Citations

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.

The 2025 Voice AI Symposium represented a transition from conceptual research to clinical implementation in vocal biomarker science. Hosted by the NIH-funded Bridge2AI-Voice consortium, the meeting convened global experts to address the methodological, ethical, and translational challenges of integrating voice-based artificial intelligence (AI) into healthcare. This mini-review synthesizes symposium insights across six domains: multimodal integration, FAIR (Findable, Accessible, Interoperable, Reusable) and CARE (Collective Benefit, Authority to Control, Responsibility, Ethics) data governance, clinical translation, interdisciplinary training, and cross-sector innovation. Research presented demonstrated voice as a latent, multimodal biomarker reflecting neurological, cardiopulmonary, and psychological states, while discussions emphasized ethical data practices and human-centered design. The implementation-focused panels underscored the importance of workflow alignment and usability for adoption in real-world care. Collectively, the symposium reflects a field advancing toward translational readiness and ethical accountability, positioning voice AI as a scalable, inclusive tool for next-generation healthcare.

Abstract Multiple myeloma (MM) is an incurable plasma cell neoplasm characterized by diverse and complex genetic abnormalities, including translocations of immunoglobulin (Ig) genes and a hyperdiploid (HRD) karyotype. Much of our current understanding of MM genetics, epigenetics, pathogenesis and response/resistance to myeloma directed therapies originated from studies on human MM-derived cell lines (HMCL). In this study, we conducted an integrated multi-omics analysis in five hyperdiploid cell lines established from serial samples from a single relapsed/refractory hyperdiploid MM patient, enabling detailed characterization of the genetic landscape and molecular alterations through disease progression.

Abstract Objective Effective communication with humans and automated voice assistants (AVA) is essential for full participation in modern life. Because AVA relies on intelligible speech, individuals with speech impairments, such as those treated for oral cavity cancer (OCC), may face barriers when interacting with AVA. We assessed self‐reported communication difficulty in patients treated for OCC related to AVA and humans. Study Design Prospective cross‐sectional cohort study. Setting Out‐patient clinics in two tertiary care centers. Methods This study was conducted between July 2024 and March 2025 and included adults (≥18 years) diagnosed with and surgically treated for OCC (experimental group) and those without speech impairments (controls). Participants completed the Speech Communication Experience Survey (SCES), which assessed perceived intelligibility when communicating with familiar partners, strangers, and AVA; and, as reported elsewhere, the Speech Handicap Index (SHI). Results In total, 159 participants were included (69 OCC, 90 controls). OCC participants were more likely to report that familiar partners, strangers, and AVA “almost always” or “always” had difficulty understanding their speech ( P < .05). Free flap reconstruction and maxillectomy were associated with greater reported communication difficulty. AVA usage frequency and overall opinions toward AVA did not significantly differ between groups. Conclusion Patients treated for OCC report significantly greater difficulty being understood by both AVA and human listeners compared to controls. These perceptions may inform peri‐operative counseling and guide the development of more inclusive AVA technologies capable of accommodating diverse speakers. Level of Evidence : 3.

Abstract Myocardial infarction (MI) triggers a systemic neutrophil response, yet the roles of distinct neutrophil subsets in cardiac remodeling remain unclear. Studying this requires murine models that accurately mirror human neutrophil dynamics. Here, we show that a minimally invasive intact-chest MI model is more pathophysiologically relevant than the standard open-chest approach for investigating post-MI immune responses. In the open-chest model, surgical trauma disrupts bone marrow homeostasis, releases large numbers of immature neutrophils, and masks MI-specific immune mechanisms. In contrast, the intact-chest model preserves bone marrow integrity and induces only a modest rise in circulating immature neutrophils, closely reflecting MI patient profiles. We further demonstrate that accumulation of immature neutrophils in the infarcted heart exacerbates cardiac dysfunction. Beyond neutrophils, the overall cardiac immune landscape differs markedly between both models. Collectively, our findings establish the intact-chest model as superior for studying post-MI inflammation and reveal immature neutrophils as mediators of adverse cardiac remodeling.

Abstract Aim Rectal prolapse is a full‐thickness intussusception of the rectum beyond the anal canal. It is often mistaken for other anorectal pathologies, leading to inaccurate referrals to colorectal surgeons and inappropriate management. However, the frequency of misdiagnosis is not well characterized. We aimed to assess the diagnostic accuracy of rectal prolapse referrals to three tertiary medical centres. Methods This is a retrospective study of patients referred for rectal prolapse to colorectal surgeons at the Mayo Clinic in Rochester, Jacksonville, and Phoenix from 2020 to 2024. The primary outcome is the accuracy of rectal prolapse diagnosis. The secondary outcomes are factors that correlate with diagnostic accuracy. Results Rectal prolapse was inaccurately diagnosed in 38.7% (186/480) of patients. Among misdiagnosed patients, the correct diagnosis was haemorrhoids (68.0%, n = 134), pelvic floor dysfunction (24.3%, n = 48) and rectocele (18.7%, n = 37). A diagnosis of rectal cancer was found in 3 patients (1.5%). The most common presenting symptoms were protrusion (66.3%, n = 345) and bleeding (33.6%, n = 175). Among the referring physicians, only 50.5% ( n = 227) performed an anorectal examination. Overall, there was significant variability in diagnostic accuracy across different specialties, with the highest accuracy from colorectal practices (84.0%) and the lowest from urologists (50.0%). Internal medicine physicians had a lower diagnostic accuracy with anorectal examination than without, though it did not reach statistical significance (44.0% vs. 59.5%, p = 0.2). Conclusion Over one‐third of rectal prolapse referrals were incorrectly diagnosed. This study highlights the opportunity for further training of referring providers on anorectal pathologies to improve diagnostic accuracy which could reduce treatment delays and optimize clinical outcomes.

Abstract Background: Hemorrhagic necrotizing pancreatitis (HNP) is a highly lethal form of pancreatitis that lacks mechanism-based therapy. Intra-acinar enzyme activation is fundamental to pancreatitis initiation, yet it does not explain why only a subset of episodes progress to catastrophic hemorrhagic necrosis. Objective: To identify determinants of progression to lethal HNP and test a mechanism-based preventive intervention. Design: Using humanized trypsinogen mouse models and secretagogue regimens, we compared high-dose cerulein with low/moderate-dose cerulein and bombesin. We quantified pancreatic protease activity, performed blinded histopathologic scoring, assessed hemorrhage/vascular disruption, and evaluated enzyme localization and ductal injury by PRSS1 immunostaining. De-identified human pancreatic histology from HNP were examined. We tested a repurposed strategy using clinically approved agents for other indications: secretin to stimulate ductal fluid secretion and isosorbide mononitrate (ISMN) to promote ductal outflow via sphincter of Oddi relaxation. Results: High-dose cerulein induced robust intrapancreatic protease activation but predominantly caused edematous pancreatitis. Paradoxically, bombesin and low/moderate-dose cerulein elicited lower total pancreatic protease activity yet produced severe, frequently lethal HNP with vascular disruption and lobular ischemic necrosis. HNP was associated with intraductal enzyme accumulation and ductal injury. Secretin or ISMN alone showed limited protection, whereas combined secretin+ISMN prevented hemorrhagic necrotizing injury. Conclusion: Pancreatitis severity is determined not only by the magnitude of enzyme activation but also by where enzyme activity is exerted, implicating intraductal enzyme accumulation as a mechanistic determinant and therapeutic target in HNP. Coordinated enhancement of ductal secretion and outflow with clinically approved agents prevents HNP in vivo, supporting a translatable prevention strategy.

Background and Aims: Liver transplantation has evolved from a treatment restricted to patients with end-stage liver disease to a therapeutic option for selected patients with primary and metastatic liver malignancies. This review explores the rapidly expanding field of transplant oncology, highlighting its role in hepatocellular carcinoma, colorectal liver metastasis, neuroendocrine liver metastasis, and intrahepatic and perihilar cholangiocarcinoma. Emphasis is placed on strategies to broaden eligibility, optimize donor organ use, and improve oncologic outcomes. Approach and Results: We synthesized current evidence from clinical series, registries, and experimental protocols to evaluate patient selection criteria, outcomes, and peri-transplant management. Key topics include downstaging approaches to meet transplant criteria, such as locoregional therapies and systemic regimens, and their prognostic implications. Advances in donor utilization have been analyzed for their capacity to expand the graft pool. In addition, the review addresses the integration of oncologic principles into immunosuppression regimens, balancing graft protection with cancer control. Collectively, the reported studies demonstrate improved survival and reduced recurrence when stringent selection and multimodal therapy were applied. Conclusions: Transplant oncology reshapes the therapeutic landscape of liver malignancies, with growing evidence supporting liver transplantation in carefully selected patients beyond traditional indications. Optimized downstaging, innovative donor strategies, and tailored immunosuppression are pivotal for safe expansion. Continued collaboration between the transplant and oncology disciplines, along with prospective trials, is essential to further define standardized protocols and solidify transplantation as a cornerstone of multidisciplinary cancer care.

INTRODUCTION: Colonoscopies reduce colorectal cancer incidence and mortality, but challenges remain in detecting all precancerous lesions. Operator fatigue, technique variability, and subtle lesions can lead to missed adenomas, highlighting the need for tools that standardize detection quality. Computer-aided detection (CADe) systems use artificial intelligence to enhance lesion detection and improve screening colonoscopy quality. This study evaluates the impact of CADe on key quality and efficiency metrics in a clinical setting. METHODS: A single-center retrospective study at an academic tertiary center analyzed 4,028 colonoscopies from October 2022 to December 2023. The CADe system was used in 4 of 8 endoscopy suites, creating a CADe and control group. Propensity matching accounted for age, sex, indication, and physician. Primary outcomes included adenoma detection rate (ADR) and polyp detection rate (PDR). Adenomas per colonoscopy (APC) and polyps per colonoscopy (PPC) were also measured. Per-polyp analyses were performed as a tertiary outcome. RESULTS: ADR was significantly higher in the CADe group (38.6%) vs control (34.2%) (rate ratio [RR] = 1.127, P < 0.05). PDR was significantly higher in the CADe group (67.2%) vs control (59.4%) (RR = 1.130, P < 0.05). APC was significantly higher in the CADe group (M = 0.406, SD 0.637) vs control (M = 0.359, SD 0.599) (RR = 1.131, P < 0.05). PPC was significantly higher in the CADe group (M = 1.297, SD 1.188) vs control (M = 1.046, SD 1.002) (RR = 1.240, P < 0.05). The increase in polyp resection with CADe was driven predominantly by ≤5 mm lesions, with comparatively smaller differences for larger polyps. DISCUSSION: Implementing CADe in clinical practice significantly improved ADR, PDR, APC, and PPC. However, the increase in ADR seems inflated by the detection of polyps ≤5 mm, whose clinical significance in reducing colorectal cancer remains uncertain.

Background: Upfront resectable pancreatic ductal adenocarcinoma (PDAC) is defined by the NCCN as disease with ≤180° portomesenteric vein (PMV) abutment. However, the clinical significance of PMV abutment in this cohort remains unexplored, and we sought to investigate its impact. Methods: This multi-institutional study included patients who underwent pancreatoduodenectomy (PD) for upfront resectable PDAC from 2002 to 2023. Patients with PDAC with ≤180° PMV abutment were compared with those without. Overall survival (OS) was compared and stratified based on whether patients underwent upfront surgery or neoadjuvant therapy (NAT). Results: Among 1,446 patients included, 521 (36.0%) had PMV abutment. Median OS for patients with PMV abutment was 28.8 months compared with 31.2 months for those without ( P =.17). In a stratified analysis of patients who underwent upfront surgery, patients with PMV abutment had worse OS (19.2 vs 27.6 months; P <.05) and lower R0 resection rates (63.1% vs 87.2%; P <.05) compared with those without. However, in patients who underwent NAT, this difference in R0 resection rate was not observed (91.4% vs 94.0%, respectively; P =.27). Furthermore, there was no significant difference in median OS with NAT (42.5 vs 51.6 months, respectively; P =.48). Conclusions: In this largest cohort to date of patients with upfront resectable PDAC, PMV abutment was associated with worse OS compared with no PMV abutment when an upfront resection strategy was used. The use of NAT in patients with PMV abutment mitigated this survival difference with increased R0 resection rates. These findings suggest that patients with upfront resectable PDAC with PMV abutment benefit from a NAT approach for optimal survival outcomes, and that the current criteria guidelines need to be redefined.