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Murine double minute 2 (MDM2) inhibitors have shown promising activity in TP53-wild type tumors and are under active investigation across a spectrum of malignancies. Herein, we report a 51-year-old female with MDM2-amplified, TP53-wild type adenoid cystic carcinoma who was treated with a MDM2 inhibitor and developed persistent pancytopenia despite drug discontinuation. Her pancytopenia was associated with 20 distinct pathogenic TP53 mutations in peripheral blood and bone marrow not present in drug-resistant tumor tissue. Plasma TP53 mutations were similarly detected among 4 other patients treated at our institution, with the number of mutations correlating strongly with duration of treatment. This case suggests that MDM2 inhibitors are associated with TP53 clonal hematopoiesis, which may confer a risk of subsequent myeloid malignancy. As multiple MDM2 inhibitor trials are ongoing, our findings underscore the need for further investigation into the potential long-term deleterious effects of these inhibitors in the hematopoietic stem and progenitor compartment., Competing Interests: Competing interests: C.C. has received research grants (to his institution) from the following: Cholangiocarcinoma Foundation, ADC Therapeutics, Oric Pharmaceuticals, Seattle Genetics, Rain Therapeutics, Kinnate, Gilead, Mersana Therapeutics, Riboscience, Takeda, Palleon, Merus, Revolution Medicines, Tango Therapeutics, and Genentech-Roche, and has received consulting fees from Boxer Capital and Guidepoint Global Advisors. The remaining authors report no competing interests., (© 2025. The Author(s).)

A potentially promising approach to targeted cancer prevention in genetically at-risk populations is the pharmacological upregulation of DNA repair pathways. SMUG1 is a base excision repair enzyme that ameliorates adverse genotoxic and mutagenic effects of hydrolytic and oxidative damage to pyrimidines. Here we describe the discovery and initial cellular activity of a small-molecule activator of SMUG1. Screening of a kinase inhibitor library and iterative rounds of structure-activity relationship studies produced compound 40 (SU0547), which activates SMUG1 by as much as 350 ± 60 % in vitro at 100 nM, with an AC 50 of 4.3 ± 1.1 µM. To investigate the effect of compound 40 on endogenous SMUG1, we performed in vitro cell-based experiments with 5-hydroxymethyl-2'-deoxyuridine (5-hmdU), a pyrimidine oxidation product that is selectively removed by SMUG1. In several human cell lines, compound 40 at 3-5 µM significantly reduces the cytotoxicity of 5-hmdU and decreases levels of double-strand breaks induced by the damaged nucleoside. We conclude that the SMUG1 activator compound 40 is a useful tool to study the mechanisms of 5-hmdU toxicity and the potentially beneficial effects of suppressing damage to pyrimidines in cellular DNA., Competing Interests: Declaration of Competing Interest The authors declare no conflicts of interest., (Copyright © 2025 Elsevier B.V. All rights reserved.)

Spontaneous neural activity coherently relays information across the brain. Several efforts have been made to understand how spontaneous neural activity evolves at the macro-scale level as measured by resting-state functional magnetic resonance imaging (rsfMRI). Previous studies observe the global patterns and flow of information in rsfMRI using methods such as sliding window or temporal lags. However, to our knowledge, no studies have examined spatial propagation patterns evolving with time across multiple overlapping 4D networks. Here, we propose a novel approach to study how dynamic states of the brain networks spatially propagate and evaluate whether these propagating states contain information relevant to mental illness. We implement a lagged windowed correlation approach to capture voxel-wise network-specific spatial propagation patterns in dynamic states. Results show systematic spatial state changes over time, which we confirmed are replicable across multiple scan sessions using human connectome project data. We observe networks varying in propagation speed; for example, the default mode network (DMN) propagates slowly and remains positively correlated with blood oxygenation level-dependent (BOLD) signal for 6-8 s, whereas the visual network propagates much quicker. We also show that summaries of network-specific propagative patterns are linked to schizophrenia. More specifically, we find significant group differences in multiple dynamic parameters between patients with schizophrenia and controls within four large-scale networks: default mode, temporal lobe, subcortical, and visual network. Individuals with schizophrenia spend more time in certain propagating states. In summary, this study introduces a promising general approach to exploring the spatial propagation in dynamic states of brain networks and their associated complexity and reveals novel insights into the neurobiology of schizophrenia., (© 2025 The Author(s). Human Brain Mapping published by Wiley Periodicals LLC.)

Schizophrenia (SZ) patients exhibit abnormal static and dynamic functional connectivity across various brain domains. We present a novel approach based on static and dynamic inter-network connectivity entropy (ICE), which represents the entropy of a given network's connectivity to all the other brain networks. This novel approach enables the investigation of how connectivity strength is heterogeneously distributed across available targets in both SZ patients and healthy controls. We analyzed fMRI data from 151 SZ patients and 160 demographically matched healthy controls (HC). Our assessment encompassed both static and dynamic ICE, revealing significant differences in the heterogeneity of connectivity levels across available functional brain networks between SZ patients and HC. These networks are associated with subcortical (SC), auditory (AUD), sensorimotor (SM), visual (VIS), cognitive control (CC), default mode network (DMN), and cerebellar (CB) functional brain domains. Elevated ICE observed in individuals with SZ suggests that patients exhibit significantly higher randomness in the distribution of time-varying connectivity strength across functional regions from each source network, compared to HC. C-means fuzzy clustering analysis of functional ICE correlation matrices revealed that SZ patients exhibit significantly higher occupancy weights in clusters with weak, low-scale functional entropy correlation, while the control group shows greater occupancy weights in clusters with strong, large-scale functional entropy correlation. K-means clustering analysis on time-indexed ICE vectors revealed that cluster with highest ICE have higher occupancy rates in SZ patients whereas clusters characterized by lowest ICE have larger occupancy rates for control group. Furthermore, our dynamic ICE approach revealed that in HC, the brain primarily communicates through complex, less structured connectivity patterns, with occasional transitions into more focused patterns. Individuals with SZ are significantly less likely to attain these more focused and structured transient connectivity patterns. The proposed ICE measure presents a novel framework for gaining deeper insight into mechanisms of healthy and diseased brain states and represents a useful step forward in developing advanced methods to help diagnose mental health conditions., (© 2025 The Author(s). Human Brain Mapping published by Wiley Periodicals LLC.)

Background: Auditory steady-state response (ASSR) abnormalities in the 40-Hz (gamma band) frequency have been observed in schizophrenia and rodent studies of N-methyl D-aspartate glutamate receptor (NMDAR) hypofunction. However, the extent to which 40-Hz ASSR abnormalities in schizophrenia resemble deficits in 40-Hz ASSR induced by acute administration of ketamine, an NMDAR antagonist, is not yet known., Methods: To address this knowledge gap, we conducted parallel EEG studies: a crossover, placebo-controlled ketamine drug challenge study in healthy subjects (Study 1) and a comparison of patients with schizophrenia and healthy controls subjects (Study 2). Time-frequency analysis of the ASSR was used to calculate baseline, broadband gamma power, evoked power, total power, phase-locking factor, and phase-locking angle., Results: Relative to healthy controls, schizophrenia patients exhibited increases in pre-stimulus broadband gamma power and reductions in 40-Hz ASSR evoked power, total power, and phase-locking factor, replicating prior studies. However, we failed to replicate previous findings of 40-Hz ASSR phase delay in schizophrenia. Relative to placebo, ketamine: increased pre-stimulus broadband gamma power, reduced 40-Hz ASSR evoked power, total power, and phase-locking factor, and advanced the phase of the 40-Hz ASSR., Conclusion: Normalized by their respective control groups/conditions, direct comparison of these measures between schizophrenia and ketamine data only revealed significant differences in phase, supporting the role of NMDAR hypofunction in mediating gamma oscillation abnormalities in schizophrenia., (Copyright © 2025. Published by Elsevier Inc.)

Neuroimaging methods rely on models of neurovascular coupling that assume hemodynamic responses evolve seconds after changes in neural activity. However, emerging evidence reveals noncanonical BOLD (blood oxygen level dependent) responses that are delayed under stress and aberrant in neuropsychiatric conditions. To investigate BOLD coupling to resting-state fluctuations in neural activity, we simultaneously recorded EEG and fMRI in people with schizophrenia and psychiatrically unaffected participants. We focus on alpha band power to examine voxelwise, time-lagged BOLD correlations. Principally, we find diversity in the temporal profile of alpha-BOLD coupling within regions of the default mode network (DMN). This includes early coupling (0-2 seconds BOLD lag) for more posterior regions, thalamus and brainstem. Anterior regions of the DMN show coupling at canonical lags (4-6 seconds), with greater lag scores associated with self-reported measures of stress and greater lag scores in participants with schizophrenia. Overall, noncanonical alpha-BOLD coupling is widespread across the DMN and other non-cortical regions, and is delayed in people with schizophrenia. These findings are consistent with a "hemo-neural" hypothesis, that blood flow and/or metabolism can regulate ongoing neural activity, and further, that the hemo-neural lag may be associated with subjective arousal or stress. Our work highlights the need for more studies of neurovascular coupling in psychiatric conditions.

VISTA is a key immune checkpoint receptor under investigation for cancer immunotherapy; however, its signaling mechanisms remain unclear. Here we identify a conserved four amino acid (NPGF) intracellular motif in VISTA that suppresses cell proliferation by constraining cell-intrinsic growth receptor signaling. The NPGF motif binds to the adapter protein NUMB and recruits Rab11 endosomal recycling machinery. We identify and characterize a class of triple-negative breast cancers with high VISTA expression and low proliferative index. In tumor cells with high VISTA levels, the NPGF motif sequesters NUMB at endosomes, which interferes with epidermal growth factor receptor (EGFR) trafficking and signaling to suppress tumor growth. These effects do not require canonical VISTA ligands, nor a functioning immune system. As a consequence of VISTA expression, EGFR receptor remains abnormally phosphorylated and cannot propagate ligand-induced signaling. Mutation of the VISTA NPGF domain reverts VISTA-induced growth suppression in multiple breast cancer mouse models. These results define a mechanism by which VISTA represses NUMB to control malignant epithelial cell growth and signaling. They also define distinct intracellular residues that are critical for VISTA-induced cell-intrinsic signaling that could be exploited to improve immunotherapy., Competing Interests: Conflicts of Interests: J.J.G. reports contracted research from Curis, Inc., consulting for Sharma Therapeutics, LLC and Guidepoint and research support (to his institution) from Hummingbird Bioscience. J.M.F. has received research support (to his institution) from AstraZeneca, Genentech, Incyte, Merus, Pfizer and PUMA. M.L.T. reports research support (to her institution) from AbbVie, Bayer, Biothera, Calithera Biosciences, EMD Serono, Genentech, Medivation, Novartis, OncoSec, Pfizer, PharmaMar, Tesaro, and Vertex and consulting/advisory fees from AbbVie, Aduro Biotech, AstraZeneca, Blueprint Medicines, Celgene, Daiichi Sankyo, Genentech/Roche, G1 Therapeutics, Guardant, Immunomedics, Lilly, Merck, Natera, and Pfizer. M.M.J. is an employee and shareholder of Guardant Health, Inc. J.D.B.K. and D.T. are employees of and hold equity in Hummingbird Bioscience.

Importance: Enhanced breast cancer screening with magnetic resonance imaging (MRI) is recommended to women with elevated risk of breast cancer, yet uptake of screening remains unclear after genetic testing., Objective: To evaluate uptake of MRI after genetic results disclosure and counseling., Design, Setting, and Participants: This multicenter cohort study was conducted at the University of Southern California Norris Cancer Hospital, the Los Angeles General Medical Center, and the Stanford University Cancer Institute. Patients were recruited from July 1, 2014, through November 30, 2016. Following multiplex gene panel testing and genetic counseling, patients responded to surveys about breast MRI screening at 3, 6, 12, and 24 months and to a final survey between 3 and 4 years after counseling. Participants met standard clinical criteria for genetic testing or had a 2.5% or greater probability of inherited cancer susceptibility. Patients were categorized based on breast cancer risk from genetic testing results and Tyrer-Cuzick model-calculated risk as having (1) a BRCA or other high-risk pathogenic variant (PV), (2) a moderate-risk PV, (3) a higher lifetime breast cancer risk (≥20%), or (4) a lower lifetime breast cancer risk (<20%). Analysis was conducted from September 28 to November 9, 2023., Interventions: Genetic testing with a 25- or 28-gene panel, and pretest and posttest genetic counseling by a genetic counselor or an advanced practice genetics nurse practitioner, which included cancer-specific screening recommendations., Main Outcomes and Measures: MRI screening adherence over time across risk groups was estimated using Cox proportional hazards regression modeling. Likelihood of screening adherence (odds ratios [ORs] with 95% CIs), controlling for potential confounders, was estimated using logistic regression., Results: This study included 638 patients, with a mean (SD) age of 50.7 (13.3) years at testing. There were 43 patients (6.7%) with a BRCA or other high-risk PV, 16 (2.5%) with a moderate-risk PV, 146 (22.9%) with higher lifetime breast cancer risk, and 433 (67.9%) with lower lifetime breast cancer risk. A total of 52 patients (8.2%) identified as Asian, 21 (3.3%) as Black, 271 (42.5%) as Hispanic, and 255 (40.0) as White. Compared with patients with lower lifetime breast cancer risk, patients with a BRCA or other high-risk PV and those with a moderate-risk PV were approximately 10 times (OR, 9.81 [95% CI, 4.05-23.86]; P < .001) and 4 times (OR, 4.12 [95% CI, 1.10-14.35]; P = .03) as likely to undergo MRI, respectively. Patients with a BRCA or other high-risk PV were nearly 16 times (OR, 15.81 [95% CI, 5.17-48.31]) as likely to report consistent yearly MRI screening compared with patients with lower lifetime risk., Conclusions and Relevance: In this study, women with inherited PVs conferring increased breast cancer risk had higher and more consistent MRI uptake than women with lower estimated risk. These findings emphasize the importance of genetic cancer risk assessment for effective enhanced breast cancer screening.