Citations

A 46-year-old female was admitted to the hospital for confusion, cognitive decline, and hallucinations with alcohol withdrawal. Her history was notable for Alcohol use disorder (AUD) and family history of Alzheimer's disease (AD). Comprehensive workup was unrevealing for metabolic encephalopathy, infection, or nutritional deficiencies. Phosphatidyl ethanol level was 1181, indicating severe alcohol misuse. Phospho-Tau 217 testing raised suspicion of AD and FDG-PET scan confirmed patterns consistent with early onset AD. AUD can precipitate earlier or more severe onset of AD. Phospho-Tau 217 can be a useful screening marker to identify people at risk of AD to prompt intensive treatment.

TPS6138 Background: Patients with early-stage oral cavity cancer (OCC; T1-2N0M0; AJCC 8th edition) have a 20-30% risk of occult nodal metastases despite clinical and radiographic evaluations. Standard-of-care treatment for most patients includes elective neck dissection (END), which requires surgical removal of the regional cervical lymph nodes, even though 70-80% of these necks are disease-free. Sentinel lymph node biopsy (SLN Bx), a less invasive procedure, could assess the first echelon lymph nodes as an alternative to END, potentially reducing morbidity and costs. A pivotal clinical trial comparing SLN Bx to END (NCT#04333537) is underway to inform efforts to establish optimal disease management for early-stage OCC. Methods: To assess the efficacy of SLN Bx in this population, we activated an international, multi-institutional, prospective phase II/III trial in July 2020, randomizing patients to two surgical arms: SLN Bx and END. A node-negative 18 F-FDG PET/CT imaging biomarker study with centralized read was required before randomization. OCC patients with a positive PET/CT remained in a registry to compare imaging findings with final neck pathology. Given the current evidence on morbidity for SLN Bx versus END, the phase II was designed to determine whether the change in patient-reported neck and shoulder function and related quality of life (QOL) from baseline to 6 months after surgery, using the Neck Dissection Impairment Index (NDII), showed a signal of superiority of SLN Bx compared to END (minimum important difference ³ 7.5; one-sided a = 0.10; 90% power). As of December 2024, 261 patients had been randomized and 203 were analyzed for the “Go/No-Go” decision to move forward into phase III. The phase III portion is a non-inferiority (NI) trial with disease-free survival (DFS) as the primary endpoint (NI margin hazard ratio 1.34 based on a 5% absolute difference in 2-year DFS; one-sided a = 0.05; 80% power, and two interim looks). The change in NDII from baseline to 6 months after surgery is a hierarchical co-primary endpoint for phase III. Phase III opened in October 2025 upon receiving a “Go” signal from phase II. Target accrual for phase III is 686 node-negative PET/CT patients, including those randomized in phase II (425 additional patients). In addition to sites requiring radiotherapy and imaging credentialing, quality assurance will include central pathology review of all negative SLN Bx cases and surgeon credentialing through an education course with SLN Bx and END case review by the surgical co-chairs. A surgical quality assurance working group will review all trial SLN Bx and END procedures. As of 01/12/26, 351 patients have been screened, and 273 of the planned 686 have been randomized. Clinical trial information: NCT#04333537 .

The major barrier to clinical translation of αCD137 immunotherapy is separating antitumor efficacy from hepatotoxicity driven by IFN-γ–producing CD8 T cells. We propose a strategy to limit toxicity by promoting contraction of excessively expanded CD8 T cells. We identify CD11c + KLRG1 + effector CD8 T cells (CD11c + T E ) as the primary source of IFN-γ, recirculating between blood and secondary lymphoid organs (SLOs), where they undergo apoptosis during contraction. We show that lymphotoxin β receptor (LTβR) signaling restrains this contraction. Mechanistically, lymphotoxin-expressing B cells activate LTβR in fibroblastic reticular cells (FRCs), suppressing apoptosis of CD11c + T E cells in the spleen and sustaining their systemic circulation and liver infiltration. Pharmacological LTβR blockade abrogates hepatotoxicity by reducing the accumulation of IFN-γ–producing CD11c + T E cells while preserving tumor-specific CD8 T cell responses. These findings identify LTβR as a key regulator of effector CD8 T cell persistence and support the use of LTβR antagonists to improve the safety of αCD137-based immunotherapy.

Substance use disorders (SUD) remain a significant source of morbidity and mortality in the United States, and access to treatment continues to be inadequate. Primary Care Clinicians (PCCs) are well-positioned to provide long-term SUD care for patients. However, multiple provider-level barriers exist. Collaborative Care Management (CoCM) has proven successful in supporting PCCs in treating psychiatric conditions, such as depression. Our group proposes an addiction-focused modified CoCM that leverages telemedicine and an electronic platform (Senyo) into primary care. This study assesses PCCs’ attitudes toward this proposed model and their likelihood (with support) of prescribing medications for alcohol and opioid use disorder. To achieve this, an anonymized and confidential electronic survey was deployed to all 489 of our institutions’ PCCs. Eighty-five completed the survey (17.4% response); the majority (94%) agreed that digital CoCM for SUD will be helpful for their practice, and 85% expressed agreement that such a model will increase their confidence and likelihood to prescribe anti-craving medications. Additionally, we found that PCCs’ comfort level in addressing SUD with patients is not associated with years in practice, clinician type (attending physicians, resident/fellow physicians, nurse practitioner or physician assistant), or their perception of currently available SUD treatment resources. Future work to evaluate practice changes, including rates of anti-craving medication prescribing and SUD-treatment outcomes after implementation of our digital CoCM will prove useful in determining the effectiveness of this model.

Suppression of insulin-like growth factor-1 (IGF-1) signaling extends mammalian life span and protects against a range of age-related diseases. Unexpectedly, we found that reduced IGF-1 signaling fails to extend the life span of mitochondrial mutator mice. Most of the longevity pathways that are normally initiated by IGF-1 suppression were either blocked or blunted in the mutator mice. These observations suggest that the prolongevity effects of IGF-1 suppression critically depend on the integrity of the mitochondrial genome, revealing an unexpected hierarchy in the pathways that control mammalian aging. Together, these findings deepen our understanding of the interactions between the hallmarks of aging and underscore the need for interventions that preserve the integrity of the mitochondrial genome.

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.

Abstract Acute kidney injury (AKI) causes rapid loss of renal function with high morbidity and mortality. Our previous research showed that neuronal nitric oxide synthase (NOS1) mediates nitric oxide-dependent dilation of the afferent arteriole, inhibiting tubuloglomerular feedback (TGF), which critically regulates single nephron glomerular filtration rate (GFR). This mechanism could affect how vulnerable the organ is to ischemic injury, but this has not been directly tested. In the present study, we generated inducible macula densa (MD)-specific NOS1 knockout mice (NKCC2-Cre-NOS1 flox/flox) using a new inducible NKCC2-Cre line crossed with NOS1 flox mice. AKI was induced by 18-min bilateral renal pedicle clamping at 37°C, followed by 48-h reperfusion. Kidney injury was assessed by measuring GFR, plasma creatinine, histology, cytokines, apoptosis, fibrotic factors, and proteomics. Complete NOS1 deletion in MD cells was confirmed through NKCC2/NOS1 immunofluorescence. MD NOS1 deletion enhanced the TGF response, which was further amplified following AKI compared with control (Cre −/−). Following AKI, compared with controls (Cre −/−), NOS1 knockouts showed a significantly lower GFR (236 ± 66 to 24 ± 22 μl/min) and higher plasma creatinine levels, alongside more severe tubular damage evidenced by H&E staining. Cytokine array analysis showed chemokines such as MCP-1 and CXCL1 and macrophage marker CD68 were significantly increased; Western blot analysis showed cleaved caspase-3 levels were significantly increased, indicating enhanced apoptosis. Additionally, fibrosis markers TIMP-1, collagen-3, and α-SMA were significantly up-regulated at both mRNA and protein levels. We further observed increased hypoxia marker hypoxia-inducible factor-1α in MD-specific NOS1 knockout mice (Cre +/−). Global label-free proteomic profiling with targeted validation identified genotype-dependent responses involving haptoglobin, Tacstd2, and Cyp20a1, linking NOS1 deficiency to exaggerated inflammatory, fibrotic, and metabolic pathways. These findings highlight a novel role of MD NOS1 and TGF in AKI pathophysiology, suggesting NOS1 targeting as a therapeutic strategy. Haptoglobin was identified as a downstream plasma signal of NOS1-dependent AKI responses, indicating potential translational value.