Citations

Abstract Echocardiography is the most widely used cardiac imaging modality, yet artificial intelligence-enabled interpretation remains limited by the inability of existing models to integrate visual assessment, quantitative measurement, and clinical reasoning within a unified framework. Here we present EchoAtlas, the first autoregressive vision-language model developed for echocardiographic interpretation. Trained on over 12.9 million question-answer pairs derived from approximately 2 million echocardiogram videos, EchoAtlas achieves 0.966 accuracy on multiple-choice questions in our internal test set and establishes a new state-of-the-art on the public MIMIC-EchoQA benchmark (0.699 vs. 0.508 previously). EchoAtlas also provides accurate quantitative measurements, segment-level regional wall motion assessment, longitudinal comparison, and diagnostic reasoning across diverse question formats — capabilities not previously demonstrated in this domain. These results highlight the potential of autoregressive vision-language models as a foundation for interactive echocardiographic interpretation, representing an early step toward scalable, auditable artificial intelligence systems in cardiology practice.

Cellular and molecular heterogeneity in the liver has been increasingly recognized to drive liver fibrosis progression, but the particular events that occur initially in response to liver injury and trigger immune cell recruitment remain unclear. Here, we identify epigenetically aberrant liver sinusoidal endothelial cells (LSECs) as key players in this process. Mechanistically, the epigenetic readers like bromodomain-containing protein 4–dependent (BRD4-dependent) super enhancers (SEs) activate proinflammatory genes, including promyelocytic leukemia (PML). The PML protein, in turn, binds BRD4 and amplifies proinflammatory angiocrine signaling through phase separation–dependent SE activation via PML/BRD4 condensate formation. In mouse models, LSEC-specific depletion of the PML/BRD4 complex mitigates liver inflammation and fibrosis. Single-cell RNA-seq reveals that epigenetically aberrant LSECs exhibit a reprogrammed proinflammatory angiocrine landscape in mouse fibrotic livers. TIMP1 + LSECs promote the recruitment of CD63 + monocyte–derived macrophages (MoMFs) during liver fibrosis progression. Thereby, PML/BRD4 in LSECs governs inflammatory immune cell recruitment in liver fibrosis. Pharmacological BRD4 inhibition or epigenetic PML-SE repression alleviates liver inflammation and fibrosis. In conclusion, PML/BRD4-mediated SE activation via phase separation drives proinflammatory angiocrine signaling in LSECs, initiating the inflammatory cascade and subsequent immune cell recruitment during liver fibrosis.

46 Background: Primary results from the randomized, multicenter, open-label, phase 3 TRITON3 (NCT02975934) study demonstrated that rucaparib significantly improved radiographic progression-free survival (rPFS) vs physician’s choice of DTX or an ARPI. ECOG PS is used as a predictor of prostate cancer survival. In this post hoc analysis, we report results from the BRCA1/2 subgroup of pts stratified by ECOG PS. Methods: Pts with disease progression after 1 prior second-generation ARPI in any setting were randomized 2:1 to rucaparib 600 mg BID or physician’s choice of DTX or ARPI (abiraterone acetate or enzalutamide). Primary endpoint was rPFS by independent radiology review (IRR). Objective response rate (ORR) for pts with measurable disease and overall survival (OS) were key secondary endpoints. Crossover from physician’s choice to rucaparib was allowed after radiographic progression was confirmed by IRR. Data cutoff was August 25, 2022. Results: Of 302 pts in the BRCA1/2 population, 147 had an ECOG status of 0 (97 rucaparib; 50 physician’s choice) and 155 had ECOG 1 (104 rucaparib; 51 physician’s choice). Baseline characteristics and demographics were generally similar between arms for pts in the ECOG 0 and ECOG 1 groups. Median rPFS favored rucaparib vs physician’s choice for pts with ECOG 0 (11.4 vs 8.2 months; HR, 0.48 [95% CI, 0.30-0.76]) and ECOG 1 (10.9 vs 6.1 months; HR, 0.48 [95% CI, 0.31-0.74]) (Table). Additionally, rPFS favored rucaparib for ECOG 0 and ECOG 1 including those whose prespecified physician’s choice was ARPI or docetaxel (Table). The confirmed ORR (95% CI) of rucaparib vs physician’s choice for ECOG 0 was 54% (37%–69%) vs 16% (3%–40%); the ORR for ECOG 1 was 37% (22%–53%) vs 18% (5%–40%), respectively. Median OS was similar between arms for rucaparib or physician’s choice; median OS was 23.7 vs 21.7 months (HR, 0.91 [95% CI, 0.61–1.37]) for ECOG 0 and 21.8 vs 20.4 months (HR, 0.85 [95% CI, 0.58–1.24]) for ECOG 1. Conclusions: Rucaparib improved rPFS and ORR in pts with BRCA-mutated prostate cancer with an ECOG PS of 0 or 1. OS was similar for these groups in both arms. These data support rucaparib as a treatment option for pts with BRCA-mutated mCRPC, whether ECOG 0 or 1. Clinical trial information: NCT02975934 . Median rPFS in patients in the ECOG 0 and ECOG 1 groups. Rucaparib, n Physician’s choice, n rPFS Rucaparib, median months rPFS Physician’s choice, median months HR (95% CI) rPFS, ECOG 0 97 50 11.4 8.2 0.48 (0.30–0.76) rPFS, ECOG 1 104 51 10.9 6.1 0.48 (0.31–0.74) rPFS, physician’s choice ARPI, ECOG 0 51 24 11.2 5.6 0.42 (0.22–0.78) rPFS, physician’s choice docetaxel, ECOG 0 46 26 11.5 8.8 0.49 (0.24–0.98) rPFS, physician’s choice ARPI, ECOG 1 52 17 11.2 4.5 0.33 (0.16–0.68) rPFS, physician’s choice docetaxel, ECOG 1 52 34 10.7 7.1 0.59 (0.34–1.01)

Abstract Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative treatment for many hematological malignancies, but graft-versus-host disease (GVHD) is a common complication. Low gut microbiome diversity is associated with higher GVHD risk and shorter survival in multiple studies. Recently, the BMT CTN 1703 clinical trial demonstrated superiority of a GVHD-prophylaxis regimen including post-transplant cyclophosphamide (PTCy) compared to the standard prophylaxis (tacrolimus and methotrexate, Tac/MTX) in terms of GVHD-free, relapse-free survival at one year among reduced intensity conditioning allo-HCT recipients. However, the effect of PTCy on the gut microbiome and its association with clinical outcome have not been described. Here, we report on a companion randomized clinical controlled trial (BMT CTN 1801), which collected 2575 longitudinal stool samples from 304 study participants. Samples were obtained up to weekly up to day 84 post allo-HCT and at less frequent intervals thereafter, up to 2 years. Microbiome diversity and absolute microbial load were lower in the PTCy group compared to the Tac/MTX group on days 14–28 post-HCT. However, diversity at the timepoint closest to neutrophil engraftment was not significantly associated with non-relapse mortality after one year or other clinical outcomes, contrary to expectations from previous studies. Microbial domination events, when a single species exceeds 30% relative abundance, were comparable across treatment arms and reflected both pathogen blooms as well as less severe disruptions of the microbial community. Clostridium scindens and secondary bile acid metabolism pathways were less prevalent in the PTCy arm than in the Tac/MTX arm post-HCT, yet presence of secondary bile acid metabolism pathways was associated with a lower risk of chronic GVHD. Given that PTCy was associated with a greater disruption of the microbiome as measured by diversity, absolute microbial abundance, and bile acid metabolism capability, but better clinical outcomes overall, these data suggest that the importance of the microbiome in modulating the host immune systems after allo-HCT is specific to different types of GVHD prophylaxis.

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.

Acute myocardial infarction (AMI) is a significant factor leading to the death of patients with coronary heart disease. Both AMI and reperfusion therapy after AMI cause myocardial cell death, which plays a significant role in heart failure. Following the restoration of blood flow during reperfusion, myocardial cells generate a large amount of oxygen free radicals, causing various forms of myocardial ischemia–reperfusion (IR) injury (IRI), ultimately leading to multiple types of myocardial cell death, among which apoptosis and necroptosis are the two major types. Given the extremely limited regenerative capacity of myocardium, inhibiting myocardial cell apoptosis and necroptosis is a key strategy for reducing mortality in patients with AMI. Both apoptosis and necroptosis are regulated by the BCL2 family of proteins, which were modulated by multiple signaling pathways, converging at BAK/BAX-mediated mitochondrial outer membrane permeabilization (MOMP), as well as mitochondrial inner membrane permeabilization (MIMP). BAK/BAX double knock out (DKO) mice showed reduced cell apoptosis, necroptosis, and infarct size in AMI animal models compared to wild type. This review describes the role of BCL2 family proteins in regulating apoptotic and necroptotic myocardial cell death during AMI and IR, explores the upstream pathways modulating apoptosis and necroptosis, and summarizes the recent advances in targeting BAK and/or BAX for cardiac protection. In addition, targeted delivery of BAK/BAX inhibitors to cardiomyocytes during AMI or myocardial IR has the potential to reduce myocardial cell death and therefore lower the mortality and enhance long-term prognosis for myocardial infarction patients.

Abstract Microglia are essential for maintaining brain homeostasis, including the sleep-wake cycle, but the underlying mechanisms remain unclear. Here, using in vivo two-photon imaging in both head-fixed and freely moving mice with simultaneous electroencephalogram–electromyogram (EEG–EMG) recording, we investigated microglial process dynamics and their interactions with locus coeruleus (LC) noradrenergic (NE) axons in the frontal cortex across sleep-wake states. During sleep or chemogenetic suppression of LC neurons, microglia enhanced their surveillance and increased interactions with NE axons. Correlative electron microscopy at nanometer resolution identified structural contacts between microglial process endings and NE boutons. Mechanistically, microglia-bouton interaction is primed by NE–β2-adrenergic receptor (β2AR) signaling, leading to enhanced Ca²⁺ activity in NE axons. These findings suggest that microglial interactions with NE axons promote cortical norepinephrine transmission and maintain stable wakefulness.

Abstract Background B-cell maturation antigen (BCMA)-targeting immunotherapies represent a promising class of treatment for the management of immunoglobulin light chain (AL) amyloidosis, a disease that is related to clonal plasma cells. Etentamig is a 2nd generation, off-the-shelf, fully human BMCA X CD3 bispecific antibody with bivalent BCMA domain and low CD3 affinity that targets both BCMA-expressing plasma cells and CD3-expressing T cells. Etentamig monotherapy is being studied in multiple myeloma (MM) in an ongoing phase 3 study (NCT06158841). Here, we report the first safety and efficacy results from M24-209, an open-label phase 1/2 study evaluating etentamig monotherapy in patients (pts) with relapsed/refractory (RR) AL amyloidosis from dose level 1 (DL1). Methods The phase 1 dose escalation (ESC) portion of the study (NCT06158854) with etentamig enrolled pts with RR AL amyloidosis with ≥1 prior lines of therapy (LOT), including a proteasome inhibitor and an anti-CD38 monoclonal antibody with no prior BCMA exposure. Eligible pts were required to have a difference in involved and uninvolved serum free light chain (dFLC) of ≥50 mg/L, and pts with Mayo Clinic 2004 cardiac risk stage IIIb with NT-proBNP ≥8500 pg/ml were excluded. Three dose groups were explored in dose ESC (etentamig dose levels [DL] 1, 2, and 3). In all cohorts, pts will receive up to 24 cycles of treatment and will be followed until disease progression. In dose ESC, the primary objectives are to determine safety/tolerability, pharmacokinetic/pharmacodynamic, and recommended phase 2 dose. The secondary objectives include evaluation of efficacy as measured by hematologic response and organ response. Responses are investigator assessed per consensus guidelines (Comenzo, et al. Leukemia. 2012. 26[11]:2317-25; Palladini G, et al. Amyloid. 2021 [Epub];28[1]:1-2). Results As of 17 July 2025, all DLs in dose ESC have been fully enrolled, and 12 pts have been treated with etentamig at DL1. Due to short follow-up, this initial report only includes data from DL1, with further follow-up data from ESC to be included at the time of presentation. Median duration of follow up in DL1 was 9.4 months (8.3–13.8) with 83% of pts continuing treatment. Median age for pts was 72 years (range, 56–85 years). Median number of prior LOT was 2 (range, 1–6), and median time from initial diagnosis was 3.6 years. Thirty-three percent have received a prior stem cell transplant and 50% previously received the regimen of daratumumab with cyclophosphamide, bortezomib, and dexamethasone in combination. Median dFLC at study baseline was 110. 5 mg/L (range, 56.6–617.5). At baseline, 83% of pts had cardiac involvement, 25% had renal involvement, and 8% had hepatic involvement. Eighty-three percent of pts had lambda AL amyloidosis. Treatment-emergent adverse events were reported in 100% (42% Grade ≥3) of pts at DL1. Cytokine release syndrome (CRS) occurred in 2 pts (17%, all Grade 1), with no instances of any grade immune effector cell-associated neurotoxicity syndrome (ICANS). CRS occurring after the first dose had median time to onset of 6.8 hours (range, 6.7–6.9). Grade ≥3 infections occurred in 1 pt (8%, all Grade 3). Grade ≥3 neutropenia also occurred in 1 pt (8%, all Grade 3), and no Grade ≥3 events of thrombocytopenia or anemia occurred. No Grade 5 events have occurred. Within the dose ESC DL1 cohort, the overall hematologic response rate was 100%, with all pts achieving ≥VGPR and 83% of pts achieving complete response (CR). The median time to CR was 0.9 months (0.3–9.3). The median duration of response has not yet been reached and 100% of pts remain in their best overall response by investigator assessment. To date, no pts have experienced hematologic progression on study. Cardiac response was observed in 30% of evaluable pts. Renal response was seen in 67% of evaluable pts. Conclusions In the DL1 cohort, etentamig showed a manageable safety profile in AL amyloidosis with low incidence and severity of CRS, no ICANS, and limited Grade ≥3 cytopenia events. Deep and rapid hematologic responses were observed with 100% ≥VGPR rate and 83% hematologic CR rate. Additional dose-level data will be presented at the time of the meeting. All pts remain in ongoing follow-up and evaluation, and the study will begin the dose expansion (EXP) portion after dose selection.