A rare case of embryonal sarcoma in the liver of a young adult: diagnostic and therapeutic perspectives.

Embryonal sarcoma of the liver (ESL) is a rare and aggressive neoplasm primarily affecting children, with its occurrence in adults being exceptionally rare. This case report details the presentation, diagnosis, and management of ESL in a 20-year-old patient, highlighting the challenges and strategic approaches required in managing such atypical presentations. The patient presented with progressive right upper quadrant abdominal pain and significant weight loss, with imaging revealing a large mixed-density mass in the right lobe of the liver. Despite the nonspecific clinical symptoms and normal tumor markers, advanced imaging techniques including MRI and CT scans played a pivotal role in the diagnostic process. The mass exhibited characteristics that led to a differential diagnosis of a possible benign condition; however, the decision for surgical resection was made based on the tumor's rapid growth and potential malignancy suggested by imaging. Histopathological examination postsurgery confirmed the diagnosis of ESL. This case illustrates the importance of considering ESL in the differential diagnosis of rapidly enlarging liver masses in adults, despite its rarity in this age group. The effective management of this case through surgical intervention without prior biopsy, due to the risk of tumor seeding, followed by adjuvant chemotherapy, reflects the critical need for a multidisciplinary approach. The outcomes from this case contribute to the existing knowledge base, providing insights into the complexities of diagnosing and treating adult cases of ESL and affirming the adaptability of pediatric protocols to adult patients.

A phase Ib randomized multicenter trial of isolated hepatic perfusion in combination with ipilimumab and nivolumab for uveal melanoma metastases (SCANDIUM II trial).

BACKGROUND: Uveal melanoma (UM) is a rare malignancy where 50% of patients develop metastatic disease primarily affecting the liver. Approximately 40% of patients with metastatic UM respond to one-time isolated hepatic perfusion (IHP) with high-dose melphalan. This phase I trial investigates the safety and clinical efficacy of IHP combined with ipilimumab (IPI) and nivolumab (NIVO). PATIENTS AND METHODS: Immunotherapy-naïve patients were randomized in this phase I trial to receive either IHP followed by IPI 3 mg/kg and NIVO 1 mg/kg (IPI3/NIVO1) for four cycles (post-operative arm), or one cycle of preoperative IPI3/NIVO1, IHP and then three cycles of IPI3/NIVO1 (pre-post-operative arm), followed by maintenance therapy with NIVO 480 mg for 1 year. RESULTS: Eighteen patients were enrolled and randomized. Three patients did not undergo IHP as planned. In total, 11/18 patients (6 in the post-operative arm and 5 in the pre-post-operative arm) did not complete the planned four cycles of IPI3/NIVO1. Toxicity to IHP was similar in both groups, but the number of immune-related adverse events (AEs) was higher in the pre-post-operative arm. Among assessable patients, overall response rate was 57% in the post-operative arm (4/7) and 22% in the pre-post-operative arm (2/9). CONCLUSIONS: Combination therapy with IHP and IPI3/NIVO1 was associated with severe AEs. The efficacy of this combination is encouraging with high response rates. One cycle of preoperative IPI/NIVO before IHP did not show potential benefits in terms of safety or efficacy.

Perception of hypotheticality in technology-based business ideas: effects on Opportunity Beliefs from a Construal Level Theory perspective.

This research investigates how entrepreneurs perceive the hypothetical nature of technologies (based on situations that are often imagined or theoretical) as a foundation for entrepreneurial endeavors and how this perception influences the formation of business Opportunity Beliefs. Drawing on the Construal Level Theory, we explore the relationship between the perceived hypotheticality of technologies and Opportunity Beliefs. Two experimental studies are conducted to examine these relationships, with Study 1 (n = 177 entrepreneurs) focusing on the perception of innovative technologies as more distant or hypothetical, and Study 2 (n = 404 entrepreneurs) delving into how the perceived distance to technology influences Opportunity Beliefs. The results indicate that entrepreneurs view more innovative technologies as more hypothetical and that hypotheticality mediates the relationship between the perceived degree of innovation and Opportunity Beliefs. We find evidence that Entrepreneurs tend to view the feasibility and fit/alignment of business opportunities more favorably when they perceive the psychological distance (hypotheticality) of the opportunity as closer rather than more distant. However, the difference this difference is nonsignificant in how they evaluate the desirability of the opportunity in any psychological distance. These results provide insight into the cognitive processes of entrepreneurs and offer implications for understanding how entrepreneurs perceive and evaluate business opportunities.

Air pollution and rhinitis.

Rhinitis arises from either allergic or non-allergic inflammation of the nasal mucosa, characterized by the infiltration of inflammatory cells into the tissue and nasal secretions, along with structural alterations in the nasal mucosa. The pathways through which air pollution affects rhinitis may diverge from those affecting asthma. This article aims to review the effects of diverse air pollutants on the nose, the correlation of climate change and pollution, and how they aggravate the symptoms of patients with rhinitis.

Ataxia-telangiectasia in Latin America: clinical features, immunodeficiency, and mortality in a multicenter study.

Ataxia-telangiectasia (AT) is a rare genetic disorder leading to neurological defects, telangiectasias, and immunodeficiency. We aimed to study the clinical and immunological features of Latin American patients with AT and analyze factors associated with mortality. Referral centers from 9 Latin American countries participated in this retrospective cohort study, and 218 patients were included. Median (IQR) ages at symptom onset and diagnosis were 1.0 (1.0-2.0)  and 5.0 (3.0-8.0) years, respectively. Most patients presented recurrent airway infections, which was significantly associated with IgA deficiency. IgA deficiency was observed in 60.8% of patients and IgG deficiency in 28.6%. T- and B-lymphopenias were also present in most cases. Mean survival was 24.2 years, and Kaplan-Meier 20-year-survival rate was 52.6%, with higher mortality associated with female gender and low IgG levels. These findings suggest that immunologic status should be investigated in all patients with AT.

Quantifying acyl-chain diversity in isobaric compound lipids containing monomethyl branched-chain fatty acids.

Compound lipids comprise a diverse group of metabolites present in living systems, and metabolic- and environmentally-driven structural distinctions across this family is increasingly linked to biological function. However, methods for deconvoluting these often isobaric lipid species are lacking or require specialized instrumentation. Notably, acyl-chain diversity within cells may be influenced by nutritional states, metabolic dysregulation, or genetic alterations. Therefore, a reliable, validated method of quantifying structurally similar even-, odd-, and branched-chain acyl groups within intact compound lipids will be invaluable for gaining molecular insights into their biological functions. Here we demonstrate the chromatographic resolution of isobaric lipids containing distinct combinations of straight-chain and branched-chain acyl groups via ultra-high-pressure liquid chromatography (UHPLC)-mass spectrometry (MS) using a C30 liquid chromatography column. Using metabolically-engineered adipocytes lacking branched-keto acid dehydrogenase A (Bckdha), we validate this approach through a combination of fatty acid supplementation and metabolic tracing using monomethyl branched-chain fatty acids and valine. We observe resolution of numerous isobaric triacylglycerols and other compound lipids, demonstrating the resolving utility of this method. This approach strengthens our ability to quantify and characterize the inherent diversity of acyl chains across the lipidome.

Highest fusion performance without harmful edge energy bursts in tokamak.

The path of tokamak fusion and International thermonuclear experimental reactor (ITER) is maintaining high-performance plasma to produce sufficient fusion power. This effort is hindered by the transient energy burst arising from the instabilities at the boundary of plasmas. Conventional 3D magnetic perturbations used to suppress these instabilities often degrade fusion performance and increase the risk of other instabilities. This study presents an innovative 3D field optimization approach that leverages machine learning and real-time adaptability to overcome these challenges. Implemented in the DIII-D and KSTAR tokamaks, this method has consistently achieved reactor-relevant core confinement and the highest fusion performance without triggering damaging bursts. This is enabled by advances in the physics understanding of self-organized transport in the plasma edge and machine learning techniques to optimize the 3D field spectrum. The success of automated, real-time adaptive control of such complex systems paves the way for maximizing fusion efficiency in ITER and beyond while minimizing damage to device components.

Neuromuscular and trunk control mediate factors associated with injury in fatigued runners.

This study aimed to determine how fatigue affects factors associated with injury, neuromuscular activity, and control in recreational runners. Previously identified injury risk factors were defined as peak vertical instantaneous loading rates (pVILR) for tibial stress fracture (TSF) and peak hip adduction (pHADD) for patellofemoral pain syndrome and iliotibial band syndrome. Kinematics, kinetics, and electromyography data were collected from 11 recreational runners throughout a fatiguing run. Three trials were collected in the first and final minutes of the run. Coactivation was quantified about the knee and ankle for the entire stance phase and anticipatory, weight acceptance (WA), and propulsion sub-phases of stance. Trunk control was quantified by the peak mediolateral lean, peak forward lean, and flexion range of motion (ROM). There were significant increases in pHADD and pVILR when fatigued. Significant decreases in coactivation around the knee were found over the entire stance phase, in the anticipatory phase, and WA phase. Coactivation decreased about the ankle during WA. Lateral trunk lean significantly increased when fatigued, but no significant changes were found in flexion ROM or lean. Mediation analyses showed changes in ankle coactivation during WA, and lateral trunk lean are significant influences on pVILR, a measure associated with TSF. Fatigue-induced adaptations of decreasing ankle coactivation during WA and increased lateral trunk lean may increase the likelihood of TSF. In this study, a fatiguing run influenced changes in control in recreational runners. Further investigation of causal fatigue-induced injuries is necessary to better understand the effects of coactivation and trunk control.

Anti-inflammatory effect of Trichospira verticillata via suppression of the NLRP3 inflammasome in neutrophilic asthma.

Trichospira verticillata is an annual herb that belongs to the family Asteraceae. Trichospira verticillata extract (TVE) elicits anti-plasmodial activity; however, there has been no detailed report about its anti-inflammatory effects and molecular mechanisms. In addition, herbal plants exhibit anti-inflammatory effects by suppressing the NLRP3 inflammasome. Therefore, the primary goal of this study was to examine the effects of TVE on NLRP3 inflammasome activation by measuring interleukin-1ß (IL-1ß) secretion. We treated lipopolysaccharides (LPS)-primed J774A.1 and THP-1 cells with TVE, which attenuated NLRP3 inflammasome activation. Notably, TVE did not affect nuclear factor-kappa B (NF-κB) signalling or intracellular reactive oxygen species (ROS) production and potassium efflux, suggesting that it inactivates the NLRP3 inflammasome via other mechanisms. Moreover, TVE suppressed the formation of apoptosis-associated speck-like protein (ASC) speck and oligomerization. Immunoprecipitation data revealed that TVE reduced the binding of NLRP3 to NIMA-related kinase 7 (NEK7), resulting in reduced ASC oligomerization and speck formation. Moreover, TVE alleviated neutrophilic asthma (NA) symptoms in mice. This study demonstrates that TVE modulates the binding of NLPR3 to NEK7, thereby reporting novel insights into the mechanism by which TVE inhibits NLRP3 inflammasome. These findings suggest TVE as a potential therapeutic of NLRP3 inflammasome-mediated diseases, particularly NA.

The impacts of governing agency: A comparison of resources in the patchwork of medicolegal death investigation systems.

In the United States, medical examiners and coroners (MECs) fill critical roles within our public health and public safety systems. These professionals are primarily charged with determining the cause and manner of death as they investigate deaths and respond to associated scenes and mass fatalities and can also help identify trends in public health crises through medicolegal death investigations. Despite their instrumental role, they are organized in disparate systems with varying governing structures, functions, staffing, caseload, budget, and access to resources. This paper examines data from the 2018 Census of Medical Examiner and Coroners to evaluate MEC operations in the United States. The findings show that MEC offices' organizational and operational governance structures greatly influence resources, workloads, and access to information and services. Standalone MEC offices were generally better resourced than those affiliated with law enforcement, public health, forensic science, district attorneys, or other agencies.1.

Environmental correlates of oyster farming in an upwelling system: Implication upon growth, biomass production, shell strength and organic composition.

Comprehending the potential effects of environmental variability on bivalves aquaculture becomes crucial for its sustainability under climate change scenarios, specially in the Humboldt Current System (HCS) where upwelling intensification leading to frequent hypoxia and acidification is expected. In a year-long study, Pacific oysters (Magallana gigas) were monitored at two depths (1.5m, 6.5m) in a bay affected by coastal upwelling. Surface waters exhibited warmer, well-oxygenated conditions and higher chlorophyll-a concentrations, while at depth greater hypoxia and acidification events occur, especially during upwelling. Surface cultured oysters exhibited 60 % larger size and 35% greater weight due to faster growth rate during the initial month of cultivation. The condition index (CI) increases in surface oysters after 10 months, whereas those at the bottom maintain a lower index. Food availability, temperature, and oxygen, correlates with higher growth rates, while pH associates with morphometric variables, indicating that larger oysters tend to develop under higher pH. Increased upwelling generally raises CI, but bottom oysters face stressful conditions such as hypoxia and acidification, resulting in lower performance. However, they acclimate by changing the organic composition of their shells and making them stronger. This study suggests that under intensified upwelling scenario, oysters would grow slowly, resulting in smaller sizes and lower performance, but the challenges may be confronted through complex compensation mechanisms among biomass production and maintenance of the shell structure and function. This poses a significant challenge for the sustainability of the aquaculture industry, emphasizing the need for adaptive strategies to mitigate the effects of climate change.

The nuclear import receptor Kapß2 modifies neurotoxicity mediated by poly(GR) in C9orf72-linked ALS/FTD.

Expanded intronic G4C2 repeats in the C9ORF72 gene cause amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD). These intronic repeats are translated through a non-AUG-dependent mechanism into five different dipeptide repeat proteins (DPRs), including poly-glycine-arginine (GR), which is aggregation-prone and neurotoxic. Here, we report that Kapß2 and GR interact, co-aggregating, in cultured neurons in-vitro and CNS tissue in-vivo. Importantly, this interaction significantly decreased the risk of death of cultured GR-expressing neurons. Downregulation of Kapß2 is detrimental to their survival, whereas increased Kapß2 levels mitigated GR-mediated neurotoxicity. As expected, GR-expressing neurons displayed TDP-43 nuclear loss. Raising Kapß2 levels did not restore TDP-43 into the nucleus, nor did alter the dynamic properties of GR aggregates. Overall, our findings support the design of therapeutic strategies aimed at up-regulating Kapß2 expression levels as a potential new avenue for contrasting neurodegeneration in C9orf72-ALS/FTD.

ACCURACY OF THE EOSINOPHILIC ESOPHAGITIS ENDOSCOPIC REFERENCE SCORE IN CHILDREN.

BACKGROUND: To assess the efficacy of applying the endoscopic reference score for EoE (EREFS) in children with symptoms of esophageal dysfunction naïve to proton pump inhibitor (PPI) therapy. METHODS: An observational cross-sectional study was conducted by reviewing reports and photographs of upper gastrointestinal endoscopies (UGE) and esophageal biopsies of patients with symptoms of esophageal dysfunction. Patients who were treated with PPI or had other conditions that may cause esophageal eosinophilia were excluded. RESULTS: Of the 2,036 patients evaluated, endoscopic findings of EoE were identified in 248 (12.2%) and more than one abnormality was observed in 167 (8.2%). Among all patients, 154 (7.6%) presented esophageal eosinophilia (≥15 eosinophils per high power field) (P<0.01). In this group, 30 patients (19.5%) had normal endoscopy. In patients with EoE, edema (74% vs 6.5%, P<0.01) and furrows (66.2% vs 2.4%, P<0.01) were more prevalent than in the control group. Association of edema and furrows was more frequent in patients with EoE than in the control group (29.2% vs 1.6%, P<0.01, OR=24.7, CI=15.0-40.5). The presence of more than one endoscopic finding had sensitivity of 80.5%, specificity of 93.4%, positive predictive value (PPV) of 50%, negative predictive value (NPV) of 98.3%, and accuracy of 92.4%. CONCLUSION: In conclusion, this study showed that endoscopic features suggestive of EoE had high specificity and NPV for diagnosing EoE in children naïve to PPI therapy. These findings highlight the importance of the EREFS in contributing to early identification of inflammatory and fibrostenosing characteristics of EoE, making it possible to identify and to avoid progression of the disease. BACKGROUND: • The EoE endoscopic reference score (EREFS) was developed and validated in adults and has been demonstrated to be an adequate tool for diagnosing and assessing treatment response in children. BACKGROUND: • The presence of more than one endoscopic finding stronglysuggests EoE. BACKGROUND: • The EoE endoscopic reference score presents high specificity and negative predictive value for diagnosing EoE in children naïve to proton pump inhibitor (PPI) therapy. BACKGROUND: • Endoscopic findings suggestive of EoE in patients naïve to treatment may be useful to characterize disease phenotype and individualize treatment according to the initial clinical presentation.

Combining Cell-Intrinsic and -Extrinsic Resistance to HIV-1 By Engineering Hematopoietic Stem Cells for CCR5 Knockout and B Cell Secretion of Therapeutic Antibodies.

Autologous transplantation of CCR5 null hematopoietic stem and progenitor cells (HSPCs) is the only known cure for HIV-1 infection. However, this treatment is limited because of the rarity of CCR5 -null matched donors, the morbidities associated with allogeneic transplantation, and the prevalence of HIV-1 strains resistant to CCR5 knockout (KO) alone. Here, we propose a one-time therapy through autologous transplantation of HSPCs genetically engineered ex vivo to produce both CCR5 KO cells and long-term secretion of potent HIV-1 inhibiting antibodies from B cell progeny. CRISPR-Cas9-engineered HSPCs maintain engraftment capacity and multi-lineage potential in vivo and can be engineered to express multiple antibodies simultaneously. Human B cells engineered to express each antibody secrete neutralizing concentrations capable of inhibiting HIV-1 pseudovirus infection in vitro . This work lays the groundwork for a potential one-time functional cure for HIV-1 through combining the long-term delivery of therapeutic antibodies against HIV-1 and the known efficacy of CCR5 KO HSPC transplantation.

Hysteresis in phase volumes, compositions and interfacial roughness in model OPV-small-molecule/polymer thin-films.

Domain morphology and composition, and the structure of interfaces between domains are key factors in the performance and stability of organic photovoltaics (OPVs) fabricated from polymer/small-molecule blends. In this study, we investigate the evolution of composition, phase-volume and interfacial roughness in model polymer/small-molecule bilayers, in response to thermal annealing. Polystyrene/fullerene mixing is studied as a function of annealing temperature, using in situ neutron reflectivity, in thin-film bilayer samples comprising pure component or mixed layers. Remarkably, we discover that thermal annealing at temperatures around or above the reported glass transition temperatures, Tg, of the components can result in extensive mass-transfer between layers, that has the superficial appearance of equilibration, but leaves the layer compositions, thicknesses, and/or the interfacial composition profile in a non-equilibrium state. This is not merely a case of slow kinetics near Tg, as subsequent heating to higher temperatures, followed by cooling, reveals pronounced hysteresis in these systems. This has important implications for the measurement of equilibrium compositions in polymer/small-molecule mixtures for OPV applications, and for device stability during operation.

Breaking the Law: Is It Correct to Use the Converse Bergmann Rule in Ceroglossus chilensis? An Overview Using Geometric Morphometrics.

The converse Bergmann's rule is a pattern of body size variation observed in many ectothermic organisms that contradicts the classic Bergmann's rule and suggests that individuals inhabiting warmer climates tend to exhibit larger body sizes compared to those inhabiting colder environments. Due to the thermoregulatory nature of Bergmann's rule, its application among ectotherms might prove to be more complicated, given that these organisms obtain heat by absorbing it from their habitat. The existence of this inverse pattern therefore challenges the prevailing notion that larger body size is universally advantageous in colder climates. Ceroglossus chilensis is a native Chilean beetle that has the largest latitudinal range of any species in the genus, from 34.3° S to 47.8° S. Within Chile, it continuously inhabits regions extending from Maule to Aysen, thriving on both native and non-native forest species. Beyond their remarkable color variation, populations of C. chilensis show minimal morphological disparity, noticeable only through advanced morphological techniques (geometric morphometrics). Based on both (1) the "temperature-size rule", which suggests that body size decreases with increasing temperature, and (2) the reduced resource availability in high-latitude environments that may lead to smaller body sizes, we predict that C. chilensis populations will follow the converse Bergmann's rule. Our results show a clear converse pattern to the normal Bergmann rule, where smaller centroid sizes were found to be measured in the specimens inhabiting the southern areas of Chile. Understanding the prevalence of the converse Bergmann's rule for ectotherm animals and how often this rule is broken is of utmost importance to understand the underlying mechanisms allowing organisms to adapt to different environments and the selective pressures they face.

Navigating job satisfaction in family firms during crisis.

Occupational health is one of the aspects significantly affected during crisis periods. It is essential to learn about the factors that improve organizational capacity in coping with such shocks. This study investigates how the working environment of a family business influences job satisfaction during crises. Conducting a survey with 516 employees at the peak of the pandemic, the research utilizes structural equation analysis, revealing that family business environments can mitigate burnout, enhance affective commitment, and consequently, boost job satisfaction. The study highlights the need to manage burnout and utilize resources, such as employee commitment, for family firms to sustain job satisfaction amidst disruptions. It deepens the comprehension of family businesses' crisis response, emphasizing the significance of human resource commitment and management. The investigation illuminates the dynamic interplay between the work environment, employee well-being, and organizational resilience, providing valuable insights for both theoretical understanding and practical application.

Detection and Distribution of Clustered Regularly Interspaced Short Palindromic Repeats (CRISPRs) in Campylobacter jejuni Isolates from Chicken Livers.

Campylobacter jejuni is the leading foodborne bacterial pathogen that causes human gastroenteritis worldwide linked to the consumption of undercooked broiler livers. Application of bacteriophages during poultry production has been used as an alternative approach to reduce contamination of poultry meat by Campylobacter. To make this approach effective, understanding the presence of the bacteriophage sequences in the CRISPR spacers in C. jejuni is critical as they may confer bacterial resistance to bacteriophage treatment. Therefore, in this study, we explored the distribution of the CRISPR arrays from 178 C. jejuni isolated from chicken livers between January and July 2018. Genomic DNA of C. jejuni isolates was extracted, and CRISPR type 1 sequences were amplified by PCR. Amplicons were purified and sequenced by the Sanger dideoxy sequencing method. Direct repeats (DRs) and spacers of CRISPR sequences were identified using the CRISPRFinder program. Further, spacer sequences were submitted to the CRISPRTarget to identify potential homology to bacteriophage types. Even though CRISPR-Cas is reportedly not an active system in Campylobacter, a total of 155 (87%) C. jejuni isolates were found to harbor CRISPR sequences; one type of DR was identified in all 155 isolates. The CRISPR loci lengths ranged from 97 to 431 nucleotides. The numbers of spacers ranged from one to six. A total of 371 spacer sequences were identified in the 155 isolates that could be grouped into 51 distinctive individual sequences. Further comparison of these 51 spacer sequences with those in databases showed that most spacer sequences were homologous to Campylobacter bacteriophage DA10. The results of our study provide important information relative to the development of an effective bacteriophage treatment to mitigate Campylobacter during poultry production.

HRAS-Mutant Cardiomyocyte Model of Multifocal Atrial Tachycardia.

BACKGROUND: Germline HRAS gain-of-function pathogenic variants cause Costello syndrome (CS). During early childhood, 50% of patients develop multifocal atrial tachycardia, a treatment-resistant tachyarrhythmia of unknown pathogenesis. This study investigated how overactive HRAS activity triggers arrhythmogenesis in atrial-like cardiomyocytes (ACMs) derived from human-induced pluripotent stem cells bearing CS-associated HRAS variants. METHODS: HRAS Gly12 mutations were introduced into a human-induced pluripotent stem cells-ACM reporter line. Human-induced pluripotent stem cells were generated from patients with CS exhibiting tachyarrhythmia. Calcium transients and action potentials were assessed in induced pluripotent stem cell-derived ACMs. Automated patch clamping assessed funny currents. HCN inhibitors targeted pacemaker-like activity in mutant ACMs. Transcriptomic data were analyzed via differential gene expression and gene ontology. Immunoblotting evaluated protein expression associated with calcium handling and pacemaker-nodal expression. RESULTS: ACMs harboring HRAS variants displayed higher beating rates compared with healthy controls. The hyperpolarization activated cyclic nucleotide gated potassium channel inhibitor ivabradine and the Nav1.5 blocker flecainide significantly decreased beating rates in mutant ACMs, whereas voltage-gated calcium channel 1.2 blocker verapamil attenuated their irregularity. Electrophysiological assessment revealed an increased number of pacemaker-like cells with elevated funny current densities among mutant ACMs. Mutant ACMs demonstrated elevated gene expression (ie, ISL1, TBX3, TBX18) related to intracellular calcium homeostasis, heart rate, RAS signaling, and induction of pacemaker-nodal-like transcriptional programming. Immunoblotting confirmed increased protein levels for genes of interest and suppressed MAPK (mitogen-activated protein kinase) activity in mutant ACMs. CONCLUSIONS: CS-associated gain-of-function HRASG12 mutations in induced pluripotent stem cells-derived ACMs trigger transcriptional changes associated with enhanced automaticity and arrhythmic activity consistent with multifocal atrial tachycardia. This is the first human-induced pluripotent stem cell model establishing the mechanistic basis for multifocal atrial tachycardia in CS.