Citations

Inadequate light penetration in tissues restricts photodynamic therapy to treating only superficial tumors. To enable x-ray–excited photodynamic therapy (XPDT) that targets deep-seated tumors, we synthesized a nanoscintillator-photosensitizer complex containing 5% Eu-doped Y 2 O 3 fluorescing at 611 nanometers and decorated with SiO 2 containing the scintillation-coupled photosensitizer methylene blue and a polyethylene glycol coating [PEGylated Y 2 O 3 :Eu@SiO 2 -methylene blue (pYSM)]. When irradiated, pYSMs generate singlet oxygen species in vitro, causing cytotoxicity with hallmarks of immunogenic cell death (calreticulin translocation to the cell membrane). Intravenously administered pYSMs home passively to pancreatic tumor xenografts and, upon 10 gray irradiation, cause significant tumor regression ( P < 0.01). On combining XPDT with anti-PD1 immunotherapy, a distant nonirradiated tumor also regresses via an increase in intratumoral activated CD8 + cytotoxic T cells. Collectively, we advance a systemically delivered XPDT strategy that mediates an antitumor effect in both irradiated and nonirradiated (abscopal) tumors when coupled with immunotherapy, converting an immunologically “cold” tumor to an immunologically “hot” tumor.

Abstract Background In breast cancer patients treated with pencil‐beam scanning proton therapy (PBS), the increased linear energy transfer (LET) near the end of the proton range can affect nearby ribs. This may associate with a higher risk of rib fractures. Purpose To study the effect of LET on rib fracture in breast cancer patients treated with PBS using a novel tool of dose‐LET volume histogram (DLVH). Methods From a prospective registry of patients treated with post‐mastectomy proton therapy to the chest wall and regional lymph nodes for breast cancer between 2015 and 2020, we retrospectively identified rib fracture cases detected after completing treatment. Contemporaneously treated control patients who did not develop rib fracture were matched to patients 2:1 considering prescription dose, boost location, reconstruction status, laterality, chest wall thickness, and treatment year. The DLVH index, V (d, l), defined as volume( V ) of the structure with at least dose(d) and dose‐averaged LET (l) (LETd), was calculated. DLVH plots between the fracture and control group were compared. Conditional logistic regression (CLR) model was used to establish the relation of V (d, l) and the observed fracture at each combination of d and l . The p ‐value derived from CLR model shows the statistical difference between fracture patients and the matched control group. Using the 2D p ‐value map derived from CLR model, the DLVH features associated with the patient outcomes were extracted. Results Seven rib fracture patients were identified, and fourteen matched patients were selected for the control group. The median time from the completion of proton therapy to rib fracture diagnosis was 12 months (range 5–14 months). Two patients had grade 2 symptomatic rib fracture while the remaining 5 were grade 1 incidentally detected on imaging. The derived p ‐value map demonstrated larger V (0–36 Gy[RBE], 4.0–5.0 keV/µm) in patients experiencing fracture ( p < 0.1). For example, the p ‐value for V (30 Gy[RBE], 4.0 keV/um) was 0.069. Conclusion In breast cancer patients receiving PBS, a larger volume of chest wall receiving moderate dose and high LETd may result in an increased risk of rib fracture.

Background Recent technologies enable real‐time 3‐dimensional intracardiac echocardiography (ICE) with the advantages of 2‐dimensional ICE and imaging capabilities of transesophageal echocardiography. The purpose of this study is to evaluate the real‐world, multicenter safety and performance of a novel 3‐dimensional ICE system in a variety of cardiac interventions used in standard clinical practice. Methods This prospective, multicenter, observational, single‐arm study enrolled patients who were scheduled for an invasive cardiac procedure involving guidance with ICE and followed until discharge or ≤48 hours postprocedure. Intracardiac imaging was performed with the 3‐dimensional ICE catheter, VeriSight Pro (Philips Inc.). Fluoroscopy was used in all cases and transesophageal echocardiography was used in some cases. The primary safety end point was device‐related adverse events. The primary efficacy end point included technical success, imaging success, and clinical success. Results Between October 2021 and November 2022, 155 patients were enrolled and screened. Percutaneous interventions performed included atrial septal defect/patent foramen ovale closures, left atrial appendage occlusion, catheter ablations, and valve procedures. No adverse events were related to the device or procedure. The technical, imaging, and clinical success rates were 98.7% (95% CI, 95.4%–99.8%), 96.1% (95% CI, 91.8%–98.6%), 94.8% (95% CI, 91.8%–98.6%), respectively. Overall, the VeriSight Pro ICE image quality was assessed to be “acceptable” or greater in relation to reference image modality among 96.2% (149 of 155) of procedures. Conclusions VeriSight ICE imaging is safe and effective in the guidance of a wide variety of percutaneous cardiovascular procedures and has provided successful and high‐quality imaging of cardiac structures.

Abstract The TopBP1-ATR axis is critical for maintaining genomic stability during DNA replication stress, yet the precise regulation of TopBP1 in replication stress responses remains poorly understood. In this study, we identified PHD and Ring Finger Domains 1 (PHRF1) as an important ATR activator through its interaction with TopBP1. Our analysis revealed a correlation between PHRF1 and genomic stability in cancer patients. Mechanistically, PHRF1 is recruited to DNA lesions in a manner dependent on its PHD domain and histone methylation. Subsequently, PHRF1 mono-ubiquitinates TopBP1 at lysine 73, which enhances the TopBP1-ATR interaction and activates ATR. Depletion of PHRF1 disrupts ATR activation and sensitizes cells to replication stress-inducing agents. Furthermore, conditional knockout of Phrf1 in mice leads to early lethality and impaired ATR-Chk1 axis signaling. Collectively, our findings establish PHRF1 as a novel E3 ligase for TopBP1, coordinating the replication stress response by enhancing TopBP1-ATR signaling.

Abstract Food allergy can be life threatening and often develops early in life, especially in infants and children with atopic dermatitis. Food allergy is induced in neonatal mice with skin barrier mutations (Flaky Tail, FT+/− mice with filaggrin and mattrin gene mutations) by epicutaneous sensitization with co-exposures to the food allergen peanut extract (PNE), the environmental allergen Alternaria alternata (Alt), and detergent (4% SDS); oral PNE-challenge induces anaphylaxis. Sensitization in these neonates also induces eosinophil infiltration into the skin and elevates skin expression of eotaxins (CCL11 and CCL24). However, roles for eosinophils in food allergy are not known. In this study, the iPhil+/− FT+/− pups, which have an inducible eosinophil-deficiency upon injection of diphtheria toxin (DTX), were sensitized and then received PNE by gavage to assess anaphylaxis. DTX depletion of eosinophils, during sensitization and oral PNE-challenge, blocked the recruitment and activation of mast cells, blocked the Alt+PNE-induced increase in plasma IL-33 and OSM, attenuated serum PNE-specific IgE/IgG1/IgG2b, and blocked oral-PNE-induced anaphylaxis. Anti-IL-5 depletion of eosinophils during sensitization/challenge also blocked anaphylaxis. When eosinophils were depleted during allergen-skin-sensitization and restored before oral PNE-challenge, anaphylaxis was blocked. In contrast, when eosinophils were present during allergen-skin-sensitization but then depleted during oral PNE-challenge, anaphylaxis was not blocked. Together, these data indicate that although eosinophils are not necessary during oral food allergen-induced anaphylaxis, eosinophils have a critical role during the development of food allergy early in life by regulating the sensitization-induced increase in mast cell numbers and food allergen-specific IgE.

Abstract Background New postoperative atrial fibrillation (POAF) occurs in about 40% after cardiac surgery. Mineralocorticoid receptor antagonists (MRA) are known to reduce chronic atrial fibrillation (AF) development and burden. We examined the impact of preoperative MRA use on POAF and also examine the atrial cell type impacted by MRA treatment during cold cardiac preservation. Methods Retrospective study of 19,042 patients who underwent cardiac surgery at Mayo Clinic in Minnesota, and performed 1:3 propensity matching to obtain 298 patients on preoperative MRA matched to 894 who were not. We also separately matched patients using preoperative diuretics. Single-nuclei RNA sequencing (snRNA-seq) examined MRA’s effects on different atrial cell types in canrenone (water soluble MRA) treated human donor hearts undergoing cold preservation followed by ex-vivo reperfusion and compared gene expression to the atria of patients with AF. Results Propensity matched preoperative MRA group had less new onset POAF (19.8% vs 31.5%, P<0.001). To account for the possibility that preoperative diuretic use and volume reduction may impact POAF, we propensity matched 298 preop diuretic users that included MRA use to another 894 patients who used a non-MRA diuretic preoperatively. Those who used preoperative MRA similarly had a lower incidence of POAF (19.8% vs 33.2%, P<0.001). No survival difference was present between the propensity matched groups that used preoperative diuretics (P=0.079). Preoperative MRA use also reduced the development of paroxysmal and chronic AF at 6 years of follow up. From our snRNA-seq data, we identified a subpopulation of atrial cardiomyocytes (CM2) that had high MR expression where canrenone suppressed the increase in MR target gene expression associated with cold preservation-reperfusion. These MR targets were conversely elevated in patients with chronic AF. Canrenone also suppressed other cardiac preservation associated genes that show elevated expression in atrial macrophages and pericytes from chronic AF atria. Conclusions Our studies show that preoperative MRA use is associated with 40% reduction in POAF as well as lowering long standing AF development by about 41%. Our cold cadiac preservation-reperfusion model showed that canrenone reduced expression of MR target genes associated with chronic AF, particular in cardiomyocytes with important roles in electrical conduction. Clinical Perspective What is New? This study shows that preoperative use of mineralocorticoid receptors antagonists (MRA) is associated with a reduced incidence of new onset perioperative atrial fibrillation after cardiac surgery utilizing cardiopulmonary bypass. We show that preoperative MRA use is associated with a lower incidence of developing more chronic paroxymal or sustained atrial fibrillation. Addition of canrenone, a clinically utilized water soluble MRA, to cardioplegia solution used during cardiac preservation can attenuate atrial inflammatory reponses and reduce signaling through molecular pathways that promote atrial fibrillation. What are the clinical implications? Perioperative use of MRAs may be considered to reduce early postoperative atrial fibrillation as well as lowering the risk of developing more chronic atrial arrhythmias. These findings support pursuing a clinical trial to determine the impact of MRA use on atrial arrhythmias following cardiac surgery in the setting of cardiopulmonary bypass with cold cardiac preservation.

Abstract The prevalence of steatotic liver disease (SLD) is rising globally, presenting a significant public health challenge. While non-contrast computed tomography (CT) scans hold promise for the opportunistic detection of SLD, their full potential has not been systematically explored. Clinical indicators, such as serum data, are crucial for monitoring the progression of SLD. We introduce a novel Multimodal AI for Opportunistic Steatotic Liver Disease Screening (MAOSS), which integrates demographic data, serum tests, conventional CT biomarkers, and deep learning-derived CT image features to enhance model performance and explainability. MAOSS employs an innovative learning strategy, trained on a large-scale dataset (n = 1,783) encompassing both histopathologically-confirmed SLD and radiologically-reported steatosis cases. The model underwent extensive retrospective validation using steatosis grades derived from both histology and MRI-PDFF across internal and external datasets (n = 913), as well as real-world patient data (n = 18,504). It accurately detected mild to severe steatosis (≥ S1) with AUCs ranging from 0.903 to 0.929. Notably, MAOSS significantly improved the overall AUC for radiologists (n = 11) from 0.709 to 0.798 (p < 0.001). Furthermore, MAOSS was applied to optimize the standard clinical pathway for a simulated primary risk screening of SLD patients (n = 1,192), resulting in the identification of 31% more patients at risk of steatohepatitis and liver fibrosis progression, highlighting its potential to enhance SLD detection and management.

Abstract Background Recurrent Clostridioides difficile infection (rCDI) is common, with a prior CDI linked to a risk of up to 65% for subsequent recurrences. Fecal microbiota, live-jslm (RBL) is the first microbiota-based product approved in the US for the prevention of rCDI in adult patients following antibiotic treatment for rCDI. This study reports the characteristics and outcomes of patients with rCDI who were administered RBL in a real-world setting. Methods Adult patients with rCDI who received RBL either at home or a clinic from healthcare professionals affiliated with a home-care provider network were included. Patients were required to have at least 8 weeks of follow-up after RBL administration, with CDI recurrence status assessed at week 8. Patient demographics, clinical characteristics, administration setting, prior medication use, and prior healthcare resource utilization were collected. The primary outcome was CDI recurrence within 8 weeks post-RBL administration. All variables were summarized descriptively using median and interquartile range (IQR) for continuous outcomes and count and percentage for categorical variables. Results Between July 2023 and March 2024, 136 patients with rCDI received RBL, of whom 73 had at least 8-week follow up and reported CDI recurrence status at week 8. Patients had a median age of 63.0 years (IQR = 47.0, 76.0), 68.5% were female, most (74.0%) had ≥ 3 prior CDI recurrences, 5.5% had received fecal microbiota transplant, and 9.6% had received bezlotoxumab (Table). One third of patients (32.9%) had previously been hospitalized and 38.4% had prior emergency room visits due to CDI. Most patients were previously treated with antibiotics for rCDI: 39.7% with vancomycin only, 11.0% with fidaxomicin only, and 43.8% with both vancomycin and fidaxomicin. All patients, except for 4 with missing data, received RBL 24-72 hours post-antibiotics. Most patients (83.6%) received RBL at home. At week 8, the overall treatment success rate (no CDI recurrence) was 87.7% (87.3% [62/71] in RBL-naïve; 100% [2/2] in previously RBL-treated). Conclusion RBL was effective in preventing recurrence of CDI at 8 weeks in a real-world setting, where most patients received RBL at home. These results suggest that RBL is effective in managing rCDI, including in a home care setting. Disclosures Sahil Khanna, MBBS, MS, Ferring Pharmaceuticals, Inc.: Grant/Research Support|Finch: Grant/Research Support|Immuron: Advisor/Consultant|Niche: Advisor/Consultant|Pfizer: Grant/Research Support|Probio Tech, LLC: Advisor/Consultant|Seres Therapeutics: Grant/Research Support|Takeda: Advisor/Consultant|Vedanta: Grant/Research Support Sanghyuk Seo, PharmD, MS, Ferring Pharmaceuticals, Inc.: Employee Min Yang, MD, PhD, Analysis Group, Inc.: I am an employee of Analysis Group, Inc., which has received consulting fees from Ferring for the conduct of this study. Viviana García-Horton, PhD, Analysis Group, Inc.: I am an employee of Analysis Group, Inc., which has received consulting fees from Ferring for the conduct of this study. Yipeng Gao, PhD, Analysis Group, Inc.: I am an employee of Analysis Group, Inc., which has received consulting fees from Ferring for the conduct of this study. Hannah Kim, PhD, Analysis Group, Inc.: I am an employee of Analysis Group, Inc., which has received consulting fees from Ferring for the conduct of this study. Loren Ormenaj, n/a, Analysis Group, Inc.: I am an employee of Analysis Group, Inc., which has receivedconsulting fees from Ferring for the conduct of this study. Amy Guo, PhD, Ferring Pharmaceuticals, Inc.: Employee

ABSTRACT Introduction Despite the emergence of drugs to treat irritable bowel syndrome (IBS), improving abdominal pain can still be challenging. α 2 δ ligands, such as gabapentin and pregabalin, are sometimes used off‐label to tackle this problem. However, evidence for efficacy is limited, and no large‐scale studies have been published. Aim To study the efficacy of the α 2 δ ligand PD‐217,014 in IBS. Methods This multi‐centre, double‐blind, randomised, placebo‐controlled, parallel group study randomised participants with Rome II‐defined IBS to 150 or 300 mg b.d. of PD‐217,014 or placebo b.d. for 4 weeks. The primary efficacy endpoint was responder, defined as having adequate relief of abdominal pain/discomfort for ≥ 50% of the active treatment period. Key secondary endpoints were change from baseline in abdominal pain, bloating, stool frequency/consistency, and global assessment of IBS symptoms. Results We randomised 330 participants [aged 19–73 years; 209 (65%) female] satisfying Rome II criteria, 322 (98%) were treated, and of whom 271 (84%) completed the study. In this study, 321 satisfied Rome IV criteria. Neither dose of PD‐217,014 improved the percentage of participants reporting adequate relief of abdominal pain/discomfort compared with placebo, either using the Rome II‐defined total cohort or Rome II and IV IBS bowel habit sub‐types. There were similar observations for secondary endpoints, and no association between abdominal pain or anxiety levels at baseline with participant improvement. PD‐217,014 was generally well tolerated. Conclusion This first large, dose‐ranging trial examining the efficacy of PD‐217,014 showed no significant efficacy in participants with IBS or bowel habit sub‐types, irrespective of their pain and anxiety levels.