bluuebunny/crossref_metadata_2025 huggingface dataset:
Probing hidden leptonic scalar portals using the NA64 experiment at CERN
Authors: Ponten A. , Sieber H. , Oberhauser B. Banto , Crivelli P. , Kirpichnikov D. , Gninenko S. N. , Hösgen M. , Bueno L. Molina , Mongillo M. , Zhevlakov A.
Published: October 2024

In this study, we demonstrate the potential of the NA64 experiment at CERN SPS to search for New Physics processes involving $$e\rightarrow \mu $$

e
→
μ

transitions after the collision of 100 GeV electrons with target nuclei. A new Dark Sector leptonic portal in which a scalar boson $$\varphi $$
φ
could be produced in the lepton-flavor-changing bremsstrahlung-like reaction, $$eN\rightarrow \mu N\varphi $$

e
N
→
μ
N
φ

, is used as benchmark process. In this work, we develop a realistic Monte Carlo simulation of the NA64 experimental setup implementing the differential and total production cross-section computed at exact tree-level and applying the Weiszäcker–Williams phase space approximation. Using this framework, we investigate the main background sources and calculate the expected sensitivity of the experiment. The results indicate that with minor setup optimization, NA64 can probe a large fraction of the available parameter space compatible with the muon $$g-2$$

g
-
2

anomaly and the Dark Matter relic predictions in the context of a new Dark Sector leptonic portal with $$10^{11}$$

10
11

EOT. This result paves the way to the exploration of lepton-flavour-changing transitions in NA64.
Inverse muon decay in a circularly polarized laser field
Authors: Chahri R. , Jakha M. , Mouslih S. , Mekaoui Y. , Manaut B. , Taj S.
Published: October 2024

In this paper, we investigate the effect of a circularly polarized laser field on the inverse muon decay process [Formula: see text] in electroweak theory with the exchange of a boson vector [Formula: see text]. Our method accounts for the dressing of incident electron and scattered muon by introducing the first-order laser-matter interaction of perturbation theory and using the relativistic Dirac–Volkov formalism. We have analyzed the behavior of the total cross-section (TCS) with charged-current as a function of the center-of-mass energy and the laser field parameters, such as the number of photons exchanged, the laser field strength and frequency. We have found that the circularly polarized laser field significantly affects the inverse muon decay process by reducing the TCS. We have also shown that the photonic energy transfer envelopes are perfectly symmetric with respect to the number of photons exchanged and rapidly drop when the indices of the Bessel functions are close to their arguments.
MANAGERIAL CHALLENGES OF SOCIAL INCUBATORS FOCUSED ON SUBSISTENCE ENTREPRENEURS
Authors: DE SORDI JOSÉ OSVALDO , NELSON REED ELLIOT , DE ÁVILA PATRÍCIA BELCHIOR , DA SILVA CRISTIANE RODRIGUES , DE AZEVEDO MARCIA CARVALHO , OTRE MARIA ALICE CAMPAGNOLI
Published: October 2024

Although social incubators provide a variety of entrepreneurial support, little is known regarding their design, implementation, operation and management. The identification and characterization of the clients and stakeholders of social incubators is complicated by multiple definitions of entrepreneurship and multiple typologies of entrepreneurs. Their ventures are accompanied by strategic and tactical confusion about objectives and populations served. This study investigates the dynamics of incubator clients’ needs and attributes as they interact with the values and interests of other stakeholders in a social incubator focused on survival entrepreneurs. Our sampling was a medium sized mixed economy town in Brazil. Our thirteen-month ethnographic study analyzed the collective struggle to transcend the tensions between social and economic values and improve the lives of vulnerable populations. Central to this struggle is the incubator management’s unique humanistic ideology coupled with the search for realistic concrete results modulated by community and client attributes. Through our analysis of various interventions that occurred within the social incubator, we discuss the importance of getting to know the vulnerable to better manage social incubators that focus on subsistence entrepreneurship. These contents are valued when discussed in the context of the evolutionary phases (or trajectory) of the vulnerable in a social incubator from welcoming through training, to improvement and other phases, until citizens’ autonomy is achieved.
COPING AND RESILIENCE IN ENTREPRENEURS
Authors: LUGO MARIA V. , HAMDAN HASAN
Published: October 2024

The relationship between self-resilience, social resilience, coping and resilient coping is explored. A cross-sectional research design is employed. Survey respondents were recruited by panel owners in Centiment. A total of 381 entrepreneurs responded to the survey. Entrepreneurs self-identified themselves as members of each of the groups under study (White, African American and Hispanic). Results were stratified, analyzed and compared by ethnicity and gender. We found a statistically significant positive relationship between self-resilience and coping, and that coping mediates the relationship between self-resilience and resilient coping. The findings could help policymakers and community ecosystems to support the development of resiliency-related skills which could have important implications especially for those in disadvantaged circumstances.
PSYCHOLOGICAL CAPITAL OF THE SOCIAL ENTREPRENEUR AND ECONOMIC PERFORMANCE OF SOCIAL ENTERPRISES IN TUNISIA: THE MODERATING ROLE OF SOCIAL PERFORMANCE
Authors: HANA ABIDI , RIDHA BECHRI
Published: October 2024

Many researchers have investigated the reasons why some social entrepreneurs are more successful than others at leading businesses and fostering their growth in developed nations, but there have been few studies on the continent of Africa. This viewpoint is relevant to the study’s focus on Tunisia. This study analyzed the relationships between the psychological capital of social entrepreneurs and the performance of social enterprises. The purpose of this study was to examine the nexus between psychological capital, social performance and the economic performance of social enterprises. The study uses a quantitative approach based on questionnaires administered to 171 social entrepreneurs. Hypothesis testing was carried out using structural equation methods on PLS 4 software. The results confirm the positive effect of the social entrepreneur’s psychological capital on the economic performance of social enterprises. Social performance exerts a double positive effect on economic performance: A direct positive effect and an indirect positive effect by acting as a moderator on the relationship between the social entrepreneur’s psychological capital and the economic performance of social enterprises. The implication of the above findings is that psychological capital is a key determinant of the performance of enterprises. Thus, social entrepreneurs are encouraged to engage in activities that can boost their psychological capital.
EXPLORING DIGITAL MARKETING ADOPTION DYNAMICS IN PAKISTANI STARTUPS THROUGH THE TECHNOLOGY-ORGANIZATION-ENVIRONMENT (TOE) FRAMEWORK
Authors: AHMED ARSALAN , MAT NORIZAN
Published: October 2024

This study investigates the factors involved in digital marketing adoption among small and medium startups (SMSs) in Pakistan using the Technology-Organization-Environment (TOE) framework. Data were collected through an online survey from 409 startups based in Karachi, Pakistan, and structural equation modeling (SEM) was used for analysis. Results indicate SMSs prioritize internal capabilities and resources for digital marketing adoption over external factors. Key factors identified in digital marketing adoption include technology knowledge, compatibility and cost while the effect of technology complexity was found to be insignificant. Top management support and digital marketing orientation were also crucial, highlighting the importance of strategic leadership and a focused digital approach. These findings highlight the distinct characteristics of SMSs compared to established SMEs, providing insights for developing targeted strategies and regulations to support the startup ecosystem. The research contributes to understanding the unique challenges and factors influencing digital marketing adoption in startups, paving the way for better and effective support mechanisms.
Surprisingly Undecidable
Authors: Al-Suwailem Sami
Published: October 2024

Undecidability reflects a fundamental limit to logical reasoning that permeates formal analysis in diverse areas of natural and social sciences. We present an intuitive approach to understanding how undecidability may emerge endogenously in modeling a wide range of real-world problems. Not only does this allow for a better understanding of these problems, but it also provides a gateway for a holistic approach to rational decision-making.
Supplemental Figure 6 from Chemotherapy Enriches for Proinflammatory Macrophage Phenotypes that Support Cancer Stem-Like Cells and Disease Progression in Ovarian Cancer
Authors: Cruz Luisjesus S. , Robinson Mikella , Stevenson Denay , Amador Isabella C. , Jordan Gregory J. , Valencia Sofia , Navarrete Carolina , House Carrie D.
Published: October 2024

Analysis of ip CSCs and CCL2/MCP-1 treatment
Supplemental Figure 4 from Chemotherapy Enriches for Proinflammatory Macrophage Phenotypes that Support Cancer Stem-Like Cells and Disease Progression in Ovarian Cancer
Authors: Cruz Luisjesus S. , Robinson Mikella , Stevenson Denay , Amador Isabella C. , Jordan Gregory J. , Valencia Sofia , Navarrete Carolina , House Carrie D.
Published: October 2024

Carboplatin-induced secretory changes
Supplemental Figure 2 from Chemotherapy Enriches for Proinflammatory Macrophage Phenotypes that Support Cancer Stem-Like Cells and Disease Progression in Ovarian Cancer
Authors: Cruz Luisjesus S. , Robinson Mikella , Stevenson Denay , Amador Isabella C. , Jordan Gregory J. , Valencia Sofia , Navarrete Carolina , House Carrie D.
Published: October 2024

complementary co-culture experiments
Data from Chemotherapy Enriches for Proinflammatory Macrophage Phenotypes that Support Cancer Stem-Like Cells and Disease Progression in Ovarian Cancer
Authors: Cruz Luisjesus S. , Robinson Mikella , Stevenson Denay , Amador Isabella C. , Jordan Gregory J. , Valencia Sofia , Navarrete Carolina , House Carrie D.
Published: October 2024

Abstract
High-grade serous ovarian cancer remains a poorly understood disease with a high mortality rate. Although most patients respond to cytotoxic therapies, a majority will experience recurrence. This may be due to a minority of drug-resistant cancer stem-like cells (CSC) that survive chemotherapy and are capable of repopulating heterogeneous tumors. It remains unclear how CSCs are supported in the tumor microenvironment (TME) particularly during chemotherapy exposure. Tumor-associated macrophages (TAM) make up half of the immune population of the ovarian TME and are known to support CSCs and contribute to cancer progression. TAMs are plastic cells that alter their phenotype in response to environmental stimuli and thus may influence CSC maintenance during chemotherapy. Given the plasticity of TAMs, we studied the effects of carboplatin on macrophage phenotypes using both THP1- and peripheral blood mononuclear cell (PBMC)–derived macrophages and whether this supports CSCs and ovarian cancer progression following treatment. We found that carboplatin exposure induces an M1-like proinflammatory phenotype that promotes SOX2 expression, spheroid formation, and CD117+ ovarian CSCs, and that macrophage-secreted CCL2/MCP-1 is at least partially responsible for this effect. Depletion of TAMs during carboplatin exposure results in fewer CSCs and prolonged survival in a xenograft model of ovarian cancer. This study supports a role for platinum-based chemotherapies in promoting a transient proinflammatory M1-like TAM that enriches for CSCs during treatment. Improving our understanding of TME responses to cytotoxic drugs and identifying novel mechanisms of CSC maintenance will enable the development of better therapeutic strategies for high-grade serous ovarian cancer.

Significance: We show that chemotherapy enhances proinflammatory macrophage phenotypes that correlate with ovarian cancer progression. Given that macrophages are the most prominent immune cell within these tumors, this work provides the foundation for future translational studies targeting specific macrophage populations during chemotherapy, a promising approach to prevent relapse in ovarian cancer.
Delayed Distant Recurrence of a Uveal Melanoma 4 Decades after Enucleation
Authors: Eide Nils A. , Noer Agate , Jespersen Henrik , Jebsen Peter , Geisler Jürgen
Published: October 2024

Introduction: This report presents a case of an exceptionally delayed distant recurrence of a choroidal melanoma, occurring 4 decades after the enucleation of the affected eye. Case Presentation: In 1977, a 29-year-old man underwent enucleation for a choroidal melanoma. At the age of 68 years, he was diagnosed with advanced prostate cancer. Although the metastatic prostate cancer responded to treatment, a persistent lung lesion warranted further examination. A lung biopsy, somewhat surprisingly, confirmed the presence of melanoma metastasis, 4 decades after the enucleation. The cells were positive for Melan-A, while no BRAF mutation was identified. Two years later, new lesions appeared in the liver, and CT showed progression with multiple new sites. A liver biopsy revealed again melanoma recurrence, and its choroidal origin was verified by the presence of a GNA11 mutation. The patient underwent radiation therapy for the lung and liver lesions, followed by immunotherapy. However, the patient died 11 months after the recurrence in the liver. In this case report, the micrometastatic melanoma cells appear to have remained dormant for an extended period, before the patient’s treatment in 1977, but the reason for the late reactivation from the dormant state remains unclear. Conclusion: The recurrence of a choroidal melanoma is substantiated by the histopathological and molecular analyses, including the finding of a GNA11 mutation. This case exemplifies a remarkably delayed distant recurrence of a choroidal melanoma, which manifested clinically 40 years following enucleation.
Application of the Clinical Outcomes, Healthcare Resource Utilization, and Related Costs Model in Chronic Obstructive Pulmonary Disease Patients
Authors: Alvarez-Martinez Carlos J. , Vélez Jorge , Goñi Clara , Sánchez-Covisa Joaquín , Juárez-Campo Mónica , Escudero Luciano , Bernal José L. , Rosillo Nicolás , Hernández Miguel , Bueno Héctor
Published: October 2024

Introduction: The change in prevalence and management of chronic obstructive pulmonary disease (COPD) led to changes in outcomes and costs. We aimed to assess current clinical outcomes, resource utilisation, and costs in COPD. Methods: Retrospective, observational study of a cohort of consecutive COPD patients who visited the emergency department (ED) of a large tertiary hospital in 2018. The study measured baseline characteristics, 30-day and 1-year mortality, readmission, re-ED visit rates, and costs using the Clinical Outcomes, HEalthcare REsource utilisatioN, and relaTed costs (COHERENT) model, validated for heart failure. This model, featuring a colour graphic system, tracks time spent in different clinical situations (home, ED, hospital), considering vital status, healthcare resource use, and related costs. Results: In 2018, 2,384 patients with a primary COPD diagnosis visited the ED. The average age was 76 years, with 40% women. Observed mortality rates were 7.6% in-hospital, 8.5% at 30 days, and 23.4% at 1 year. The readmission rates were 9.9% and 36.1%, respectively. The cohort’s 1-year cost was approximately EUR 14.6 million (USD 15.95 million), with a median cost per patient of EUR 3,298 (USD 3,603.96). Hospitalisation incurred the highest costs, with initial hospitalisation and readmissions accounting for 44.7% and 42.6% of expenditures, respectively. Conclusion: One-year mortality and readmission rates for patients with COPD visiting the ED remain high with a significant economic impact on the health system. This burden justifies special programs to improve their care.
The Role of Advanced Glycation End Products in Saphenous Vein Graft Failure
Authors: Akgümüş Alkame , Boyraz Bedrettin , Balun Ahmet
Published: October 2024

Objective: We aimed to investigate the relationship between advanced glycation end product (AGE) levels in patients with saphenous vein graft (SVG) failure and in patients without SVG failure. Subjects and Methods: In our study, 55 patients with a history of previous coronary artery bypass grafting (CABG) surgery, who subsequently underwent coronary angiography for any reason and were found to have either SVG occlusion or significant lesions, were included as study patients. Additionally, 55 patients who have had CABG surgery without SVG failure for at least 1 year served as the control group. AGE values of the patients were measured using the skin autofluorescence method. Results: In our study results, we observed a significant difference in AGE levels between the two groups of patients with similar demographic characteristics (SVG failure groups AGE 3.2 [2.8–3.6] vs. control groups AGE 2.4 [2.1–2.7] p < 0.001). In the receiver operating characteristic curve analysis, we determined the ability of AGE levels to detect SVG failure with an area under the curve of 0.869. We found that in patients with AGE >3, it could detect SVG failure with a sensitivity of 70.9% and a specificity of 87.3%. Conclusions: Our results demonstrate that AGE levels can predict SVG failure risk inexpensively, easily, and quickly.
Patent Foramen Ovale and Oxygenation in Patients with Cystic Fibrosis
Authors: Belt Haley , Enakpene Evbu O. , Jensen Judy L. , Moe Alice P. , Carveth Holly , Cahill Barbara C. , Hatton Nathan , Liou Theodore G. , Tandar Anwar
Published: October 2024

Introduction: Patent foramen ovale (PFO) affects about 25% of the population. We studied outcomes in cystic fibrosis (CF). Methods: We conducted a case-control study of patients with CF (PwCF) and age- and sex-matched controls who underwent agitated saline contrast (bubble) echocardiography, 1998–2020. We assessed PFO impacts using linear, logistic, quasi-Poisson, and Cox proportional hazards models. Result: Fifty-nine of 64 PwCF and 88 of 93 controls underwent bubble studies to investigate unexplained hypoxemia or dyspnea. PwCF had higher mean pulmonary artery pressure (PAP: 6.9 mm Hg, 95% confidence interval [CI] = 2.35–11.4), reduced tricuspid annular plane systolic excursion (TAPSE: −3.78 mm, CI = −5.64 to −1.93) and similar right ventricular diastolic sizes. Without hypoxemia, the PFO incidence was similar between PwCF and controls; with hypoxemia, PFO was more common in CF (odds ratio = 5.00, CI = 1.32–19.0). In CF, oxygen supplementation occurred at a percent-predicted forced expiratory volume in 1 s (FEV1%), 22.5 points higher with PFO. Adjusted for FEV1%, PFO was associated with 0.59 more prior-year pulmonary exacerbations (CI = 0.20–0.98) and shorter time to next exacerbation (hazard ratio = 1.86, CI = 1.06–3.26). Associations between PFO and hypoxemia or exacerbations were insensitive to PAP, TAPSE, and CF transmembrane regulator protein modulator treatments. PFO was not associated with CF time to death or lung transplantation (median 1.87 years) adjusted for age, sex, FEV1%, and prior-year exacerbation counts. Conclusion: PFO in CF is associated with hypoxemia at higher FEV1% and more pulmonary exacerbations but not survival.
COVID-19 Is a Coronary Artery Disease Risk Equivalent and Exhibits a Genetic Interaction With ABO Blood Type
Authors: Hilser James R. , Spencer Neal J. , Afshari Kimia , Gilliland Frank D. , Hu Howard , Deb Arjun , Lusis Aldons J. , Wilson Tang W.H. , Hartiala Jaana A. , Hazen Stanley L. , Allayee Hooman
Published: October 2024

BACKGROUND:

COVID-19 is associated with acute risk of major adverse cardiac events (MACE), including myocardial infarction, stroke, and mortality (all-cause). However, the duration and underlying determinants of heightened risk of cardiovascular disease and MACE post–COVID-19 are not known.

METHODS:

Data from the UK Biobank was used to identify COVID-19 cases (n=10 005) who were positive for polymerase chain reaction (PCR
+
)-based tests for SARS-CoV-2 infection (n=8062) or received hospital-based
International Classification of Diseases version-10 (ICD-10
) codes for COVID-19 (n=1943) between February 1, 2020 and December 31, 2020. Population controls (n=217 730) and propensity score—matched controls (n=38 860) were also drawn from the UK Biobank during the same period. Proportional hazard models were used to evaluate COVID-19 for association with long-term (>1000 days) risk of MACE and as a coronary artery disease risk equivalent. Additional analyses examined whether COVID-19 interacted with genetic determinants to affect the risk of MACE and its components.

RESULTS:

The risk of MACE was elevated in COVID-19 cases at all levels of severity (HR, 2.09 [95% CI, 1.94–2.25];
P
<0.0005) and to a greater extent in cases hospitalized for COVID-19 (HR, 3.85 [95% CI, 3.51–4.24];
P
<0.0005). Hospitalization for COVID-19 represented a coronary artery disease risk equivalent since incident MACE risk among cases without history of cardiovascular disease was even higher than that observed in patients with cardiovascular disease without COVID-19 (HR, 1.21 [95% CI, 1.08–1.37];
P
<0.005). A significant genetic interaction was observed between the
ABO
locus and hospitalization for COVID-19 (
P
interaction
=0.01), with risk of thrombotic events being increased in subjects with non-O blood types (HR, 1.65 [95% CI, 1.29–2.09];
P
=4.8×10
−5
) to a greater extent than subjects with blood type O (HR, 0.96 [95% CI, 0.66–1.39];
P
=0.82).

CONCLUSIONS:

Hospitalization for COVID-19 represents a coronary artery disease risk equivalent, with post–acute myocardial infarction and stroke risk particularly heightened in non-O blood types. These results may have important clinical implications and represent, to our knowledge, one of the first examples of a gene-pathogen exposure interaction for thrombotic events.
Home-Time, Mortality, and Readmissions Among Patients Hospitalized With Heart Failure: A Baseline Prior to IMPLEMENT-HF
Authors: Tang Amber B. , Solomon Nicole , Chiswell Karen , Greene Stephen J. , Yancy Clyde W. , Jessup Mariell , Kittleson Michelle , Butler Javed , Sweitzer Nancy K. , Goldberg Lee R. , Lindenfeld Jo-Ann , Lewis Eldrin F. , Peterson Pamela N. , Paul Sara , Serdynski Lynn Mallas , Rutan Christine , Congdon Michelle , Cherkur Sruthi , Fonarow Gregg C.
Published: October 2024

BACKGROUND:

Home-time is an emerging, patient-centered outcome that represents the amount of time a patient spends alive and outside of health care facility settings, comprising of hospitals, skilled nursing facilities, and acute rehabilitation centers. Studies evaluating home-time in the context of heart failure are limited, and the impact of quality improvement interventions on home-time has not been studied.

METHODS:

Medicare beneficiaries aged 65 years or older who were hospitalized for heart failure in the Get With the Guidelines-Heart Failure registry between 2019 and 2021 were included. Postdischarge home-time, mortality, and readmission rates at 30 days and 1 year were calculated with the goal of establishing baseline metrics before the initiation of IMPLEMENT-HF, a multicenter quality improvement program aimed at improving heart failure management.

RESULTS:

Overall, 66 019 patients were included across 437 sites. Median 30-day and 1-year home-time were 30 (18–30) and 333 (139–362) days, respectively. Only 22.1% of patients experienced 100% home-time in the year after discharge. Older patients spent significantly less time at home, with a median 1-year home-time of 302 (86–359) compared with 345 (211–365) days in patients over 85 and those between 65 and 74 years old, respectively (
P
<0.001). Black patients also experienced the least amount of home-time with only 328 (151–360) days at 1-year follow-up. Rates of heart failure readmission and all-cause mortality 1-year post-discharge were high at 29.8% and 37.0%, respectively.

CONCLUSIONS:

In this contemporary multicenter cohort, patients hospitalized with heart failure spent a median of 91.2% of their time in the year after discharge alive and at home, largely driven by high mortality rates. These findings serve as a preimplementation baseline for IMPLEMENT-HF, which will evaluate the impact of targeted heart failure initiatives on home-time and other clinical outcomes.
Abstract Mo001: Inhibition of TAOK1-mediated Cardiomyocyte Death Attenuates Doxorubicin-Induced Cardiotoxicity
Authors: Kogure Masaya , Kitani Tomoya , SUGA TAKAOMI , Ogata Takehiro , Ikeda Koji , Matoba Satoaki
Published: October 2024

Background and Objective:
Doxorubicin (Dox)-induced cardiotoxicity (DIC) is one of the most serious side effects of cancer treatments. However, no effective treatment is currently available. In this study, we aimed to identify novel therapeutic targets using CRISPR/Cas9-based screening of human cardiomyocytes derived from pluripotent stem cells (hPSC-CMs).

Methods and Results:
We performed a kinase-focused CRISPR gene knockout screen in hPSC-CMs and identified thousand and one amino acid protein kinase 1 (TAOK1
)
as a potential regulator of DOX-induced cardiomyocyte death. We generated TAOK1-knockout (KO) hPSC-CMs using CRISPR/Cas9 and found that TAOK1-KO hPSC-CMs showed higher cell viability than control KO cells after 1μM DOX treatment (49.3% vs. 30.5%, P = 0.03). TAOK1-KO decreased DOX-induced ROS production (-58.8%, P = 0.01) and DNA damage (-28.8%, P < 0.01) in hPSC-CMs. Transcriptome analysis using RNA-seq of TAOK1-KO hPSC-CMs identified 483 differentially expressed genes, and Hallmark pathway analysis revealed upregulation of the oxidative phosphorylation pathway (FDR < 0.01) in TAOK1-KO hPSC-CMs compared to the control. Extracellular flux analysis demonstrated higher basal and maximal respiratory capacity in TAOK1-KO hPSC-CMs compared to control after DOX treatment (1.2 vs. 0.6, and 3.8 vs. 2.0 pmol/min/μg, respectively, P < 0.01 for all). Next, we overexpressed TAOK1 in hPSC-CMs using adenovirus vector and found that TAOK1 overexpression (OE) augmented DOX-induced cell viability reduction in hPSC-CMs compared to control after 0.5μM DOX treatment (-63.4 % vs. -19.2%, P < 0.01). Western blot analysis showed that DOX-induced p38 phosphorylation was suppressed by TAOK1-KO (P < 0.01) and enhanced (P = 0.01) by TAOK1-OE in hPSC-CMs. Augmented DOX-induced cardiomyocyte death in TAOK1-OE hPSC-CMs was partially rescued by inhibitors of p38 MAPK or apoptosis. Lastly, we demonstrated that TAOK1 suppression using AAV-mediated gene silencing mitigated the decline in the left ventricular ejection fraction in a mouse model of DIC (-30.0% vs. -17.7%, P < 0.01). Histological analysis of heart tissue revealed that TAOK1 suppression reduced myocardial fibrosis and apoptosis of cardiac cells in a mouse model of DIC (6.6% vs. 4.3%, P = 0.02, and 0.31% vs. 0.18%, P< 0.01, respectively).

Conclusion:
Our results suggest that TAOK1 regulates DOX-induced cardiomyocyte death; thus, its inhibition could be a potential therapeutic approach for DIC.
Abstract Mo002: Pharmacological Inhibition of p38 MAPK Attenuates Doxorubicin-induced Cardiotoxicity, Senescence, and Inflammation in C57BL/6 mice
Authors: Dabour Mohamed , Abdelgawad Ibrahim , sadaf bushra , DANIEL MARY RAPHEL , Grant Marianne , Zordoky Beshay
Published: October 2024

Introduction:
Doxorubicin (DOX)-induced cardiotoxicity has been associated with induction of senescence, inflammation, and activation of the p38 mitogen-activated protein kinase (MAPK) pathway. Losmapimod (LOSM), an orally active p38 MAPK inhibitor, is an anti-inflammatory agent with cardioprotective effects. Nevertheless, the effect of LOSM against DOX-induced cardiotoxicity has not been reported.

The objective

of the current work is to determine the effects of LOSM on DOX-induced chronic cardiotoxicity in C57BL/6 mice with particular focus on senescence and inflammatory pathways.

Methods:
Five-week-old C57BL/6 mice were fed diet containing LOSM (estimated daily intake 12 mg/kg/day) or a control diet for four days. Thereafter, mice were randomized to receive six weekly intraperitoneal injections of either DOX (4 mg/kg/week for 6 weeks) or saline. Three days after the last injection, cardiac function was assessed by trans-thoracic echocardiography. Gene expressions of senescence and inflammatory markers were quantified using real-time PCR and serum inflammatory markers were assessed by Luminex.

Results:
LOSM ameliorated DOX-induced cardiac dysfunction as evidenced by mitigated DOX-induced reduction in left ventricular fraction and fractional shortening. Notably, LOSM attenuating DOX-induced upregulation of

p21
Cip1

, a marker of senescence, in the heart and the liver. Additionally, LOSM demonstrated anti-inflammatory effects, with reduced cardiac interleukin-1α and interleuken-6 gene expression in DOX-treated mice suggesting a senomorphic effect of LOSM. Systemic inflammation, assessed by serum cytokine levels, showed decreased interleukin-6 concentration in both DOX-treated mice and LOSM-treated mice.

Conclusion:
This is the first study to determine the effect of pharmacological inhibition of p38 MAPK against DOX-induced cardiotoxicity in vivo. Our study underscores the potential therapeutic efficacy of p38 MAPK inhibition in ameliorating DOX-induced cardiotoxicity, offering insights into novel strategies for mitigating chemotherapy-related cardiac complications, and suggesting a possible senomorphic effects of losmapimod.
Abstract Mo011: Selective silencing of p38δ is cardioprotective in female mice during doxorubicin chemotherapy
Authors: Trampel Katy , O Reilly Daniel , Gross Katherine , George Sharon Ann , Khvorova Anastasia , Efimov Igor , Efimova Tatiana
Published: October 2024

Introduction:
Dose-dependent cardiotoxicity limits the efficacy of chemotherapeutic agent doxorubicin (DOX). p38δ is one of four p38 mitogen-activated protein kinase isoforms that regulate DOX-induced cardiotoxicity (DIC). p38δ genetic deletion protects female mice from DIC. In the absence of selective pharmacologic inhibitors of p38δ, docosanoic acid (DCA) conjugate-mediated delivery of chemically engineered small interfering RNA (siRNA) provides a novel avenue to achieve selective, efficient, durable, and nontoxic in vivo p38δ silencing in the heart.

Hypothesis:
The selective silencing of p38δ is cardioprotective from DIC in female mice.

Methods:
Following the screening of a panel of p38δ-selective siRNA sequences, the lead siRNA si-p38δ-1, with the highest silencing efficacy and potency in vitro, was identified. 15-week-old female mice were subcutaneously injected with 20 mg/kg of DCA-conjugated chemically stabilized si-p38δ-1 (n = 3) or the non-targeting control (NTC) siRNA (n = 3) twice 10 hours apart. p38δ silencing in mouse hearts was measured 14 days later by assessing mRNA and protein expression. To evaluate the effect of p38δ silencing after acute DOX treatment, the mice were administered si-p38δ-1 (n = 5) or NTC (n = 5), followed by DOX treatment (30 mg/kg) six days later. The study concluded 11 days after DOX treatment. Morbidity was assessed by assigning health scores daily. Electrocardiography, echocardiography, and optical mapping were performed to evaluate cardiac function.

Results:
si-p38δ-1 led to 80% silencing of p38δ in mouse hearts 14 days after administration, without any cardiotoxic effects. si-p38δ-1-treated female mice exhibited diminished DOX-induced morbidity (p = 0.003) and were protected from developing calcium alternans (CAs) 11 days post-DOX treatment, compared to NTC-treated counterparts. Thus, DOX-induced CAs, indicative of calcium mishandling, were observed in 75% (3/4) NTC-treated mice and 0% (0/5) si-p38δ-1-treated mice.

Conclusion:
Efficient and well-tolerated in vivo p38δ silencing by si-p38δ-1 in mouse hearts mitigated DOX-induced morbidity and calcium mishandling in female mice, highlighting the therapeutic potential of p38δ silencing for alleviating DIC in female cancer patients.
Abstract Mo035: Double (Dual) Sequential Defibrillation Versus Standard Defibrillation for Refractory Ventricular Fibrillation: A Systematic Review and Meta-Analysis
Authors: Ali Rola , Barsoum Basiem , Lago Rodrigo
Published: October 2024

Background:
Refractory ventricular fibrillation (RVF) is VF that persists despite 3 or more single defibrillation attempts. Double sequential defibrillation (DSD) is a proposed defibrillation strategy for RVF that employs delivering 2 rapid sequential, transthoracic electric shocks from 2 separate defibrillators. This meta-analysis aims to identify evidence in the literature surrounding the use of DSD and compare its efficacy with standard defibrillation (SD) in patients with RVF.

Methods:
We conducted our meta-analysis in compliance with the PRISMA guidelines. PubMed, Embase, and Cochrane databases were used to retrieve articles. We included studies that evaluated and compared the utility of DSD versus SD in cardiac arrest adult patients who received 3 or more standard defibrillatory shocks for RVF. Our predefined outcomes of interest were VF termination (VFT), return of spontaneous circulation (ROSC), survival to hospital admission (SHA), and survival to hospital discharge (SHD). Odds ratio (OR) and 95% confidence intervals (CIs) were calculated using the random-effects model. Heterogeneity was assessed by I
2
statistic.

Results:
A total of 8 studies (2 randomized controlled trials and 6 observational studies) involving 1,579 patients were included in the meta-analysis. No statistically significant difference existed between DSD and SD in terms of VFT (OR, 1.58; 95% CI, 0.84-2.99; p= 0.15; I
2
=0.54), ROSC (OR, 0.91; 95% CI, 0.53-1.55; p= 0.72; I
2
=0.76), SHA (OR, 1.18; 95% CI, 0.54-2.55; p= 0.68; I
2
=0.79), and SHD (OR, 1.03; 95% CI, 0.49-2.17; p= 0.94; I
2
=0.69). Substantial heterogeneity was noticed across the analysed studies.

Conclusion:
Despite the growing use of DSD for the management of RVF, there remains insufficient evidence to support its widespread implementation. This meta-analysis demonstrated that DSD had no statistically significant advantage over SD. However
,
due to limited data in the literature further clinical trials with large sample sizes are warranted to assess the efficacy and clinical impact of DSD, and whether it can potentially be integrated into resuscitation protocols.
Abstract Mo047: DNA METHYLATION AND TRANSCRIPTIONAL MARKERS OF MYOCARDIAL REVERSE REMODELING IN HF PATIENTS ON LVAD SUPPORT
Authors: Shankar Thirupura S , Marchetti Marco , Srinivasan Harini , Lunde J Ty , Selzman Craig , Javier Hernandez Edgar , Tristani-Firouzi Martin , Drakos Stavros , Wever-Pinzon Omar
Published: October 2024

Heart failure (HF) involves global genome modifications. Adverse structural and function remodeling that occurs in HF was initially considered to be irreversible. However, ~15% of HF patients on left ventricular assist device (LVAD) support show significant structural and functional reverse remodeling, distinguishing them as responders (R), while ~85% are non-responders (NR). DNA methylation and transcriptional changes that exert myocardial recovery is not well understood.

To address this, we performed whole-genome bisulphite sequencing and RNA sequencing on paired myocardial biopsies from HF patients (n=84) before (pre-LVAD) and after LVAD unloading (post-LVAD).

Post-LVAD samples showed activation of pathways including TGFβ signaling, PTEN and Fatty acid oxidation compared to pre. Integrating DNA methylation and transcriptomics data revealed hypomethylation (upregulation) of genes including
Scaper, Frat1
and
Magi1
and hypermethylation (downregulation) of
Tpp3
and
Icam.
Overall, suggesting a unique ECM-specific stabilization pathway post-LVAD unloading.

Segregating samples based on their response to LVAD unloading, pathways such as inflammation and fibrotic signaling were activated in postNR compared to preNR. Hypomethylation of
Magi1
and hypermethylation of
Tppp3
was observed in postNR suggesting cross-linking proteins and destabilization of microtubule formation as potential mechanisms of functional regression in NR. Conversly, postR showed activation of deubiquitination, oxidative phosphorylation and NLR signaling compared to preR. Finally, we observed integrin signaling, syndecan interaction, collagen degradation and wound healing pathways were activated in postR compared to postNR. Hypomethylation of actin cytoskeleton (
Myl12a
), microtubule/motor proteins (
Kif5b
) and tropomyosin (
Tpm3
) were observed in postR, suggesting a plausible reverse remodeling mechanism mediated by ECM degradation and stabilization of myocardium in these patients. Western blot analysis also showed a trend towards an increase in collagen in postNR compared to postR (n=4, p=0.06). Finally, a mouse model of HF and recovery was used and pathways including ECM degradation and cardioprotective signaling were activated in mice that recovered from HF compared to mice that did not. Overall, our data suggests a unique ECM regulation pathway to contribute towards myocardial reverse remodeling in HF patients.
Abstract Mo052: Electrocardiographic behavior, arrhythmias, and mortality in two calcium management strategies (cytoplasmic and mitochondrial) in hearts under ischemia.
Authors: Vasques Enio , Kim Vasques Bruna , TAVARES JOSÉ GUSTAVO , Menezes-Rodrigues Francisco Sandro , caricati-neto afonso , Melo THIAGO , Monteiro da Cunha Jose Eduardo , Rodrigues Tiago
Published: October 2024

Background:
The disruption of calcium homeostasis in ischemic hearts is determinant for triggering the arrhythmic phenomena and death. Interventions that act on calcium levels in cytoplasm and mitochondria might interrupt or minimize these outcomes. Trisulfate disaccharide (TD) acts by accelerating the sodium-calcium exchanger, decreasing cytosolic calcium levels. Ruthenium red (RuR) is a mitochondrial uniporter inhibitor that blocks calcium influx into mitochondria. Both agents can be useful in calcium overload elicited by myocardial ischemia (MI), modifying electrocardiographic (EKG) parameters that predict arrhythmia, arrhythmic phenomena, and cell death.

Objectives:
To compare the behavior of Tp-Te and QTc EKG intervals, arrhythmia rates, and mortality in ischemic hearts under the action of TD and RuR.

Materials and Methods:
Adult Wistar rats (n=24) were divided in 3 groups, i.e, Control: MI with no treatment (n=8), TD: MI treated with TD 0.2 mg/kg IV (n=8), and RuR:MI treated with RuR 1 mg/kg IV (n=8). Rats were monitored by EKG and submitted to surgical MI by ligation of anterior descending artery during 10 minutes followed by reperfusion thereafter. The Tp-Te and QT intervals were analyzed before and at 10 minutes of ischemia and 10 minutes after the onset of reperfusion. The incidence of arrhythmias and mortality were determined throughout the recording time.

Results:
The Tp-Te and QTc intervals increased during ischemia in all groups (Control, TD and RuR), which were normalized after 10 minutes reperfusion only in TD group. The observed arrhythmias (atrioventricular block, ventricular tachycardia, and torsade of pointes) had a higher incidence in the control group and the lower incidences, with statistically significant differences, were achieved in TD and RuR groups, whose incidence was similar in these both groups. Sustained arrhythmias led to a 50% mortality in the control group and 25% in RuR group. No mortality in TD group was observed.

Conclusion:
The strategy of decreasing cytosolic calcium levels by the action of TD has proved to be more effective than the blockade of mitochondrial calcium uptake by RuR, with further normalization of EKG parameters predictors of mortality, and absence of sustained arrhythmias and mortality, suggesting that the management of cytosolic calcium levels is more effective than only the management of mitochondrial calcium in MI model.
Abstract Mo058: Cellular and Subcellular Ventricular Localization of the Fast Transient Outward Potassium Channels in the Murine Heart
Authors: Gorman Renee , Backx Peter
Published: October 2024

Introduction:
Cardiac fast transient outward potassium currents (I
to,f
) are formed by KCND2 (Kv4.2) and KCND3 (Kv4.3) channels in mice and primarily KCND3 in humans. Rapid I
to,f
activation induces early phase 1 repolarization of action potentials (APs), which has been linked strongly to the modulation of excitation-contraction coupling (ECC). Consequently, variations in I
to,f
densities underlie regional differences in ventricular APs and myocardial contractile properties. To investigate further the role of I
to,f
in cardiac function, we created mice with fluorescently labelled KCND2 (KCND2-GFP) and KCND3 (KCND3-RFP).

Methods and Results:
The expression patterns of I
to,f
in the ventricles were examined using frozen histological sections. Remarkably, KCND2 and KCND3 were preferentially localized to the intercalated discs (ICDs) by >50%, with expression also in lateral membranes and within t-tubules (i.e. a sarcomeric pattern), yet KCND3 showed a greater t-tubule localization. Additionally, KCND2 expression was, as expected, greater (
P
<0.048, two-way ANOVA; n=3) in the epi- versus endo-myocardium of both ventricles, whereas KCND3 lacked (
P
>0.172; n=3) a distinct gradient. Moreover, KCND2 expression inversely correlated with the temporal sequence of ventricular activation, whereby the posterobasal regions that depolarize last show elevated Kv4.2 (
P
=0.009, unpaired t-test; n=3) compared to the anterolateral endocardium activated first. In contrast, Kv4.3 demonstrates a relatively uniform expression.

Conclusions:
The regional expression patterns of I
to,f
in ventricles and preferential I
to,f
expression in t-tubules support previous studies suggesting that I
to,f
controls the regional variations in the timing and amplitude of ECC. We are currently exploring the possible differential actions of KCND2 versus KCND3 in ECC and the potential consequence of ICD localization of I
to,f
on ephaptic coupling.
Abstract Mo069: Phospholamban Acetylation Enhances Cardiomyocyte Calcium Cycling Under Conditions of High-Fat Feeding
Authors: Mushala Bellina , Cho Ellen , Stoner Michael , Gibson Greg , Sembrat John , Bugga Paramesha , Scott Iain , Robia Seth , Manning Janet
Published: October 2024

Background:
Diet-induced obesity (DIO) is an increasing driver of cardiovascular disease and cardiac dysfunction. The breakdown of excessive fat and sugar intake increases the presence of intracellular acetyl-CoA, which promotes the acetylation of available lysines, altering the stability and activity of these proteins. While numerous proteins involved in cardiac health have been identified as targets of acetylation, the impact of acetylation on calcium handling sarcoplasmic reticulum (SR) proteins, particularly the SERCA2a regulator phospholamban, remains poorly understood.

Hypothesis:
Phospholamban acetylation is upregulated by exposure to high fat conditions, in turn driving SERCA2a activity and promoting faster calcium SR reuptake.

Approach:
Left ventricle (LV) tissue from DIO mice and controls, and human LV tissue from control and diabetic patients, was collected and analyzed using immunoblotting and acetylation was quantified by immunoprecipitation with acetyl-lysine antibodies.Isolated working hearts from DIO and control mice were assessed before and after treatment with acute HDAC activator ITSA-1 and SIRT1 activator SRT1720 to promote deacetylation. Adult ventricular cardiomyocytes were isolated from DIO and control mice, and DIO cells were incubated in media containing excess lipid substrates (1% Lipid Mix 1, Millipore Sigma) and ITSA-1 orSRT1720. Changes in stimulated calcium dynamics were assessed using Fura-2AM and Fluo-4AM imaging. Acetylmimetic/acetylation incompetent PLN mutants were transfected into cultured cells to evaluate SERCA2a binding, oligomerization, and FRET efficiency.

Results:
Phospholamban acetylation significantly increased in LV tissue from both DIO mice and human diabetic patients. Acute treatment of isolated hearts and isolated cardiomyocytes from DIO mice with HDAC and SIRT1 activators significantly reduced contractility, relaxation, and SR calcium reuptake rates. Mutations in PLN mimicking or preventing lysine acetylation altered oligomerization and SERCA2a binding.

Conclusions:
Obesity increases the acetylation of phospholamban and enhances the reuptake of calcium into the SR, while deacetylation reverses these effects. These data directly tie nutritive status to a novel phospholamban post-translational modification that may directly impact myocardial calcium handling and contractile function.
Abstract Mo074: Overexpression of IPP2 Impairs Intracellular Calcium Handling, Leading to Arrhythmogenic Events
Authors: Eom Gwang Hyeon , Yoon Somy
Published: October 2024

Cardiac arrhythmias, which are disruptions in the heart's electrical activities, critically affect the ventricular conduction system, impairing efficient blood circulation. These disturbances result in irregular heartbeats, contributing to patient mortality or causing harm to distant organs via embolic events. Given the severe implications, a profound understanding of the molecular mechanisms driving arrhythmia is crucial for devising specific treatments. This study unveils a pioneering link between the overexpression of IPP2 (Protein Phosphatase 1 Regulatory Inhibitor Subunit 2), driven by the Myh6 promoter (termed TgIPP2), and the onset of age-dependent cardiac arrhythmias. The electrical abnormalities observed in TgIPP2 overexpressing mice include a spectrum of dysfunctions such as axis deviations, elongated QRS and PR intervals, absence of P waves, AV dissociation, ventricular tachyarrhythmia, and heightened T waves. Investigating the pathophysiology behind these electrical anomalies, we subjected young adult mice to catecholamine challenges at low doses and conducted surface electrocardiogram (EKG) monitoring. TgIPP2 mice demonstrated a notable increase in arrhythmogenic episode frequency and duration following 0.2 mg/kg isoproterenol injection compared to their control counterparts. Through a protein phosphorylation analysis, we identified a key regulator of the ryanodine receptor, which modulates calcium release from the sarcoplasmic reticulum, correlating with the extended PR intervals and the delayed peaking of T waves. Therapeutic trials employing RyR blockers, specifically dantrolene, successfully normalized the erratic cardiac rhythms in aged TgIPP2 mice. However, beta blockers or L-type calcium channel blockers induced sudden cardiac death in this model. The study reveals that IPP2-induced aberrant phosphorylation disrupts calcium homeostasis, leading to arrhythmias.

In conclusion, our research marks a significant advancement in understanding arrhythmogenic mechanisms, demonstrating that IPP2 overexpression directly triggers arrhythmia, particularly affecting the atrioventricular (AV) node, atria, and ventricles. The discovery that aberrant phosphorylation, especially of the RyR regulator, plays a pivotal role in initiating cardiac arrhythmias opens new pathways for targeted anti-arrhythmic therapies.