Transcriptomics Coupled with Proteomics Reveals Osimertinib-induced Myocardial Mitochondrial Dysfunction.

Osimertinib, an irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) used for cancer treatment, can cause significant cardiac toxicity. However, the specific mechanism of osimertinib-induced cardiotoxicity is not fully understood. In this study, we administered osimertinib to mice and neonatal rat ventricular myocytes (NRVMs). We observed significant structural and functional damage to the hearts of these mice, along with a marked increase in cardiac injury biomarkers and accompanying ultrastructural damage to mitochondria. We integrated 4D label-free protein quantification and RNA-Seq methods to analyze the sequencing data of NRVMs under osimertinib treatment (0 and 2.5µM). Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis evidenced that differentially expressed genes (DEGs)and differentially expressed proteins (DEPs) were distinctly enriched for oxidative phosphorylation (OXPHOs). Simultaneously, osimertinib primarily affected the contents of adenosine triphosphate (ATP). Further investigations revealed that osimertinib disrupts the functions of the ATP synthase (complex V), leading to a reduction in ATP production. Taken together, our data demonstrated that osimertinib causes mitochondrial dysfunction, which in turn leads to the onset of cardiac toxicity.

Interferon-γ predicts the treatment efficiency of immune checkpoint inhibitors in cancer patients.

PURPOSE: Immune checkpoint inhibitors (ICIs) have improved the prognosis of cancer patients significantly with few predictive makers for treatment efficiency. Since interferon-gamma (IFN-γ) displayed its association with immunotherapy, we explored the correlation between IFN-γ and the efficacy of ICIs in tumor treatment. METHODS: We retrospectively examined cancer patients who received immune checkpoint inhibitors as first-line therapy at the Fourth Hospital of Hebei Medical University. The patients were divided into a low concentration group of IFN-γ (≤ 1.2 pg/mL) and a high concentration group (≥ 1.3 pg/mL) to evaluate the efficacy, which was indicated by the objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS) and overall survival (OS). RESULTS: Thirty-five patients with low IFN-γ and 56 patients with high IFN-γ were involved in the evaluation, and the DCR was significantly different between these two groups (p = 0.009) with a high group of 81.4% (95% CI 69-94%) and a low group of 51.9% (95% CI 32-72%). The subsequent Kaplan-Meier survival analysis showed that the high IFN-γ patients displayed longer median OS than that of the low IFN-γ patients (p = 0.049), while no statistical difference existed for PFS (p = 0.971). The multivariate analysis also confirmed that the high IFN-γ level was independently associated with a better prognosis (HR: 0.318 95% CI 0.113-0.894, p = 0.030). CONCLUSIONS: Basal serum IFN-γ levels were associated with the DCR and OS of cancer patients with higher IFN-γ exhibiting beneficial efficiency for ICIs treatment.

Downregulation of hERG channel expression by tyrosine kinase inhibitors nilotinib and vandetanib predominantly contributes to arrhythmogenesis.

Cardiotoxicity by tyrosine kinase inhibitors remains an important concern. Nilotinib and vandetanib clinically carry high proarrhythmic risk and the exact mechanism underlying arrhythmogenesis is not fully understood. In this study, we investigated the effects of nilotinib and vandetanib on the abundance of human ether-á-go-go-related gene (hERG) K+ channel and assessed the potential role of acute hERG blockage versus chronic effects in arrhythmogenesis. We found that both nilotinib and vandetanib prolonged the field potential duration reflecting the repolarisation process and induced cellrythmias of human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) in a time-and concentration-dependent manner after, after chronic exposure. Patch-clamp recordings revealed significant reductions of hERG current densities by nilotinib or vandetanib after chronic incubation with hERG-HEK293 cells in addition to the acute inhibition. Western blot analysis showed that nilotinib and vandetanib decreased mature hERG protein (155-kDa) expression, in a greater extent than that of the immature form (135-kDa). A serum and glucocorticoid kinase 1 (SGK1) activator, C4-ceramide, prevented the nilotinib-and vandetanib-induced hERG protein downregulation and thus the incidence of cellrrhythmias. Taken together, our data demonstrated that the downregulation of hERG channel abundance on the cellular membrane predominantly contributed to the proarrhythmic effect of nilotinib and vandetanib.

Ginsenoside Rg2 Attenuated Trastuzumab-Induced Cardiotoxicity in Rats.

AIM: Trastuzumab (TZM) is a monoclonal antibody drug for HER2-positive breast cancer by targeting epidermal growth factor 2, but it has significant cardiotoxicity. Ginsenoside Rg2 has shown a variety of biological activities. This study was aimed at investigating whether Rg2 attenuates TZM-induced cardiotoxicity. METHODS: A model of TZM-induced cardiotoxicity was established in Wistar rats, and the rats were pretreated with Rg2. After echocardiography analysis, the rats were killed and the hearts were dissected for RNAseq analysis. Primary human cardiomyocytes (HCMs) were treated with TZM with or without pretreatment with Rg2 and then subjected to a colony formation assay, flow cytometry analysis, and Western blot analysis for the detection of caspase-3, caspase-9, and BAX. RESULTS: TZM induced LV dysfunction in rats, but Rg2 could attenuate TZM-induced LV dysfunction. The mRNA levels of caspase-3, caspase-9, and BAX were significantly higher in TZM-treated rats. The colony formation ability of HCMs was significantly lower in TZM-treated cells but was recovered after pretreatment with Rg2. The apoptosis rate of HCMs was significantly higher in TZM-treated cells but was significantly lower after pretreatment with Rg2. Moreover, protein levels of caspase-3, caspase-9, and BAX were significantly higher in TZM-treated cells but were significantly lower after pretreatment with Rg2. CONCLUSION: Ginsenoside Rg2 inhibited TZM-induced cardiotoxicity, and the mechanism may be related to the downregulation of the expression of proapoptotic proteins caspase-3, caspase-9, and BAX and the inhibition of TZM-induced apoptosis in cardiomyocytes. Ginsenoside Rg2 has a potential to be applied in patients with breast cancer to prevent TZM-induced cardiotoxicity.

Study on the Technology of Monodisperse Droplets by a High-Throughput and Instant-Mixing Droplet Microfluidic System.

In this study, we report a novel high-throughput and instant-mixing droplet microfluidic system that can prepare uniformly mixed monodisperse droplets at a flow rate of mL/min designed for rapid mixing between multiple solutions and the preparation of micro-/nanoparticles. The system is composed of a magneton micromixer and a T-junction microfluidic device. The magneton micromixer rapidly mixes multiple solutions uniformly through the rotation of the magneton, and the mixed solution is sheared into monodisperse droplets by the silicone oil in the T-junction microfluidic device. The optimal conditions of the preparation of monodisperse droplets for the system have been found and factors affecting droplet size are analyzed for correlation; for example, the structure of the T-junction microfluidic device, the rotation speed of the magneton, etc. At the same time, through the uniformity of the color of the mixed solution, the mixing performance of the system is quantitatively evaluated. Compared with mainstream micromixers on the market, the system has the best mixing performance. Finally, we used the system to simulate the internal gelation broth preparation of zirconium broth and uranium broth. The results show that the system is expected to realize the preparation of ceramic microspheres at room temperature without cooling by the internal gelation process.

Clinical characteristics and risk factors for death in patients with stress cardiomyopathy in the ICU.

BACKGROUND: This study aimed to investigate the clinical manifestations and risk factors for 28-day mortality in patients with stress cardiomyopathy (SC) in the intensive care unit (ICU). METHODS: This retrospective study was carried out from April 2015 to March 2021. Fifty-five patients in the ICU were diagnosed with SC. Two patients were excluded due to a history of atrial fibrillation (AF), and 53 patients were enrolled in the study. Baseline demographics and clinical characteristics were collected, and the 28-day mortality rate was calculated. Multivariate and univariate logistic regression analyses were used to determine the significant predictors of 28-day mortality. RESULTS: Of the 53 patients, almost half (47.17%) were male. The most common stress trigger was sepsis (37.74%). Due to sedation and tracheal intubation, 49.06% of SC patients were unable to express their symptoms, and only 3.77% of patients presented with chest pain. The proportion of patients with complications of systolic heart failure and cardiogenic shock was 77.36% and 39.62%, respectively. The mean Acute Physiology and Chronic Health Evaluation (APACHE) II score when patients were admitted into the ICU was 21.17±8.41, and the Sequential Organ Failure Assessment (SOFA) score at diagnosis of SC was 9.30±4.56. Eighteen (33.96%) SC patients had new-onset AF while in the ICU. The 28-day mortality rate in patients with SC in the ICU was 64.15%. Univariate analysis found that 5 variables [SOFA score at diagnosis of SC, estimated glomerular filtration rate (eGFR) <60 mL/min at diagnosis of SC, maximum norepinephrine dose, new-onset AF, and systolic heart failure] were correlated with 28-day mortality in patients with SC in the ICU. Multivariate logistic regression analysis suggested SOFA score at diagnosis of SC (P=0.042), eGFR <60 mL/min at diagnosis of SC (P=0.027), and new-onset AF (P=0.043) as independent predictors of 28-day mortality. CONCLUSIONS: Male patients with SC were relatively more common in the ICU than in the cardiology unit. Sepsis was a common stress trigger. The 28-day mortality rate was very high. The SOFA score and eGFR <60 mL/min at diagnosis of SC and new-onset AF may have influenced patients' short-term prognosis.

Characteristic antimicrobial resistance of clinically isolated Stenotrophomonas maltophilia CYZ via complete genome sequence.

OBJECTIVES: Stenotrophomonas maltophilia is an important multidrug-resistant pathogen that is associated with various serious nosocomial infections. In our study, we investigated the antimicrobial resistance traits of clinical S. maltophilia strain CYZ isolated from the sputum of an immunocompromised patient. METHODS: The whole genome sequence of S. maltophilia CYZ was investigated using a PacBio RS II system. The functions of all the predicted genes were annotated by the COG, GO and KEGG databases. Several types of antibiotics were selected to test the antimicrobial susceptibility, and a phylogenetic tree was constructed based on 16S rRNA gene sequence. RESULTS: The genome of S. maltophilia CYZ has a length of 4,517,685 bp and contains 4077 predicted genes, with an average G + C content of 66.65%. Functional genomic analysis via the annotations of the COG and GO databases revealed that the isolate exhibited specific means to resist antibiotics. The annotated genes involved in flagella, pili or fimbriae, biofilm formation, polysaccharide and cyclic di-GMP may contribute to promote the ability of antimicrobial resistance. This strain showed susceptibility to levofloxacin, trimethoprim/sulfamethoxazole and minocycline according to antimicrobial susceptibility testing. The phylogenetic relationship indicated that S. maltophilia CYZ was closely related to S. maltophilia strains isolated from the nosocomial environment. CONCLUSIONS: The current results give a better understanding of the genetic characteristics of antimicrobial resistance in S. maltophilia CYZ and provide a genetic basis for further study of the phenotype.

Stress cardiomyopathy following thyroidectomy in a premenopausal woman with thyroid cancer: case report and review of the literature.

Stress cardiomyopathy (SC) is a poorly recognized heart disease that was initially regarded as a benign condition. Recently, it has been shown that SC may be associated with severe clinical complications including death and that its prevalence is probably underestimated. The disease is characterized by transient systolic and diastolic left ventricular (LV) dysfunction with a variety of wall-motion abnormalities. It predominantly affects postmenopausal women and is often preceded by an emotional or physical trigger, but the condition has also been reported with no evident trigger. The striking preponderance of postmenopausal females suggests a hormonal influence. Potentially, declining oestrogen levels after menopause increase the susceptibility to SC in women. Oestrogens can influence vasomotor tone via up-regulation of endothelial NO synthase. Also, there is evidence that oestrogens can attenuate catecholamine-mediated vasoconstriction and decrease the sympathetic response to mental stress in perimenopausal women. Rare cases of SC following thyroidectomy in premenopausal women have been described. Currently, the pathogenesis of SC remains obscure, several possible hypotheses include catecholamine induced myocardial spasm or catecholamine related myocardial stunning, metabolic disorders and coronary microvascular damage. So prompt diagnosis and optimal management are crucial to obtaining a good outcome for the patient. We report an extremely rare case of SC induced by thyroidectomy in a premenopausal woman with cancer, and share our personal experience by reviewing the literature.

Synthesis and Characterization of Zirconium Nitride Nanopowders by Internal Gelation and Carbothermic Nitridation.

Zirconium compounds has been widely attention over the last decades due to its excellent physical and chemical properties. Zirconium nitride nanopowders were synthesized via a simple direct carbothermic nitridation process of internal gel derived zirconia in the presence of nano-sized carbon black. The effects of reaction temperature, dwell time and molar ratio of carbon black to Zr (C/Zr) on the phase composition, grain size and crystal parameters of products were studied. Based upon the analysis of crystallite phase evolution and microstructure characterization, it was found that zirconium oxynitride is intermediate product and then O atoms in oxynitride were extracted by oxygen getter, carbon black. Anion sites were directly replaced by N atoms to form rock-salt type nitride in carbothermic nitridation process.

Self-assembled full nanowire P(VDF-TrFE) films with both anisotropic and high bidirectional piezoelectricity.

With the explosive growth of flexible electronics, the prototype piezoelectric polymer poly(vinylidene fluoride-trifluoroethylene) [P(VDF-TrFE)] has gained tremendous attention due to potential applications in flexible sensors, energy harvesters, and new smart devices. However, full realization of these applications is still challenging due to the lack of high quality films with strong piezoelectricity, which requires tailored molecular organization. Here we report unique 'full nanowire' P(VDF-TrFE) films with substantially enhanced bidirectional performance by a simple self-assembly via selective vapor annealing. Structural analysis showed that the solvent molecules significantly enhanced the copolymer chain mobility, giving highly ordered nanowires, whose quantity increased with time and finally formed a full flat-on lamellar nanowire array with backbones highly aligned along the film plane, leading to high lateral piezoelectricity as revealed by vector piezoresponse force microscopy and confirmed by electrical measurements. Surprisingly, the nanowire films also showed a much higher vertical piezoelectric coefficient (-35.2 pC N-1 directly measured by using a Berlincourt meter) than that of usually crystallized films owing to simultaneously enhanced molecular order and dipole switching ability. The scalability of the new method might boost industrial applications, and the findings may provide hints on new routes to nanostructured polymers with novel functionalities and deepen our understanding of the self-assembly of random copolymers.

Dynamic characteristics of a deformable capsule in a simple shear flow.

The dynamic characteristics of a two-dimensional deformable capsule in a simple shear flow are studied with an immersed boundary-lattice Boltzmann method. Simulations are conducted by varying the Reynolds number (Re) from 0.0125 to 2000 and the dimensionless shear rate (G) from 0.001 to 0.5. The G-Re plane can be divided into four regions according to the deformation dependence on the parameters considered: viscous dominant, inertia dominant, transitional, and anomalous regions. There are four typical dynamic behaviors over the G-Re plane: steady deformation, prerupture state, quasisteady deformation, and continuous elongation. Analysis indicates that the pressure distribution and its variations due to the interplay of the fluid inertia force, the viscous shear stress, and the membrane elastic force determines the complex behaviors of the capsule. The effects of the bending rigidity and the internal-to-external viscosity ratio on the dynamics of the capsule are further studied. It is found that the capsule experiences smaller deformation when the higher bending rigidity is included, and the low bending rigidity does not have a remarkable influence on the capsule deformation. The capsule normally experiences smaller deformation due to the increase of the internal-to-external viscosity ratio.

Mitochondrial Dynamics in Rat Heart Induced by 5-Fluorouracil.

BACKGROUND Patients treated with 5-FU can develop rare but potentially severe cardiac effects, including cardiomyopathy, angina pectoris, ventricular tachycardia, heart failure, acute myocardial infarction, and cardiogenic shock. The specific pathologies and mechanisms are not fully understood. Research found that mitochondrial dynamics are widely detected in many angiocardiopathies. Therefore, in the present study we studied the mitochondrial damage and explored the role of mitochondrial fusion/fission proteins on myocardium of rats treated with 5-fluorouracil (5-FU). MATERIAL AND METHODS Thirty male SD rats were randomly divided into 3 groups with 10 rats in each group: (1) control group, (2) low 5-FU group (25 mg/kg), (3) high 5-FU group (50 mg/kg). The animals received intraperitoneal injection for 5 consecutive days. We assessed alterations in mitochondrial morphology, ATP content, mitochondrial membrane potential, and mitochondria fusion/fission proteins expression in hearts of rats receiving intraperitoneal injection with different doses of 5-FU. RESULTS 5-FU intraperitoneal injection induced ultra-structural damage in hearts, such as mitochondrial swelling, cristae disorder, and vacuolization. These changes were accompanied by decreases of mitochondrial membrane potential. The low dose of 5-FU led to a slight increase in ATP content. However, the high 5-FU dose caused a more significant reduction compared with the control group. Furthermore, 5-FU intraperitoneal injection significantly increased specific mitochondrial fission proteins (Drp1 and Fis1) and decreased mitochondrial fusion proteins (Opa1, Mfn1, and Mfn2) in rat hearts. However, no changes in cardiac structure and function were detected by echocardiogram. The high dose caused more damage to mitochondrial function than the low dose. CONCLUSIONS Mitochondrial damage is a potentially important mechanism and early indicator for 5-FU-induced cardiovascular disease.

A Numerical Simulation of Cell Separation by Simplified Asymmetric Pinched Flow Fractionation.

As a typical microfluidic cell sorting technique, the size-dependent cell sorting has attracted much interest in recent years. In this paper, a size-dependent cell sorting scheme is presented based on a controllable asymmetric pinched flow by employing an immersed boundary-lattice Boltzmann method (IB-LBM). The geometry of channels consists of 2 upstream branches, 1 transitional channel, and 4 downstream branches (D-branches). Simulations are conducted by varying inlet flow ratio, the cell size, and the ratio of flux of outlet 4 to the total flux. It is found that, after being randomly released in one upstream branch, the cells are aligned in a line close to one sidewall of the transitional channel due to the hydrodynamic forces of the asymmetric pinched flow. Cells with different sizes can be fed into different downstream D-branches just by regulating the flux of one D-branch. A principle governing D-branch choice of a cell is obtained, with which a series of numerical cases are performed to sort the cell mixture involving two, three, or four classes of diameters. Results show that, for each case, an adaptive regulating flux can be determined to sort the cell mixture effectively.

The promises of big data and small data for travel behavior (aka human mobility) analysis.

The last decade has witnessed very active development in two broad, but separate fields, both involving understanding and modeling of how individuals move in time and space (hereafter called "travel behavior analysis" or "human mobility analysis"). One field comprises transportation researchers who have been working in the field for decades and the other involves new comers from a wide range of disciplines, but primarily computer scientists and physicists. Researchers in these two fields work with different datasets, apply different methodologies, and answer different but overlapping questions. It is our view that there is much, hidden synergy between the two fields that needs to be brought out. It is thus the purpose of this paper to introduce datasets, concepts, knowledge and methods used in these two fields, and most importantly raise cross-discipline ideas for conversations and collaborations between the two. It is our hope that this paper will stimulate many future cross-cutting studies that involve researchers from both fields.

IB-LBM study on cell sorting by pinched flow fractionation.

Separation of two categories of cells in pinched flow fractionation(PFF) device is simulated by employing IB-LBM. The separation performances at low Reynolds number (about 1) under different pinched segment widths, flow ratios, cell features, and distances between neighboring cells are studied and the results are compared with those predicted by the empirical formula. The simulation indicates that the diluent flow rate should approximate to or more than the flow rate of particle solution in order to get a relatively ideal separation performance. The discrepancy of outflow position between numerical simulation and the empirical prediction enlarges, when the cells become more flexible. Too short distance between two neighboring cells could lead to cell banding which would result in incomplete separation, and the relative position of two neighboring cells influences the banding of cells. The present study will probably provide some new applications of PFF, and make some suggestions on the design of PFF devices.

Additive effect of polymorphisms in the ß2 -adrenoceptor and NADPH oxidase p22 phox genes contributes to the loss of estimated glomerular filtration rate in Chinese.

Because increased oxidative stress may mediate the detrimental actions of enhanced sympathetic nervous activity on renal function and vice versa, we investigated the effect of the polymorphic Arg16Gly in the ß2 -adrenoceptor (ADRB2) gene, Trp64Arg in the ß3 -adrenoceptor (ADRB3) gene and C242T in the NADPH oxidase p22phox (CYBA) gene on estimated glomerular filtration rate (eGFR) in a Chinese population. Initially recruited from different outpatient services of HeBei General Hospital in northern China, 668 individuals were finally included in the study, with complete demographic information. Laboratory tests were performed and estimated glomerular filtration rate (eGFR) was derived from the Modification of Diet in Renal Disease (MDRD) equation for the Chinese population. Plasma noradrenaline levels and genotype were determined by HPLC and the TaqMan method, respectively. Only across the Arg16Gly polymorphism did eGFR show significant difference: it was lower in individuals with the Gly16Gly variation, who also had the highest plasma noradrenaline levels. This polymorphism remained a significant determinant of eGFR after multivariate analysis. Of importance, the multifactor dimensionality reduction method further detected a significant synergism between the Arg16Gly and C242T polymorphisms in reducing eGFR. These observations clarify the effects of the studied polymorphisms on eGFR and exemplify gene-gene interactions influencing renal function.

Effects of low-dose spironolactone combined with irbesartan on cardiac hypertrophy induced by pressure overload in rats.

BACKGROUND: The mineralocorticoid receptor (MR) blockade in the heart is an attractive therapeutic option for the treatment of heart failure. However, the use of MR antagonist is limited by an increased incidence of hyperkalemia owing to MR blockade in the kidney. This study was designed to evaluate and compare the effectiveness of a low, non-pressure-lowering dose of spironolactone (Sp) with that of a conventional blood pressure-lowering dose combined with irbesartan on pathological cardiac remodeling as well as serum potassium level in pressure-overload rats. METHODS: The pressure-overloaded myocardial remodelling was produced by partial abdominal aortic constriction (PAAC) in rats. Four weeks after PAAC, animals were respectively treated with vehicle, irbesartan (15 mg/kg) alone, low-dose Sp (1 mg/kg) or conventional-dose of Sp (20 mg/kg) in combination with irbesartan for consecutive four weeks. RESULTS: The result demonstrated that compared to irbesartan monotherapy, the combination of irbesartan and spironolactone both in low- and conventional-dose exhibited additional cardioprotection against PAAC-induced cardiac remodelling. Low-dose spironolactone was as effective in inhibiting cardiac hypertrophy, fibrosis and in improving diastolic function as high dose. Low-dose spironolactone did not lead to a rise in potassium serum levels, but high dose did. CONCLUSIONS: This study suggests that combined low dose of spironolactone and irbesartan may be an effective and safety therapeutic strategy for cardiac hypertrophy and heart failure.