Integrative oncology (IO) modalities aim to improve the quality of life of persons with cancer, including strategies to manage treatment and disease-related symptoms. As evidence increases to include IO in supportive care, interest grows globally. Understanding barriers to IO recommendation is key to facilitating its uptake. Members of the Multinational Association of Supportive Care in Cancer (MASCC) and the Society for Integrative Oncology (SIO) were invited to complete an online survey in Fall 2023 assessing barriers to IO recommendation on a 5-point scale. Descriptive statistics assessed demographic data and general counts of scaled agreement, while logistic regression analysis evaluated perceived barriers in relation to relevant covariates. Over 80

Resilience to cardiac stress is essential for health, yet the relationship between cardiomyocyte (CM) stress response and local microenvironment remains unclear. Here, we combined MERFISH spatial transcriptome profiling with Cellouette, an improved cell segmentation method, to determine CM-microenvironment relationships in a mouse model of ventricular pressure overload. We report the shape, transcription profile, spatial organization, and physical connectivity for >400,000 cells across stressed and healthy tissues. Under stress, CMs adopted a spectrum of emergent transcriptional states, with advanced states marked by a metabolic and pro-fibrotic shift. To discover CM-environment relationships, we performed a network analysis of physical cell connectivity combined with cell-type-specific profiling. We found that pro-fibrotic CM progression was tightly linked to distinct local microenvironments, and CM metabolic shifts could be inferred from transcriptional patterns in neighboring non-CM cells, revealing microenvironmental imprints of disease. We thus provide a resource for understanding the heterogeneity of outcome during cardiac pressure overload.

[This corrects the article DOI: 10.1371/journal.pone.0319867.].

The immune mechanisms underlying Kawasaki disease (KD), a febrile systemic vasculitis in children, are poorly understood. Reports indicate elevated levels of circulating IL-33 in acute KD patients; however, if IL-33 contributes to the pathogenesis of KD vasculitis remains unclear. Here, we used the Lactobacillus casei cell wall extract (LCWE)-induced murine model of KD to determine the contribution of IL-33 to vasculitis development. We observed increased expression of Il33 transcripts and IL-33 protein in LCWE-induced cardiovascular lesions. Bone marrow chimera experiments suggest that IL-33 production by both hematopoietic and stromal cells is important for LCWE-induced KD vasculitis; however, single-cell RNA sequencing, spatial transcriptomics, and flow cytometric analysis revealed that stromal cells were the predominant sources of IL-33. Furthermore, immune cells infiltrating LCWE-induced cardiovascular lesions expressed Il1rl1 transcripts, coding for the IL-33 receptor ST2. In vitro stimulation of bone marrow-derived macrophages with IL-33 enhanced their production of IL-1b and TNF-α. In vivo blockade of IL-33, using either neutralizing IL-33 antibody or Il33-/- mice, effectively attenuated LCWE-induced cardiovascular inflammation. Our results indicate that IL-33 contributes to LCWE-induced vascular inflammation through redundant mechanisms across multiple immune cell subsets rather than a single population and highlight IL-33 as a potential therapeutic target.

Bladder outlet obstruction leads to pathological remodeling and emergence of lower urinary tract symptoms. Although relief of obstruction is associated with symptomatic improvement, it is not universally successful, reflecting persistent alterations in the bladder. Reliable surrogate biomarkers of obstruction are lacking, particularly early in the disease course before irreversible damage to the bladder may have occurred. In this study, re-analysis of publicly available transcriptomic datasets from diverse rodent models of obstruction identified tissue transcripts including Cthrc1, Grem1, Ltbp2 and Msn that were induced in response to injury. Candidate markers were validated experimentally in an independent model of neurogenic obstruction demonstrating time-dependent changes. Candidate markers were also attenuated with either surgical removal of obstruction or treatment with anticholinergic medication or inosine. Integrated analysis of tissue transcriptomics data and tissue and urine proteomics data from a model of neurogenic obstruction revealed significant concordance between markers observed in tissue and urine. Urinary proteomics analysis identified a statistically significant increase in MSN in patients with neurogenic bladder compared to unaffected controls. These findings identify tissue and urine biomarkers of both non-neurogenic and neurogenic obstruction that may reflect early changes in obstructive uropathy that could be monitored in a non-invasive manner.

BACKGROUND:Interstitial cystitis/bladder pain syndrome (IC/BPS) is a poorly understood and underdiagnosed syndrome of chronic bladder/pelvic pain with urinary frequency and urgency. Conflicting data exist regarding associated phenotypes, and little is known of its genetic aetiology. METHODS:We conducted a retrospective case-control analysis of electronic medical record (EMR) and retrospective case-control analysis of exome sequencing (ES) to identify phenotypes related to and rare variant risk factors for IC/BPS. Retrospective EMR data were collected from a national network of research sites in eMERGE-III. ES data were acquired from two research cohorts of individuals with IC/BPS and family members in addition to unaffected individuals stored at Columbia University Irving Medical Center. We determined odds ratios and P values for phenotypes associated with IC/BPS in eMERGE, odds ratios and P values for genes and gene-sets enriched for rare damaging variants in individuals with IC/BPS, and P values indicating overlap of genes enriched with rare damaging variants in individuals with IC/BPS with canonical gene sets. FINDINGS:Using the eMERGE data, we compared 193 individuals with IC/BPS to 99,482 individuals without and confirmed known phenotypic associations such as gastroesophageal reflux disease (odds ratio [OR] 2.3, P = 1.6 × 10-5, logistic regression) and irritable bowel syndrome (OR 8.5, P = 3.3 × 10-21, logistic regression). Notable associations, including anaphylactic shock (OR 8.8, P = 1.3 × 10-11, logistic regression), intervertebral disc disorders (OR 2.6, P = 2.6 × 10-6, logistic regression), and laxity of ligament or hypermobility syndrome (OR 15.3, P = 2.0 × 10-5, logistic regression), were detected. In an exome ultra-rare variant gene-level collapsing analysis with 348 IC/BPS and 11,627 controls, no gene association reached study-wide statistical significance. Gene-set analyses extended the previously reported association with ATP2C1 and ATP2A2 (OR, 7.4; 95% CI, 1.6-26.4; Padjusted = 0.033, Cochran-Mantel-Haenszel test [CMH]), implicated in Mendelian desquamating skin disorders but did not provide evidence for other proposed pathogenic pathways. Pathway analysis detected associations with "anaphase-promoting complex-dependent catabolic process" (P = 6.2 × 10-6, Fisher's exact tests [FET]), the "regulation of MAPK cascade" (P = 5.5 × 10-6, FET) and "integrin binding" (P = 1.1 × 10-9, FET). INTERPRETATION:Individuals with IC/BPS should be screened for related phenotypes, and previously unreported phenotypic associations with IC/BPS. Perturbations in biological networks for epithelial integrity and cell cycle progression in IC/BPS pathogenesis provide a roadmap for its future investigation. FUNDING:This publication was supported by the Centers for Disease Control and Prevention of the U.S. Department of Health and Human Services (HHS) as part of a financial assistance award totaling $2,400,000 with 60 percent funding from the CDC/HHS (U01DP006634-01). The contents are those of the author(s) and do not necessarily represent the official views of, nor are they endorsed by, the CDC/HHS or the U.S. Government (CAB). National Institutes of Health grant 1K08HG012374 (JEM). New York-Presbyterian Samberg Scholar (JEM). Thrasher Early Career Research Award (JEM). NIH/NIDDK CAIRIBU Interactions Core U24-DK-127726 (CAB). NICHD Boston Children's Hospital Intellectual and Developmental Disabilities Research Center Molecular Genetics Core Facility U54HD090255. NIDDK George M. O'Brien Urology Cooperative Research Centers Program U54DK104309 (AGG). The eMERGE Network was initiated and funded by NHGRI through the following grants: Phase III: U01HG8657 (Group Health Cooperative/University of Washington); U01HG8685 (Brigham and Women's Hospital); U01HG8672 (Vanderbilt University Medical Center); U01HG8666 (Cincinnati Children's Hospital Medical Center); U01HG6379 (Mayo Clinic); U01HG8679 (Geisinger Clinic); U01HG8680 (Columbia University Health Sciences); U01HG8684 (Children's Hospital of Philadelphia); U01HG8673 (Northwestern University); U01HG8701 (Vanderbilt University Medical Center serving as the Coordinating Center); U01HG8676 (Partners Healthcare/Broad Institute); and U01HG8664 (Baylor College of Medicine).

The use of glucagon-like peptide-1 receptor agonists (GLP-1RAs) has expanded rapidly for the management of diabetes and obesity. However, beyond glycemic control, GLP-1RAs have demonstrated consistent cardiometabolic benefits, including reductions in major adverse cardiovascular events, mediated through anti-inflammatory, endothelial, and metabolic mechanisms. Cardiac surgery induces a profound physiological stress response characterized by systemic inflammation, ischemia-reperfusion injury, endothelial dysfunction, and metabolic derangements. Despite this strong mechanistic overlap, the role of GLP-1RAs in the perioperative cardiac surgical setting remains incompletely understood. This review endeavors to synthesize current mechanistic and clinical evidence and evaluate the potential role of GLP-1RAs in enhancing myocardial resilience during cardiac surgery. GLP-1 signaling targets multiple pathways implicated in perioperative myocardial injury. GLP-1RAs reduce epicardial adipose tissue activity and inflammatory cytokine signaling associated with postoperative atrial fibrillation. In ischemia-reperfusion injury, GLP-1 signaling reduces oxidative stress, inflammation, and cardiomyocyte cell death. Additionally, these agents improve endothelial function through nitric oxide-mediated vasodilation and modulation of mitogen-activated protein kinases signaling, suggesting a role in mitigating cardiopulmonary bypass-associated microvascular dysfunction. GLP-1RAs also enhance perioperative metabolic stability by improving glycemic control and reducing insulin requirements. However, perioperative use is complicated by the associated risk of delayed gastric emptying and aspiration risk. GLP-1RAs demonstrate strong biological plausibility for improving myocardial resilience during cardiac surgery. However, clinical evidence in surgical patients remains limited, and definitive benefit has not been fully established. Prospective, cardiac-surgery-specific studies are needed to determine whether mechanistic advantages translate into measurable improvements perioperatively and in the long term.

Myeloperoxidase (MPO)-induced oxidative stress plays an important role in the pathogenesis of abdominal aortic aneurysms (AAA). MPO protein released from activated inflammatory cells can circulate and be taken up into blood vessels, but the mechanisms that regulate vascular MPO uptake, and how this might impact abdominal aortic aneurysms (AAA) formation, are poorly understood. Given that MPO utilizes hydrogen peroxide (H2O2) to generate the oxidant hypochlorous acid (HOCl), and that Nox4 is a major producer of vascular H2O2, we hypothesized that vascular Nox4 promotes MPO uptake to cooperate in AAA formation. We found that aortic MPO uptake along with Nox4 expression and H2O2 levels were significantly increased in angiotensin II (AngII)-induced AAA mice. Increased aortic MPO uptake was also confirmed by ex vivo incubation of AngII- or calcium chloride (CaCl2)-treated aorta. Notably, global deletion of Nox4 prevented AngII-induced aortic MPO uptake ex vivo, while Nox4 KO mice were protected against AngII-induced AAA formation. Furthermore, overexpression of human MPO by liver-specific AAV in MPO KO mice increased circulating MPO levels and aortic MPO accumulation while promoting AAA formation. Vascular Nox4 expression contributes to aortic MPO uptake, providing a novel mechanistic linkage whereby MPO and Nox4 cooperate to promote AAA.

Biological systems comprise diverse, interconnected cell types whose functional dynamics and molecular identities are tightly coupled, yet difficult to capture simultaneously at high spatiotemporal resolution. Electrophysiology provides real-time measurements of cellular activity but with limited molecular context, whereas transcriptomics profiles gene expression without dynamic physiological readouts. Here, we introduce in situ graphene-sequencing, a platform that integrates chronic electrophysiology with imaging-based, spatially resolved transcriptomics (STARmap). The system combines stretchable mesh nanoelectronics for long-term, single-cell-level interfacing with transparent graphene/poly(3,4-ethylenedioxythiophene) polystyrene sulfonate electrodes, enabling seamless integration of electrical recording and optical imaging. By coupling electrophysiology with STARmap, the platform enables multimodal analysis of heterogeneous tissue microenvironments. We demonstrate in situ graphene-sequencing by charting multimodal profiles of human-induced pluripotent stem cell-derived cardiomyocyte and endothelial cell co-cultures, examining how spatial heterogeneity is associated with electrophysiological activity and gene expression. This approach provides an integrative framework for studying how tissue microenvironments shape cell behavior and molecular states.

BACKGROUND:Stroke remains a leading cause of death and disability, underscoring the urgent need for treatments that enhance recovery. GDF11 (growth differentiation factor 11), a member of the TGF-beta (transforming growth factor-beta) superfamily, is a circulating protein involved in cellular development and tissue repair. GDF11 has gained attention for its potential regenerative properties in aging and disease contexts, making it a candidate for stroke recovery therapies.METHODS:The therapeutic benefits of rGDF11 (recombinant GDF11) were evaluated using a rat ischemic stroke model, in which focal cerebral infarcts were induced in 8- to 10-week-old young adult male Sprague-Dawley rats by permanently occluding the proximal right middle cerebral artery. Rats received single or multiple doses of rGDF11 (0.1-4 mg/kg) or vehicle from 24 to 72 hours post-injury. Sensorimotor functions were evaluated, and brain and serum samples were examined to determine the mechanisms of action and identify biomarkers, using immunofluorescence, target-specific ELISAs, and an aptamer-based proteomics platform.RESULTS:We confirmed rGDF11 activity in vitro and in established in vivo mouse models of cardiac hypertrophy and glucose metabolism and assessed the efficacy of rGDF11 treatment in 6 preclinical stroke studies using independent Contract Research Organizations, with all study animals and treatment groups blinded. All 6 studies revealed consistent improvement in sensorimotor outcomes with rGDF11. rGDF11-treated rats showed increased cortical vascularization and radial glia in the ventricular zone. Serum analysis revealed that rGDF11 caused dose-dependent decreases in CRP (C-reactive protein) and identified novel pharmacodynamic biomarkers and pathways associated with potential mechanisms of action of rGDF11.CONCLUSIONS:These results demonstrate that systemically delivered rGDF11 enhances neovascularization, reduces inflammation, promotes neurogenesis, and improves sensorimotor function post-injury in a rat model of ischemic stroke. More importantly, these data define an optimized and clinically feasible rGDF11 dosing regimen for therapeutic development in ischemic stroke and identify a panel of candidate pharmacodynamic and mechanistic biomarkers to support clinical translation.

Circulating Growth Differentiation Factors 11 and 8 (GDF11/8) exist in both latent and active forms, and it is unclear if specific forms can predict disease outcomes. Our data suggest that a dual-specific aptamer selectively binds GDF11/8 after prodomain activation. In 11,609 patients at risk for future cardiovascular events, low dual-specific aptamer-detected GDF11/8 levels strongly predicted adverse outcomes, including cardiovascular events (HR = 0.43, p = 9.1 × 10⁻⁶³) and all-cause mortality (HR = 0.33, p = 4.8 × 10⁻⁴⁰). Use of selective aptamers suggested that results observed with the dual-specific aptamer for cardiovascular and mortality risk replicated with a GDF8 aptamer although with a smaller effect size. In a second cohort of 4110 individuals (ARIC), low dual-specific aptamer-detected GDF11/8 levels also predicted increased 8 year dementia risk (HR = 0.66, p = 0.00148). Our findings reveal that activation of GDF11/8 may be a factor in future aging-related cardiovascular and cognitive decline.

Context and objectives. To explore the feasibility of implementing the joint guideline on integrative medicine for pain management in oncology, published by the Society for Integrative Oncology (SIO) and the American Society of Clinical Oncology (ASCO), for integrative oncology (IO) services in supportive and palliative care. Methods. A qualitative research methodology was co -designed by the SIO-ASCO guideline committee, with the Society for Complementary Medicine, Israel Medical Association (IMA). A questionnaire with five open-ended questions exploring barriers and enablers to implementing the guideline was distributed to chairs and board members of nine IMA-affiliated medical societies; four deans of Israeli medical schools; and nurses from the Israeli Society for Oncology Nursing. Respondent narratives were qualitatively analyzed using ATLAS.Ti software for systematic coding. Results. Questionnaires were completed by 52 physicians and nurses from medical oncology, hematology, gynecological oncology, pediatric oncology, palliative medicine, pain, family medicine, internal medicine, and integrative medicine. The SIOASCO guidelines were endorsed by nine IMA-affiliated societies. The domains identified included the importance of guideline implementation in clinical practice; barriers and facilitators to implementation; practical aspects required for this implementation (e.g., IO training); clinical indications for referral; budget -related issues; and clinical and administrative models enabling practical implementation of the guideline. Conclusion. We found across-the-board consensus among the nine IMA-affiliated societies supporting the current guideline. This, while identifying potential facilitators and barriers in order to address the implementation of the SIO-ASCO guideline recommendations. Published by Elsevier Inc. All rights reserved.

Purpose:Bladder exstrophy (BE) poses challenges both during the surgical repair and throughout follow-up. In 2013, a multi-institutional BE consortium was initiated, which included utilization of unified surgical principles for the complete primary repair of exstrophy (CPRE), real-time coaching, ongoing video capture and review of video footage, prospective data collection, and routine patient data analysis, with the goal of optimizing the surgical procedure to minimize devastating complications such as glans ischemia and bladder dehiscence while maximizing the rate of volitional voiding with continence and long-term protection of the upper tracts. This study reports on our short-term complications and intermediate-term continence outcomes. Materials and Methods:A single prospective database for all patients undergoing surgery with a BE epispadias complex diagnosis at 3 institutions since February 2013 was used. For this study, data for children with a diagnosis of classic BE who underwent primary CPRE from February 2013 to February 2021 were collected. Data recorded included sex, age at CPRE, adjunct surgeries including ureteral reimplantations and hernia repairs at the time of CPRE, osteotomies, and immobilization techniques, and subsequent surgeries. Data on short-term postoperative outcomes, defined as those occurring within the first 90 days after surgery, were abstracted. In addition, intermediate-term outcomes were obtained for patients operated on between February 2013 and February 2017 to maintain a minimum follow-up of 4 years. Outcomes included upper tract dilation on renal and bladder ultrasound, presence of vesicoureteral reflux, cortical defects on nuclear scintigraphy, and continence status. Bladder emptying was assessed with respect to spontaneous voiding ability, need for clean intermittent catheterization, and duration of dry intervals. All operating room encounters that occurred subsequent to initial CPRE were recorded. Results:CPRE was performed in 92 classic BE patients in the first 8 years of the collaboration (62 boys), including 46 (29 boys) during the first 4 years. In the complete cohort, the median (interquartile range) age at CPRE was 79 (50.3) days. Bilateral iliac osteotomies were performed in 89 (97%) patients (42 anterior and 47 posterior). Of those undergoing osteotomies 84 were immobilized in a spica cast (including the 3 patients who did not have an osteotomy), 6 in modified Bryant's traction, and 2 in external fixation with Buck's traction. Sixteen (17%) patients underwent bilateral ureteral reimplantations at the time of CPRE. Nineteen (21%) underwent hernia repair at the time of CPRE, 6 of which were associated with orchiopexy. Short-term complications within 90 days occurred in 31 (34%), and there were 13 subsequent surgeries within the first 90 days. Intermediate-term outcomes were available for 40 of the 46 patients, who have between 4 and 8 years of follow-up, at a median of 5.7 year old. Thirty-three patients void volitionally, with variable dry intervals. Conclusions:Cumulative efforts of prospective data collection have provided granular data for evaluation. Short-term outcomes demonstrate no devastating complications, that is, penile injury or bladder dehiscence, but there were other significant complications requiring further surgeries. Intermediate-term data show that boys in particular show encouraging spontaneous voiding and continence status post CPRE, while girls have required modification of the surgical technique over time to address concerns with urinary retention. Overall, 40% of children with at least 4 years of follow-up are voiding with dry intervals of > 1 hour.

Abstract Background Heart failure (HF) with preserved or mildly reduced ejection fraction includes a heterogenous group of patients. Reclassification into distinct phenogroups to enable targeted interventions is a priority. This study aimed to identify distinct phenogroups, and compare phenogroup characteristics and outcomes, from electronic health record data. Methods 2,187 patients admitted to five UK hospitals with a diagnosis of HF and a left ventricular ejection fraction ≥ 40% were identified from the NIHR Health Informatics Collaborative database. Partition-based, model-based, and density-based machine learning clustering techniques were applied. Cox Proportional Hazards and Fine-Gray competing risks models were used to compare outcomes (all-cause mortality and hospitalisation for HF) across phenogroups. Results Three phenogroups were identified: (1) Younger, predominantly female patients with high prevalence of cardiometabolic and coronary disease; (2) More frail patients, with higher rates of lung disease and atrial fibrillation; (3) Patients characterised by systemic inflammation and high rates of diabetes and renal dysfunction. Survival profiles were distinct, with an increasing risk of all-cause mortality from phenogroups 1 to 3 (p < 0.001). Phenogroup membership significantly improved survival prediction compared to conventional factors. Phenogroups were not predictive of hospitalisation for HF. Conclusions Applying unsupervised machine learning to routinely collected electronic health record data identified phenogroups with distinct clinical characteristics and unique survival profiles.