Faculty Bibliography

Necroptosis triggers an inflammatory cascade associated with antimicrobial defense. No prospective human study has yet explored the role of necroptosis in colorectal cancer development. We conducted quantitative analysis of biomarkers for necroptosis [transient receptor potential cation channel subfamily M member 7 (TRPM7) and phosphorylated mixed lineage kinase domain-like protein], inflammation [cyclooxygenase-2 (COX-2)], apoptosis [BCL2-associated X (BAX) and terminal deoxynucleotidyl transferase dUTP nick end labeling], and cell proliferation (Ki67). This was done using tissue microarray biospecimens from the Cooperative Human Tissue Network and rectal biopsies from a longitudinal study within the Personalized Prevention of Colorectal Cancer Trial. In the human colorectal adenoma-carcinoma sequence, we observed an inverse expression trend between BAX and TRPM7; TRPM7 decreased from normal mucosa to small and large adenomas but significantly increased in early colorectal cancer stages (Ptrend = 0.004). It maintained high levels through all cancer stages. An increased COX-2 intensity in the epithelium was noted during tumorigenesis (Ptrend = 0.02) and was significantly associated with an elevated risk of metachronous polyps (odds ratio = 3.04; 95% confidence interval, 1.07-8.61; Ptrend = 0.02). The combined composite index scores of TRPM7 and COX-2 were strongly linked to 6- to 47-fold increased risks for metachronous adenoma/serrated polyps, whereas combined scores of phosphorylated mixed lineage kinase domain-like protein or TRPM7 with BAX were associated with an 11.5- or 13.3-fold elevated risk for metachronous serrated polyps. In conclusion, our findings suggest that COX-2 expression within normal-looking colorectal mucosa is significantly associated with an increased risk of metachronous colorectal polyp. Furthermore, our results propose the hypothesis that synergistic interactions among necroptosis, inflammation, and apoptosis could play a pivotal role in human colorectal tumorigenesis. Prevention Relevance: Our findings suggest that COX-2 expression and combined scores of COX-2, TRPM7, and BAX hold promise for predicting the risk of metachronous polyps and could potentially serve as a tool for assessing the effectiveness of chemopreventive agents in preventing colorectal cancer during intervention trials.

BACKGROUND:PAH exposure is associated with adverse health outcomes, but exposure sources in pregnancy are not well-understood. OBJECTIVES/OBJECTIVE:We examined associations between urinary OH-PAHs during pregnancy and environmental tobacco smoke (ETS) and short-term ambient air pollution exposure. Participants included 1603 pregnant non-smokers in three cohorts from 7 sites across the USA. We also examined associations with intake of foods typically high in PAHs in one cohort with dietary assessment data (n = 801). METHODS:quartile adjusted for specific gravity, site, batch, household income, education, employment status, neighborhood deprivation index, season, and year. For the food model, PAH dietary intakes were estimated using food frequency questionnaire data and standard portion weights from a national database. RESULTS:was not associated with any OH-PAH, nor was self-reported dietary intake. CONCLUSIONS:and diet measured via usual intakes appear less influential. Our findings underscore the importance of policies/actions to reduce environmental tobacco smoke exposure among pregnant people.

Concerns persist about the potential impact of prenatal exposure to bisphenols (BP) and their replacement analogues on childhood asthma and allergies. Previous studies on single and small cohorts had limited statistical power, few investigated analogues BPF and BPS, and even fewer examined atopic outcomes. Our objective was to assess whether prenatal exposures to individual environmental bisphenols (BPA, BPF, BPS) influence risk of childhood asthma, allergic rhinitis, and atopic dermatitis. Data from the U.S. Environmental Influences on Child Health Outcomes (ECHO) consortium were harmonized on measures of prenatal urinary BPA, BPF and BPS and asthma and allergic rhinitis (ages 5-9 years) and atopic dermatitis (up to age 3 years) from 1905 mother-child pairs that were collected between 1998 and 2017. Across the 2012 federal ban of BPA from certain infant products, median BPA levels decreased from 1.11 ng/ml to 0.86 ng/ml; median BPF levels decreased from 0.51 ng/ml to 0.39 ng/ml; and median BPS levels increased from 0.23 ng/ml to 0.31 ng/ml (dilution adjusted; p < 0.001 for all three median comparisons). Prenatal measures of BPA, BPF, and BPS were unrelated to the risk of childhood asthma, allergic rhinitis, or atopic dermatitis in the total population. Modest sex-dependent effects were observed: only among girls, second tertile levels of BPF was associated with a reduced odds of asthma (odds ratio (OR) 0.27, 95% confidence interval (CI) 0.08, 0.93); a continuous index of prenatal BPS was associated with reduced odds of atopic dermatitis (OR 0.64, 95% CI 0.44, 0.93). The ongoing and changing patterns of exposure to bisphenols in the U.S. population require further study with additional attention to time windows of exposure and co-occurring social determinants of health, to continue to inform current policies and evaluate the importance of limiting exposure to BPA and its analogues on childhood asthma, allergic rhinitis, and atopic dermatitis.

Iron in the brain is essential to neurodevelopmental processes, as it supports neural functions, including processes of oxygen delivery, electron transport, and enzymatic activity. However, the development of brain iron before birth is scarcely understood. By estimating R2* (1/T2*) relaxometry from a sizable sample of fetal multiecho echo-planar imaging (EPI) scans, which is the standard sequence for functional magnetic resonance imaging (fMRI), across gestation, this study investigates age and sex-related changes in iron, across regions and tissue segments. Our findings reveal that brain R2* levels significantly increase throughout gestation spanning many different regions, except the frontal lobe. Furthermore, females exhibit a faster rate of R2* increase compared to males, in both gray matter and white matter. This sex effect is particularly notable within the left insula. This work represents the first MRI examination of iron accumulation and sex differences in developing fetal brains. This is also the first study to establish R2* estimation methodology in fetal multiecho functional MRI.

BACKGROUND:Cardiovascular risk models have been developed primarily for incident events. Well-performing models are lacking to predict secondary cardiovascular events among people with a history of coronary heart disease, stroke, or heart failure who also have chronic kidney disease (CKD). We sought to develop a proteomics-based risk score for cardiovascular events in individuals with CKD and a history of cardiovascular disease. METHODS:We measured 4638 plasma proteins among 1067 participants from the Chronic Renal Insufficiency Cohort (CRIC) and 536 individuals from the Atherosclerosis Risk in Communities Cohort (ARIC). All had non-dialysis-dependent CKD and coronary heart disease, heart failure, or stroke at study baseline. A proteomic risk model for secondary cardiovascular events was derived by elastic net regression in CRIC, validated in ARIC, and compared to clinical models. Biologic mechanisms of secondary events were characterized through proteomic pathway analysis. RESULTS:A 16-protein risk model was superior to the Framingham risk score for secondary events, including a modified score that included estimated glomerular filtration rate (eGFR). In CRIC, the annualized area under the receiver operating characteristic (AUC) within 1 to 5 years ranged between 0.77 and 0.80 for the protein model and 0.57 and 0.72 for the clinical models. These findings were replicated in the ARIC validation cohort. Biologic pathway analysis identified pathways and proteins for cardiac remodeling and fibrosis, vascular disease, and thrombosis. CONCLUSIONS:The proteomic risk model for secondary cardiovascular events outperformed clinical models based on traditional risk factors and eGFR.

BACKGROUND AND OBJECTIVE/OBJECTIVE:Innovations have improved outcomes in advanced prostate cancer (PC). Nonetheless, we continue to lack high-level evidence on a variety of topics that greatly impact daily practice. The 2024 Advanced Prostate Cancer Consensus Conference (APCCC) surveyed experts on key questions in clinical management in order to supplement evidence-based guidelines. Here we present voting results for questions from APCCC 2024. METHODS:Before the conference, a panel of 120 international PC experts used a modified Delphi process to develop 183 multiple-choice consensus questions on eight different topics. Before the conference, these questions were administered via a web-based survey to the voting panel members ("panellists"). KEY FINDINGS AND LIMITATIONS/UNASSIGNED:Consensus was a priori defined as ≥75% agreement, with strong consensus defined as ≥90% agreement. The voting results show varying degrees of consensus, as discussed in this article and detailed in the Supplementary material. These findings do not include a formal literature review or meta-analysis. CONCLUSIONS AND CLINICAL IMPLICATIONS/CONCLUSIONS:The voting results can help physicians and patients navigate controversial areas of clinical management for which high-level evidence is scant or conflicting. The findings can also help funders and policymakers in prioritising areas for future research. Diagnostic and treatment decisions should always be individualised on the basis of patient and cancer characteristics, and should incorporate current and emerging clinical evidence, guidelines, and logistic and economic factors. Enrolment in clinical trials is always strongly encouraged. Importantly, APCCC 2024 once again identified important gaps (areas of nonconsensus) that merit evaluation in specifically designed trials.

AIMS/HYPOTHESIS/OBJECTIVE:39-47 mmol/mol [5.7-6.4%] or fasting glucose 5.6-6.9 mmol/l) is associated with elevated risks of microvascular and macrovascular complications. It is unknown to what extent these risks in prediabetes remain after accounting for progression to diabetes. METHODS:In 10,310 participants from the Atherosclerosis Risk in Communities (ARIC) Study (aged 46-70 years, ~55% women, ~20% Black adults) without diabetes at baseline (1990-1992), we used Cox regression to characterise age- and sex-adjusted associations of prediabetes with ~30 year incidence of complications (composite and separately), including atherosclerotic CVD (ASCVD), heart failure, chronic kidney disease (CKD) and all-cause mortality before and after accounting for intervening incidence of diabetes, modelled as a time-varying variable. We calculated the excess risk of complications in prediabetes remaining after accounting for progression to diabetes. RESULTS:Of the 60% of adults with prediabetes at baseline, ~30% progressed to diabetes (median time to diabetes, 7 years). Over the maximum follow-up of ~30 years, there were 7069 events (1937 ASCVD, 2109 heart failure, 3288 CKD and 4785 deaths). Prediabetes was modestly associated with risk of any complication (HR 1.21 [95% CI 1.15, 1.27]) vs normoglycaemia. This association remained significant after accounting for progression to diabetes (HR 1.18 [95% CI 1.12, 1.24]) with 85% (95% CI 75, 94%) of the excess risk of any complication in prediabetes remaining. Results were similar for the individual complications. CONCLUSIONS/INTERPRETATION/CONCLUSIONS:Progression to diabetes explained less than one-quarter of the risks of clinical outcomes associated with prediabetes. Prediabetes contributes to the risk of clinical outcomes even without progression to diabetes.

OBJECTIVE:To compare hospitalization rates between African American (AA) and European American (EA) deceased-donor (DD) kidney transplant (KT) recipients during over a10-year period. METHOD/METHODS:Data from the Scientific Registry of Transplant Recipients and social determinants of health (SDoH), measured by the Social Deprivation Index, were used. Hospitalization rates were estimated for kidney recipients from AA and EA DDs who had one kidney transplanted into an AA and one into an EA, leading to four donor/recipient pairs (DRPs): AA/AA, AA/EA, EA/AA, and EA/EA. Poisson-Gamma models were fitted to assess post-transplant hospitalizations. RESULT/RESULTS:Unadjusted hospitalization rates (95% confidence interval) were higher among all DRP involving AA, 131.1 (122.5, 140.3), 134.8 (126.3, 143.8), and 102.4 (98.9, 106.0) for AA/AA, AA/EA, and EA/AA, respectively, compared to 97.1 (93.7, 100.6) per 1000 post-transplant person-years for EA/EA pairs. Multivariable analysis showed u-shaped relationships across SDoH levels within each DRP, but findings varied depending on recipients' race, i.e., AA recipients in areas with the worst SDoH had higher hospitalization rates. However, EA recipients in areas with the best SDoH had higher hospitalization rates than their counterparts. CONCLUSIONS:Relationship between healthcare utilization and SDoH depends on DRP, with higher hospitalization rates among AA recipients living in areas with the worst SDoH and among EA recipients in areas with the best SDoH profiles. SDoH plays an important role in driving disparities in hospitalizations after kidney transplantation.

BACKGROUND/UNASSIGNED:Children from racial and ethnic minority groups are at greater risk for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, but it is unclear whether they have increased risk for post-acute sequelae of SARS-CoV-2 (PASC). Our objectives were to assess whether the risk of respiratory and neurologic PASC differs by race/ethnicity and social drivers of health. METHODS/UNASSIGNED:We conducted a retrospective cohort study of individuals <21 years seeking care at 24 health systems across the U.S, using electronic health record (EHR) data. Our cohort included those with a positive SARS-CoV-2 molecular, serology or antigen test, or with a COVID-19, multisystem inflammatory disease in children, or PASC diagnosis from February 29, 2020 to August 1, 2022. We identified children/youth with at least 2 codes associated with respiratory and neurologic PASC. We measured associations between sociodemographic and clinical characteristics and respiratory and neurologic PASC using odds ratios and 95% confidence intervals estimated from multivariable logistic regression models adjusted for other sociodemographic characteristics, social vulnerability index or area deprivation index, time period of cohort entry, presence and complexity of chronic respiratory (respectively, neurologic) condition and healthcare utilization. FINDINGS/UNASSIGNED:Among 771,725 children in the cohort, 203,365 (26.3%) had SARS-CoV-2 infection. Among children with documented infection, 3217 children had respiratory PASC and 2009 children/youth had neurologic PASC. In logistic regression models, children <5 years (Odds Ratio [OR] 1.78, 95% CI 1.62-1.97), and of Hispanic White descent (OR 1.19, 95% CI 1.05-1.35) had higher odds of having respiratory PASC. Children/youth living in regions with higher area deprivation indices (OR 1.25, 95% CI 1.10-1.420 for 60-79th percentile) and with chronic complex respiratory conditions (OR 3.28, 95% CI 2.91-3.70) also had higher odds of respiratory PASC. In contrast, older (OR 1.57, 95% CI 1.40-1.77 for those aged 12-17 years), non-Hispanic White individuals and those with chronic pre-existing neurologic conditions (OR 2.04, 95% CI 1.78-2.35) were more likely to have a neurologic PASC diagnosis. INTERPRETATION/UNASSIGNED:Racial and ethnic differences in healthcare utilization for neurologic and respiratory PASC may reflect social drivers of health and inequities in access to care. FUNDING/UNASSIGNED:National Institutes of Health.