Citations

BACKGROUND: Technetium-based cardiac amyloid radionuclide imaging enables noninvasive diagnosis of transthyretin amyloid cardiomyopathy (ATTR-CM), but conventional planar and visual semiquantitative approaches have important limitations. We developed the quantitative 3-dimensional Mayo 3D Score, defined as the ratio of mean left ventricular myocardial radiotracer uptake to right atrial blood-pool uptake using computed tomography (CT)-fused single-photon emission CT (SPECT) volumes of interest, and sought to validate its diagnostic performance against myocardial pathology. METHODS: Consecutive patients who underwent 99m Tc-pyrophosphate SPECT/CT at Mayo Clinic for suspected ATTR-CM between June 2017 and January 2025 with archived myocardial tissue were included. Baseline characteristics, including demographics, echocardiogram, biomarkers, visual semiquantitative, and Mayo 3D Score metrics, were collected. Myocardial specimens underwent histopathologic confirmation of amyloid, with amyloid subtype determination and further semiquantitative grading of amyloid burden and deposition patterns. RESULTS: Among 230 patients (median age, 72 years; 78% male), 107 (47%) had ATTR-CM, of whom 9 had hereditary ATTR-CM. The Mayo 3D Score showed excellent discrimination against pathology (area under the receiver operating characteristic curve, 0.92 [0.88–0.96]), exceeding planar Perugini (0.87 [0.83–0.92]; P =0.006), and heart-to-contralateral lung ratio (0.86 [0.81–0.91]; P =0.004) and comparable to SPECT Perugini (0.90 [0.86–0.94]; P =0.12). A cutoff ≥1.0 yielded 86.0% sensitivity, 92.7% specificity, 91.1% positive predictive value, and 88.4% negative predictive value. Among ATTR-positive cases, the Mayo 3D Score correlated strongly with semiquantitative amyloid burden (Spearman ρ=0.69), was higher in pericellular than nodular deposition patterns ( P <0.001), and was not associated with vascular involvement ( P =0.42). CONCLUSIONS: In patients with suspected ATTR-CM undergoing 99m Tc-pyrophosphate SPECT/CT, the Mayo 3D Score demonstrated superior diagnostic performance compared with planar metrics and comparable to SPECT Perugini, while correlating with myocardial ATTR burden and deposition patterns on pathology. These findings support its integration as a quantitative adjunct within clinical diagnostic ATTR-CM workflows.

Hypothyroidism, also called&nbsp;underactive thyroid&nbsp;or&nbsp;low thyroid, is a&nbsp;disorder of the endocrine system&nbsp;in which the&nbsp;thyroid gland&nbsp;does not produce enough&nbsp;thyroid hormone.&nbsp;It can cause a number of symptoms, such as&nbsp;poor ability to tolerate cold, a&nbsp;feeling of tiredness,&nbsp;constipation,&nbsp;depression, and&nbsp;weight gain.&nbsp;Occasionally there may be swelling of the front part of the neck due to&nbsp;goiter.&nbsp;Untreated cases of hypothyroidism during&nbsp;pregnancy&nbsp;can lead to delays in&nbsp;growth and intellectual development&nbsp;in the baby or&nbsp;congenital iodine deficiency syndrome.<br /> Worldwide,&nbsp;too little iodine&nbsp;in the diet is the most common cause of hypothyroidism.&nbsp;Hashimoto's thyroiditis&nbsp;is the most common cause of hypothyroidism in countries with sufficient dietary iodine.&nbsp;Less common causes include previous treatment with&nbsp;radioactive iodine, injury to the&nbsp;hypothalamus&nbsp;or the&nbsp;anterior pituitary&nbsp;gland, certain medications,&nbsp;a lack of a functioning thyroid at birth, or previous&nbsp;thyroid surgery.&nbsp;The diagnosis of hypothyroidism, when suspected, can be confirmed with&nbsp;blood tests&nbsp;measuring&nbsp;thyroid-stimulating hormone&nbsp;(TSH) and&nbsp;thyroxine&nbsp;levels.

ABSTRACT Aims Metabolic dysfunction‐associated steatotic liver disease (MASLD) is increasingly linked to cognitive decline, yet the hepatic factors associated with imaging‐derived neurovascular coupling (NVC) remain unclear. This study aimed to investigate whether liver stiffness or liver fat content was more closely associated with resting‐state CBF‐ReHo surrogate measures. Materials and Methods A total of 130 participants including 98 MASLD patients and 32 age‐ and education‐matched healthy controls (HCs) underwent clinical assessment, neuropsychological testing, and multi‐modal MRI. Liver stiffness and fat content were quantified using MR elastography (MRE) and MRI‐proton density fat fraction (PDFF). Imaging‐derived NVC was assessed using global cerebral blood flow (CBF)‐regional homogeneity (ReHo) coupling and voxel‐wise CBF/ReHo ratios, interpreted as resting‐state surrogates rather than direct stimulus‐evoked NVC. Multivariable regression and exploratory mediation analyses were employed. Results Compared to HCs and patients with lower liver stiffness (MASLD_low), those with higher liver stiffness (MASLD_high) showed reduced global CBF‐ReHo coupling and altered CBF/ReHo ratios, primarily localized to the bilateral superior temporal pole/superior temporal gyrus (TPOsup). In multivariable regression, liver stiffness remained independently associated with TPOsup CBF/ReHo ratios ( p < 0.001). Exploratory mediation analysis showed a statistically significant indirect association between hepatocellular injury markers and TPOsup CBF/ReHo ratios involving MRE‐derived liver stiffness (95% CI: 0.0795–0.2790). Conclusions Within this cohort and the observed PDFF range, MRE‐derived liver stiffness was more closely associated with imaging‐derived NVC surrogate measures than liver fat content in MASLD. These findings are hypothesis‐generating and require validation in longitudinal studies.

Objective: To determine whether normothermic machine perfusion (NMP) mitigates the historical survival disadvantage of donation after circulatory death (DCD) liver transplantation compared with donation after brain death (DBD) livers. Summary Background Data: NMP has improved outcomes in DCD LT compared with static cold storage (SCS), but whether it eliminates the historical disparity relative to DBD transplantation remains uncertain. Methods: We performed a retrospective cohort study of adult LT at a high-volume US center between 2019 and 2024. Outcomes of DCD-NMP grafts were compared with DCD-SCS, DBD-SCS, and DBD-NMP grafts. Primary outcomes were 1-year graft and patient survival. Secondary outcomes included early allograft dysfunction (EAD), hepatic artery thrombosis (HAT), primary nonfunction (PNF), biliary anastomotic strictures (BAS), and ischemic cholangiopathy (IC). Results: Among 1338 liver transplants (DBD-SCS n=527; DBD-NMP n=142; DCD-SCS n=255; DCD-NMP n=414), DCD-NMP grafts had a significantly higher donor risk profile ( P <0.001) yet demonstrated survival comparable to DBD transplantation. One-year graft survival was 94% for DCD-NMP versus 93% for DBD grafts and 86% for DCD-SCS, and 1-year patient survival was 98% for DCD-NMP versus 94% to 95% for DBD grafts and 93% for DCD-SCS. In adjusted models, DCD-SCS was associated with increased hazards of graft loss (adjusted hazard ratio: 2.48; P <0.001) and death (adjusted hazard ratio: 2.39; P =0.004), whereas DBD groups did not differ from DCD-NMP. Incidence of EAD was lower with DCD-NMP (21.7%) than DCD-SCS (50.2%) and similar to DBD grafts (21.1%–26.4%); HAT and PNF were rare (≤1.3%). At 1 year, BAS occurred in 36% of DCD grafts versus 17% to 23% of DBD grafts. IC occurred in 7.7% of DCD-NMP compared with 22% of DCD-SCS and ≤1.5% of DBD grafts. Retransplantation due to IC was infrequent overall (1.3%), but more common in DCD-SCS (4.7%) than DCD-NMP (1.0%) and DBD grafts (≤0.4%). Conclusions: NMP enables safe utilization of DCD liver allografts and achieves graft and patient survival comparable to DBD LT, mitigating the historical disadvantage of DCD grafts. These findings support routine integration of NMP into clinical practice and efforts to standardize its implementation.

Abstract Background: The limited efficacy of oncolytic virotherapy (OV) in gastrointestinal malignancies has been attributed to an immunologically inert tumor microenvironment. While cisplatin is widely used as a cytotoxic agent, its immunomodulatory effects remain incompletely defined. We hypothesized that cisplatin may reprogram the tumor immune landscape to enable more effective OV-mediated anti-tumor responses. Methods: We evaluated the effects of cisplatin in combination with two distinct oncolytic platforms, vesicular stomatitis virus (VSV) and adenovirus (AdV), across both in vitro and in vivo colorectal cancer models. In vivo efficacy was assessed using MC38 subcutaneous and peritoneal metastatic models, with analysis of tumor growth, survival, and toxicity. Immune profiling was performed using single-cell RNA sequencing (scRNA-seq), flow cytometry, and bulk RNA sequencing to interrogate changes in CD8+ T cell states and functional programs. Guided by these preclinical findings, a clinical trial combining XELOX, PD-1 blockade, and OV therapy was initiated (ChiCTR2500107607). Results: Cisplatin markedly enhanced OV-mediated anti-tumor efficacy across models, resulting in sustained tumor control and improved survival in both subcutaneous and peritoneal disease settings. This effect was conserved across viral platforms, indicating a virus-agnostic interaction. Mechanistically, cisplatin induced a robust interferon (IFN)–dominant transcriptional program, characterized by upregulation of interferon-stimulated genes, including IRF7, IRF9, and ISG15. Single-cell analysis revealed that combination therapy reshaped the CD8+ T cell compartment, promoting the expansion of a population with transcriptional and functional features of central memory T cells (Tcm), alongside reduced exhaustion signatures. These changes were accompanied by enhanced cytokine signaling pathways associated with T cell maintenance and function, including IL-2, IL-7, and IL-15. In vitro, the combination of cisplatin and OV increased tumor cell death and interferon-γ production, supporting a model in which cytotoxic and immunostimulatory effects are mechanistically linked. A phase I clinical trial has been initiated. In gastric cancer, patients with retroperitoneal metastases are being treated with OV in combination with PD-1 blockade (ongoing). In colorectal cancer, the strategy is being evaluated in the neoadjuvant setting with an rectal preservation approach. Conclusions: Our findings identify a previously unrecognized role for cisplatin in priming an interferon-driven immune program that promotes Tcm differentiation and function, thereby enabling durable responses to oncolytic virotherapy. This work provides a mechanistic rationale for leveraging chemotherapy-induced immune reprogramming to enhance viro-immunotherapy and supports the clinical translation of this strategy in gastrointestinal malignancies. Citation Format: Joseph Brandon. Parker, Zhongyi Dong, Tao Liu, Qisen Guo, Haoyu Zhang, Bo Ni, Long Bai, Yiwen Chen, Jiasheng Zong, Xiang Xia, Jiaojiao Zheng, Hoang Tran Pham, Aya Elalfy, Demarcus Ingram, Ahmed Abdel-Hakeem, Muhammad Ali, Shannon Hartzell, Zizhen Zhang, Vivienne Yang. Cisplatin primes an interferon-driven CD8+ central memory T cell program to enable oncolytic virotherapy in gastrointestinal cancer malignancies [abstract]. In: Proceedings of AACR Drug Discovery and Development (AACR D3) Conference; 2026 Jul 21-24; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(14_Suppl):Abstract nr B024.

ABSTRACT Lupus nephritis requires long-term immunosuppressive therapy, which is often associated with severe systemic side effects. Therefore, new therapeutic strategies that maintain high efficacy while minimizing adverse effects is essential. Although nanomedicine has advanced systemic and kidney-targeted drug delivery, a reliable method for glomerulus-specific delivery is lacking. Collagen IV (Col4)-alpha 3, located in the glomerular basement membrane (GBM) at the blood–tissue interface through fenestrated capillary endothelium, represents an ideal target for glomeruli delivery. Herein, we developed a novel liposomal nanoparticle conjugated with a Col4-alpha 3 binding peptide (Col4-α3-NPs) for selective glomerular targeting. Prednisolone-loaded Col4-α3-NPs were administered to lupus-prone mice twice weekly for 8 weeks. Kidney injury and function were evaluated biweekly, and renal immune cell populations were analyzed by flow cytometry at study completion. The results show that rhodamine-labeled NPs predominantly accumulate in kidney glomeruli 48 hours after intravenous injection. The Col4-NP system demonstrated stable and prolonged release of the encapsulated drug for over 48 hours. Lupus-prone mice treated with prednisolone-loaded Col4-NPs showed significantly improved renal function and histology, including a 30% increase in glomerular filtration rate (GFR), a 56% reduction in proteinuria, and decreased IgG deposition and fibrosis. Notably, treatment also enhanced renal regulatory T cell (Treg) populations. These findings suggest that glomerulus-targeted Col4-α3-NPs hold significant translational promise. This platform may offer an effective, site-specific treatment for lupus nephritis while minimizing systemic side effects and could be adapted for other glomerular diseases requiring targeted therapy.

Abstract INTRODUCTION: Pleuropulmonary blastoma (PPB) and Sertoli-Leydig cell tumor (SLCT) are DICER1-related tumors for which novel therapies are urgently needed. A subset of Wilms tumors are also associated with germline or somatic variants in DICER1. Current therapies include cytotoxic chemotherapy, radiation, and surgery, but there are limited options for patients with recurrent disease. Antibody-Drug Conjugates (ADC) have emerged as promising therapies for several solid tumors. Aberrantly expressed cell surface proteins, including Preferentially Expressed Antigen in Melanoma (PRAME), represent potential targets for immunotherapeutic treatments like CAR-T cell and antibody-based therapies in malignant cancers, including DICER1-associated tumors. METHODS: Individuals diagnosed with PPB, SLCT, and Wilms tumor who enrolled in the International PPB/DICER1 Registry, International OTST Registry, and/or UT Southwestern Pediatric Hematology-Oncology Biorepository were selected for analysis. We analyzed ten PPB samples (four PDX, six primary tumor), four SLCT samples (all primary tumor), and 54 Wilms tumor samples (4 PDX, 50 primary tumor). DICER1 hotspot variants were verified in all 14 PPB and SLCT samples, while none of the Wilms tumor samples we analyzed exhibited DICER1 hotspot variants. Mapped and normalized whole-transcriptome sequencing reads were used to examine expression of 73 targets of antibody- or cell-based therapies that are clinically approved or under clinical investigation on clinicaltrials.gov. Genes with a median expression exceeding 2.5 transcripts per million (TPM) were considered expressed in a given tumor type; this threshold was selected to be permissive in identifying potential targets for further evaluation. RESULTS: Of the 73 genes of interest, 21 targetable cell-surface genes met a median expression threshold of 2.5 TPM in at least one tumor type: 11 genes in PPB, 16 in SLCT, and 14 in Wilms. Seven genes (FN1, PRAME, MCAM, CD248, IL11RA, CD276 (B7-H3), and MRC2) were expressed at this level in all three tumor types. Additional genes were expressed above this level in only two of the tumor types; PDGFRA in PPB and SLCT; GPC2 and TYRO3 in SLCT and Wilms tumor; and CSPG4, ERBB2, FZD10 in PPB and Wilms tumor. Six genes were exclusively expressed in SLCT (AXL, GPNMB, PROM1, KDR, ITGA6, FGFR4), and two were unique to Wilms tumor (GPC1, ULBP3). Of these, PRAME was previously reported as frequently expressed in DICER1-associated tumors; little has been reported about the remaining potential targets. CONCLUSION: PPB, SLCT, and Wilms tumor express several potential immunotherapy targets by RNA-seq. Expression of these potential targets should be investigated by immunostaining in a wider panel of tumors. Further study on the potential for ADCs or CAR-T cell therapies to treat DICER1-related conditions is needed. Citation Format: Brenya McNally, BS, Paige H.R. Mallinger, MS, David Huntsman, MD, FRCPC, FCCMG, Yemin Wang, PhD, Joyce Zhang, PhD, Claudette R. Fraire, PhD, Peter J. Schoettler, MD, Kris Ann P. Schultz, MD, Kenneth S. Chen, MD. Identifying potential cell-surface targets for therapeutic treatment of DICER1-related cancers [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Breaking Barriers in the Fight against Rare Cancers; 2026 Jul 18-20; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(14_Suppl):Abstract nr A018.

Most patients with chest pain do not have acute myocardial infarction (AMI), yet post-AMI rule-out disposition remains variable. Detectable but sub-99th percentile high-sensitivity cardiac troponin I (hs-cTnI) provides additional prognostic information. We evaluated the economic value of hs-cTnI-guided hospitalizations among non-AMI patients. We analyzed 1481 non-AMI chest pain visits with detectable baseline hs-cTnI across 29 U.S. emergency departments (2014–2016) in the prospective HIGH-US trial using the Atellica IM TnIH assay(Siemens Healthcare Diagnostics, Tarrytown, NY, US). We compared observed standard-of-care admissions with modeled pathways incorporating hs-cTnI thresholds and risk scores, assessing admission rates, costs, and diagnostic accuracy for 30-day death/MI. Overall, 1.0% (n = 15/1481) experienced 30-day death/MI. Standard-of-care admitted 59% of patients with 93% sensitivity and 41% specificity. The modeled pathway using hs-cTnI ≥ 5 ng/L plus non-low risk scores was associated with reduced projected admission of 41%, higher specificity of 60%, and the same 93% sensitivity. Estimated per-patient diagnostic costs were lower under Scenario 1 (noninvasive diagnostic testing only; $1025 vs. $1139) and under Scenario 2 (including inpatient/invasive procedures; $2672 vs. $3536). In subgroups, higher hs-cTnI thresholds conferred further economic benefit without compromising sensitivity. Incorporating sub-99th percentile hs-cTnI thresholds alongside risk scores may support more efficient resource use while maintaining safety, although findings require prospective validation.

Abstract Background Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous syndrome comprising multiple pathophysiological phenotypes. HFpEF trials have largely enrolled diverse populations and reported average treatment effects, consistently yielding neutral results that may obscure drug-specific benefits within distinct subgroups. To address this issue, we employ an interaction-based that incorporates treatment-by-variable interactions to uncover drug-specific responses. Methods We leveraged four HFpEF clinical trials (TOPCAT, RELAX, NEAT-HFpEF, INDIE-HFpEF) and developed a framework comprising two complementary approaches. The first employed a prognostic responder model to evaluate whether conventional responder definitions reflect treatment-specific benefit or instead capture favorable clinical trajectories common to both treatment and placebo groups. The second used an interaction-based individual treatment effect (ITE) modeling to identify baseline variables that modify therapy effect, distinguishing drug-specific response from prognostic phenotypes. Results Although the prognostic responder model demonstrated good discrimination, further analisys suggested it primarily captured a prognostic signal associated with favorable clinical trajectories common to both treatment and placebo arms. In contrast, the ITE model identified distinct, drug-specific effect modifiers across trials (cardiorenal-inflammatory for spironolactone (TOPCAT), NO-mediated anti-inflammatory for isosorbide mononitrate (NEAT-HFpEF), afterload-reducing for inorganic nitrite (INDIE-HFpEF), and anti–volume-overload for sildenafil (RELAX). Each ITE model demonstrated significance only within its own trial suggesting drug-specific signal. Conclusions The proposed method identifies mechanism-specific effect modifiers, and uncovers clinically meaningful heterogeneity in treatment response, which is not captured by conventional MCID-based approaches. Although exploratory, these findings support phenotype-guided therapy in HFpEF and argue for phenotype-informed trial design to enhance treatment-effect detection and therapy targeting. Graphical Abstract

Synaptic transmission can be tuned through plasticity mechanisms that regulate synaptic strength, structure, and number. In vivo measurements demonstrate remarkable spine dynamics, with subsets of synapses persisting for months. This correlates with the longevity of certain memories, which can persist for an organism’s lifetime. The molecular basis supporting the long-term stability of specific synapses and the long-term durability of memories remains unknown. At the protein level, most proteins persist for a relatively short amount of time before they are degraded and replaced with new molecules. However, recent work has identified a population of proteins, including those present at the synapse, that are exceptionally long-lived. It has been speculated that long-lived proteins (LLPs) could contribute to long-term synapse stability, function, and memory. Here, we used stable isotope labeling in mammals to first identify LLPs in the post synaptic density (PSD) of the hippocampus and subsequently determine if protein turnover rates varied by sex or following learning. We identified synaptic LLPs and found that both sex and experience can regulate synaptic protein turnover rates. We identified sex-dependent changes in protein turnover rates in autism spectrum disorder risk genes, including increased stability of Gabrg2, a GABA-A receptor subunit, in male mice. Furthermore, we observed stabilization of a subset of PSD proteins, such as Shank3, following contextual fear conditioning. We propose that sex- and experience-dependent changes in protein turnover rates could help explain sex-differences in psychiatric risk and aid our understanding of the molecular mechanisms that support learning and memory.