Complex Disease Research Articles

Inhibitors of the mTOR signaling pathway can play an important role in breast cancer immunopathogenesis.

This study explores the critical role of inhibitors targeting the mammalian target of rapamycin (mTOR) signaling pathway in breast cancer research and treatment. The mTOR pathway, a central regulator of cellular processes, has been identified as a crucial factor in the development and progression of breast cancer. The essay explains the complex molecular mechanisms through which mTOR inhibitors, such as rapamycin and its analogs, exert their anticancer effects. These inhibitors can stop cell growth, proliferation, and survival in breast cancer cells by blocking critical signaling pathways within the mTOR pathway. Furthermore, the essay discusses the implications of using mTOR inhibitors as a comprehensive therapeutic strategy. It emphasizes the potential benefits of combining mTOR inhibitors with other treatment approaches to enhance the effectiveness of breast cancer treatment. The evolving landscape of breast cancer research underscores the significance of mTOR as a therapeutic target and highlights ongoing efforts to improve and optimize mTOR inhibitors for clinical use. In conclusion, the essay asserts that inhibitors of the mTOR signaling pathway offer a promising approach in the fight against breast cancer. These inhibitors provide a focused and effective intervention targeting specific dysregulations within the mTOR pathway. As research advances, the integration of mTOR inhibitors into customized combination therapies holds excellent potential for shaping a more effective and personalized approach to breast cancer treatment, ultimately leading to improved outcomes for individuals affected by this complex and diverse disease.

Single Nucleotide Polymorphisms (SNPs) in the Shadows: Uncovering their Function in Non-Coding Region of Esophageal Cancer.

Esophageal cancer is a complex disease influenced by genetic and environmental factors. Single nucleotide polymorphisms (SNPs) in non-coding regions of the genome have emerged as crucial contributors to esophageal cancer susceptibility. This review provides a comprehensive overview of the role of SNPs in non-coding regions and their association with esophageal cancer. The accumulation of SNPs in the genome has been implicated in esophageal cancer risk. Various studies have identified specific locations in the genome where SNPs are more likely to occur, suggesting a location-specific response. Chromatin conformational studies have shed light on the localization of SNPs and their impact on gene transcription, posttranscriptional modifications, gene expression regulation, and histone modification. Furthermore, miRNA-related SNPs have been found to play a significant role in esophageal squamous cell carcinoma (ESCC). These SNPs can affect miRNA binding sites, thereby altering target gene regulation and contributing to ESCC development. Additionally, the risk of ESCC has been linked to base excision repair, suggesting that SNPs in this pathway may influence disease susceptibility. Somatic DNA segment alterations and modified expression quantitative trait loci (eQTL) have also been associated with ESCC. These alterations can lead to disrupted gene expression and cellular processes, ultimately contributing to cancer development and progression. Moreover, SNPs have been found to be associated with the long non-coding RNA HOTAIR, which plays a crucial role in ESCC pathogenesis. This review concludes with a discussion of the current and future perspectives in the field of SNPs in non-coding regions and their relevance to esophageal cancer. Understanding the functional implications of these SNPs may lead to the identification of novel therapeutic targets and the development of personalized approaches for esophageal cancer prevention and treatment.

Lactucin ameliorates FFA-induced steatosis in HepG2 cells by modulating mitochondrial homeostasis through the SIRT1/PGC-1α signaling axis

Nonalcoholic fatty liver disease is a complex disease involving abnormal liver metabolism. Its strong association with metabolic dysfunction has led to a change in nomenclature to metabolism dysfunction-associated fatty liver disease (MAFLD). MAFLD pathogenesis involves abnormal accumulation of hepatic lipids that lead to the production of excess free fatty acids (FFAs), which in turn cause an imbalance in hepatic mitochondrial function. Lactucin, a natural compound extracted from Cichorium glandulosum Boiss. et Huet, regulates liver metabolism and protects the liver. However, the potential mechanisms underlying the lactucin-mediated effects in MAFLD require further investigation. In the present study, HepG2 cells were treated with FFAs to establish an in vitro model of MAFLD. Parameters related to lipid accumulation and mitochondrial function, including triglycerides (TG), oil red O-stained lipid droplets, reactive oxygen species (ROS), mitochondrial membrane potential (JC-1), adenine triphosphate (ATP), and complex III were analysed. Morphology of the mitochondria were evaluated by transmission electron microscopy. Furthermore, key proteins in the sirtuin 1 (SIRT1)/peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) signalling axis and mitochondrial quality control were analysed. The SIRT1 inhibitor EX-527 was used to verify the key role of the SIRT1 signalling pathway. Western blotting showed that lactucin upregulated the expression of SIRT-1, PGC-1α, Nrf1, Tfam, Mfn2, and Opa1, and promoted mitochondrial biosynthesis and kinetics. The results suggest that lactucin restores mitochondrial dynamic homeostasis by upregulating the SIRT1/PGC-1α signalling axis, thereby reducing FFA-induced lipid accumulation in HepG2 cells.

Repercussion of Primary Nucleation Pathway: Dementia and Cognitive Impairment.

Neurodegenerative diseases, such as Alzheimer's, Parkinson's, and prion disease, are characterized by the conversion of normally soluble proteins or peptides into aggregated amyloidal fibrils. These diseases result in the permanent loss of specific types of neurons, making them incurable and devastating. Research on animal models of memory problems mentioned in this article contributes to our knowledge of brain health and functionality. Neurodegenerative disorders, which often lead to cognitive impairment and dementia, are becoming more prevalent as global life expectancy increases. These diseases cause severe neurological impairment and neuronal death, making them highly debilitating. Exploring and understanding these complex diseases offer significant insights into the fundamental processes essential for maintaining brain health. Exploring the intricate mechanisms underlying neurodegenerative diseases not only holds promise for potential treatments but also enhances our understanding of fundamental brain health and functionality. By unraveling the complexities of these disorders, researchers can pave the way for advancements in diagnosis, treatment, and ultimately, improving the lives of individuals affected by neurodegenerative diseases.

Comparison of Short Fast Fourier Transform and Continuous Wavelet Transform in Study of Stride Interval

Neurodegenerative diseases (NDD) are a heterogeneous group of complex diseases characterized by neuronal loss and progressive degeneration of different areas of the nervous system. Gait analysis presents an early recognition system for NDD which is important to increase the patient’s awareness of their health conditions. However, it is very difficult to identify and formulate suitable digital biomarkers from the data collected from gait experiments such as stride interval and swing. The objective of this paper is to compare the result of Short - Time Fourier Transform (STFT) and Continuous Wavelet Transform (CWT) on the collected stride interval of healthy young people and healthy old people. In this paper, STFT and CWT are performed on the collected stride interval and from the result of the STFT and CWT, further features are extracted like instantaneous RMS and maximum RMS value. STFT is performed on the collected stride interval from a window length of 64 to 512 while CWT is performed on the collected stride interval from the scale of 128 to 2048. The processing time of the STFT and CWT with varied window lengths and scales respectively are collected. Besides, the actual maximum time from the time - frequency plot derived from STFT and CWT is also collected. Both STFT and CWT show that the young group has a higher maximum RMS, an indication of higher stride interval than the old group and higher variance, an indication of higher gait complexity. The suitable window lengths for STFT in analyzing the stride interval are 64 and 128 while the scale for CWT should be set to the lowest scale. Overall, STFT with a window length of 64 and 128 is better in analyzing the stride interval due to low processing time at the expense of slightly less accurate time - frequency representation.

Modulation of biomineralization morphology by phosphorylated collagen peptides: insights into osteogenesis imperfecta pathophysiology.

Osteogenesis imperfecta (OI) is a hereditary skeletal disorder characterized by bone fragility and deformities, primarily attributed to defects in type I collagen, the most abundant structural protein in humans. Multiple phosphorylation sites have been detected within collagen, suggesting that phosphorylation may influence mineralization processes, thereby impacting the development of OI. In this study, we investigated the modulation of biomineralization morphology by phosphorylated collagen peptides mimicking Gly-Ser mutations in osteogenesis imperfecta. A series of collagen peptide sequences, including GPO13S, GPO13pS, GPO12S, GPO12pS, GPO11S, and GPO11pS, were synthesized to explore the role of phosphorylation in peptide stability and its templating effect on biomineralization. The CD results indicated that the phosphorylation of Gly-pSer mutants reduces the stability of collagen peptides. SEM images revealed that phosphorylated peptides acted as templates, guiding the morphology of calcium carbonate into either olive-like or spherical structures, depending on their conformational state of the peptides. Non-phosphorylated peptides maintained a calcite crystal structure. The XRD patterns predominantly exhibited peaks associated with calcite and vaterite for GPO13pS-CaCO3, GPO12pS-CaCO3, and GPO11pS-CaCO3, and peaks associated with calcite for GPO13S-CaCO3, GPO12S-CaCO3, and GPO11S-CaCO3, indicating a transformation of mesocrystals influenced by peptide phosphorylation. Our findings elucidate the crucial role of phosphorylated collagen peptides in mediating biomineralization morphology and polymorph selection, offering insights into the complex pathophysiology of OI.

Association between completeness of revascularization and cardiovascular outcomes in patients with diabetes and non-ST elevation myocardial infarction: a population-based registry analysis

Abstract Introduction Approximately one-third of the patients presenting with non-ST elevation myocardial infarction (NSTEMI) have diabetes. From these, two-thirds have multivessel coronary disease. The impact of completeness of revascularization in this population remains unclear. Purpose To evaluate the contemporary patterns of coronary revascularization among patients with diabetes and NSTEMI, and the clinical outcomes stratified by anatomic completeness of revascularization. Methods All patients with diabetes and multivessel disease admitted for NSTEMI between April 2009 and March 2020 in Ontario, Canada were included. Patients with previous coronary artery bypass graft surgery (CABG) at any time, percutaneous coronary intervention (PCI) in the previous 90 days, or shock were excluded. Patients were classified in four groups, from the most to the least complete revascularization strategy: CABG, complete revascularization with PCI, incomplete revascularization with PCI, or no revascularization. Outcomes included all-cause death and the composite of all-cause death, myocardial infarction, and stroke. Multivariable Cox regression was used to account for confounding (demographics, comorbidities, left ventricular function, coronary anatomy, laboratory tests, and diabetes treatment). Results We included 14,511 patients (mean age: 68.7±11.5y; 69.6% males). A total of 4,525 (31.2%) patients were treated with CABG, 3,008 (20.7%) with complete PCI, 3,624 (25.0%) with incomplete PCI and 3,354 (23.1%) were not revascularized. Patients with more complex coronary disease were more frequently treated with CABG, while PCI was more common in those with less complex disease (p<0.001; Fig 1). The mean number of grafts in the CABG group was 3.4±1.0. The mean number of stents in the complete and incomplete PCI groups was 2.4±1.3 and 1.7±0.9, respectively. Adjusted 5-y risks of all-cause death following CABG, complete PCI, incomplete PCI and no revascularization were, respectively, 25.9%, 29.8%, 32.2%, and 39.4%. Over a median follow-up of 5.8ys, CABG was associated with reduced all-cause death compared with complete PCI (HR 0.82; 95%CI 0.75 - 0.90), incomplete PCI (HR 0.73; 95%CI 0.67 - 0.80), or no revascularization (HR 0.54; 95%CI 0.50 - 0.58); p<0.001 for all (Fig 2). Adjusted 5-y risks of the composite endpoint following CABG, complete PCI, incomplete PCI and no revascularization were, respectively, 34.0%, 41.5%, 44.6%, and 52.9%. CABG was associated with reduced rates of the composite endpoint compared with complete PCI (HR 0.75; 95%CI 0.69 - 0.81), incomplete PCI (HR 0.67; 95%CI 0.62 - 0.72), or no revascularization (HR 0.50; 95%CI 0.47 - 0.54); p<0.001 for all. Conclusion In this contemporary real-world cohort study, almost a quarter of the patients with diabetes and NSTEMI did not receive any revascularization procedure. Cardiovascular outcomes were incrementally improved with CABG or complete revascularization with PCI, compared to no revascularization.Figure 1Figure 2

Impact of fractional flow reserve measurement on angina frequency in the invasive arm of the ISCHEMIA trial

Abstract Introduction Fractional flow reserve (FFR) is an invasive, lesion-specific surrogate for myocardial ischemia. The use of FFR to guide lesion selection for revascularization is believed to improve outcomes compared to an angiographic approach because it allows categorization of lesions based on hemodynamic significance. Lesions that are not hemodynamically significant can be safely deferred while the revascularization of significant lesions has been reported to improve quality of life compared to medical therapy alone. Purpose To compare the outcomes of patients randomized to the invasive (INV) arm of the ISCHEMIA trial who underwent FFR during initial angiography with those whose treatment was guided by angiography alone. Methods The ISCHEMIA data set was obtained from the National Heart, Lung, and Blood Institute under a data use agreement. Subjects randomized to the INV arm who underwent FFR were compared to those who underwent angiography alone. Categorial variables were compared using the chi-squared or Fisher’s exact test. Continuous variables were compared using the student T-test or Wilcoxon rank sum test. Multivariable linear mixed effects regression was used to evaluate the association of FFR use on SAQ7 AF score as well as assess changes across five years of follow-up. Covariates included in the model were based on their univariate and clinical significance. All tests were two-sided and P<0.05 was considered statistically significant. Results Of the 5,179 patients with chronic coronary syndromes and at least moderate ischemia on stress testing, 2588 were assigned to the INV strategy and 2210 had data available for analysis. Of these individuals, 410 (19%) had FFR performed during their diagnostic angiogram. Females comprised 24% of FFR patients and 24% of non-FFR patients (P=0.85). FFR patients were older than non-FFR patients (65.7 [8.7] years vs. 64.3 [9.6] years, P=0.006). The incidence of hypertension, diabetes, smoking, or prior MI at baseline did not differ between groups. Mean ejection fraction did not differ between groups. Fewer FFR patients had severe ischemia at baseline (45% vs. 52%) and more had mild or moderate ischemia (54% vs. 48%) (P=0.009). FFR patients had fewer native vessels with >70% stenosis than non-FFR patients (1.0[0.9] vs. 1.5[1.0], P<0.001), and less complex disease as assessed by the Duke jeopardy score (P<0.001). On multivariable linear mixed effects regression, FFR was not associated with a significant change in the SAQ AF score (0.56 (-0.85 – 1.97; P=0.44)), after adjusting for other covariates. However, the SAQ7 AF score was 0.22 units less in those that underwent FFR compared to those that did not (95%CI=-0.44 – -0.01; P=0.043) when assessed over follow-up time. Conclusion ISCHEMIA patients randomized to an INV strategy who underwent physiologic assessment with FFR had no improvement in angina frequency compared to those who underwent angiography alone.

Alarin regulates RyR2 and SERCA2 to improve cardiac function in heart failure with preserved ejection fraction

Heart failure with preserved ejection fraction (HFpEF), a complex disease that is increasingly prevalent due to population aging, pose significant challenges in its treatment. The present study utilized the HFpEF rat model and H9C2 cells as research subjects to thoroughly investigate the potential mechanisms of alarin in protecting cardiac function in HFpEF. The study shows that under HFpEF conditions, oxidative stress significantly increases, leading to myocardial structural damage and dysfunction of calcium ion channels, which ultimately impairs diastolic function. Alarin, through its interaction with NADPH oxidase 1 (NOX1), effectively alleviates oxidative stress and modulates the activities of type 2 ryanodine receptor (RyR2) and sarcoplasmic/endoplasmic reticulum calcium ATPase 2 (SERCA2), thereby facilitating the restoration of Ca2+ homeostasis and significantly improving cardiac function in the HFpEF model. This research not only uncovers the cardioprotective effects of alarin and its underlying molecular mechanisms but also provides new insights and potential therapeutic targets for HFpEF treatment strategies, suggesting a promising future for alarin and related therapies in the management of this debilitating condition.

Druggable targets for Parkinson’s disease: transcriptomics based Mendelian randomization study

Parkinson’s disease (PD) is a prevalent neurodegenerative disorder. Currently available drugs for PD, can only relieve the symptoms of PD, but cannot prevent the progression of the disease and have serious side effects. Other new druggable therapeutic targets for PD are needed. First, six GEO datasets with transcriptomic data from the substantia nigra (SN) region of the brain were downloaded to find dysregulated druggable genes in PD. Then, Mendelian randomization (MR) and summary statistics-based MR (SMR) analysis were conducted using eQTL data from both brain tissue and blood to investigate the relationship between gene expression and PD. Next, the association between the expression of candidate druggable targets and disease stage was validated in an additional dataset GSE49036. Finally, a phenome-wide MR analysis was carried out to investigate the potential impact of candidate druggable genes on several other complex diseases or traits. Our study revealed 313 differentially expressed genes that may be directly targetable and have an impact on PD (FDR-p < 0.1). Through MR and SMR analysis, P2RX7 and RNASET2 were identified as feasible PD therapeutic targets, which were highly expressed in PD tissues and increased as the Braak stages increased. Phenome-wide MR analysis revealed other effects of targeting RNASET2. This study presents genetic support for the potential therapeutic properties of targeting P2RX7 and RNASET2, which will be useful for developing druggable therapeutic targets for PD.

Oral low-dose rapamycin treatment prevents aortic aneurysms in marfan mice

Abstract Background/Introduction Marfan syndrome (MFS) is a hereditary connective tissue disorder caused by fibrillin-1 (FBN1) gene mutations. Life-threatening complications are cardiovascular, e.g. thoracic aortic aneurysms and dissections. The pathophysiological cause is the increased release of transforming growth factor β-1 (TGF-β1) from the FBN1-deficient extracellular matrix (ECM) and structural disintegrity. Overactivation of the mechanistic target of rapamycin (mTOR) pathway has been demonstrated in the murine mgR/mgR model of MFS. Short-term administration of rapamycin significantly reduced aortic aneurysm formation and increased the life span in these mice. Purpose To assess the effect of an early continuous oral low-dose rapamycin treatment on the aortic aneurysm formation in the FBN1 hypomorphic mgR/mgR mouse model. Methods Male and female 3-4 week-old mgR/mgR mice were orally administered vehicle or rapamycin through diet (8mg/kg/KG) and sacrificed after 11 weeks. Rapamycin concentration was measured by liquid chromatography-mass spectrometry in whole blood. Aortic diameter was studied using echocardiography. Histopathological and immunofluorescence analyses were performed using aortic tissue sections and techniques. Results Blood rapamycin concentration following oral administration remained below detection level. Rapamycin normalized the aortic wall thickness and the diameter in female mgR/mgR mice to levels of the littermate control mice but not in male mgR/mgR mice. The circumferentially distributed elastin fibres remained significantly intact in sections of the ascending aorta of female mice. Echocardiography revealed that rapamycin-treated female mice stayed below a cut-off value for aortic aneurysms of 2 mm inner aortic diameter eight weeks after starting therapy. In contrast, vehicle-treated female animals already exceeded this value after five weeks. In female but not in male mice, the abundance of the mTOR downstream target phosphorylated ribosomal protein S6 was effectively suppressed by low-dose rapamycin up to levels detected in control animals. At the same time, extracellular matrix proteins like the proteoglycan aggrecan (ACAN) and the related chondroitin sulfate were significantly decreased in female mice. The abundance of ADAMTS5 transglutaminase-2 and xylosyltransferase-1, key enzymes involved in the turnover of proteoglycans and biosynthesis of glycosaminoglycan chains, was improved by the rapamycin treatment in female mice. No decrease in mTOR activity could be detected in male mgR/mgR animals. Here, the ACAN and chondroitin sulphate levels also remained at the level of the vehicle-treated animals. Conclusions Chronic low-dose rapamycin treatment reduced aneurysm formation only in female mgR/mgR mice, since the dose was too low for male mgR/mgR mice, by affecting the composition and organization of key ECM components essential for maintaining aortic homeostasis and mechanical properties.

The influence of genetic mutations on multilayer global longitudinal strain values in patients with hypertrophic cardiomyopaty

Abstract Background Hypertrophic cardiomyopathy (HCM) is a hereditary heart muscle disorder characterized by diverse genetic mutations. Multilayer global longitudinal strain (GLS) analysis has emerged as a valuable tool for assessing myocardial function. This study aimed to investigate the influence of genetic mutations on myocardial deformation patterns in HCM patients using multilayer GLS analysis. Methods A total of 83 adult patients diagnosed with HCM were included in the study. Genetic testing was performed to identify specific genetic mutations associated with HCM. Echocardiographic assessments were conducted to measure multilayer GLS values for endocardial, mid-myocardial, and epicardial layers. Patients were divided into gene-positive and gene-negative groups for comparative analysis. Results In the gene-negative group (n=41), the mean age was 57.1 ± 11.0 years, whereas in the gene-positive group (n=42), it was 55.5 ± 11.6 years (p=0.516). Significant differences were observed in endocardial (-16.1 ± 2.3 vs. -13.4 ± 3.2, p &amp;lt; 0.001) and mid-myocardial (-14.2 ± 2.1 vs. -12.3 ± 3.1, p = 0.002) GLS involvement between gene-negative and gene-positive HCM patients. However, no significant disparity in epicardial strain was detected. Conclusion The findings demonstrated a greater involvement of the endocardial and mid-myocardial layers in the group of HCM patients with positive genetic mutations. Multilayer GLS analysis has the potential to aid in the identification of subtle alterations in myocardial function associated with specific genetic mutations, contributing to refined risk assessment and personalized management strategies for HCM patients.

Out-of-hospital cardiac arrest in patients with psoriasis

Abstract Background Psoriasis is a complex autoinflammatory disease that has been associated with atherosclerosis, higher risks of cardiovascular diseases, and electrocardiographic changes. Whether these risk factors lead to higher risks of out-of-hospital cardiac arrest (OHCA) is undetermined. Purpose To investigate whether psoriasis is associated with OHCA. Method Using the nationwide Danish Cardiac Arrest Registry, we identified adult (≥18 years) OHCA patients of presumed cardiac cause with and without psoriasis between June 1st 2001 and December 31st 2019. The association of cardiac arrest was estimated using time-varying Cox regression fitted with a nested case-control design where we matched up to five controls per case on age, sex and year of OHCA and 4 comorbidities: ischemic heart disease, congestive heart failure, cardiovascular risk factors, and major extra cardiac organ disease. In subgroup analyses, the main analysis was repeated in patients with severe psoriasis (presence of inpatient hospital contact during the previous year) as compared to mild psoriasis. Results We included 43,967 OHCA cases and matched with 219,772 controls from the general population. The median age was 72 years, 68% were male and 26% had ischemic heart disease, 21% had congestive heart failure, 57% had cardiovascular risk factors, and 33% had extra cardiac organ disease (Table 1). We identified 1,145 (2.6%) cases and 4,971 (2.3%) controls who had psoriasis. Compared with cardiac arrest cases without psoriasis, cases with psoriasis had similar age and sex distribution, prevalence of ischemic heart disease, and congestive heart failure, but a higher prevalence of cardiovascular risk factors, major extra cardiac organ disease and Charlson score distribution. Psoriasis was significantly associated with higher hazard ratios of OHCA: HR 1.16 [95% confidence interval: 1.08 - 1.23] (Figure 1). Compared to no psoriasis, having severe psoriasis was significantly associated with higher hazard of OHCA: HR 1.98 [95% confidence interval: 1.10 - 3.61], while mild psoriasis was not (Figure 1). Conclusion In this nationwide nested case-control study, psoriasis was significantly associated with increased hazard of out-of-hospital cardiac arrest. Furthermore, the association was only significant with severe psoriasis compared to those without psoriasis, while mild psoriasis was not. This study highlights the importance of examining cardiovascular risk factors and prioritizing prevention of cardiovascular disease in patients with psoriasis.Figure 1Table 1

SLC16A8 is a causal contributor to age-related macular degeneration risk

Age-related macular degeneration (AMD), a complex neurodegenerative disease, is a leading cause of visual impairment worldwide with a strong genetic component. Genetic studies have identified several loci, but few causal genes with functional characterization. Here we highlight multiple lines of evidence which show a causal role in AMD for SLC16A8, which encodes MCT3, a retinal pigment epithelium (RPE) specific lactate transporter. First, in an unbiased, genome-wide analysis of rare coding variants we show multiple SLC16A8 rare variants are associated with AMD risk, corroborating previous borderline significant reports from AMD rare variant studies. Second, we report a novel SLC16A8 mutation in a three-generation family with early onset macular degeneration. Finally, mis-expression in multiple model organisms shows functional and anatomic retinal consequences. This study highlights the important role for SLC16A8 and lactate regulation towards outer retina/RPE health and highlights a potential new therapeutic opportunity for the treatment of AMD.

Reduced Na current in dystrophin-deficient ventricular cardiomyocytes is rescued by tenascin-C inhibition

Abstract Background Duchenne muscular dystrophy (DMD) is an X-linked hereditary disease triggered by the deficiency of the structural protein dystrophin, which leads to muscular degeneration mainly affecting young males. Major contributors to early death in DMD patients are cardiac arrhythmias and dystrophic cardiomyopathy. One cause for arrhythmias is impaired ventricular impulse conduction, which leads to ventricular asynchrony and reentrant mechanisms. We recently showed that the disruption of dystrophin results in a significant reduction of Na current in ventricular cardiomyocytes (vCMs) of the dystrophin-deficient mdx mouse model for human DMD. Na current reduction provides a mechanistic explanation for the impaired ventricular conduction and accompanying arrhythmias in the dystrophic heart. The extracellular matrix protein tenascin-C (TN-C) is a significant remodeling factor in the injured and diseased heart and is strongly upregulated in dystrophic cardiomyopathy. To this date, it is unknown how the upregulation of TN-C in DMD patients affects dystrophic cardiomyopathy. Purpose In this study, we examined the effect of TN-C inhibition on diminished Na currents in dystrophin-deficient vCMs. Methods We compared four different mouse genotypes with each other, namely wild-type, dystrophin-deficient mdx, TN-C-deficient and dystrophin- plus TN-C-deficient mice. Furthermore, a cohort of mdx mice was injected with TN-C siRNA twice a week for 9 weeks to investigate the effect of TN-C knockdown. Hearts from adult male mice were enzymatically digested using a Langendorff system to isolate single vCMs. Na currents were then measured with the whole cell patch clamp technique. Results Na current densities were increased in TN-C deficient vCMs compared to wild-type vCMs. Accordingly, 24-hour incubation of wild-type vCMs with human recombinant TN-C resulted in a significant decrease in Na current. Na currents of vCMs from mdx mice were reduced, but restored to the wild-type level in vCMs from TN-C-deficient mdx mice. Moreover, vCMs of TN-C siRNA-treated mdx mice had significantly increased Na currents compared to control mdx vCMs. Conclusion Upregulation of TN-C in dystrophin-deficient vCMs reduces Na currents, whereas inhibition of TN-C prevents this reduction. Therefore, inhibition of TN-C in DMD patients may be considered as a potential new therapeutic strategy to improve ventricular conduction and reduce arrhythmia vulnerability.

Cardiovascular health in women with turner's syndrome: a 3-year single centre audit

Abstract Background Turner’s syndrome (TS) is the most common genetic abnormality affecting females and is characterised by complete or partial absence of the X chromosome. Mortality is predominantly related to cardiovascular disease (1). Risk of life-threatening aortic dissection is 40 per 100,000 (2). Indexed aorta size (ASI) to body surface area (BSA) &amp;gt;20mm/m² is considered abnormal. An ASI of ≥25mm/m² is associated with increased risk of aortic dissection (3). Despite this there is a paucity of data in the literature regarding TS cardiovascular disease and providing evidence-based care can be challenging. Purpose Define cardiovascular disease, with focus upon aortopathy in our TS Cardiovascular Clinic (TCC). Methods Single centre retrospective medical record analysis of 248 women with TS (2021-2024) Results Patient baseline characteristics; mean age 37 years (range 18-75yrs), height 150cm (132-169cm), weight 62kg (37-130kg), BSA 1.55m² (1.19-2.17m²). 65 patients (29%) had bicuspid aortic valve (BAV), 19 (8%) and 5 (3%) had repaired and un-repaired aortic coarctation (CoA) respectively. 30 (13%) had other congenital heart disease, with most common was partial anomalous pulmonary venous connection (12 patients: 5%). 22/248 patients had previous aortic root surgery; 20 elective (mean ASI 29mm/m², range 26-33mm/m², mean age at time of surgery 42 years); 2 presented with aortic dissection (ASI 21mm/m²; pregnant, BAV &amp; 24mm/m²; tri-leaflet aortic valve, TAV). Data was available for 221 unoperated patients (figure 1). The site of maximal dimension was observed at the sinus of Valsalva in 70% compared to 30% at the ascending aorta. 130 patients (59%) had maximal ASI of &amp;lt;20mm/m². Dimensions of 20-23mm/m² and 23-25mm/m² were seen in 64 (29%) and 18 (8%) patients respectively. 7 patients (3%) had a maximal ASI of &amp;gt;25mm/m². 4 patients (2%) had an absolute maximal dimension of 40mm with ASI of 23mm/m² for all four. 9/11 patients with dimension ≥25mm/m² or 40mm had a body mass index (BMI) &amp;gt;25kg/m². Review of medical history for patients at and above threshold for risk of aortic dissection revealed referral to or previous discussion in an Aortic multi-disciplinary meeting (MDT) with a plan for ongoing surveillance. 57 patients (35%) with TAV had significant aortopathy (mean age 46years, range 19-75years) compared with 33 (51%) with BAV (mean age 39yrs, range 22-72 years) (figure 2). Review of patients &amp;gt;55years of age demonstrated a very similar burden of aortopathy in both TAV (14%) and BAV (15%) populations. Conclusions A high burden of cardiovascular disease exists within our TS population. There is a very high prevalence of aortopathy, increasingly with age and both with and without the presence of a bicuspid aortic valve. More published data is needed to help better define those at risk.

KardioNet Digital - a structured care model involving digital tools for intersectoral communication and a patient-focused strategy for treatment of heart failure

Abstract Introduction Inefficiencies and discontinuities in care at the interfaces within Germany's healthcare system, especially between acute and outpatient care, present significant challenges in managing patients with heart failure (HF). The management complexity of HF has increased with the advent of new digital tools, though patient acceptance of these tools remains contentious. The prevention of loss of diagnostic and therapeutic information for this complex disease is crucial for cross-sectoral communication (hospital - office-based cardiologist - general practitioner) and quality of care. Purpose Our goal was to examine the impact of digital app-supported coordination of HF management across different healthcare providers from hospital discharge to the ambulatory sector and to assess patients' acceptance of a structured care program. A patient-focused digital strategy, supported by a Heart Failure Nurse (HFN), aimed to facilitate structured follow-up and patient empowerment, focusing on patient-reported outcomes and experiences (refer to Table 1). Results Out of 401 patients screened during their hospital stay for HF, only 57 (14.9% male, 12.6% female) participated in the KardioNet Digital (KND) program. NYHA classifications were I (3.5%), II (49.1%), III (40.4%), and IV (7.1%); Diagnoses included CMP (26, 45.6%), CAD (19, 33.3%), valvular HF (8, 14.0%), and others (4, 7.0%). The mean age was 55.03 years, with a notable difference in participation based on age (≥70 years: 9.5% male, 33.3% female; &amp;lt;70 years: 90.5% male, 66.7% female). Age was a significant determinant of program participation. Patients who regularly used the app benefited from several features: A total of 35 alerts (17 patients) were triggered for reasons such as bodyweight increase (2kg or more) and device-induced alerts (i.e. false shock delivery, 3x slow-VT, Syncope), leading the HFN to contact the patients. This early intervention prevented rehospitalization due to decompensation of heart failure in 11 patients (64.7%) and addressed device-related alarms for organizing an emergency hospital visit by HFN. Despite substantial incentives, such as support from an HFN and expedited appointments with specialists for follow-up therapy, refusal rates were high (refer to Table 2). Conclusion A structured, digitally supported cross-sectoral care model for heart failure patients can potentially improve care coordination and outcomes. However, the success of such programs critically depends on patient willingness and the seamless integration into existing healthcare structures. Despite valuable incentives, we observed low acceptance of the program. Even among motivated participants (14.1%), there is a significant need for substantial support and education on digital literacy for the widespread implementation of digital tools in real-world settings for the treatment of heart failure.Workflow of structured digital supportReasons for Declining Participation

Gene-gene and gene-environment interaction in coronary artery disease risk

Abstract Coronary Artery Disease (CAD) is a lethal illness that kills millions of individuals each year worldwide. This disorder is multifactorial, resulting in the complex interplay of genetic, epigenetic, and environmental factors. Exploring gene-gene and gene-environment interactions is essential to understanding the aetiology of common complex diseases like CAD. Aim We proposed investigating the interaction between two genetic variants robustly associated with CAD by GWAS (MTHFR rs1801133 and APOE rs7412/rs429358) in cardiovascular susceptibility. After that, consider whether there was a new interaction between this genetic association and environment (hypertension, dyslipidemia and smoking). Methods A case-control study enrolled 3,157 individuals, 1,721 coronary patients (with at least 70% stenosis of one or more major coronary arteries or its primary branches on the coronary angiography) and 1,436 controls without CAD. Traditional risk factors were investigated, and the two polymorphisms were performed by TaqMan real-time PCR. Bivariate analysis was used to study genotypic proportions between CAD and non-CAD patients with respective odds ratios (OR). Logistic regression analysis displayed the interaction between the two genetic variants each other and with some important environmental risk factors. Results In bivariate analysis, the genetic models were studied for both genes, being the dominant model the one which showed significance for CAD. In MTHFR, 57.8% of the patients and 53.4% of the controls presented the CT+TT genotype (OR=1.20; p=0.013). In APOE, 26.5% of the patients and 22.3% of the controls had E2E4;E3E4+E4E4 (OR=1.26; p=0.006). The first multivariate logistic regression showed a synergistic interaction between the two genetic variants (OR=1.50; p=0.001). After adjusting for conventional risk factors, the logistic regression analysis entered the MTHFR rs1801133 and APOE rs7412/rs429358, showing a combined interaction effect between those genes and smoking status with an OR of 3.44 (p&amp;lt;0.0001), with hypertension (OR=1.55; p=0.002) and with dyslipidemia (OR=1.71; p&amp;lt;0.0001). Conclusion According to our results, the genetic interaction between APOE and MTHFR synergistically affected the susceptibility to CAD. This interaction, linked to conventional risk factors, consistently increased the risk of CAD in our population, particularly in the group of genetic carriers who did not quit smoking.

Metabolic Reprogramming in Cancer: Implications for Immunosuppressive Microenvironment.

Cancer is a complex and heterogeneous disease characterised by uncontrolled cell growth and proliferation. One hallmark of cancer cells is their ability to undergo metabolic reprogramming, which allows them to sustain their rapid growth and survival. This metabolic reprogramming creates an immunosuppressive microenvironment that facilitates tumour progression and evasion of the immune system. In this article, we review the mechanisms underlying metabolic reprogramming in cancer cells and discuss how these metabolic alterations contribute to the establishment of an immunosuppressive microenvironment. We also explore potential therapeutic strategies targeting metabolic vulnerabilities in cancer cells to enhance immune-mediated anti-tumour responses. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT02044861, NCT03163667, NCT04265534, NCT02071927, NCT02903914, NCT03314935, NCT03361228, NCT03048500, NCT03311308, NCT03800602, NCT04414540, NCT02771626, NCT03994744, NCT03229278, NCT04899921.

Dual phenotypes in recurrent astrocytoma, IDH-mutant; coexistence of IDH-mutant and IDH-wildtype components: a case report with genetic and epigenetic analysis

Mutations in the isocitrate dehydrogenase (IDH) gene are recognized as the key drivers in the oncogenesis of astrocytoma and oligodendroglioma. However, the significance of IDH mutation in tumor maintenance and malignant transformation has not been elucidated. We encountered a unique case of IDH-mutant astrocytoma that, upon malignant transformation, presented two distinct intratumoral components: one IDH-wildtype and one IDH-mutant. The IDH-wild-type component exhibited histological findings similar to those of small cell-type glioblastoma with a higher Ki-67 index than the IDH-mutant component. Despite their genetic divergence, both components exhibited similar comprehensive methylation profiles within the CpG island and were classified into methylation class of “Astrocytoma, IDH-mutant; High Grade” by the German Cancer Center (DKFZ) classifier v11.4. Phylogenetic analysis demonstrated that the IDH-wildtype component emerged as a subclonal component of the primary tumor. Detailed molecular analyses revealed that the loss of the IDH mutation was induced by the hemizygous loss of the entire arm of chromosome 2, on which IDH1 gene is located. Notably, the IDH-wild-type subclones uniquely acquired CDKN2A/B homozygous deletion and PDGFRA amplification, which is a marker of the aggressive phenotype of astrocytoma, IDH-mutant. Because these genetic abnormalities can drive oncogenic pathways, such as the PI3K/AKT/mTOR and RB signaling pathway, IDH-mutant gliomas that acquired these mutations were no longer dependent on the initial driver mutation, the IDH mutation. Molecular analysis of this unique case provides insight that in a subset of astrocytoma, IDH-mutant that acquired these genetic abnormalities, IDH mutation may not play a pivotal role in tumor growth and acquisition of these genetic abnormalities may contribute to the acquisition of resistance to IDH inhibitors.