Citations

Cancer health disparities represent profound inequalities in incidence, outcomes, and survivorship across populations. While traditionally examined through distinct lenses of either molecular biology or social epidemiology, these disparities arise from the complex interplay of genetic susceptibility, epigenetic dysregulation, and social determinants of health (SDoH). This review proposes that DNA damage and genomic instability serve as a critical mechanistic bridge, integrating exposures from the societal level to cellular dysfunction. We synthesize evidence demonstrating how SDoH—such as systemic inequities, environmental exposures, and chronic stress—converge with genetic and epigenetic factors to disproportionately increase DNA damage burden, impair repair mechanisms, and accelerate tumorigenesis in marginalized communities. Using the elevated gastrointestinal cancer rates among Native Hawaiians and Pacific Islanders (NH/PI) as a case study, we illustrate how historical, environmental, and socioeconomic factors interact with biological pathways to drive disparities. The review highlights key advances in DNA damage research—from somatic mutation theory to the modern understanding of chronic genomic stress—and explores how innovations in single-cell genomics, biomarker discovery, and computational modeling can unravel disparity etiologies. We argue that a translational framework linking social exposure data to molecular biomarkers of DNA damage is essential for moving beyond descriptive disparities to mechanistic understanding. Ultimately, addressing cancer equity requires interdisciplinary strategies that bridge molecular oncology, public health, and community-engaged research, targeting the root causes where social inequities become biologically embedded as genomic instability.

Abstract INTRODUCTION The Consortium for Clarity in Alzheimer's disease related dementias (ADRD) Research Through Imaging (CLARiTI) is a study that aims to collect standardized imaging and plasma biomarkers on 2000 Clinical Core participants enrolled across all Alzheimer's Disease Research Centers (ADRC) sites. We sought to summarize the known heterogeneity across centers regarding scientific focus and initial enrollment plans for CLARiTI. METHODS We developed and distributed a survey capturing information on the 36 CLARiTI site's theme/expertise, recruitment plans, and the intersection of CLARiTI with other ADRC imaging efforts. RESULTS Anticipated CLARiTI enrollees spanned 11 different categories of suspected etiologies underlying impairment. A wide range of risk factors were endorsed across sites regarding the enrollment of unimpaired individuals. Variability also existed regarding site‐level strategies in enrollment into CLARiTI versus other imaging efforts. DISCUSSION We anticipate that the 2000 individuals that will enroll into CLARiTI will reflect the clinical heterogeneity already in place across the ADRC network. Highlights The ADRC Consortium for Clarity in ADRD Research Through Imaging (CLARiTI) will leverage and contribute to the existing Alzheimer's Disease Research Centers (ADRC) program by supporting standardized imaging and plasma collection across all centers. We summarize the variation in scientific focus and enrollment plans across ADRC sites participating in CLARiTI. The anticipated CLARiTI cohort will reflect the clinical heterogeneity that already exists across the ADRC network. CLARiTI will contribute to scientific goals related to the detection of multi‐etiological signatures relevant for Alzheimer's disease and related disorders (ADRDs).

Background: Calcific aortic valve stenosis (CAVS) is characterized by the progressive accrual of aortic valvular calcium (AVC), resulting in impaired valvular compliance and mechanics and impaired cardiac function leading to heart failure (HF). In a phase 2 trial of 23 patients with moderate CAVS, ataciguat (ATA), a soluble guanylate cyclase activator, relative to placebo slowed the deposition of AVC, decreases in aortic valve area (AVA; by continuity equation), and increases in diastolic dysfunction and left ventricular (LV) mass. ATA may have other favorable effects on ventricular, valvular, and/or vascular pathophysiology relevant to patients with CAVS. Hypothesis: We hypothesized that slowing the rate of AVC deposition is associated with improvements in valvular compliance and in measures of cardiac structure and function. Methods: A phase 2 study randomized patients with moderate CAVS 1:1 to receive ATA 200 mg/day or placebo for up to 12 months (NCT02481258). The primary endpoint was change in AVC assessed by cardiac CT, and measures of aortic valve function and cardiac structure and function were also assessed. AVA was calculated by the Modified Gorlin (Hakki) equation to additionally assess valvular compliance. Correlations between AVC, AVA, and other measures of cardiac structure and function were assessed by exploratory linear mixed models. Results: Changes in AVC from baseline were negatively correlated with changes in AVA (slope = −0.0002 [95% CI −0.0004, 0.0001]; Figure 1), such that patients with the least AVC deposition had minimal changes in AVA. Reciprocally, changes from baseline in AVA were positively correlated with changes in cardiac output (CO; slope = 0.16 [95% CI 0.13, 0.18]; Figure 2). Treatment with ATA, compared with placebo, was associated with improvements in systolic function. Changes in AVC deposition correlated with changes in CO (slope = −0.0007 [95% CI −0.0021, 0.0008]; Figure 3), and measured improvements in CO were generally more observed in patients with less of an increase in AVC, which were more frequently observed in those treated with ATA compared with placebo. Conclusions: These data suggest that slowing the rate of AVC deposition with ATA may result in improvements in CO through improved myocardial function and valvular compliance. Larger controlled trials are needed to assess such favorable myocardial/valvular effects that may help to preserve functional capacity and slow progression to HF.

AbstractBackgroundNeuritic plaques with fibrillar beta‐amyloid (Aβ) peptides and tau‐protein neurofibrillary tangles, hallmark features of Alzheimer’s disease (AD) pathology, have been concomitantly associated with white matter (WM) integrity loss, while a unique effect of each pathology on WM integrity in a more demographically diverse population remains unknown.MethodTo examine the degree to which each pathology affects WM integrity in a more diverse non‐demented cohort, Aβ and tau PET, diffusion‐weighted imaging (DWI), and cognition (memory and executive function composites) were examined from the U.S. POINTER neuroimaging participants (N=608; age=68.34±5.2; 61.8% females; 29% Aβ+) and a subset of Alzheimer’s Disease Neuroimaging Initiative (ADNI) participants (N=291; age=72.85±7.3; 50% females; 39% Aβ+) (Table). Aβ‐positivity was determined using tracer‐specific standardized cut‐offs. Tau SUVR was estimated for each Braak stage. For WM integrity, voxel‐based GLMs were applied to FSL‐processed fractional anisotropy (FA) maps using Braak stage tau SUVR and Aβ‐positivity status, along with covariates of age, sex, and b‐value profiles.ResultIn U.S. POINTER, independent from Aβ‐positivity status, greater tau burden in Braak stages I and II was related to lower FA across the tracts including the superior longitudinal fasciculus, fornix (cres), corpus callosum, and anterior thalamic radiation (Figure). Average FA from supra‐threshold clusters for Braak I and II significantly predicted executive function but not episodic memory. No association between FA and tau burden in Braak stages III/IV or V/VI was found. In the ADNI sample, greater tau burden in Braak I was related to lower FA mostly in left inferior longitudinal fasciculus and left uncinate fasciculus, while negative associations with FA became more diffuse with tau load in Braak III/IV and V/VI. Average FA from supra‐threshold clusters significantly predicted both episodic memory and executive function scores. Across both samples, after accounting for tau burden in each Braak stage, there were no association between Aβ‐positivity status and WM integrity.ConclusionDistinct associations between tau burden, WM integrity, and cognition were found across the studies, indicating greater impact of early tau burden on WM integrity in U.S. POINTER, accounting for Aβ‐positivity status. Factors contributing to the distinct associations across studies need further investigation.

AbstractBackgroundNeuritic plaques with fibrillar beta‐amyloid (Aß) peptides and tau‐protein neurofibrillary tangles, hallmark features of Alzheimer’s disease (AD) pathology, have been concomitantly associated with white matter (WM) integrity loss, while a unique effect of each pathology on WM integrity in a more demographically diverse population remains unknown.MethodTo examine the degree to which each pathology affects WM integrity in a more diverse non‐demented cohort, Aß and tau PET, diffusion‐weighted imaging (DWI), and cognition (memory and executive function composites) were examined from the U.S. POINTER neuroimaging participants (N = 608; age = 68.34±5.2; 61.8% females; 29% Aß+) and a subset of Alzheimer’s Disease Neuroimaging Initiative (ADNI) participants (N = 291; age = 72.85±7.3; 50% females; 39% Aß+) (Table). Aß‐positivity was determined using tracer‐specific standardized cut‐offs. Tau SUVR was estimated for each Braak stage. For WM integrity, voxel‐based GLMs were applied to FSL‐processed fractional anisotropy (FA) maps using Braak stage tau SUVR and Aß‐positivity status, along with covariates of age, sex, and b‐value profiles.ResultIn U.S. POINTER, independent from Aß‐positivity status, greater tau burden in Braak stages I and II was related to lower FA across the tracts including the superior longitudinal fasciculus, fornix (cres), corpus callosum, and anterior thalamic radiation (Figure). Average FA from supra‐threshold clusters for Braak I and II significantly predicted executive function but not episodic memory. No association between FA and tau burden in Braak stages III/IV or V/VI was found. In the ADNI sample, greater tau burden in Braak I was related to lower FA mostly in left inferior longitudinal fasciculus and left uncinate fasciculus, while negative associations with FA became more diffuse with tau load in Braak III/IV and V/VI. Average FA from supra‐threshold clusters significantly predicted both episodic memory and executive function scores. Across both samples, after accounting for tau burden in each Braak stage, there were no association between Aß‐positivity status and WM integrity.ConclusionDistinct associations between tau burden, WM integrity, and cognition were found across the studies, indicating greater impact of early tau burden on WM integrity in U.S. POINTER, accounting for Aß‐positivity status. Factors contributing to the distinct associations across studies need further investigation.

Abstract Traumatic injury to the spinal cord initiates a series of pathological cellular processes that exacerbate tissue damage at and beyond the original site of injury. This secondary damage includes oxidative stress and inflammatory cascades that can lead to further neuronal loss and motor deficits. Microglial activation is an essential component of these secondary signaling cascades. The voltage-gated proton channel, Hv1, functionally expressed in microglia has been implicated in microglia polarization and oxidative stress in ischemic stroke. Here, we investigate whether Hv1 mediates microglial/macrophage activation and aggravates secondary damage following spinal cord injury (SCI). Following contusion SCI, wild-type (WT) mice showed significant tissue damage, white matter damage and impaired motor recovery. However, mice lacking Hv1 (Hv1-/-) showed significant white matter sparing and improved motor recovery. The improved motor recovery in Hv1-/- mice was associated with decreased interleukin-1β, reactive oxygen/ nitrogen species production and reduced neuronal loss. Further, deficiency of Hv1 directly influenced microglia activation as noted by decrease in microglia numbers, soma size and reduced outward rectifier K+ current density in Hv1-/- mice compared to WT mice at 7 d following SCI. Our results therefore implicate that Hv1 may be a promising potential therapeutic target to alleviate secondary damage following SCI caused by microglia/macrophage activation.

Abstract Traumatic injury to the spinal cord initiates a series of pathological cellular processes that exacerbate tissue damage at and beyond the original site of injury. This secondary damage includes oxidative stress and inflammatory cascades that can lead to further neuronal loss and motor deficits. Microglial activation is an essential component of these secondary signaling cascades. The voltage-gated proton channel, Hv1, functionally expressed in microglia has been implicated in microglia polarization and oxidative stress in ischemic stroke. Here, we investigate whether Hv1 mediates microglial/macrophage activation and aggravates secondary damage following spinal cord injury (SCI). Following contusion SCI, wild-type (WT) mice showed significant tissue damage, white matter damage and impaired motor recovery. However, mice lacking Hv1 (Hv1-/-) showed significant white matter sparing and improved motor recovery. The improved motor recovery in Hv1-/- mice was associated with decreased interleukin-1β, reactive oxygen/ nitrogen species production and reduced neuronal loss. Further, deficiency of Hv1 directly influenced microglia activation as noted by decrease in microglia numbers, soma size and reduced outward rectifier K+ current density in Hv1-/- mice compared to WT mice at 7d following SCI. Our results therefore implicate that Hv1 may be a promising potential therapeutic target to alleviate secondary damage following SCI caused by microglia/macrophage activation.

Investigators have dedicated considerable effort to understanding the molecular basis underlying Fanconi Anemia (FA), a rare human genetic disease featuring an extremely high incidence of cancer and many congenital defects. Among those studies, FA group D2 protein (FANCD2) has emerged as the focal point of FA signaling and plays crucial roles in multiple aspects of cellular life, especially in the cellular responses to DNA damage. Here, we discuss the recent and relevant studies to provide an updated review on the roles of FANCD2 in the DNA damage response.