy, which may predate its clinical presentation.

ABSTRACTBackgroundBlau syndrome is a rare, autosomal dominant granulomatous disease caused by mutations in the NOD2/CARD15 gene. While the classic triad of arthritis, dermatitis, and uveitis is well known, the full range of cutaneous manifestations remains underexplored.ObjectiveTo expand the understanding of cutaneous findings in Blau syndrome, correlate these findings with NOD2 variants, and evaluate treatment outcomes across organ systems.MethodsA retrospective review of medical records from January 1999 to January 2024 identified 14 patients with Blau syndrome supported by the presence of NOD2 variants. Clinical data on dermatological features, genetics, and treatment responses were analyzed and categorized into specific and non‐specific cutaneous findings.ResultsOf the 14 patients with Blau syndrome, 85% (12/14) demonstrated skin involvement. Specific findings included lichenoid or granulomatous papules and nodules (50%, 6/12), while non‐specific findings (83%, 10/12) were more diverse, including dermatitis (6/10), chronic urticaria (5/10), ichthyosiform eruptions (4/10), vasospastic disorders (5/10), and oral/genital ulcers (2/10). Skin biopsies in three patients with specific findings revealed non‐caseating granulomas. Genetic analysis identified multiple NOD2 variants, though no clear genotype–phenotype correlation was observed. TNF‐alpha inhibitors demonstrated efficacy in controlling ocular and joint disease.ConclusionBlau syndrome presents with a broader spectrum of cutaneous findings than previously recognized. These findings highlight the importance of dermatological evaluation and a multidisciplinary approach to optimize diagnosis and management.