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Despite the known benefits of data-driven approaches, the lack of approaches for identifying functional neuroimaging patterns that capture both individual variations and inter-subject correspondence limits the clinical utility of rsfMRI and its application to single-subject analyses. Here, using rsfMRI data from over 100k individuals across private and public datasets, we identify replicable multi-spatial-scale canonical intrinsic connectivity network (ICN) templates via the use of multi-model-order independent component analysis (ICA). We also study the feasibility of estimating subject-specific ICNs via spatially constrained ICA. The results show that the subject-level ICN estimations vary as a function of the ICN itself, the data length, and the spatial resolution. In general, large-scale ICNs require less data to achieve specific levels of (within- and between-subject) spatial similarity with their templates. Importantly, increasing data length can reduce an ICN's subject-level specificity, suggesting longer scans may not always be desirable. We also find a positive linear relationship between data length and spatial smoothness (possibly due to averaging over intrinsic dynamics), suggesting studies examining optimized data length should consider spatial smoothness. Finally, consistency in spatial similarity between ICNs estimated using the full data and subsets across different data lengths suggests lower within-subject spatial similarity in shorter data is not wholly defined by lower reliability in ICN estimates, but may be an indication of meaningful brain dynamics which average out as data length increases.

Resting-state functional magnetic resonance imaging is currently the mainstay of functional neuroimaging and has allowed researchers to identify intrinsic connectivity networks (aka functional networks) at different spatial scales. However, little is known about the temporal profiles of these networks and whether it is best to model them as continuous phenomena in both space and time or, rather, as a set of temporally discrete events. Both categories have been supported by series of studies with promising findings. However, a critical question is whether focusing only on time points presumed to contain isolated neural events and disregarding the rest of the data is missing important information, potentially leading to misleading conclusions. In this work, we argue that brain networks identified within the spontaneous blood oxygenation level-dependent (BOLD) signal are not limited to temporally sparse burst moments and that these event present time points (EPTs) contain valuable but incomplete information about the underlying functional patterns. We focus on the default mode and show evidence that is consistent with its continuous presence in the BOLD signal, including during the event absent time points (EATs), i.e., time points that exhibit minimum activity and are the least likely to contain an event. Moreover, our findings suggest that EPTs may not contain all the available information about their corresponding networks. We observe distinct default mode connectivity patterns obtained from all time points (AllTPs), EPTs, and EATs. We show evidence of robust relationships with schizophrenia symptoms that are both common and unique to each of the sets of time points (AllTPs, EPTs, EATs), likely related to transient patterns of connectivity. Together, these findings indicate the importance of leveraging the full temporal data in functional studies, including those using event-detection approaches.

Many studies have shown that schizophrenia patients have aberrant functional network connectivity (FNC) among brain regions, suggesting schizophrenia manifests with significantly diminished (in majority of the cases) connectivity. Schizophrenia is also associated with a lack of hemispheric lateralization. Hoptman et al. (2012) reported lower inter-hemispheric connectivity in schizophrenia patients compared to controls using voxel-mirrored homotopic connectivity. In this study, we merge these two points of views together using a group independent component analysis (gICA)-based approach to generate hemisphere-specific timecourses and calculate intra-hemisphere and inter-hemisphere FNC on a resting state fMRI dataset consisting of age- and gender-balanced 151 schizophrenia patients and 163 healthy controls. We analyzed the group differences between patients and healthy controls in each type of FNC measures along with age and gender effects. The results reveal that FNC in schizophrenia patients shows less hemispheric asymmetry compared to that of the healthy controls. We also found a decrease in connectivity in all FNC types such as intra-left (L_FNC), intra-right (R_FNC) and inter-hemisphere (Inter_FNC) in the schizophrenia patients relative to healthy controls, but general patterns of connectivity were preserved in patients. Analyses of age and gender effects yielded results similar to those reported in whole brain FNC studies.

The regional distribution of white matter (WM) abnormalities in schizophrenia remains poorly understood, and reported disease effects on the brain vary widely between studies. In an effort to identify commonalities across studies, we perform what we believe is the first ever large-scale coordinated study of WM microstructural differences in schizophrenia. Our analysis consisted of 2359 healthy controls and 1963 schizophrenia patients from 29 independent international studies; we harmonized the processing and statistical analyses of diffusion tensor imaging (DTI) data across sites and meta-analyzed effects across studies. Significant reductions in fractional anisotropy (FA) in schizophrenia patients were widespread, and detected in 20 of 25 regions of interest within a WM skeleton representing all major WM fasciculi. Effect sizes varied by region, peaking at (d=0.42) for the entire WM skeleton, driven more by peripheral areas as opposed to the core WM where regions of interest were defined. The anterior corona radiata (d=0.40) and corpus callosum (d=0.39), specifically its body (d=0.39) and genu (d=0.37), showed greatest effects. Significant decreases, to lesser degrees, were observed in almost all regions analyzed. Larger effect sizes were observed for FA than diffusivity measures; significantly higher mean and radial diffusivity was observed for schizophrenia patients compared with controls. No significant effects of age at onset of schizophrenia or medication dosage were detected. As the largest coordinated analysis of WM differences in a psychiatric disorder to date, the present study provides a robust profile of widespread WM abnormalities in schizophrenia patients worldwide. Interactive three-dimensional visualization of the results is available at www.enigma-viewer.org.

Schizophrenia patients exhibit well-documented visual processing deficits. One area of disruption is visual integration, the ability to form global objects from local elements. However, most studies of visual integration in schizophrenia have been conducted in the context of an active attention task, which may influence the findings. In this study we examined visual integration using electroencephalography (EEG) in a passive task to elucidate neural mechanisms associated with poor visual integration. Forty-six schizophrenia patients and 30 healthy controls had EEG recorded while passively viewing figures comprised of real, illusory, or no contours. We examined visual P100, N100, and P200 event-related potential (ERP) components, as well as neural synchronization in the gamma (30-60 Hz) band assessed by the EEG phase locking factor (PLF). The N100 was significantly larger to illusory vs. no contour, and illusory vs. real contour stimuli while the P200 was larger only to real vs. illusory stimuli; there were no significant interactions with group. Compared to controls, patients failed to show increased phase locking to illusory versus no contours between 40-60 Hz. Also, controls, but not patients, had larger PLF between 30-40 Hz when viewing real vs. illusory contours. Finally, the positive symptom factor of the BPRS was negatively correlated with PLF values between 40-60 Hz to illusory stimuli, and with PLF between 30-40 Hz to real contour stimuli. These results suggest that the pattern of results across visual processing conditions is similar in patients and controls. However, patients have deficits in neural synchronization in the gamma range during basic processing of illusory contours when attentional demand is limited.

BackgroundOlfaction plays an important role in mammalian social behavior. Olfactory deficits are common in schizophrenia and correlate with negative symptoms and low social drive. Despite their prominence and possible clinical relevance, little is understood about the pathological mechanisms underlying olfactory deficits in schizophrenia and there are currently no effective treatments for these deficits. The prosocial neuropeptide oxytocin may affect the olfactory system when administered intranasally to humans and there is growing interest in its therapeutic potential in schizophrenia.MethodsTo examine this model, we administered 40IU of oxytocin and placebo intranasally to 31 patients with a schizophrenia spectrum illness and 34 age-matched healthy control participants in a randomized, double-blind, placebo-controlled, cross-over study. On each test day, participants completed an olfactory detection threshold test for two different odors: (1) lyral, a synthetic fragrance compound for which patients with schizophrenia have specific olfactory detection threshold deficits, possibly related to decreased cyclic adenosine 3',5'-monophosphate (cAMP) signaling; and (2) anise, a compound for which olfactory detection thresholds change with menstrual cycle phase in women.ResultsOn the placebo test day, patients with schizophrenia did not significantly differ from healthy controls in detection of either odor. We found that oxytocin administration significantly and selectively improved olfactory detection thresholds for lyral but not for anise in patients with schizophrenia. In contrast, oxytocin had no effect on detection of either odor in healthy controls.DiscussionOur data indicate that oxytocin administration may ameliorate olfactory deficits in schizophrenia and suggest the effects of intranasal oxytocin may extend to influencing the olfactory system. Given that oxytocin has been found to increase cAMP signaling in vitro a possible mechanism for these effects is discussed.

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.

The concept of patient engagement has been widely studied for decades in the fields of medicine, nursing, psychology, social science, public health, and policy, and increased levels of patient engagement have been shown to improve health outcomes and strengthen reported experiences of care. Despite this, little research has been done to evaluate what patient engagement looks like within the context of a genetic counseling session. Additionally, there is limited literature from researchers based in the United States that aims to better understand patient engagement in non-English-speaking populations. This study is part of a larger protocol entitled "Multilingual Education Research in Genetic counseling Engagement (MERGE)," and it explores the elements that make up patient engagement in the context of pre-test genetic counseling for hereditary cancer risk among English- and Spanish-speaking patients. Eligible patients were 18 years or older at the time of their genetic counseling visit, had a personal or family history of breast cancer (if English-speaking) or a personal or family history of any cancer (if Spanish-speaking), and had not previously been seen for hereditary cancer genetic counseling. Out of 40 enrolled participants, 60% of patients (24/40) were English-speaking, while 40% of patients (16/40) were Spanish-speaking. In this study, English transcripts were generated from audio-recordings of clinical, standard-of-care genetic counseling sessions. The transcripts were qualitatively coded by two raters using an inductive approach, allowing for big Q thematic analysis. Six major themes were identified, describing ways in which patients show engagement and participate in decision-making during a pre-test genetic counseling session. All data were analyzed collectively, as assessment of differences between the language groups was not a primary analysis question. From the six themes, a definition of patient engagement in genetic counseling is proposed such that it consists of four "components" that together promote shared decision-making: Application of Education; Expression of Emotions; Feelings of Ownership; and Therapeutic Alliance. This working definition of patient engagement in genetic counseling has overlap with previous research on patient engagement in healthcare and with the Reciprocal-Engagement Model of genetic counseling. Future research on this topic can investigate methods for measuring and improving patient engagement across different settings and service delivery models., (© 2024 The Author(s). Journal of Genetic Counseling published by Wiley Periodicals LLC on behalf of National Society of Genetic Counselors.)

Objective: We hypothesized that a method to segment human airways from clinical cases and import them into a case presentation environment in Virtual Reality (VR) could be developed to model and visualize complex airway stenosis for efficient surgical planning., Methods: One normal and two pathological airways modeled from CT scans at a slice thickness of 0.625 mm were processed. A multidisciplinary team composed of airway surgeons, VR engineers, educators, and radiologists collaborated to create a clinically relevant VR rendering and explanatory Narrations of the three clinical cases. Segmentation and postprocessing were completed in the Mimics Innovation Suite v24 from Materialize. Structures were segmented from the level of bifurcation of common carotid arteries to the level of bifurcation of the main bronchi, including cartilaginous and bony airway structures, vessels, and soft tissues. They were then postprocessed into 3D image volumes and imported into syGlass (IstoVisio Inc.), a VR software., Results: Direct visualization and free manipulation of these 3D airway models within the VR environment provided improved geometrical and anatomical details compared to traditional two-dimensional (2D) CT. Then, specialized presentation and active learning tools developed for scientific communication using the VR environment permitted the creation of VR Narrations to explain pathological cases., Conclusion: The method to segment human airways from clinical cases used in this paper, combined with intuitive VR tools to overlay segmentation and image data in an active learning environment, shows potential in the use of 3D airway modeling and VR in clinical practice for the description and surgical planning of complex airways. Further work is needed to validate the use of these models in clinical practice and patient education., Level of Evidence: Level 4., (© 2024 Wiley Periodicals LLC.)

With the increasing availability of large-scale multimodal neuroimaging datasets, it is necessary to develop data fusion methods which can extract cross-modal features. A general framework, multidataset independent subspace analysis (MISA), has been developed to encompass multiple blind source separation approaches and identify linked cross-modal sources in multiple datasets. In this work, we utilized the multimodal independent vector analysis (MMIVA) model in MISA to directly identify meaningful linked features across three neuroimaging modalities-structural magnetic resonance imaging (MRI), resting state functional MRI and diffusion MRI-in two large independent datasets, one comprising of control subjects and the other including patients with schizophrenia. Results show several linked subject profiles (sources) that capture age-associated decline, schizophrenia-related biomarkers, sex effects, and cognitive performance. For sources associated with age, both shared and modality-specific brain-age deltas were evaluated for association with non-imaging variables. In addition, each set of linked sources reveals a corresponding set of cross-modal spatial patterns that can be studied jointly. We demonstrate that the MMIVA fusion model can identify linked sources across multiple modalities, and that at least one set of linked, age-related sources replicates across two independent and separately analyzed datasets. The same set also presented age-adjusted group differences, with schizophrenia patients indicating lower multimodal source levels. Linked sets associated with sex and cognition are also reported for the UK Biobank dataset., (© 2024 The Author(s). Human Brain Mapping published by Wiley Periodicals LLC.)

Colorectal cancer (CRC) is the third leading cause of cancer mortality in the United States. Familial adenomatous polyposis (FAP) is a hereditary syndrome that raises the risk of developing CRC, with total colectomy as the only effective prevention. Even though FAP is rare (0.5% of all CRC cases), this disease model is well suited for studying the early stages of malignant transformation as patients form many polyps reflective of pre-cancer states. In order to spatially profile and analyze the pre-cancer and tumor microenvironment, we have performed single-cell multiplexed imaging for 52 samples: 12 normal mucosa,16 FAP mucosa,18 FAP polyps, 2 FAP adenocarcinoma, and 4 sporadic colorectal cancer (CRCs) using Co-detection by Indexing (CODEX) imaging platform. The data revealed significant changes in cell type composition occurring in early stage polyps and during the malignant transformation of polyps to CRC. We observe a decrease in CD4+/CD8+ T cell ratio and M1/M2 macrophage ratio along the FAP disease continuum. Advanced dysplastic polyps show a higher population of cancer associated fibroblasts (CAFs), which likely alter the pre-cancer microenvironment. Within polyps and CRCs, we observe strong nuclear expression of beta-catenin and higher number neo-angiogenesis events, unlike FAP mucosa and normal colon counterparts. We identify an increase in cancer stem cells (CSCs) within the glandular crypts of the FAP polyps and also detect Tregs, tumor associated macrophages (TAMs) and vascular endothelial cells supporting CSC survival and proliferation. We detect a potential immunosuppressive microenvironment within the tumor 'nest' of FAP adenocarcinoma samples, where tumor cells tend to segregate and remain distant from the invading immune cells. TAMs were found to infiltrate the tumor area, along with angiogenesis and tumor proliferation. CAFs were found to be enriched near the inflammatory region within polyps and CRCs and may have several roles in supporting tumor growth. Neighborhood analyses between adjacent FAP mucosa and FAP polyps show significant differences in spatial location of cells based on functionality. For example, in FAP mucosa, naive CD4+ T cells alone tend to localize near the fibroblast within the stromal compartment. However, in FAP polyp, CD4+T cells colocalize with the macrophages for T cell activation. Our data are expected to serve as a useful resource for understanding the early stages of neogenesis and the pre-cancer microenvironment, which may benefit early detection, therapeutic intervention and future prevention., Competing Interests: Competing interests MPS is a cofounder and scientific advisor of Crosshair Therapeutics, Exposomics, Filtricine, Fodsel, iollo, InVu Health, January AI, Marble Therapeutics, Mirvie, Next Thought AI, Orange Street Ventures, Personalis, Protos Biologics, Qbio, RTHM, SensOmics. MPS is a scientific advisor of Abbratech, Applied Cognition, Enovone, Jupiter Therapeutics, M3 Helium, Mitrix, Neuvivo, Onza, Sigil Biosciences, TranscribeGlass, WndrHLTH, Yuvan Research. MPS is a cofounder of NiMo Therapeutics. MPS is an investor and scientific advisor of R42 and Swaza. MPS is an investor in Repair Biotechnologies. W.J.G. is a consultant and equity holder for 10x Genomics, Guardant Health, Quantapore and Ultima Genomics, and cofounder of Protillion Biosciences, and is named on patents describing ATAC-seq. EDE is an employee and stockholder of Labcorp Genetics and an advisor and stockholder of Taproot Health, Exir Bio, and ROMTech. The remaining authors declare no competing interests.

Although three-dimensional (3D) genome architecture is crucial for gene regulation, its role in disease remains elusive. We traced the evolution and malignant transformation of colorectal cancer (CRC) by generating high-resolution chromatin conformation maps of 33 colon samples spanning different stages of early neoplastic growth in persons with familial adenomatous polyposis (FAP). Our analysis revealed a substantial progressive loss of genome-wide cis-regulatory connectivity at early malignancy stages, correlating with nonlinear gene regulation effects. Genes with high promoter-enhancer (P-E) connectivity in unaffected mucosa were not linked to elevated baseline expression but tended to be upregulated in advanced stages. Inhibiting highly connected promoters preferentially represses gene expression in CRC cells compared to normal colonic epithelial cells. Our results suggest a two-phase model whereby neoplastic transformation reduces P-E connectivity from a redundant state to a rate-limiting one for transcriptional levels, highlighting the intricate interplay between 3D genome architecture and gene regulation during early CRC progression., Competing Interests: Competing interests: G.K., A.J., D.L. and Z.S. are employees and shareholders of Ultima Genomics. M.P.S is a cofounder and scientific advisor of Personalis, Qbio, SensOmics, January AI, Mirvie, Protos, NiMo and Onza and is on the advisory board of Genapsys. E.D.E. is an employee and stockholder of Invitae and an advisor and stockholder of Taproot Health and Exir Bio. W.J.G. has affiliations with Guardant Health (consultant and scientific advisory board), Protillion Biosciences (Scientifica cofounder) and 10x and has licensed patents associated with ATAC-seq. All other authors declare no competing interests., (© 2024. The Author(s).)

Familial adenomatous polyposis (FAP) is a genetic disease causing hundreds of premalignant polyps in affected persons and is an ideal model to study transitions of early precancer states to colorectal cancer (CRC). We performed deep multiomic profiling of 93 samples, including normal mucosa, benign polyps and dysplastic polyps, from six persons with FAP. Transcriptomic, proteomic, metabolomic and lipidomic analyses revealed a dynamic choreography of thousands of molecular and cellular events that occur during precancerous transitions toward cancer formation. These involve processes such as cell proliferation, immune response, metabolic alterations (including amino acids and lipids), hormones and extracellular matrix proteins. Interestingly, activation of the arachidonic acid pathway was found to occur early in hyperplasia; this pathway is targeted by aspirin and other nonsteroidal anti-inflammatory drugs, a preventative treatment under investigation in persons with FAP. Overall, our results reveal key genomic, cellular and molecular events during the earliest steps in CRC formation and potential mechanisms of pharmaceutical prophylaxis., Competing Interests: Competing interests: M.P.S. is a cofounder and scientific advisor of Personalis, SensOmics, Qbio, January AI, Fodsel, Filtricine, v Protos, RTHM, Iollo, Marble Therapeutics, Crosshair Therapeutics, NextThought and Mirvie. He is a scientific advisor of Jupiter, Neuvivo, Swaza, Mitrix, Yuvan, TranscribeGlass and Applied Cognition. A. Kundaje has affiliations with Biogen (consultant), SerImmune (scientific advisory board (SAB)), RavelBio (scientific cofounder and SAB) and PatchBio (SAB). K.C. is currently an AstraZeneca employee. W.J.G. has affiliations with Guardant Health (consultant and SAB), Protillion Biosciences (scientific cofounder) and 10x and has licenced patents associated with ATAC-seq. E.D.E. is an employee and stockholder of Labcorp, and advisor and stockholder of Taproot Health, Exir Bio and ROMTech. The other authors declare no competing interests., (© 2024. The Author(s).)