THBru attenuates diabetic cardiomyopathy by inhibiting RAGE-dependent inflammation.

Diabetic cardiomyopathy (DCM) is a complication of diabetes mellitus characterized by heart failure and cardiac remodeling. Previous studies show that tetrahydroberberrubine (THBru) retrogrades cardiac aging by promoting PHB2-mediated mitochondrial autophagy and prevents peritoneal adhesion by suppressing inflammation. In this study we investigated whether THBru exerted protective effect against DCM in db/db mice and potential mechanisms. Eight-week-old male db/db mice were administered THBru (25, 50 mg·kg-1·d-1, i.g.) for 12 weeks. Cardiac function was assessed using echocardiography. We showed that THBru administration significantly improved both cardiac systolic and diastolic function, as well as attenuated cardiac remodeling in db/db mice. In primary neonatal mouse cardiomyocytes (NMCMs), THBru (20, 40 µM) dose-dependently ameliorated high glucose (HG)-induced cell damage, hypertrophy, inflammatory cytokines release, and reactive oxygen species (ROS) production. Using Autodock, surface plasmon resonance (SPR) and DARTS analyses, we revealed that THBru bound to the domain of the receptor for advanced glycosylation end products (RAGE), subsequently leading to inactivation of the PI3K/AKT/NF-κB pathway. Importantly, overexpression of RAGE in NMCMs reversed HG-induced inactivation of the PI3K/AKT/NF-κB pathway and subsequently counteracted the beneficial effects mediated by THBru. We conclude that THBru acts as an inhibitor of RAGE, leading to inactivation of the PI3K/AKT/NF-κB pathway. This action effectively alleviates the inflammatory responses and oxidative stress in cardiomyocytes, ultimately leading to ameliorated DCM.

Genetic dissection of the impact of lncRNA AI662270 during the development of atherosclerosis.

BACKGROUND: Atherosclerosis is driven by synergistic interactions between pathological biomechanical and lipid metabolic factors. Long noncoding RNAs (LncRNAs) have been implicated in atherogenesis. The purpose of this study was to investigate the potential mechanism of lncRNA AI662270 on macrophage cholesterol transport in atherosclerosis. METHODS: Apolipoprotein E deficiency (ApoE-/-) mice were fed a high fat diet for 16 weeks to construct atherosclerotic model, and the mice were injected with recombinant lentivirus carrying AI662270 gene to overexpress AI662270. Macrophages were cleared by liposomal clondronate in vivo. Fundamental experiments and functional assays, hematoxylin and eosin staining, oil red O staining and others, were performed to evaluate the function of AI662270 on atherogenesis. Peritoneal macrophages were treated with oxidized low density lipoprotein (ox-LDL) to simulate in vitro model. Mechanism assays, RNA-interacting protein immunoprecipitation, RNA-protein pulldown and others, were performed to study the regulatory mechanism of AI662270 in macrophages. RESULTS: The novel AI662270 was mainly enriched in macrophages, but not in endothelial cells, smooth muscle cells and fibroblasts of mouse atherosclerotic lesions and was upregulated by ox-LDL. Overexpression of AI662270 resulted in lipid accumulation, larger atherosclerotic plaques and cardiac dysfunction in vivo. After macrophages were removed, the pro-atherogenic effect of AI662270 disappeared. Downregulation of AI662270 in macrophages protected against foam cell formation by potentiating cholesterol efflux and reducing intracellular total cholesterol. The opposite effect was observed in macrophage-specific AI662270-overexpressed cells in vitro. AI662270 bound to adenosine triphosphate-binding cassette transporter A1 (Abca1) responsible for regulating cholesterol efflux in macrophages. Forced expression of AI662270 in macrophages decreased Abca1 expression. The reverse occurred when expression of AI662270 was repressed. CONCLUSION: These findings reveal an essential role for AI662270 in atherosclerosis progression by regulating cholesterol efflux from macrophages.

Nitidine chloride induces cardiac hypertrophy in mice by targeting autophagy-related 4B cysteine peptidase.

Nitidine chloride (NC) is a standard active component from the traditional Chinese medicine Zanthoxylum nitidum (Roxb.) DC. (ZN). NC has shown a variety of pharmacological activities including anti-tumor activity. As a number of anti-tumor drugs cause cardiotoxicity, herein we investigated whether NC exerted a cardiotoxic effect and the underlying mechanism. Aqueous extract of ZN (ZNE) was intraperitoneally injected into rats, while NC was injected into beagles and mice once daily for 4 weeks. Cardiac function was assessed using echocardiography. We showed that both ZNE administered in rats and NC administered in mice induced dose-dependent cardiac hypertrophy and dysfunction, whereas administration of NC at the middle and high dose caused death in Beagles. Consistently, we observed a reduction of cardiac autophagy levels in NC-treated mice and neonatal mouse cardiomyocytes. Furthermore, we demonstrated that autophagy-related 4B cysteine peptidase (ATG4B) may be a potential target of NC, since overexpression of ATG4B reversed the cardiac hypertrophy and reduced autophagy levels observed in NC-treated mice. We conclude that NC induces cardiac hypertrophy via ATG4B-mediated downregulation of autophagy in mice. Thus, this study provides guidance for the safe clinical application of ZN and the use of NC as an anti-tumor drug.

DUOX1 Gene Missense Mutation Confers Susceptibility on Type 2 Amiodarone-Induced Thyrotoxicosis.

Possible triggers and genetic markers involved in pathogenesis of amiodarone-induced thyrotoxicosis (AIT) or amiodarone-induced hypothyroidism (AIH) are currently unknown. This study aimed to analyze the association between polymorphisms in the genes involved in thyroid hormones biosynthesis and metabolism. Thirty-nine consecutive patients with confirmed type 2 amiodarone-induced thyrotoxicosis were enrolled; 39 patients on the same therapy for at least 6 months without thyroid pathology were included as a control group. A comparative study was carried out to determine the distribution and genotypes of polymorphic markers of the (Na)-iodide symporter (NIS) genes (rs7250346, C/G substitution), thyroid stimulating hormone receptor (TSHR) (rs1991517, C/G substitution), thyroid peroxidase (TPO) (rs 732609, A/C substitution), DUOX 1-1 (C/T substitution), DUOX 1-2 (G/T substitution), DUOX 1-3 (C/T substitution), glutathione peroxidase 3 (GPX3) (C/T substitution), glutathione peroxidase 4 (GPX4) (C/T substitution). Statistical analysis was performed using Prism (Version 9.0.0 (86)). This study showed that the risk of AIT2 is 3.18 times higher in the G/T of the DUOX1 gene carriers. This study is the first report of genetic markers associated with amiodarone-related adverse events conducted in humans. The obtained results indicate the necessity for a personalized approach to amiodarone administration.

Impact of Hypoxia-Hyperoxia Exposures on Cardiometabolic Risk Factors and TMAO Levels in Patients with Metabolic Syndrome.

Along with the known risk factors of cardiovascular diseases (CVDs) constituting metabolic syndrome (MS), the gut microbiome and some of its metabolites, in particular trimethylamine-N-oxide (TMAO), are actively discussed. A prolonged stay under natural hypoxic conditions significantly and multi-directionally changes the ratio of gut microbiome strains and their metabolites in feces and blood, which is the basis for using hypoxia preconditioning for targeted effects on potential risk factors of CVD. A prospective randomized study included 65 patients (32 females) with MS and optimal medical therapy. Thirty-three patients underwent a course of 15 intermittent hypoxic-hyperoxic exposures (IHHE group). The other 32 patients underwent sham procedures (placebo group). Before and after the IHHE course, patients underwent liver elastometry, biochemical blood tests, and blood and fecal sampling for TMAO analysis (tandem mass spectrometry). No significant dynamics of TMAO were detected in both the IHHE and sham groups. In the subgroup of IHHE patients with baseline TMAO values above the reference (TMAO ≥ 5 µmol/l), there was a significant reduction in TMAO plasma levels. But the degree of reduction in total cholesterol (TCh), low-density lipoprotein (LDL), and regression of liver steatosis index was more pronounced in patients with initially normal TMAO values. Despite significant interindividual variations, in the subgroup of IHHE patients with MS and high baseline TMAO values, there were more significant reductions in cardiometabolic and hepatic indicators of MS than in controls. More research is needed to objectify the prognostic role of TMAO and the possibilities of its correction using hypoxia adaptation techniques.

Low-Intensity Pulsed Ultrasound Prevents the Oxidative Stress Induced Endothelial-Mesenchymal Transition in Human Aortic Endothelial Cells.

BACKGROUND/AIMS: Endothelial-mesenchymal transition (EndMT) has been shown to take part in the generation and progression of diverse diseases, involving a series of changes leading to a loss of their endothelial characteristics and an acquirement of properties typical of mesenchymal cells. Low-intensity pulsed ultrasound (LIPUS) is a new therapeutic option that has been successfully used in fracture healing. However, whether LIPUS can inhibit oxidative stress-induced endothelial cell damages through inhibiting EndMT remained unknown. This study aimed to investigate the protective effects of LIPUS against oxidative stress-induced endothelial cell damages and the underlying mechanisms. METHODS: EndMT was induced by H2O2 (100 µm for seven days). Human aortic endothelial cells (HAECs) were exposed to H2O2 with or without LIPUS treatment for seven days. The expression of EndMT markers (CD31, VE-cadherin, FSP1 and α-SMA) were analyzed. The levels of total and phosphorylated PI3K and AKT proteins were detected by Western Blot analysis. Cell chemotaxis was determined by wound healing and transwell assay. RESULTS: LIPUS relieved EndMT by decreasing ROS accumulation and increasing activation of the PI3K signaling cascade. LIPUS alleviated the migration of EndMT-derived mesenchymal-like cells through reducing extracellular matrix (ECM) deposition that is associated with matrix metallopeptidase (MMP) proteolytic activity and collagen production. CONCLUSION: LIPUS produces cytoprotective effects against oxidative injuries to endothelial cells through suppressing the oxidative stress-induced EndMT, activating the PI3K/AKT pathway under oxidative stress, and limiting cell migration and excessive ECM deposition.

A single-lead ECG based cardiotoxicity detection in patients on polychemotherapy.

Background: Anti-cancer treatment can be fraught with cardiovascular complications, which is the most common cause of death among oncological survivors. Without appropriate cardiomonitoring during anti-cancer treatment, it becomes challenging to detect early signs of cardiovascular complications. In order to achieve higher survival rates, it is necessary to monitor oncological patients outpatiently after anti-cancer treatment administration. In this regard, we aim to evaluate the efficacy of single-lead ECG remote monitoring to detect cardiotoxicity in cancer patients with minimal cardiovascular diseases after the first cycle of polychemotherapy. Materials and methods: The study included patients 162 patients over 18 years old with first diagnosed different types of solid tumors, planed for adjuvant (within 8 weeks after surgery) or neoadjuvant polychemotherapy. All patients were monitored, outpatiently, during 14-21 days (depending on the regimen of polychemotherapy) after polychemotherapy administration using single-lead ECG. Results: QTc > 500 mc prolongation was detected in 8 patients (6.6 %), first-diagnosed arial fibrillation was detected in 11 patients (9 %) in period after chemotherapy administration. Moreover, left ventricular diastolic dysfunction using single-lead ECG after polychemotherapy was detected in 49 (40.1 %) patients with sensitivity 80 %, specificity 95 %, AUC 0.88 (95 % CI, 0.82-0.93). Conclusions: The side effects of cancer treatment may cause life-threatening risks. Early identification of cardiotoxicity plays a vital role in the solution of this problem. Using portable devices to detect early cardiotoxicity is a simple, convenient and affordable screening method, that can be used for promptly observation of patients.

The Blood Plasma Lipidomic Profile in Atherosclerosis of the Brachiocephalic Arteries.

According to the World Health Organization, ischemic stroke is the second leading cause of death in the world. Frequently, it is caused by brachiocephalic artery (BCA) atherosclerosis. Timely detection of atherosclerosis and its unstable course can allow for a timely response to potentially dangerous changes and reduce the risk of vascular complications. Omics technologies allow us to identify new biomarkers that we can use in diagnosing diseases. This research included 90 blood plasma samples. The study group comprised 52 patients with severe atherosclerotic lesions BCA, and the control group comprised 38 patients with no BCA atherosclerosis. Targeted and panoramic lipidomic profiling of their blood plasma was carried out. There was a statistically significant difference (p < 0.05) in the values of the indices saturated fatty acids (FAs), unsaturated FAs, monounsaturated FAs, omega-3, and omega-6. Based on the results on the blood plasma lipidome, we formed models that have a fairly good ability to determine atherosclerotic lesions of the brachiocephalic arteries, as well as a model for identifying unstable atherosclerotic plaques. According only to the panoramic lipidome data, divided into groups according to stable and unstable atherosclerotic plaques, a significant difference was taken into account: p value < 0.05 and abs (fold change) > 2. Unfortunately, we did not observe significant differences according to the established plasma panoramic lipidome criteria between patients with stable and unstable plaques. Omics technologies allow us to obtain data about any changes in the body. According to our data, statistically significant differences in lipidomic profiling were obtained when comparing groups with or without BCA atherosclerosis.

Tetrahydroberberrubine exhibits preventive effect on obesity by activating PGC1α-mediated thermogenesis in white and brown adipose tissue.

The escalating prevalence of obesity presents formidable challenges, necessitating the development of effective therapeutic strategies. In this study, we aimed to elucidate the preventive effects on obesity of tetrahydroberberrubine (THBru), a derivative of berberine (BBR) and to unravel its underlying mechanism. Using an obese mouse model induced by a high-fat diet (HFD), THBru was found to markedly ameliorate obesity, as evidenced by reduced body weight, decreased Lee's index, diminished fat mass in epididymal white adipose tissue (WAT) and brown adipose tissue (BAT), alongside improved dyslipidemia. Notably, at the same dose, THBru exhibited superior efficacy compared to BBR. RNA-sequencing and gene set enrichment analysis indicated THBru activated thermogenesis, which was further confirmed in WAT, BAT, and 3T3-L1 cells. Bioinformatics analysis of RNA-sequencing data revealed the candidate gene Pgc1α, a key regulator involved in thermogenesis. Moreover, THBru was demonstrated to elevate the expression of PGC1α by stabilizing its mRNA in WAT, BAT and 3T3-L1 cells. Furthermore, PGC1α knockdown blocked the pro-thermogenic and anti-obesity action of THBru both in vivo and in vitro. This study unravels the preventive effects of THBru on obesity through the activation of PGC1α-mediated thermogenesis, thereby delineating its potential therapeutic implications for obesity and associated disorders.

Exhaled breath analysis in adult patients with cystic fibrosis by real-time proton mass spectrometry.

BACKGROUND: Proton-transfer reaction time-of-flight mass spectrometry (PTR-TOF-MS) is a promising tool for a rapid online determination of exhaled volatile organic compounds (eVOCs) profiles in patients with cystic fibrosis (CF). OBJECTIVE: To detect VOC breath signatures specific to adult patients with CF compared with controls using PTR-TOF-MS. METHODS: 102 CF patients (54 M/48, mean age 25.6 ± 7.8 yrs) and 97 healthy controls (56 M/41F, mean age 25.8 ± 6.0 yrs) were examined. Samples from normal quiet breathing and forced expiratory maneuvers were analyzed with PTR-TOF-MS (Ionicon, Austria) to obtain VOC profiles listed as ions at various mass-to-charge ratios (m/z). RESULTS: PTR-TOF-MS analysis was able to detect 167 features in exhaled breath from CF patients and healthy controls. According to cluster analysis and LASSO regression, patients with CF and controls were separated. The most significant VOCs for CF were indole, phenol, dimethyl sulfide, and not indicated: m/z = 297.0720 ([C12H13N2O7 and C17H13O5]H + ), m/z = 281.0534 ([C19H7NO2, C12H11NO7 and C16H9O5]H + ) during five-fold cross-validation both in forced expiratory maneuver and in normal quiet breathing. CONCLUSION: PTR-TOF-MS is a promising method for determining the molecular composition of exhaled air specific to CF.

MiR-203 improves cardiac dysfunction by targeting PARP1-NAD+ axis in aging murine.

Heart aging is a prevalent cause of cardiovascular diseases among the elderly. NAD+ depletion is a hallmark feature of aging heart, however, the molecular mechanisms that affect NAD+ depletion remain unclear. In this study, we identified microRNA-203 (miR-203) as a senescence-associated microRNA that regulates NAD+ homeostasis. We found that the blood miR-203 level negatively correlated with human age and its expression significantly decreased in the hearts of aged mice and senescent cardiomyocytes. Transgenic mice with overexpressed miR-203 (TgN (miR-203)) showed resistance to aging-induced cardiac diastolic dysfunction, cardiac remodeling, and myocardial senescence. At the cellular level, overexpression of miR-203 significantly prevented D-gal-induced cardiomyocyte senescence and mitochondrial damage, while miR-203 knockdown aggravated these effects. Mechanistically, miR-203 inhibited PARP1 expression by targeting its 3'UTR, which helped to reduce NAD+ depletion and improve mitochondrial function and cell senescence. Overall, our study first identified miR-203 as a genetic tool for anti-heart aging by restoring NAD+ function in cardiomyocytes.

Diabetic Retinopathy Diagnosis Based on Convolutional Neural Network in the Russian Population: A Multicenter Prospective Study.

BACKGROUND: Diabetic retinopathy is the most common complication of diabetes mellitus and is one of the leading causes of vision impairment globally, which is also relevant for the Russian Federation. OBJECTIVE: To evaluate the diagnostic efficiency of a convolutional neural network trained for the detection of diabetic retinopathy and estimation of its severity in fundus images of the Russian population. METHODS: In this cross-sectional multicenter study, the training data set was obtained from an open source and relabeled by a group of independent retina specialists; the sample size was 60,000 eyes. The test sample was recruited prospectively, 1186 fundus photographs of 593 patients were collected. The reference standard was the result of independent grading of the diabetic retinopathy stage by ophthalmologists. RESULTS: Sensitivity and specificity were 95.0% (95% CI; 90.8-96.4) and 96.8% (95% CI; 95.5- 99.0), respectively; positive predictive value - 98.8% (95% CI; 97.6-99.2); negative predictive value - 87.1% (95% CI, 83.4-96.5); accuracy - 95.9% (95% CI; 93.3-97.1); Kappa score - 0.887 (95% CI; 0.839-0.946); F1score - 0.909 (95% CI; 0.870-0.957); area under the ROC-curve - 95.9% (95% CI; 93.3-97.1). There was no statistically significant difference in diagnostic accuracy between the group with isolated diabetic retinopathy and those with hypertensive retinopathy as a concomitant diagnosis. CONCLUSION: The method for diagnosing DR presented in this article has shown its high accuracy, which is consistent with the existing world analogues, however, this method should prove its clinical efficiency in large multicenter multinational controlled randomized studies, in which the reference diagnostic method would be unified and less subjective than an ophthalmologist.

Personalized Medicine in Coronary Artery Disease: Where Are We in 2022?

Coronary artery disease (CAD) is the leading cause of morbidity and mortality in developed and in most developing countries [...].

Remote Screening for Atrial Fibrillation by a Federal Cardiac Monitoring System in Primary Care Patients in Russia: Results from the Prospective Interventional Multicenter FECAS-AFS Study.

Background: Screening for atrial fibrillation has the potential to significantly reduce cardiovascular morbidity and mortality. However, questions in regard to how to screen, on whom to screen, and the optimal setting of screening remain unanswered. Objective: To assess the applicability of a federal cardiac monitoring for atrial fibrillation (AF) screening and remote heart rhythm monitoring in patients at high cardiovascular risk in a mixed urban and rural population in Russia. Methods: This is a prospective multicenter cohort study including 3249 individuals with high cardiovascular risk (mean age 56 ± 12.8 years) from the larger Moscow region who were screened for AF using a smartphone-case based single-lead ECG monitor over a period of 18 month. The endpoints were considered as number of newly diagnosed AF; mean time to diagnosis; number of patients for the first time assigned to anticoagulation therapy; frequency of adverse events. Results: A trial fibrillation was diagnosed in 126 patients, 36 of them for the first time. The mean time to diagnosis was 3 ± 2 days. Of 36 patients, the CHA2DS2-VASc score was ≥1 in 34 cases, ≥2 in 29 cases. Anticoagulant therapy was first induced in 31 patients. One death in newly diagnosed group and two deaths in chronic group were registered. There were a total of eight hospitalizations: one in newly diagnosed and seven in chronic AF patients. Conclusion: Our results indicate that a Federal AF screening system in patients at high cardiovascular risk by using a smartphone-case based single lead ECG which is supported by centrally located ECG specialist and central data management is feasible and reliable when performed in a mixed urban and rural area. Further studies are needed to evaluate the full potential of this approach.

LncRNA LOC105378097 inhibits cardiac mitophagy in natural ageing mice.

BACKGROUND: The development of heart ageing is the main cause of chronic disability, disease and death in the elderly. Ample evidence has established a pivotal role for significantly reduced mitophagy in the ageing heart. However, the underlying mechanisms of mitophagy deficiency in ageing heart are little known. The present study aimed to explore the underlying mechanisms of lncRNA LOC105378097 (Senescence-Mitophagy Associated LncRNA, lncR-SMAL) actions on mitophagy in the setting of heart ageing. METHODS: The expression of lncR-SMAL was measured in serum from different ages of human and heart from different ages of mice through a quantitative real-time polymerase chain reaction. The effects of lncR-SMAL on heart function of mice were assessed by echocardiography and pressure-volume measurements system. Cardiac senescence was evaluated by hematoxylin-eosin staining, senescence-associated ß-galactosidase staining, flow cytometry and western blot analysis of expression of ageing related markes p53 and p21. Cardiomyocyte mitophagy was assessed by western blot, mRFP-GFP-LC3 adenovirus particles transfection and mito-Keima staining. Interaction between lncR-SMAL and Parkin was validated through molecular docking, RNA immunoprecipitation (RIP) and RNA pull-down assay. Ubiquitination assay was performed to explore the molecular mechanism of Parkin inhibition. The effects of lncR-SMAL on mitochondrial function were investigated through electron microscopic examination, JC-1 staining and oxygen consumption rates analysis. RESULTS: The heart-enriched lncR-SMAL reached the expression crest in the serum of human at an age of 60. Exogenously overexpression of lncRNA SMAL deteriorated cardiac function exactly as natural ageing and inhibited the associated cardiomyocytes mitophagy by depressing Parkin protein level. Improved heart ageing and mitophagy caused by Parkin overexpression were reversed by lncR-SMAL in mice. In contrast, the loss of lncR-SMAL in AC16 cells induced the upregulation of Parkin protein and ameliorated mitophagy and mitochondrial dysfunction, resulting in alleviated cardiac senescence. Besides, we found the interaction between lncR-SMAL and Parkin protein through computational docking analysis, pull-down and RIP assay. This would contribute to the promotive effect of lncR-SMAL on Parkin ubiquitination and decrease Parkin protein stability. CONCLUSIONS: The present study for the first time demonstrates a heart-enriched lncRNA, SMAL, that inhibits the mitophagy of cardiomyocytes via the downregulation of Parkin protein, which further contributes to heart ageing and cardiac dysfunction in natural ageing mice.

Endothelial to mesenchymal transition contributes to nicotine-induced atherosclerosis.

Rationale: Nicotine exposure via cigarette smoking is strongly associated with atherosclerosis. However, the underlying mechanisms remain poorly understood. The current study aimed to identify whether endothelial to mesenchymal transition (EndMT) contributes to nicotine-induced atherosclerosis. Methods: ApoE-/- mice were administered nicotine in their drinking water for 12 weeks. The effects of nicotine on EndMT were determined by immunostaining on aortic root and RNA analysis in aortic intima. In vitro nicotine-treated cell model was established on human aortic endothelial cells (HAECs). The effects of nicotine on the expression of EndMT-related markers, ERK1/2 and Snail were quantified by real-time PCR, western blot and immunofluorescent staining. Results: Nicotine treatment resulted in larger atherosclerotic plaques in ApoE-/- mice. The vascular endothelial cells from nicotine-treated mice showed mesenchymal phenotype, indicating EndMT. Moreover, nicotine-induced EndMT process was accompanied by cytoskeleton reorganization and impaired barrier function. The α7 nicotine acetylcholine receptor (α7nAChR) was highly expressed in HAECs and its antagonist could effectively relieve nicotine-induced EndMT and atherosclerotic lesions in mice. Further experiments revealed that ERK1/2 signaling was activated by nicotine, which led to the upregulation of Snail. Blocking ERK1/2 with inhibitor or silencing Snail by small interfering RNA efficiently preserved endothelial phenotype upon nicotine stimulation. Conclusion: Our study provides evidence that EndMT contributes to the pro-atherosclerotic property of nicotine. Nicotine induces EndMT through α7nAChR-ERK1/2-Snail signaling in endothelial cells. EndMT may be a therapeutic target for smoking-related endothelial dysfunction and cardiovascular disease.

Diagnostic Value of Combinatorial Markers in Colorectal Carcinoma.

Objectives: Blood-based tests have been shown to be an effective strategy for colorectal cancer (CRC) detection in screening programs. This study was aimed to test the performance of 20 blood markers including tumor antigens, inflammatory markers, and apolipoproteins as well as their combinations. Methods: In total 203 healthy volunteers and 102 patients with CRC were enrolled into the study. Differences between healthy and cancer subjects were evaluated using Wilcoxon rank-sum test. Several multivariate classification algorithms were employed using information about different combinations of biomarkers altered in CRC patients as well as age and gender of the subjects; random sub-sampling cross-validation was done to overcome overfitting problem. Diagnostic performance of single biomarkers and multivariate classification models was evaluated by receiver operating characteristic (ROC) analysis. Results: Of 20 biomarkers, 16 were significantly different between the groups (p-value ≤ 0.001); ApoA1, ApoA2 and ApoA4 levels were decreased, whereas levels of tumor antigens (e.g. carcinoembriogenic antigen) and inflammatory markers (e.g., C-reactive protein) were increased in CRC patients vs. healthy subjects. Combinatorial markers including information about all 16 significant analytes, age and gender of patients, demonstrated better performance over single biomarkers with average accuracy on test datasets ≥95% and area under ROC curve (AUROC) ≥98%. Conclusions: Combinatorial approach was shown to be a valid strategy to improve performance of blood-based CRC diagnostics. Further evaluation of the proposed models in screening programs will be performed to gain a better understanding of their diagnostic value.

Evaluation of discriminative capacity of two formulas of CKD-EPI to predict complications after the first episode of heart failure with preserved ejection fraction.

Background: Determining the prognosis of heart failure with preserved ejection fraction (HFpEF) is problematic, as the ejection fraction cannot be used. Formulae that estimate glomerular filtration rate (eGFR) may be potential prognosticators for this condition, since renal dysfunction is a well-known predictor of poor outcomes of all forms of heart failure. Methods: A prospective observational study of 117 HFpEF patients (average age 71.6±9.1 years; 65.8% women) who had eGFR determined after their first episode of cardiac decompensation by two different chronic kidney disease epidemiology collaboration (CKD-EPI) equations. The ability to predict hospitalizations and mortality over 24 months by the two equations were compared. Results: The CKD-EPI formula based on serum creatinine only performed poorly. However, the CKD-EPI equation that used both serum creatinine and serum cystatin C was associated with unfavorable outcome: eGFR <45 mL/min/1.73 m2 predicted 24-month mortality (HR=4.21 [1.32;13.43], p=0.02) and the combined endpoint of mortality and hospitalization (HR 2.45 [1.42;4.22], p=0.001). . Conclusions: eGFR by the CKD-EPI equation based on serum creatinine and cystatin C levels, but not by the CKD-EPI creatinine only equation, predicts the outcome of HFpEF patients.

Transcriptomics-Guided Personalized Prescription of Targeted Therapeutics for Metastatic ALK-Positive Lung Cancer Case Following Recurrence on ALK Inhibitors.

Non-small cell lung carcinoma (NSCLC) is the major cause of cancer-associated mortality. Identification of rearrangements in anaplastic lymphoma kinase (ALK) gene is an effective instrument for more effective targeted therapy of NSCLC using ALK inhibitors dramatically raising progression-free survival in the ALK-mutated group of patients. However, the tumors frequently develop resistance to ALK inhibitors. We describe here a case of 48 y.o. male patient with ALK-positive NSCLC who was clinically managed for 6.5 years from the diagnosis. The tumor was surgically resected, but 8 months later multiple brain metastases were discovered. The patient started receiving platinum-based chemotherapy and then was enrolled in a clinical trial of second-generation ALK inhibitor ceritinib, which resulted in a 21 months stabilization. Following disease relapse, the patient was successfully managed for 33 months with different lines of chemo- and local ablative therapies. Chemotherapy regimens, including off-label combination of crizotinib + bevacizumab + docetaxel, were selected using the cancer transcriptome data-guided bioinformatical decision support system Oncobox. These therapies led to additional stabilization for 22 months. Survival of our patient after developing resistance to ALK inhibitor was longer for 16 months than previously reported average survival for such cases. This case shows that transcriptomic-guided sequential personalized prescription of targeted therapies can be effective in terms of survival and quality of life in ALK-mutated NSCLC.

Emodin alleviates cardiac fibrosis by suppressing activation of cardiac fibroblasts via upregulating metastasis associated protein 3.

Excess activation of cardiac fibroblasts inevitably induces cardiac fibrosis. Emodin has been used as a natural medicine against several chronic diseases. The objective of this study is to determine the effects of emodin on cardiac fibrosis and the underlying molecular mechanisms. Intragastric administration of emodin markedly decreased left ventricular wall thickness in a mouse model of pathological cardiac hypertrophy with excess fibrosis induced by transaortic constriction (TAC) and suppressed activation of cardiac fibroblasts induced by angiotensin II (AngII). Emodin upregulated expression of metastasis associated protein 3 (MTA3) and restored the MTA3 expression in the setting of cardiac fibrosis. Moreover, overexpression of MTA3 promoted cardiac fibrosis; in contrast, silence of MTA3 abrogated the inhibitory effect of emodin on fibroblast activation. Our findings unraveled the potential of emodin to alleviate cardiac fibrosis via upregulating MTA3 and highlight the regulatory role of MTA3 in the development of cardiac fibrosis.