Faculty Bibliography

OBJECTIVES/OBJECTIVE:The gut microbiome plays a crucial role in regulating systemic immunity and has been implicated in several chronic inflammatory diseases. Intestinal expansions of Ruminococcus gnavus (RG), a dominant gut commensal, correlate with disease flares in lupus nephritis (LN), but the underlying mechanism remains unknown. METHODS:In a Pilot cohort of patients with biopsy-proven LN, subsetted by gut microbiota community, immune status was characterised using bulk-blood RNA sequencing libraries, serum levels of representative host proteins, and levels of immunoglobulin (Ig)G antibodies to the novel lipoglycan (LG) produced by pathogenic RG strains. A Validation LN cohort was evaluated for blood transcriptomic profiles and levels of anti-LG antibodies. In murine models, mechanistic hypotheses were tested after RG gut colonisation or after intraperitoneal injection with an LG preparation, with outcomes determined by transcriptomic analyses, platelet functional readouts, and tissue histology. RESULTS:In a Pilot cohort of patients with LN, RG gut expansions were associated with high-level platelet, neutrophil, and monocyte activation. Serum levels of platelet factor 4 and release of neutrophil extracellular traps (NETs) were significantly higher in patients with high serum IgG antibody against the novel RG-specific LG, a marker of in vivo immune exposure. An LN Validation cohort confirmed these correlates and showed that anti-LG antibodies serve as a surrogate for thromboinflammatory profile in this LN-associated endotype. In mice, gut colonisation with LG-producing RG strains or a single LG injection caused megakaryocytosis and platelet activation; RG colonisation with LG-producing strains induced tubulointerstitial injury with NETosis. In vivo responses to LG toxin were Toll-like receptor 2-dependent. CONCLUSIONS:Gut expansions of the RG pathobiont may contribute to autoimmune pathogenesis through the LG toxin and cause LN flares through thromboinflammatory mechanisms in this previously unrecognised LN endotype.

The integrated stress response (ISR) coordinates cellular adaptation to diverse stress conditions. In Drosophila, two bZIP transcription factors, Xrp1 and crc (ATF4 homolog), are induced during ISR. Crc protein can dimerize with two CEBP factors in vitro, but the in vivo relevance of those interactions remained unknown. Here, we report that the CEBPG homolog, Irbp18, is an essential partner of crc during ISR. Specifically, Irbp18 is broadly required for the transcriptional induction of ISR target genes in the photoreceptors of ninaE^G69D, a Drosophila model of retinitis pigmentosa. Moreover, CUT&RUN analysis indicates that Irbp18 loss reduces or abolishes crc binding to target DNAs in photoreceptors and impairs crc's ability to induce target transcripts upon overexpression. Functionally, Irbp18 loss causes retinal degeneration and suppresses ISR signaling in parkin mutants, a model of Parkinson's disease. Together, these findings identify Irbp18 as a cofactor for crc, impacting pathological outcomes in Drosophila models of degeneration.

Primordial germ cells (PGCs) are the first cells specified in the Drosophila embryo and are precursors to the germline. Their formation requires suppression of somatic fates, achieved by degrading the receptor tyrosine kinase Torso at the posterior pole through the ubiquitin ligase adaptor germ cell-less (GCL). Although Torso is known to antagonize PGC formation, the underlying mechanisms remained unclear. Here, we combine optogenetic Ras activation and Ras effector loop mutants to show that Ras suppresses PGC formation independently of the canonical Raf/MEK/ERK pathway. We identify an unexpected early role for Torso in activating phosphoinositide 3-kinase (PI3K), generating membrane domains enriched in phosphatidylinositol (3,4,5)-trisphosphate (PIP3). Elevated PI3K activity disrupts PGC formation, while reduced PI3K activity creates ectopic PGCs. We demonstrate that GCL remodels the posterior pole membrane by suppressing Torso-dependent PI3K activation. Clearing PIP3 enables myosin II enrichment, allowing for PGC formation. Together, our findings reveal how antagonistic Torso and GCL activities establish the soma-germline boundary by organizing cortical lipids.

Mutations in the gene encoding the microtubule-associated protein tau (MAPT) that are causal for frontotemporal dementia result in nuclear envelope deformation and disrupted nucleocytoplasmic transport when expressed in human neurons. A small-molecule inhibitor of the acetyltransferase NAT10 has been shown to correct similar nuclear membrane defects in Hutchinson-Gilford progeria syndrome, primarily by modulating microtubule dynamics. We report here that NAT10 inhibition and loss of function correct nuclear membrane abnormalities in human MAPT-mutant neurons. Similarly, NAT10 inhibition and haploinsufficiency correct neuronal nuclear shape defects and extend lifespan in vivo in a Drosophila model of tauopathy. NAT10 inhibition changes microtubule dynamics and corrects aberrant nucleocytoplasmic transport, and NAT10 directly interacts with regulators of microtubule dynamics in human MAPT-mutant neurons. We conclude that NAT10 mediates neuronal pathologies in tauopathies and is a potential therapeutic target in these diseases.

Peritoneal cavity fluid and mesothelial surfaces host distinct resident macrophage populations, among which include the well-described Gata6⁺ large cavity macrophages (LCMs) in peritoneal fluid. Here, we reveal that LCMs arise from two separable differentiation pathways. In the quantitatively minor pathway, monocytes gave rise to LYVE1⁺ LCMs but few Gata6⁺ LCMs. This pathway did not require the transcription factor Gata6 but was severely impaired in mice bearing three mutations in the -165 kb Zeb2 enhancer (Zeb2

Tumor-infiltrating T cells have been the primary focus of cancer immunotherapy; however, accumulating evidence points to a critical role for B cells and plasma cells in shaping responses to immune checkpoint blockade. In this study, we investigated the humoral immune response in 38 patients with hepatocellular carcinoma treated with neoadjuvant anti-programmed cell death protein 1 (PD-1) therapy. In responders, defined by more than 50% tumor necrosis, we observed on-treatment enrichment of clonally expanded IgG1⁺ plasma cells within the tumor. Clonal tracking revealed that anti-PD-1 treatment expanded preexisting B cell clones associated with favorable clinical outcomes. Moreover, serum from responders contained IgG1 antibodies specific to cancer/testis antigens, including NY-ESO-1, and these humoral responses were linked to tumor-reactive T cell activity. We independently validated these findings across seven additional cohorts, encompassing single-cell and bulk sequencing data from 500 patients, spatial transcriptomics from seven patients and survival analyses from 1,582 patients. Our findings apply to recently approved treatments, such as PD-1 and vascular endothelial growth factor A (VEGF-A) blockade, but not to chemotherapy alone, suggesting broad relevance to individuals treated with immunotherapy. Collectively, our results demonstrate that PD-1 blockade induces tumor-specific IgG1⁺ plasma cell responses that complement cellular immunity and contribute to clinical benefit, underscoring a coordinated humoral-cellular axis in effective antitumor immunity.

BACKGROUND/UNASSIGNED:As anatomy curricula in medical schools transition from cadaveric dissection to digital alternatives, medical educators must seek novel strategies to maintain student engagement. To address this challenge, we aimed to integrate an online module and lecture on facial transplantation (FT) into the head and neck anatomy medical school curriculum and assess its effectiveness. METHODS/UNASSIGNED:An online learning module paired with a lecture was created, with shared learning objectives based on the principles of FT. Through multimedia learning, clinically relevant content was used to teach anatomy through surgical videos supplemented with animations. Knowledge assessments followed National Board of Medical Examiners guidelines and were validated by 4 experts. Pre- and posttests evaluated confidence, knowledge, and satisfaction. RESULTS/UNASSIGNED:< 0.001). Students agreed that the module was stimulating, interesting, clear, effective, and allowed for better learning, and stated that they would recommend it to others. Eighty-five percent of students rated the lecture overall as excellent. CONCLUSIONS/UNASSIGNED:FT provides an engaging and effective application for preclinical medical students to integrate curricular content. Involvement of plastic surgeons in the curriculum can create motivating opportunities for students to enhance their medical education and anatomical knowledge, while receiving an early introduction to fundamental principles of plastic and reconstructive surgery.

Squamous cell carcinomas (SCCs) are common epithelial malignancies frequently associated with EZH2 upregulation, which correlates with aggressive growth and poor prognosis. EZH2 functions as the catalytic subunit of Polycomb repressive complex 2 (PRC2), which deposits the repressive H3K27me3 histone mark, yet PRC2 function in SCC pathogenesis remains unresolved. Here, we uncover a paradox: although EZH2 is elevated, the PRC2-catalyzed H3K27me3 is profoundly reduced in human SCC and complementary murine models. Mechanistically, we identify that oncogenic Ras signaling causes degradation of the PRC2 subunit EED, destabilizing PRC2 and depleting H3K27me3. Loss of EED reprograms keratinocytes into an aggressive tumor-specific cell state and induces paracrine factors that remodel the tumor microenvironment, driving metastasis. Remarkably, reintroducing EED suppresses tumor growth via restoring PRC2 integrity and H3K27me3 levels, revealing the reversibility of this epigenetic collapse. These findings link oncogenic signaling to epigenetic reprogramming and uncover PRC2 reconstitution as a potential therapeutic option in epithelial cancers.

Atherosclerotic cardiovascular disease (ASCVD) and cancer are increasingly recognized as interconnected diseases linked by shared immune mechanisms rather than merely overlapping risk factors. Common exposures such as smoking, obesity, diabetes, and dyslipidemia, together with aging and clonal hematopoiesis of indeterminate potential (CHIP), establish a chronic inflammatory milieu that drives both pathologies through coordinated reprogramming of myeloid and lymphoid compartments. Within this framework, a forward cardio-oncology axis is increasingly recognized, in which cancer therapies including chemotherapies, radiation, and immune checkpoint inhibitors induce cardiovascular injury, manifesting as cardiomyopathy, accelerated atherosclerosis, and immune-mediated myocarditis. Complementing this, a reverse axis has emerged in which cardiovascular injury states such as myocardial infarction, ischemia, and heart failure actively promote cancer initiation and progression through hematopoietic remodeling, extracellular vesicle-mediated communication, cardiac-derived factors, and immunosuppressive myeloid bias. At the tissue level, immune checkpoint pathways including PD-1, PD-L1, CTLA-4, LAG-3, and TIM-3 form spatially organized regulatory networks within atherosclerotic plaques. Their therapeutic perturbation restores T cell activity but may disrupt local immune homeostasis and promote plaque instability. In parallel, inflammatory cytokines such as IL-1β, IL-6, and TNF-α, often amplified by CHIP-associated clones, provide a mechanistic bridge linking atherogenesis with tumor immune evasion. Together, these observations support a unified view of ASCVD and cancer as immune-driven diseases connected by bidirectional axes of interaction. This review integrates emerging mechanistic and clinical evidence and outlines how immune-based stratification and targeted modulation of inflammation may enable more precise management of patients at the intersection of cardiovascular disease and cancer.

Animals live in a world of microbes and must distinguish pathogens from benign commensals. A new study shows how animals use enteric neurons to sense components of the bacterial cell wall and how a pathogen-derived molecule blocks this mechanism.