Citations

Abstract Black/African American populations, globally, bear the greatest prostate cancer (CaP) burden compared to other racial/ethnic groups. Addressing CaP disparities in Black men is complex, requiring a patient-centered, community-centric and comprehensive approach. This study integrates iCCaRE Consortium findings and broader literature to address unmet needs in survivorship care. The iCCaRE Consortium implemented five complementary pilot studies using mixed-methods designs, including feasibility trials, qualitative research, and observational analyses across the United States and sub-Saharan Africa. Descriptive statistics, subgroup analyses, and qualitative thematic analyses were performed across these studies. Collectively, projects addressed multilevel determinants including social, behavioral, and biological drivers of disparities. Project 1 implemented a Virtual Reality Assistant (ViRA) across clinical and community settings, with ongoing evaluation in pragmatic trials. Project 2 showed strong patient preference for home-based cancer care. Project 3 enrolled demonstrated trends toward improved health-related quality of life. Project 4 identified key themes influencing survivorship experiences. Project 5 identified biological mechanisms linking stress, immune modulation, and symptom burden. The iCCaRE pilot projects demonstrate the feasibility and early impact of a consortium-based, transdisciplinary approach to addressing CaP disparities in Black men. These findings highlight the importance of integrating patient-centered interventions, community engagement, and biological insights to inform scalable strategies aimed at improving survivorship outcomes and advancing health equity. The iCCaRE Consortium demonstrates that a transatlantic, patient-centered, and multidisciplinary approach integrating social, clinical, and biological factors can generate scalable strategies to improve survivorship outcomes and advance equity in CaP care for Black men.

Abstract Background Immunosuppression (IS) is required in AAV-mediated gene therapy to maximize safety and efficacy, in part to mitigate potential hepatotoxicity and prevent immune-mediated loss of transgene expression. However, prolonged IS increases the risk of complications, including infections. MYBPC3-associated HCM patients have limited treatment options. MyPEAK-1 is a first-in-human trial to assess the safety and efficacy of TN-201, a gene replacement therapy, which was designed to address the underlying genetic cause of MYBPC3-associated HCM in symptomatic adults. Objective To describe the safety and refinement of the IS regimen and monitoring used during the dosing of Cohorts 1 and 2 in the MyPEAK-1 trial. Methods The dose-escalation study utilized two cohorts (n=3 each) receiving 3E13 vg/kg (Cohort 1) or 6E13 vg/kg (Cohort 2) of TN-201 as a single IV infusion. All patients received prophylactic prednisone (starting at 1 mg/kg, maximum 80 or 60 mg/day) and sirolimus (target trough level of 4–8 ng/mL). Prednisone was tapered over several weeks, with variable timing depending on safety laboratory results. The dose of prednisone and timing of sirolimus were adjusted to reduce IS burden in Cohort 2. Specifically, sirolimus was initiated earlier (Day -7 vs Day -3) and the maximum starting dose of prednisone was reduced (from 80 to 60 mg/day). Monitoring frequency was increased to weekly throughout the course of IS. An independent data safety monitoring board provided safety oversight. Results All six patients successfully completed the IS regimen. TN-201 was generally well-tolerated at both dose levels (follow-up >52 weeks and >12 weeks in Cohort 1 and 2, respectively). Adjustments to the IS regimen and monitoring during Cohort 1 facilitated a significantly shorter course of IS in Cohort 2, with a mean duration of prednisone use of 256 vs 81 days. Despite receiving a higher dose of TN-201, peak transaminase levels, reflecting liver inflammation, were lower in Cohort 2 than Cohort 1. There was no clinical TMA in either cohort. Mean sirolimus trough levels remained consistent between groups (7.2 vs 7.4 ng/mL). Increases in MyBP-C protein, decreases in circulating cardiac biomarkers, and a reduction in LV hypertrophy were observed during follow up. Conclusion Standardized adjustments to the prophylactic immunosuppressive regimen in the MyPEAK-1 trial successfully managed the immunogenicity of AAV9-based gene therapy. Cohort 2 patients required lower cumulative corticosteroid doses without compromising safety or cardiac transduction. These refinements enabled lower cumulative steroid exposure and shorter IS durations in the higher-dose cohort. These results suggest that individualized, protocol-driven IS is effective in controlling the immune response to TN-201 while supporting transgene expression, paving the way for continued investigation of this gene therapy clinical investigation in MYBPC3-associated HCM population.Corticosteroid duration and daily doseFor image description, please refer to the figure legend and surrounding text.

Abstract This brief report details the initial findings from a Phase 1b/2 trial of TN-201, an adeno-associated virus serotype 9 (AAV9) gene therapy for MYBPC3-associated hypertrophic cardiomyopathy (HCM), a condition with significant morbidity, increased risk of mortality, and no approved therapy for the majority of patients. TN-201 was well tolerated, and changes to the management of potential immune responses resulted in a shorter period of immunosuppression. These results show consistent transduction and expression of TN-201 in cardiomyocytes, corresponding with increases in MyBP-C levels, reductions or stabilization of cardiac biomarkers, and reductions in key measures of left ventricular (LV) hypertrophy.

AbstractIntroductionAcute myeloid leukemia (AML) remains one of the deadliest hematopoietic malignancies. A better understanding of the molecular biology governing AML may lead to improved risk stratification and facilitate the development of novel therapies. Proteins are responsible for much of the biology of cells. Several studies have examined the global proteome in bulk mononuclear cells (MNCs) from AML specimens, which are comprised a heterogenous population of cells at various stages of differentiation.MethodsGiven the potential impact of the nonleukemic cells on protein expression profiles, we applied an integrative proteogenomic approach utilizing next‐generation sequencing and mass spectrometry‐based proteomics to identify novel protein biomarkers in unsorted MNCs and viable leukemic blasts (VLBs) isolated from blood and bone marrow specimens obtained at the time of AML diagnosis.ResultsWe identified significant differences in protein expression between VLBs and MNCs. Subsequent studies (N = 27) focused on proteomic profiling of VLBs that identified novel candidate biomarkers associated with mutational genotypes and clinical outcome, some of which were recapitulated in an independent cohort of patients. Using mass spectrometry, we also detected mutated protein products, some of which were predicted via in silico analyses to be potential neoantigens amenable to adoptive immunotherapy. As previously described, analyses comparing transcript and protein expression showed an overall modest correlation between mRNA and protein dataset, but enriching for genes associated with mutations significantly improved the protein–RNA correlation.ConclusionTogether, the results provide insight into the biology of VLBs and demonstrate the gains derived from examining the proteome in addition to genome and transcriptome.

Background: Improvement in renal function (IRF) in acute decompensated heart failure is associated with adverse outcomes. The mechanisms driving this paradox remain undefined. Methods: Using the ROSE-AHF study (Renal Optimization Strategies Evaluation–Acute Heart Failure), 277 patients were grouped according to renal function, with IRF defined by a ≥20% increase (N=75), worsening renal function by a ≥20% decline (N=53), and stable renal function (SRF) by a <20% change (N=149) in estimated glomerular filtration rate between baseline and 72 hours. Three well-validated renal tubular injury markers, NGAL (neutrophil gelatinase-associated lipocalin), NAG (N-acetyl-β-d-glucosaminidase), and KIM-1 (kidney injury molecule 1), were evaluated at baseline and 72 hours. Patients were also classified by the pattern of change in these markers. Results: Patients with IRF had the lowest admission estimated glomerular filtration rate (IRF, 37 [28 to 51] mL/min per 1.73 m 2 ; worsening renal function, 43 [35 to 55] mL/min per 1.73 m 2 ; and SRF, 43 [32 to 55] mL/min per 1.73 m 2 ; P trend =0.032) but greater cumulative urine output (IRF, 8780 [7025 to 11 208] mL; worsening renal function, 7860 [5555 to 9765] mL; and SRF, 8150 [6325 to 10 456] mL; P trend =0.024) and weight loss (IRF, –9.0 [–12.4 to –5.3] lb; worsening renal function, –5.1 [–8.1 to –1.3] lb; and SRF, –7.1 [–11.9 to –3.2] lb; P trend <0.001) despite similar diuretic doses ( P trend =0.16). There were no differences in the relative change in NGAL, NAG, or KIM-1 between renal function groups ( P trend >0.19 for all). Patients with IRF had worse survival than patients with SRF (27% versus 54%; hazard ratio, 1.98 [1.10–3.58]; P =0.024). Conclusions: IRF during decongestive therapy for acute decompensated heart failure was not associated with improved markers of renal tubular injury and was associated with worsened survival, likely driven by the presence of greater underlying cardiorenal dysfunction and more severe congestion.

ObjectiveThis study aimed to compare the prevalence and incidence of vocal fold pathologies among undergraduate classical, musical theatre, and contemporary commercial music (CCM) students over two‐time points.MethodsThis study is part of a longitudinal investigation. Videostroboscopic examinations were rated, with consensus among three of four expert blinded raters confirming the presence of pathology. Association between genre of singer and the presence of pathology, interrater reliability, and intra‐rater reliability were calculated. Prevalence and incidence of pathologies were compared across genres.ResultsDuring first‐year evaluations, 32% of musical theatre, 18% of CCM, and 0% of classical students had vocal pathologies. The prevalence at third‐year evaluations showed 22% of classical, 39% of musical theatre, and 27% of CCM participants having vocal fold pathologies. The incidence of pathologies was 67% of musical theatre students compared to 22% of classical students and 27% of CCM students. The four raters demonstrated fair to moderate interrater agreement. Singing Voice Handicap Index‐10 scores were normal for CCM singers at both time points but elevated for musical theatre and classical singers.ConclusionNo classical singers were found to have pathology during first‐year evaluations, although CCM and musical theatre singers showed evidence of vocal fold pathologies. At third‐year evaluations, all three genres had an apparent increase in prevalence of pathologies. Implications of this study suggest that more time in the field and intense voice usage may lead to a greater risk of pathology for all singers, regardless of genre.Level of Evidence2 Laryngoscope, 133:2317–2324, 2023

Aims Remote monitoring of pulmonary artery pressure has reduced heart failure (HF) hospitalizations in chronic HF as elevation of pulmonary artery pressure provides information that can guide treatment. The venous system is characterized by high capacitance, thus substantial increases in intravascular volume can occur before filling pressures increase. The inferior vena cava (IVC) is a highly compliant venous conduit and thus a candidate for early detection of change in intravascular volume. We aimed to compare IVC cross‐sectional area using a novel sensor with cardiac filling pressures during experimental manipulation of volume status, vascular tone, and cardiac function. Methods and results Experiments were conducted in sheep to manipulate volume status (colloid infusion), vascular tone (nitroglycerin infusion) and cardiac function (rapid cardiac pacing). A wireless implantable IVC sensor was validated ex‐vivo and in‐vivo , and then used to measure the cross‐sectional area of the IVC. Right‐ and left‐sided cardiac filling pressures were obtained via right heart catheterization. The IVC sensor provided highly accurate and precise measurements of cross‐sectional area in ex‐vivo and in‐vivo validation. IVC area changes were more sensitive than the corresponding changes in cardiac filling pressures during colloid infusion ( p < 0.001), vasodilatation ( p < 0.001) and cardiac dysfunction induced by rapid pacing ( p ≤ 0.02). Conclusions Inferior vena cava area can be remotely and accurately measured in real time with a wireless implantable sensor. Changes in IVC area are more sensitive than corresponding changes in filling pressures following experimental volume loading and fluid redistribution. Additional research is warranted to understand if remote monitoring of the IVC may have advantages over pressure‐based monitors in HF.

Abstract Platinum-based DNA cross-linking agents are widely used anti-cancer drugs. Tumor resistance to platinum compounds is a major determinant of patient survival, including in high grade serous ovarian cancer (HGSOC). Remarkably, despite &gt;30 years of literature on platinum responses in human cancer, none of these findings is used clinically as a predictive biomarker to stratify patients for platinum resistance, nor exploited therapeutically to treat platinum-resistant disease. Thus, understanding mechanisms of platinum resistance is an urgent goal, both to identify predictive biomarkers of platinum response (to spare patients with platinum-resistant tumors futile platinum therapy) and to develop efficacious therapies for platinum-resistant disease. To better understand mechanisms underlying platinum resistance in HGSOC, we performed comprehensive, dynamic (+/-carboplatin), multiomic profiling of DNA, RNA, protein and post-translational modifications (phosphorylation, ubiquitination, acetylation) to identify the cellular networks that respond to platinum treatment and associate with platinum resistance in three HGSOC intra-patient cell line pairs (PEA1S/PEA2R, PEO1S/PEO4R, PEO14S/PEO23R). The cell line pairs were derived from ascites or pleural effusions (Langdon et al., 1988) from three patients both before (PEA1S, PEO1S, PEO14S) and after (PEA2R, PEO4R, PEO23R, respectively) their tumors became clinically platinum resistant (i.e., in vivo development of resistance). The molecular profiles revealed extensive responses to carboplatin and differential responses between platinum-sensitive and platinum-resistant cells. Higher oxidative phosphorylation and fatty acid oxidation (FAO) pathway expression were observed in the platinum-resistant cells, which was further validated in patient-derived xenograft (PDX) models. We show that pharmacologic inhibition or CRISPR knockout of CPT1A, which represents a rate limiting step of FAO, sensitize HGSOC cells to platinum. Thus, FAO, and CPT1A in particular, represent a candidate therapeutic target to overcome platinum resistance in HGSOC. Citation Format: Hong Wang, Dongqing Hugang, Shrabanti Chowdhury, Sara Savage, Richard Ivey, Jacob Kennedy, Jeffrey Whiteaker, Chenwei Lin, Xiaonan Hou, Catherine Huntoon, Uliana Voytovich, Zahra Shire, Qing Yu, Steven Gygi, Andrew Hoofnagle, Zachary Herbert, Anna Calinawan, Larry Karnitz, S. John Weroha, Scott Kaufmann, Bing Zhang, Pei Wang, Michael Birrer, Amanda Paulovich. Multiomic analysis identifies CPT1A and fatty acid oxidation as a potential therapeutic target in platinum-refractory high grade serous ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1426.

Abstract Although high-grade serous ovarian cancers (HGSOC) are highly chemosensitive with an 85% initial response rate to platinum-based chemotherapy, 15% of patients are “exceptional nonresponders,” with platinum-refractory tumors that remain stable or progress during treatment. Unfortunately, we have no predictive biomarkers to identify refractory patients up front, and they receive futile chemotherapy through which most patients become too ill to be eligible for clinical trials. Hence, no progress has been made in treating these deadly tumors. The goal of this study is to identify mechanisms of platinum refractoriness to: i) predict refractory HGSOCs up front and ii) identify potential new drug targets in refractory disease to point to desperately needed new therapeutic approaches. Of note, 80-90% of patients who are initially platinum responsive will relapse and develop platinum-resistant disease, and it is possible that findings in platinum-refractory tumors might also provide insights into platinum-resistant tumors. Our NCI Clinical Proteomic Tumor Analysis Consortium (CPTAC)-funded approach combines genomic and proteomic (“proteogenomic”) analyses of both preclinical models (0, 8, and 24 hours post-platinum exposure) and treatment-naïve human tumors. For preclinical models, we studied a well-characterized collection of patient-derived xenograft (PDX) models (10 sensitive, 10 refractory), as well as intrapatient HGSOC cell line pairs derived from patients before and after the development of platinum resistance. For the PDX models, proteogenomic profiling included RNASeq, WES, global proteomics, and phosphoproteomics at all 3 time points (0, 8, 24 hours). For cell line models (3 sensitive, 3 resistant), proteogenomic profiling was performed at all 3 timepoints (0, 8, 24 hours), and experiments were performed in complete biologic triplicate. Analyses included RNASeq, WES, global proteomics, phosphoproteomics, ubiquitin proteome, acetylated proteome, and pTyr. A large collection of 275 human HGSOCs (an approximate equal balance of platinum sensitive and refractory tumors) is currently undergoing proteomic profiling, and genomic profiles (WGS, RNASeq) will be performed on a subset. In parallel, we have performed a comprehensive review of 31 years of published work on platinum responses of human cancers, identifying ~700 genes implicated in the response and scoring each gene with respect to strength of the published evidence. Using a Bayesian approach, we are integrating the curated candidates from the literature with our empirical proteogenomic datasets to identify a candidate signature for detecting platinum-refractory disease prior to chemotherapy. We are also performing gene-regulatory network analysis to identify potential drivers of chemo response. NextGen, targeted, multiplex, multiple reaction monitoring mass spectrometry-based assays are being developed to quantify proteins in the signature for validation studies, using independent patient cohorts. This abstract is also being presented as Poster A62. Citation Format: Jacob J. Kennedy, Shrabanti Chowdhury, Sara R. Savage, Xiaonan Hou, Catherine J. Huntoon, Richard G. Ivey, Qing Yu, Chenwei Lin, Dongqing Huang, Lei Zhao, Uliana J. Voytovich, Regine M. Schoenherr, Zahra Shire, Steven J. Skates, Jeffrey R. Whiteaker, Andrew N. Hoofnagle, Samuel C. Mok, Bing Zhang, Larry M. Karnitz, S. John Weroha, Steven P. Gygi, Scott H. Kaufmann, Pei Wang, Michael J. Birrer, Amanda G. Paulovich. Proteogenomic approach to identify mechanisms of platinum refractoriness in high-grade serous ovarian cancers [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research; 2019 Sep 13-16, 2019; Atlanta, GA. Philadelphia (PA): AACR; Clin Cancer Res 2020;26(13_Suppl):Abstract nr PR02.