bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract Mo025: Noninvasive cardiac phenotyping in patients treated with chemo- and immunotherapy for breast cancer
Authors: Khashami Fatemeh , Dimitrov Ivan E , Fuetterer Maximilian , Kozerke Sebastian , Harrison Crystal , Huynh Mai , Park Jae Mo , Kovacs Zoltan , Malloy Craig , Henning Anke , Unni Nisha , Zaha Vlad 
Published: October 2024

Current breast cancer diagnosis and treatment protocols achieve survival rates of>80% at 10 years.However, long-term cancer survivors have>4-fold higher incidence of cardiovascular complications, including heart failure.Early potentially reversible changes that may underlie downstream irreversible loss of mechanical function are unknown.Therefore, we aimed to test the feasibility of a noninvasive cardiac phenotyping protocol in patients undergoing treatment for breast cancer with doxorubicin, without or with immune checkpoint inhibitors, including multiparametric proton cardiac magnetic resonance(CMR) imaging and novel metabolic carbon13MR.
A comprehensive set of studies included conventional 1HCMR,as well as metabolic 13CCMR using hyperpolarized(HP)[1-13C] pyruvate, following an oral glucose load. 13CCMR with HP[1-13C] pyruvate allows the detection of downstream metabolites of injected pyruvate within the myocardium: bicarbonate from mitochondrial oxidation and lactate from anaerobic cytosolic metabolism.HP[1-13C]pyruvate was prepared using dynamic nuclear polarization in a commercial polarizer.Imaging and spectroscopy(MRS) of hyperpolarized pyruvate was conducted using a 13C transmit/receive Helmholtz loop-pair coil on a 3Tscanner.13C data were acquired from a short-axis slice, ECG-triggered in end-systole. ProtonCMR images were analyzed using Circle, and 13CCMR images were analyzed using MATLAB. The left ventricular mid-myocardium and blood pool were segmented for metabolite quantitation.
Baseline cardiac studies were performed in a consecutive series of 25 women treated for breast cancer. Of these 14(56%) were Caucasian, 3(12%) were Hispanic, 5(20%) Black, and 3(12%) Asian, with ages ranging 46±11 years.Patients received standard-of-care treatment plans based on the tumor type: 11 patients were treated with dose-dense anthracycline and cyclophosphamide, and 14 also received pembrolizumab. The comprehensive baseline phenotyping protocol is planned to be repeated after standard of care therapy in all patients. Baseline data are presented in Table1, with values reported as mean±standard deviation.
Noninvasive cardiac phenotyping, including dynamic detection of metabolic substrate utilization is feasible,without showing significant adverse effects,and is well tolerated in a diverse group of patients.Completion of this protocol post-oncological therapy may allow to detect early changes in cardiac function due to chemo-and immunotherapy in susceptible patients.
Abstract Mo073: Elucidating the Role of Cardiac Radiotherapy on the Sympathetic Nervous System as a Treatment for Ventricular Tachycardia
Authors: Ng Sherwin , Rentschler Stacey 
Published: October 2024

Ventricular tachycardia (VT) is a dangerous arrhythmia that occurs in structurally and electrically heterogenous regions of the diseased heart, leading to sudden cardiac arrest and death if left untreated. One of the main drivers underlying the arrhythmogenic substrate is abnormal remodeling of the autonomic nervous system after cardiac injury, resulting in a heterogenous distribution of sympathetic innervation and subsequent ventricular arrhythmia. In patients with VT refractory to conventional therapy, noninvasive cardiac stereotactic body radiotherapy (SBRT) has emerged as a promising new treatment. Here, we investigated whether cardiac radiotherapy homogenizes the arrhythmogenic substrate through induction of cardiac sympathetic nerve innervation and activity in a closed-chest ischemia reperfusion murine model of ischemic heart failure.
Using single nucleus-RNA sequencing, we identified global transcriptomic changes in the left ventricle 6 weeks after 25 Gray (Gy) cardiac X-ray radiation. Notably, these changes included increased expression of neurotrophins such as brain derived neurotrophic factor, a growth factor essential for neuronal survival and development, in irradiated hearts compared to sham controls. Consequently, Western blot and immunofluorescence showed increased expression of the sympathetic neuronal markers tyrosine hydroxylase and neuropeptide Y at the scar border zone of irradiated mice. Similar immunofluorescence results were observed at the irradiated border zone from the explanted heart of a patient previously targeted with 25 Gy compared to a nontargeted remote region within the same heart. These findings suggest a novel role for radiation-induced remodeling of the sympathetic nervous system in the anti-arrhythmic response to SBRT.
Abstract Mo108: Sex-specific Impact of Glutathione Precursor-supplemented Diet on the Aging Mouse Heart
Authors: Angelini Aude , Garcia Marquez Grecia , Malovannaya Anna , Fiorotto Marta , Salzman Alexander , Jain Antrix , Trial JoAnn , Taffet George , Cieslik Katarzyna 
Published: October 2024

Common features of the aging heart include dysregulated metabolism, inflammation, and fibrosis, which can all contribute to diastolic dysfunction. Imbalanced oxidative stress can exacerbate each of these conditions, worsening the age-related cardiac defects.
Therefore, we hypothesized that increasing natural antioxidant defenses (glutathione) may favor a healthier cardiac aging phenotype. Twenty-one month-old mice were fed for 12 weeks with a diet supplemented in two glutathione precursors, Glycine and N-Acetyl Cysteine (GlyNAC) or with a control diet. Heart function was measured noninvasively and longitudinally at baseline and then every 6 weeks.
We found that GlyNAC reduced the age-associated increase in left atrial volume in old male, but not in old female mice ( 12% ± 3% in GlyNAC vs 20% ± 2% in control males (*); 11% ± 3% in GlyNAC vs 16% ± 3% in control females; * P=0.03). It also improved exercise performance in males. Subsequent unbiased cardiac proteome analysis identified that GlyNAC modestly changed global protein expression in males and pointed to the significant changes in two pathways: mitochondria-metabolism and extracellular matrix. Further analysis performed on mitochondrial extracts determined that GlyNAC diet led to an increase in Ndufb8, a subunit of the mitochondrial respiratory chain complex (1.76±0.3 in GlyNAC males vs 0.7±0.1 in control males, P=0.02). In the GlyNAC old male mitochondria, we found an improved catalytic activity for CPT1b (7.51±0.79 vs 3.74±0.32 in control males; P=0.002) and an increased CrAT activity (1.99±0.23 vs 1.06±0.08 in control males; P=0.005). Both enzymes are involved in fatty acid metabolism. Hearts from GlyNAC-fed old males exhibited enrichment in Fmod, a protein that can inhibit collagen fibril formation (1.08±0.03 vs 0.89±0.05, P=0.01), possibly reducing extracellular matrix stiffness. In females, the expression or enzymatic activities of these proteins were not affected by the GlyNAC-supplemented diet.
In summary, our study supports the concept that aged male and female hearts exhibit basic phenotypical differences that may affect the response to interventions. These observations may have direct relevance in cardiac gerontology.
Abstract Mo134: Restoring NaV1.5 Mutant Functionality in Arrhythmia with ManNAc Supplementation
Authors: Tarantino Adriana , Melgari Dario , Lavota Ivana , Rota Paola , Frosio Anthony , Rivolta Ilaria , Pappone Carlo , Anastasia Luigi 
Published: October 2024

The SCN5A gene encodes the human cardiac sodium channel NaV1.5, essential for cardiac excitability and action potential propagation. Mutations in SCN5A are linked to various cardiac disorders, including Brugada Syndrome (BrS), typically leading to channel loss-of-function. Understanding alterations in NaV1.5 expression and sodium current density is vital for comprehending arrhythmogenesis and formulating therapeutic strategies.
Post-translational modifications, especially sialylation, significantly impact channel functionality. We previously demonstrated that BrS patients show decreased protein sialylation, correlating with reduced sodium channel activity. This study aimed to investigate sialic acid's role in regulating NaV1.5 activity, testing if sialylation induction via mannosamine (ManNAc) supplementation could restore channel activity in-vitro. Preliminary tests with exogenous sialidases and ManNAc supplementation affirmed our hypothesis.
We examined ManNAc's effect on NaV1.5 mutants common in BrS, which typically exhibit partial functional loss. We overexpressed mutations p.A344S, p.K1479A, and p.G1406R in HEK293A cells and measured sodium currents before and after ManNAc supplementation to stimulate sialic acid synthesis. ManNAc effectively restored sodium currents in mutants with intracellular and extracellular loop mutations. However, the p.1406G>A mutant, affecting the pore structure, showed no improvement, suggesting that sialic acid mainly influences channel membrane trafficking rather than direct glycosylation. This underscores the complexity of sialic acid's role and points to trafficking pathways as potential therapeutic targets. Notably, the treatment neither increased nor decreased sodium currents in wild-type NaV1.5 channels or in the CaV3.2 calcium channel, underscoring its specificity.
In summary, our findings demonstrate that ManNAc supplementation can selectively restore the function of certain NaV1.5 mutants without affecting wild-type channels, highlighting the potential of targeting sialylation pathways for SCN5A-related arrhythmia treatments. Future research should aim to unravel these mechanisms further, providing insights into novel treatments for SCN5A-related arrhythmias.
Abstract Mo139: PDE1, 3 and 4 Inhibition and GPCR Agonism in the Regulation of cAMP Signaling
Authors: Fitch Michael , Kelly Evan , Muller Grace 
Published: October 2024

Modulators of cardiac cyclic adenosine 3’5’-monophosphate (cAMP) and/or its effector protein kinase A (PKA) are used to treat heart disease. Elucidating the mechanisms of endogenous and pharmacological modulators of cAMP, including phosphodiesterase (PDE) inhibitors, is key to predicating alternative drug therapies for heart failure (HF). PDEs regulate confined cAMP/PKA signaling pathways, depending on PDE isoform and localization. PDE3 regulates the SR and sarcolemmal membrane cAMP pools, controlling calcium influx and efflux at these domains. PDE1 regulates sarcolemmal cAMP/PKA signaling. Despite these differences, inhibitors of either increase heart contractility. However, inhibition of PDE3 is pro-arrhythmic, unlike that of PDE1. The regulation of localized cAMP signaling is key to controlled regulation of cell function, with ramifications for HF, and which GPCR lies upstream of PDE1 remains unknown. We hypothesized that the three cAMP-hydrolyzing cardiac PDEs (1, 3, 4) that are found in the human heart would regulate distinct cAMP signaling pathways.
Using the cAMP biosensor EPAC-SH187, we performed fluorescence resonance energy transfer experiments in healthy guinea pig adult ventricular myocytes. Cells were treated with inhibitors of PDEs 1, 3, and 4 along with GPCR agonists isoproterenol, glucagon (gcg), and amthamine (amt), respectively for β-adrenergic, gcg and histamine H2 receptors at sub-maximal doses. Cell function and calcium data were obtained using IonOptix.
We first asked if PDEi would synergistically regulate pools of cAMP, and found that PDE4i does at pools of cAMP generated by beta-agonism. PDE3i regulates that generated by amt at the H2R, with comparable effects observed in simultaneous or prior H2R stimulation. The combination of these sub-saturating doses exerted strong inotropic and lusitropic effects in paced myocytes. In neither of these domains, PDE1i changed cAMP levels. However, PDE1i intriguingly attenuated the level of gcg-stimulated cAMP production, suggesting a feedback loop mechanism.
We conclude that PDEs 1, 3, and 4 regulate distinct pools of cAMP. Importantly, we demonstrate this in a species where the myocardial expression of these PDEs match that of humans as opposed to smaller rodent models.
Abstract Tu052: RPN6-Serine14 Phosphorylation by PKA Protects Against Systolic Overload-Induced Cardiac Remodeling and Heart Failure
Authors: Ahammed Md Salim , Wu Penglong , Yang Liuqing , Sternburg Jack , Liang Huiyun , Li Faqian , liu Jin , Wang Xuejun 
Published: October 2024

The ubiquitin-proteasome system is the main proteolytic pathway for quality control (PQC) and regulatory degradation of proteins in living cells. Systolic overload, as seen in hypertension and aortic stenosis, is a leading cause of heart failure (HF). Proteasome functional insufficiency is implicated in HF caused by systolic overload. Previous studies have established that Ser14-RPN6 phosphorylation (pS14-RPN6) mediates the activation of 26S proteasomes by protein kinase A. However, the pathophysiological significance of pS14-RPN6 in systolic overload remains to be established.
We hypothesize that pS14-RPN6 helps maintain proteostasis and protects the heart during systolic overload.
We observed a significant increase in myocardial pS14-RPN6 and ubiquitin conjugates in human HF of ischemic or non-ischemic etiologies (p=0.020, p=0.034) and similarly in wild type (WT) mice after 2 weeks of transverse aortic constriction (TAC) (p<0.0001, p=0.001).

To investigate the role of pS14-RPN6 in vivo, our lab created

Rpn6
S14A

(S14A) knock-in mice where Ser14-Rpn6 phosphorylation is blocked. Here we have compared the responses to TAC between WT and S14A mice.

We found that TAC-induced increases in myocardial proteasome peptidase activities were significantly attenuated, and accumulation of ubiquitin conjugates exacerbated in S14A mice (p<0.0001; p<0.0005). Serial echocardiography revealed that S14A mice displayed significantly greater left ventricular (LV) end-diastolic posterior wall thickness and LV mass to body weight ratios at 1- and 12-week post-TAC (p=0.024, 0.0003; p=0.005, 0.01), and lower ejection fraction at 12-week post-TAC than WT mice (p=0.035). S14A mice also showed greater heart weight to tibial length (TL) and ventricular weight to TL ratios at 1 and 12-week post-TAC (1-week, p=0.043, 0.039; 12-week, p=0.007, 0.006). Wheat germ agglutinin and picrosirius red staining indicated a greater cardiomyocyte cross-sectional area and cardiac fibrosis in 12-week post-TAC S14A mice vs. WT mice (p<0.0001; p=0.005).
These novel findings demonstrate compellingly that myocardial pS14-RPN6 helps maintain proteostasis, curtails cardiac hypertrophy and delays heart failure occurrence during systolic overload
Abstract Tu131: Counteracting Cardiac Ischemia and Reperfusion Injury: the role of Sialidase Neu3
Authors: Piccoli Marco , Coviello Simona , Borella Rossana , Lavota Ivana , Cirillo Federica , Ghiroldi Andrea , Pappone Carlo , Anastasia Luigi 
Published: October 2024

Coronary reperfusion procedures are crucial for restoring blood flow to the heart tissue after an acute myocardial infarction. However, they also lead to ischemia and reperfusion injury (IRI), which exacerbate the damage and promote heart failure. Despite the urgent need for cardioprotective strategies against IRI, none have been clinically implemented, emphasizing the need for a comprehensive understanding of the pathophysiology of IRI. Our research team found that sialidase Neu3, an enzyme responsible for the removal of sialic acid from glycosphingolipids, is modulated during IRI in vivo. Constitutive overexpression of Neu3 in rat cardiomyoblasts was shown to attenuate IRI through activation of the reperfusion injury salvage kinase (RISK) and HIF-1α signaling pathways.
To further investigate the role of Neu3 in promoting cardioprotection, in this study we developed an inducible Neu3 overexpression model in human cardiac cells and mice.
Inducible upregulation of Neu3 significantly improved cell resistance and reduced oxidative stress in AC16 cells exposed to IRI in vitro. These effects were attributed to Neu3-mediated maintenance of mitochondrial membrane potential, which was impaired in control cells. When looking at the upregulated genes exclusively in cells overexpressing the sialidase Neu3, RNAseq analysis revealed the predominant activation of MAP kinases typical of the RISK pathway.
We also generated, for the first time, αMHC-Cre/LSL-Neu3 mice overexpressing Neu3 in an inducible and cardiomyocyte-specific manner. These mice showed no significant differences in cardiac morphology and functionality compared to wild-type animals. However, the Neu3-overexpressing mice exhibited a significant reduction in infarct size and improved cardiac functionality after surgical induction of IRI.
These results suggest that Neu3 is a promising target for improving cardioprotection and attenuating the incidence and severity of myocardial infarction.
A comparative analysis of the sensitivity and BOLD contamination of the VASO response at 3 Tesla: ME-DEPICTING vs. ME-EPI readouts
Authors: Devi Ratnamanjuri , Lepsien Jöran , Mildner Toralf , Möller Harald E. 
Published: October 2024

Abstract
‘Non-BOLD fMRI’ data acquired at non-zero echo time (TE) suffer from contamination by the Blood Oxygenation Level Dependent (BOLD) signal due to the unavoidable signal decay caused by transverse relaxation. This contamination further reduces their already low inherent functional sensitivities and makes their correction essential. The Slice-Saturation Slab-Inversion Vascular Space Occupancy (SS-SI–VASO), for instance, cancels out BOLD contributions from VASO data, reflecting cerebral blood volume (CBV) changes, via a dynamic division approach. Alternatively, multi-echo (ME) data provide the possibility of extrapolating to TE=0. Acquisitions at very short TE would minimize the need for such corrections. The center-out EPI variant (‘DEPICTING’) is one such readout which allows for short TE. The ME 2D DEPICTING was compared here against a traditional ME 2D EPI for its sensitivity to functional changes in the VASO signal. The two BOLD-correction schemes were also evaluated. Clear differences in functional sensitivity were observed for the uncorrected VASO data obtained from the first echo, TE1, of the two readouts. VASO data corrected by ME extrapolation were, however, found to be almost identical in their sensitivity for detecting CBV changes for both readouts. An excessively high increase in VASO signal sensitivity observed with the dynamic division correction for both readouts revealed a near-perfect linear dependence on TE of VASO signal changes. This could be attributed to the substantial intravascular BOLD contributions at 3 T. In the present data, extravascular ΔR2* fraction was found to be around ~50–60%. ME extrapolation is, hence, recommended to avoid overestimation of functional CBV changes at commonly used TEs.
Diurnal Changes in Cloud Cover in Eastern Gabon and Their Impacts on Energy Balance, Light Availability, and Water Demand: A Case Study of the 2022 Dry Season
Authors: Magnan Martin , Philippon Nathalie , Moron Vincent , Mariscal Armand , Liandrat Olivier 
Published: October 2024

Abstract
Western central Africa is atypical of the equatorial domain as the main dry season is cloudier than the rainy seasons. To understand this cloud cover’s diurnal evolution, we set up an infrared camera and acquired measurements of the total cloud cover fraction (TCF) and cloud optical depth at Bambidie, Gabon (0°44′30.5″S, 12°58′12.4″E), from May to October 2022. Diurnal variations in TCF can be summarized into four types, mostly discretized through the timing and duration of clouds clearing in the afternoon [early afternoon clearing (EaC), late afternoon clearing (LaC), and clear night (CNi)], while one type [no clearing (NoC)] shows overcast conditions all day long. Meteorological measurements show that NoC days record 50 W m−2 less shortwave incoming surface radiation, resulting in daytime temperatures 1°C lower than the seasonal norm, but 20% more diffuse light and 0.5 mm day−1 less ETo. Conversely, EaC days record 50 W m−2 more shortwave incoming surface radiation, leading to temperatures 1.5°C higher than the seasonal norm, but 40% more direct light. The larger water demand (0.5 mm day−1 more ETo) is partly compensated by more frequent rainfall at nighttime. The satellite estimates of Satellite Application Facilities for supporting Nowcasting and very short-range Forecasting (SAFNWC) capture the TCF variations for most of the four types well. They confirm that TCF is dominated by very low and low clouds whose dissipation in the afternoon and evolution into fractional and cumuliform convective clouds explains the clearings on EaC and LaC days. Satellite estimates also show that the four types of days extracted at Bambidie are representative of a larger-scale cloud cover evolution in western central Africa, with a west–east gradient in the timing of afternoon cloud dissipation.
Gene Therapy for Hearing Loss: A Review
Authors: Swain Santosh Kumar 
Published: October 2024

Background: Hearing impairment is the most prevalent sensory deficiency among humans. Scientists have been actively studying the genetic factors behind human hearing loss in recent years. A considerable proportion of hearing impairment cases can be due to genetic aetiologies. Numerous specific genes have been linked to inherited hearing impairments. At present, scientists globally are engaged in genomics-driven research and development related to hearing. Methods: The search for recent research articles on gene therapy for hearing loss was done with databases Scopus, PubMed, Medline and Google Scholar. This review article discusses the gene therapy for hearing loss. Results: Screening approaches, coupled with next-generation sequencing technologies, are being employed to analyse groups of individuals affected by hearing loss who are suspected to share common genetic mutations. This approach aims to accurately diagnose patients with hearing impairments. Conclusion: This review article discusses gene therapy techniques for the restoration or preservation of hearing, focusing on methods for delivering genes to target cells using viral or non-viral vectors. The review also covers technology targeted at creating gene therapy as a potential therapeutic option in the near future and emphasises recent developments in gene therapy for hearing loss.
Recommendations of the Queensland children’s gender service external evaluation and their implications for health policy in Australia
Authors: Spencer Jillian , Amos Andrew James , Clarke Patrick Hubert John 
Published: October 2024

Objective To review the evaluation process and the implications for Australian health policy of the 2024 external clinical service evaluation of the Queensland Children's Gender Service (QCGS) and its recommendations. Conclusions Failing to perform a systematic review of the relevant literature, and adhering to discredited and ideologically based guidelines, the Review made recommendations lacking evidentiary support that have major implications for Queensland and other Australian health services. The evaluation report’s recommendations reveal eight areas of concern about the clinic’s functioning.