Neutrophil extracellular traps mediate cardiomyocyte ferroptosis via the Hippo-Yap pathway to exacerbate doxorubicin-induced cardiotoxicity.

Doxorubicin-induced cardiotoxicity (DIC), which is a cardiovascular complication, has become the foremost determinant of decreased quality of life and mortality among survivors of malignant tumors, in addition to recurrence and metastasis. The limited ability to accurately predict the occurrence and severity of doxorubicin-induced injury has greatly hindered the prevention of DIC, but reducing the dose to mitigate side effects may compromise the effective treatment of primary malignancies. This has posed a longstanding clinical challenge for oncologists and cardiologists. Ferroptosis in cardiomyocytes has been shown to be a pivotal mechanism underlying cardiac dysfunction in DIC. Ferroptosis is influenced by multiple factors. The innate immune response, as exemplified by neutrophil extracellular traps (NETs), may play a significant role in the regulation of ferroptosis. Therefore, the objective of this study was to investigate the involvement of NETs in doxorubicin-induced cardiomyocyte ferroptosis and elucidate their regulatory role. This study confirmed the presence of NETs in DIC in vivo. Furthermore, we demonstrated that depleting neutrophils effectively reduced the occurrence of doxorubicin-induced ferroptosis and myocardial injury in DIC. Additionally, our findings showed the pivotal role of high mobility group box 1 (HMGB1) as a critical molecule implicated in DIC and emphasized its involvement in the modulation of ferroptosis subsequent to NETs inhibition. Mechanistically, we obtained preliminary evidence suggesting that doxorubicin-induced NETs could modulate yes-associated protein (YAP) activity by releasing HMGB1, which subsequently bound to toll like receptor 4 (TLR4) on the cardiomyocyte membrane, thereby influencing cardiomyocyte ferroptosis in vitro. Our findings suggest that doxorubicin-induced NETs modulate cardiomyocyte ferroptosis via the HMGB1/TLR4/YAP axis, thereby contributing to myocardial injury. This study offers a novel approach for preventing and alleviating DIC by targeting alterations in the immune microenvironment.

Isovalent electronic systems B+13 and BeB12: structural interchange of GM and TS.

Fluxional Wankel motor molecules have received considerable attention in recent years in both chemistry and nanoscience. Based on extensive first-principles theory calculations, we present herein the smallest neutral quasi-planar alkaline-earth metal-doped Wankel motor complex Cs BeB12 (BeB2@B10), which is isovalent with C2v B+13 (B3@B10+). The global minimum (GM) Cs BeB12 (1) and transition state (TS) Cs BeB12 (2) correspond to the C2v TS (4) and C2v GM (3) of B+13, respectively. Molecular dynamics simulations show that, with ten equivalent GMs and ten equivalent TSs intervals, the B10 outer ring in BeB12 (1/2) overcomes the rotational energy barrier to rotate almost freely around the BeB2 triangular core above 800 K in a rotation angle of 36° in each step. Detailed bonding analyses indicate that, in addition to the ten localized periphery B-B bonds, both Cs BeB12 (1) and Cs BeB12 (2) possess three delocalized bonding systems over the molecular framework satisfying the (4n+2) Hückel rule, making the neutral complex 2σ + π triply aromatic in nature and highly stable in thermodynamics.

Nicotine exacerbates endothelial dysfunction and drives atherosclerosis via extracellular vesicle-miRNA.

AIMS: Nicotine, a major component of tobacco, is an important factor contributing to atherosclerosis. However, the molecular mechanisms underlying the link between nicotine and atherosclerosis are unclear. As extracellular vesicles (EVs) are involved in intercellular communication in atherosclerosis, we investigated whether their influence on arterial pathophysiology under nicotine stimulation. METHODS AND RESULTS: EVs from the serum of smokers (smoker-EVs) were significantly increased and exacerbated endothelial inflammation, as well as apoptosis according to functional studies. Meanwhile, inhibition of EVs blunted the nicotine-induced atherosclerosis progression, and injection of nicotine-induced EVs promoted atherosclerosis progression in ApoE-/- mice. Furthermore, quantitative reverse transcription-polymerase chain reaction analysis revealed a remarkable increase in miR-155 levels in smoker-EVs, which was correlated with carotid plaque formation in patients measured by ultrasound imaging. Moreover, CD14 levels were significantly increased in EVs from smokers (representing EVs derived from monocytes), indicating that monocytes are an important source of smoker-EVs. DNA methylation and the transcription factor HIF1α may contribute to increased miR-155 levels in monocytes, as assessed with bisulfite conversion sequencing and chromatin immunoprecipitation. Mechanistically, EVs encapsulated miR-155 induced endothelial cell dysfunction by directedly targeting BCL2, MCL1, TIMP3, BCL6, and activating NF-κB pathway, as verified in a series of molecular and biological experiments. Injecting EVs from nicotine-stimulated monocytes promoted plaque formation and triggered vascular endothelial injury in ApoE-/- mice, whereas inhibition of miR-155 weakened this effect. CONCLUSION: Our findings revealed an EV-dependent mechanism of nicotine-aggravated atherosclerosis. Accordingly, we propose an EV-based intervention strategy for atherosclerosis management.

Two-dimensional speckle tracking echocardiography help identify breast cancer therapeutics-related cardiac dysfunction.

BACKGROUND: Cancer therapeutics-related cardiac dysfunction (CTRCD) from different chemotherapy strategies are underdetermined by echocardiography. As an imaging marker of subclinical cardiac dysfunction, two-dimensional speckle tracking echocardiography (2D-STE) may assist in identifying the impact patterns of different CTRCD. METHODS: A total of 67 consecutive patients with invasive ductal breast carcinoma who will undertake neoadjuvant chemotherapy were enrolled and grouped according to their different chemotherapy regimens based on their biopsy results. Group A included 34 patients who received anthracycline without trastuzumab, whereas Group B had 33 patients who received trastuzumab without anthracycline. Echocardiography was performed at three time-points, i.e., baseline (T0), cycle-2 (T2), and cycle-4 (T4) of chemotherapy. Conventional echocardiographic measurements and 2D-STE strain values, and myocardial work (MW) parameters, were compared between different groups at different time-points. RESULTS: The mean age had no statistical difference between the two groups. E/e' was the only conventional echocardiographic parameter that had variation in group A (P < 0.05). Compared with baseline, GLS in group A decreased at T2, and GCS decreased at T4 (P < 0.05). GLS and GCS in group B both decreased at T4 (P < 0.05). More patients in group A had a more than 15% fall of baseline GLS rather than GCS at T2 (P < 0.05), however, there was no difference of either GLS or GCS decline rate at T4 between the two groups. All the MW parameters in group A had variations overtime, whereas only GCW in group B (P < 0.05). CONCLUSION: Early subclinical myocardial dysfunction can be identified by 2D-STE in breast cancer patients with chemotherapy, and GLS provides profound value in demonstrating the temporal changes in early myocardial damage induced by anthracycline. LV contractility injury in patients with trastuzumab may be mild at first but increases in severity with exposure time as early as cycle-4. Awareness of these differences may help to stratify the prevention of late cardiovascular events caused by different CTRCDs. In addition, GCW may be the most sensitive myocardial work parameter of CTRCD.

A prediction model for major adverse cardiovascular events in patients with heart failure based on high-throughput echocardiographic data.

Background: Heart failure (HF) is a serious end-stage condition of various heart diseases with increasing frequency. Few studies have combined clinical features with high-throughput echocardiographic data to assess the risk of major cardiovascular events (MACE) in patients with heart failure. In this study, we assessed the relationship between these factors and heart failure to develop a practical and accurate prognostic dynamic nomogram model to identify high-risk groups of heart failure and ultimately provide tailored treatment options. Materials and methods: We conducted a prospective study of 468 patients with heart failure and established a clinical predictive model. Modeling to predict risk of MACE in heart failure patients within 6 months after discharge obtained 320 features including general clinical data, laboratory examination, 2-dimensional and Doppler measurements, left ventricular (LV) and left atrial (LA) speckle tracking echocardiography (STE), and left ventricular vector flow mapping (VFM) data, were obtained by building a model to predict the risk of MACE within 6 months of discharge for patients with heart failure. In addition, the addition of machine learning models also confirmed the necessity of increasing the STE and VFM parameters. Results: Through regular follow-up 6 months after discharge, MACE occurred in 156 patients (33.3%). The prediction model showed good discrimination C-statistic value, 0.876 (p < 0.05), which indicated good identical calibration and clinical efficacy. In multiple datasets, through machine learning multi-model comparison, we found that the area under curve (AUC) of the model with VFM and STE parameters was higher, which was more significant with the XGboost model. Conclusion: In this study, we developed a prediction model and nomogram to estimate the risk of MACE within 6 months of discharge among patients with heart failure. The results of this study can provide a reference for clinical physicians for detection of the risk of MACE in terms of clinical characteristics, cardiac structure and function, hemodynamics, and enable its prompt management, which is a convenient, practical and effective clinical decision-making tool for providing accurate prognosis.

Analysis of diastolic left ventricular wall shear stress in normal people of different age groups.

Background: Diastolic wall shear stress (WSS), assessed by using vector flow mapping (VFM), is the result of the interaction between the blood flow and the ventricular wall. This study aimed to evaluate the trend of left ventricular (LV) WSS in normal subjects. Methods and results: A total of 371 healthy volunteers were recruited and divided into four age groups (group I: 18-30 years; group II: 31-43 years; group III: 44-56 years; group IV: 57-70 years). LV WSS of different age groups was measured at each diastolic phase (P1: isovolumic diastolic period, P2: rapid filling period, P3: slow filling period, and P4:atrial contraction period) to evaluate the change trend of LV WSS. In each age group, LV WSS coincided with a trend of increasing-decreasing-increasing during P1-P4 (P < 0.05). Besides, among groups I, II, III, and IV, WSS of anterolateral, inferoseptal, and anteroseptal in P1 and WSS of inferolateral, inferoseptal, and anteroseptal in P4 all showed an increasing trend with age (P < 0.05). Regarding sex differences, women had greater diastolic WSS compared to men (P < 0.05). Conclusion: LV WSS showed a regular variation and had specific age- and sex-related patterns in different diastolic phases.

Melatonin alleviates arginine vasopressin-induced cardiomyocyte apoptosis via increasing Mst1-Nrf2 pathway activity to reduce oxidative stress.

Heart failure patients have elevated arginine vasopressin (AVP) levels, which are involved in inducing peripheral vasoconstriction and cardiac hypertrophy. This hypertrophy, along with cardiomyocyte apoptosis, results from oxidative stress. Therefore, the antioxidant drug, melatonin (Mel), is commonly used to treat cardiac hypertrophy and apoptosis; however, whether it could alleviate AVP-induced myocardialinjury remains to be addressed. In this study, high AVP doses were found to induce H9c2 cardiomyoblast apoptosis, demonstrated by increased terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL)-positive cells, pro-apoptotic B-cell lymphoma-2 (Bcl-2)-associated X protein (Bax) up-regulation, and anti-apoptotic Bcl-2 downregulation. This AVP-induced apoptotic increase, along with lowered cell viability, was also associated with higher reactive oxygen species (ROS) levels and lowered mitochondrial membrane potentials (MMP), which were all reversed upon Mel administration. Further investigations found that apoptosis, ROS, and MMP outcomes under high AVP were associated with Mst1-nuclear factor erythroid 2-related factor 2 (Nrf2) pathway suppression, yielding mitochondrial dysfunction, and Mel reversed them via promoting Mst1 phosphorylation, which then activated Nrf2 to increase anti-oxidative enzyme production. These findings were supported by siRNA gene suppression, where knocking down either Nrf2 or Mst1 abrogated the anti-apoptotic effects of Mel in cardiomyoblasts. Therefore, Mel could reduce cardiomyoblast apoptosis under high AVP levels, via Mst1-Nrf2 pathway re-activation, to enhance anti-oxidative responses.

Magnetic and near-infrared-II fluorescence Au-Gd nanoclusters for imaging-guided sensitization of tumor radiotherapy.

The significant role of multifunctional nanoprobes with complementary advantages in magnetic and near-infrared-II (NIR-II, 1000-1700 nm) fluorescence properties has been documented in precision cancer theranostics. However, certain limitations, including the large size (>10 nm), low NIR-II fluorescence quantum yield (QY < 1.0%), and inefficient magnetic performance (relaxation rate < 5.0 s-1 mM-1) of nanoprobes, restrict their biomedical applications and clinical translation. Albumin-based biomineralization was adopted to prepare bright NIR-II Au NCs, which were further conjugated with DTPA and Gd ions to produce magnetic and NIR-II Au-Gd NCs. Albumin-based biomineralization helped to develop ultrasmall Au-Gd nanoclusters with ultrasmall size (∼2 nm), high NIR-II fluorescence QY (∼3.0%), and effective magnetic resonance imaging (MRI) performance (relaxation rate (r1) = 22.6 s-1 mM-1). On the one hand, Au-Gd NCs achieved NIR-II fluorescence and MRI dual-modal imaging of tumors with a high signal-to-background ratio (SBR = 8.2) in mice. On the other hand, their effective metabolism simultaneously through the kidney and liver minimized their toxicity in vivo. Moreover, compared to the control group, the survival time of tumor-bearing mice was extended by three times when Au-Gd NCs with high-Z elements were used to perform dual-modal imaging-guided sensitization of tumor radiotherapy. Thus, ultrasmall nanoprobes with complementary imaging modalities and therapeutic functions manifest great potential in cancer precision diagnosis and therapy.

Extracellular vesicle-packaged mitochondrial disturbing miRNA exacerbates cardiac injury during acute myocardial infarction.

Mounting evidence suggests that extracellular vesicles (EVs) are effective communicators in biological signalling in cardiac physiology and pathology. However, the role of EVs in cardiac injury, particularly in ischemic myocardial scenarios, has not been fully elucidated. Here, we report that acute myocardial infarction (AMI)-induced EVs can impair cardiomyocyte survival and exacerbate cardiac injury. EV-encapsulated miR-503, which is enriched during the early phase of AMI, is a critical molecule that mediates myocardial injury. Functional studies revealed that miR-503 promoted cardiomyocyte death by directly binding to peroxisome proliferator-activated receptor gamma coactivator-1ß (PGC-1ß) and a mitochondrial deacetylase, sirtuin 3 (SIRT3), thereby triggering mitochondrial metabolic dysfunction and cardiomyocyte death. Mechanistically, we identified endothelial cells as the primary source of miR-503 in EVs after AMI. Hypoxia induced rapid H3K4 methylation of the promoter of the methyltransferase-like 3 gene (METTL3) and resulted in its overexpression. METTL3 overexpression evokes N6-methyladenosine (m6 A)-dependent miR-503 biogenesis in endothelial cells. In summary, this study highlights a novel endogenous mechanism wherein EVs aggravate myocardial injury during the onset of AMI via endothelial cell-secreted miR-503 shuttling.

Melatonin alleviates doxorubicin-induced mitochondrial oxidative damage and ferroptosis in cardiomyocytes by regulating YAP expression.

Doxorubicin (Dox) is a high-efficiency agent for cancer therapy. However, it causes cardiotoxicity which limits its clinical application. Despite more efforts has been made to seek protective decisions, unfortunately, the poor prognosis suggests the need for new treatments. As a powerful mitochondrial antioxidant, melatonin (Mel) has been found to confer cardioprotection against various cardiovascular diseases. Currently, the mechanism through which Mel confers protection is not well understood. In this study, we established a Dox-induced cardiotoxicity model in H9c2 cardiomyocytes, zebrafish, and SD rats to explore the mechanism by which Mel alleviates Dox-induced cardiotoxicity. In vivo and in vitro experiments showed that Dox significantly decreased the viability of H9c2 cells, induced apoptosis, myocardial injury, and effectively up-regulated the expression of p-YAP but down-regulated the expression of YAP. Furthermore, we found that Dox significantly up-regulated the expression of ferroptosis-associated protein ACSL4 and down-regulated expression of GPX4. Interestingly, these effects of Dox were reversed following treatment with Mel, indicating that ferroptosis mediated the protective effects of Mel against Dox-induced cardiomyocyte injury. Furthermore, we used YAP-siRNA in vitro and verteporfin (Ver) in vivo to down-regulate the expression level of YAP. The results showed that YAP down-regulation abolished the protective effects of Mel including apoptosis, mitochondrial lipid peroxidation, and ferroptosis. Collectively, these results show that Mel regulates ferroptosis by modulating YAP expression to counteract Dox-induced cardiotoxicity.

Prediction of heptagonal bipyramidal nonacoordination in highly viable [OB-M©B7O7-BO]- (M = Fe, Ru, Os) complexes.

Non-spherical distributions of ligand atoms in coordination complexes are generally unfavorable due to higher repulsion than for spherical distributions. To the best of our knowledge, non-spherical heptagonal bipyramidal nonacoordination is hitherto unreported, because of extremely high repulsion among seven equatorial ligand atoms. Herein, we report the computational prediction of such nonacoordination, which is constructed by the synergetic coordination of an equatorial hepta-dentate centripetal ligand (B7O7) and two axial mono-dentate ligands (-BO) in the gear-like mono-anionic complexes [OB-M©B7O7-BO]- (M = Fe, Ru, Os). The high repulsion among seven equatorial ligand B atoms has been compensated by the strong B-O bonding. These complexes are the dynamically stable (up to 1500 K) global energy minima with the HOMO-LUMO gaps of 7.15 to 7.42 eV and first vertical detachment energies of 6.14 to 6.66 eV (being very high for anions), suggesting their high probability for experimental realization in both gas-phase and condensed phases. The high stability stems geometrically from the surrounded outer-shell oxygen atoms and electronically from meeting the 18e rule as well as possessing the σ + π + δ triple aromaticity. Remarkably, the ligand-metal interactions are governed not by the familiar donation and backdonation interactions, but by the electrostatic interactions and electron-sharing bonding.

Right atrial papillary fibroelastoma arising from the Chiari network detected by echocardiography: a case report and literature review.

PURPOSE: To improve our understanding of cardiac papillary fibroelastomaand provide evidence for its treatment and prognosis. MATERIALS AND METHODS: We report a 54-year-old Chinese male who was hospitalized for a 14-day headache with a previous vertebral aneurysm history. A right atrial mass arising from the Chiari network was detected by echocardiography and complete tumor resection was performed finally. Pathologic findings confirmed the diagnosis of cardiac papillary fibroelastoma. The recovery of the patient was uneventful and follow-up echocardiographic examination revealed no recurrence of the tumor. RESULTS: Transthoracic echocardiography revealed a mobile, sessile mass in the right atrium without obstructing the orifice of the tricuspid valve. The subsequent transesophageal echocardiography confirmed the presence of a 1.56cm × 1.24cm mobile, sessile, irregular mass arising from the Chiari network (Fig. 1) and showed no evidence of patent foramen ovale. CONCLUSIONS: Early recognition and surgical excision is essential for patients with cardiac papillary fibroelastoma.

Rhodiola crenulata extract decreases fatty acid oxidation and autophagy to ameliorate pulmonary arterial hypertension by targeting inhibiton of acylcarnitine in rats.

Pulmonary arterial hypertension (PAH) is a devastating pulmonary circulation disease lacking high-efficiency therapeutics. The present study aims to decipher the therapeutic mechanism of Rhodiola crenulata, a well-known traditional chinese medicine with cardiopulmonary protection capacity, on PAH by exploiting functional lipidomics. The rat model with PAH was successfully established for first, following Rhodiola crenulata water extract (RCE) treatment, then analysis of chemical constituents of RCE was performed, additional morphologic, hemodynamic, echocardiographic measurements were examined, further targeted lipidomics assay was performed to identify differential lipidomes, at last accordingly mechanism assay was done by combining qRT-PCR, Western blot and ELISA. Differential lipidomes were identified and characterized to differentiate the rats with PAH from healthy controls, mostly assigned to acylcarnitines, phosphatidylcholines, sphingomyelin associated with the PAH development. Excitingly, RCE administration reversed high level of decadienyl-L-carnitine by the modulation of metabolic enzyme CPT1A in mRNA and protein level in serum and lung in the rats with PAH. Furthermore, RCE was observed to reduce autophagy, confirmed by significantly inhibited PPARγ, LC3B, ATG7 and upregulated p62, and inactivated LKB1-AMPK signal pathway. Notably, we accurately identified the constituents in RCE, and delineated the therapeutic mechansim that RCE ameliorated PAH through inhibition of fatty acid oxidation and autophagy. Altogether, RCE might be a potential therapeutic medicine with multi-targets characteristics to prevent the progression of PAH. This novel findings pave a critical foundation for the use of RCE in the treatment of PAH.

3D Uranyl Organic Frameworks Supported by Rigid Octadentate Carboxylate Ligand: Synthesis, Structure Diversity, and Luminescence Properties.

Seven three dimensional (3D) uranyl organic frameworks (UOFs), formulated as [NH4 ][(UO2 )3 (HTTDS)(H2 O)] (1), [(UO2 )4 (HTTDS)2 ](HIM)6 (2, IM=imidazole), [(UO2 )4 (TTDS)(H2 O)2 (Phen)2 ] (3, Phen=1,10-phenanthroline), [Zn(H2 O)4 ]0.5 [(UO2 )3 (HTTDS)(H2 O)4 ] (4), and {(UO2 )2 [Zn(H2 O)3 ]2 (TTDS)} (5), {Zn(UO2 )2 (H2 O)(Dib)0.5 (HDib)(HTTDS)} (6, Dib=1,4-di(1H-imidazol-1-yl)benzene) and [Na]{(UO2 )4 [Cu3 (u3 -OH)(H2 O)7 ](TTDS)2 } (7) have been hydrothermally prepared using a rigid octadentate carboxylate ligand, tetrakis(3,5-dicarboxyphenyl)silicon(H8 TTDS). These UOFs have different 3D self-assembled structures as a function of co-ligands, structure-directing agents and transition metals. The structure of 1 has an infinite ribbon formed by the UO7 pentagonal bipyramid bridged by carboxylate groups. With further introduction of auxiliary N-donor ligands, different structure of 2 and 3 are formed, in 2 the imidazole serves as space filler, while in 3 the Phen are bound to [UO2 ]2+ units as co-ligands. The second metal centers were introduced in the syntheses of 4-7, and in all cases, they are part of the final structures, either as a counterion (4) or as a component of framework (5-7). Interesting, in 7, a rare polyoxometalate [Cu3 (µ3 -OH)O7 (O2 CR)4 ] cluster was found in the structure. It acts as an inorganic building unit together with the dimer [(UO2 )2 (O2 CR)4 ] unit. Those uranyl carboxylates were sufficiently determined by single crystal X-ray diffraction, and their topological structures and luminescence properties were analyzed in detail.

Circulating Exosomes Control CD4+ T Cell Immunometabolic Functions via the Transfer of miR-142 as a Novel Mediator in Myocarditis.

CD4+ T cells undergo immunometabolic activation to mount an immunogenic response during experimental autoimmune myocarditis (EAM). Exosomes are considered key messengers mediating multiple T cell functions in autoimmune responses. However, the role of circulating exosomes in EAM immunopathogenesis and CD4+ T cell dysfunction remains elusive. Our objective was to elucidate the mechanism of action for circulating exosomes in EAM pathogenesis. We found that serum exosomes harvested from EAM mice induced CD4+ T cell immunometabolic dysfunction. Treatment with the exosome inhibitor GW4869 protected mice from developing EAM, underlying that exosomes are indispensable for the pathogenesis of EAM. Furthermore, by transfer of EAM exosomes, we confirmed that circulating exosomes initiate the T cell pathological immune response, driving the EAM pathological process. Mechanistically, EAM-circulating exosomes selectively loaded abundant microRNA (miR)-142. We confirmed methyl-CpG binding domain protein 2 (MBD2) and suppressor of cytokine signaling 1 (SOCS1) as functional target genes of miR-142. The miR-142/MBD2/MYC and miR-142/SOCS1 communication axes are critical to exosome-mediated immunometabolic turbulence. Moreover, the in vivo injection of the miR-142 inhibitor alleviated cardiac injury in EAM mice. This effect was abrogated by pretreatment with EAM exosomes. Collectively, our results indicate a newly endogenous mechanism whereby circulating exosomes regulate CD4+ T cell immunometabolic dysfunction and EAM pathogenesis via cargo miR-142.

Quantitative shear wave elastography in primary invasive breast cancers, based on collagen-S100A4 pathology, indicates axillary lymph node metastasis.

BACKGROUND: The purpose of this study was to evaluate the value of quantitative shear wave elastography (SWE) in indicating the axillary lymph node metastasis (LNM) of invasive breast cancers (IBCs) and to investigate if S100A4 plays a key role in promoting metastasis and increasing stiffness in IBC. METHODS: The differences in SWE of 223 IBC patients were compared between the LNM+ and LNM- groups and the optimal cutoff values of SWE for diagnosing LNM were calculated. We searched the gene expression omnibus (GEO) to determine whether S100A4 was more highly expressed in IBCs that were LNM+ than in those that were LNM-. Sirius red and immunohistochemical staining were used to examine the collagen deposition and S100A4 expression of included tissue samples, and correlations of SWE and S100A4 expression with collagen deposition were analyzed. RESULTS: The optimal cutoff values for Emax (the maximum stiff value), Emean (the mean stiff value), and EmeanR (the ratio of Emean between mass and parenchyma) for diagnosing axillary LNM were 111.05 kPa, 79.80 kPa, and 6.89, respectively. GSE9893 exhibited more increased S100A4 expression in IBCs that were LNM+ than in those that were LNM-. Collagen volume fraction (CVF) and the average optical density of S100A4 (AODS100A4) in the LNM+ group were significantly higher than those in the LNM- group. Emax, Emean, EmeanR, and AODS100A4 were all positively correlated with CVF. CONCLUSIONS: SWE in primary IBC could be useful for indicating axillary LNM. S100A4 may be a factor that regulates cancer-associated collagen deposition and metastasis; however, prospective molecular biological studies are needed.

Melatonin attenuates doxorubicin-induced cardiotoxicity through preservation of YAP expression.

There are increasing concerns related to the cardiotoxicity of doxorubicin in the clinical setting. Recently, melatonin has been shown to exert a cardioprotective effect in various cardiovascular diseases, including cardiotoxic conditions. In this study, we examined the possible protective effects of melatonin on doxorubicin-induced cardiotoxicity and explored the underlying mechanisms related to this process. We found that in vitro doxorubicin treatment significantly decreased H9c2 cell viability and induced apoptosis as manifested by increased TUNEL-positive cells, down-regulation of anti-apoptotic protein Bcl-2, as well as up-regulation of pro-apoptotic protein Bax. This was associated with increased reactive oxygen species (ROS) levels and decreased mitochondrial membrane potentials (MMP). In vivo, five weeks of doxorubicin treatment significantly decreased cardiac function, as evaluated by echocardiography. TUNEL staining results confirmed the increased apoptosis caused by doxorubicin. On the other hand, combinational treatment of doxorubicin with melatonin decreased cardiomyocyte ROS and apoptosis levels, along with increasing MMP. Such doxorubicin-melatonin co-treatment alleviated in vivo doxorubicin-induced cardiac injury. Western Blots, along with in vitro immunofluorescence and in vivo immunohistochemical staining confirmed that doxorubicin treatment significantly down-regulated Yes-associated protein (YAP) expression, while YAP levels were maintained under co-treatment of doxorubicin and melatonin. YAP inhibition by siRNA abolished the protective effects of melatonin on doxorubicin-treated cardiomyocytes, with reversed ROS level and apoptosis. Our findings suggested that melatonin treatment attenuated doxorubicin-induced cardiotoxicity through preserving YAP levels, which in turn decreases oxidative stress and apoptosis.

Value of dual Doppler echocardiography for prediction of atrial fibrillation recurrence after radiofrequency catheter ablation.

BACKGROUND: Increasing evidence has been presented which suggests that left ventricular (LV) diastolic dysfunction may play an important role in the development of atrial fibrillation (AF). However, the potential for LV diastolic dysfunction to serve as a predictor of AF recurrence after radiofrequency catheter ablation remains unresolved. METHODS: Dual Doppler and M-PW mode echocardiography were performed in 67 patients with AF before ablation and 47 patients with sinus rhythm. The parameters measured within identical cardiac cycles included, the time interval between the onset of early transmitral flow peak velocity (E) and that of early diastolic mitral annular velocity (e') (TE-e'), the ratio of E to color M-mode Doppler flow propagation velocity (Vp)(E/Vp), the Tei index, the ratio of E and mitral annular septal (S) peak velocity in early diastolic E/e'(S) and the ratio of E and mitral annular lateral (L) peak velocity E/e'(L). A follow-up examination was performed 1 year after ablation and patients were divided into two groups based on the presence or absence of AF recurrence. Risk estimations for AF recurrence were performed using univariate and multivariate logistic regression. RESULTS: TE-e', E/Vp, the Tei index, E/e'(S) and E/e'(L) were all increased in AF patients as compared with the control group (p <  0.05). At the one-year follow-up examination, a recurrence of AF was observed in 21/67 (31.34%) patients. TE-e' and the Tei index within the recurrence group were significantly increased as compared to the group without recurrence (p <  0.001). Results from multivariate analysis revealed that TE-e' can provide an independent predictor for AF recurrence (p = 0.001). CONCLUSIONS: Dual Doppler echocardiography can provide an effective and accurate technique for evaluating LV diastolic function within AF patients. The TE-e' obtained within identical cardiac cycles can serve as an independent predictor for the recurrence of AF as determined at 1 year after ablation.

Probing the Fluxional Bonding Nature of Rapid Cope rearrangements in Bullvalene C10H10 and Its Analogs C8H8, C9H10, and C8BH9.

Bullvalene C10H10 and its analogs semibullvalene C8H8, barbaralane C9H10, and 9-Borabarbaralane C8BH9 are prototypical fluxional molecules with rapid Cope rearrangements at finite temperatures. Detailed bonding analyses performed in this work reveal the existence of two fluxional π-bonds (2 2c-2e π → 2 3c-2e π → 2 2c-2e π) and one fluxional σ-bond (1 2c-2e σ → 1 4c-2e σ → 1 2c-2e σ) in their ground states and transition states, unveiling the universal π + σ double fluxional bonding nature of these fluctuating cage-like species. The highest occupied natural bond orbitals (HONBOs) turn out to be typical fluxional bonds dominating the dynamics of the systems. The 13C-NMR and 1H-NMR shielding tensors and chemical shifts of the model compound C8BH9 are computationally predicted to facilitate future experiments.

Low-dimensional functional networks of cage-like B40 with effective transition-metal intercalations.

As the first all-boron fullerene observed in experiments, cage-like borospherene B40 has attracted considerable attention in recent years. However, B40 has been proved to be chemically reactive and tends to coalesce with one another via the formation of covalent bonds. We explore herein the possibility of low-dimensional functional networks of B40 with effective transition-metal intercalations. We find that the four equivalent B7 heptagons on the waist of each B40 can serve as effective ligands to coordinate various transition metal centers in exohedral motifs. The intercalated metal atoms entail these networks with a variety of intriguing properties. The two-dimensional (2D) Cr2B40 network is a ferromagnetic metal while the 2D Zn2B40 network becomes semiconducting. In contrast, other 2D M2B40 (M = Sc, Ti, V, Mn, Fe, Co, Ni and Cu) networks and 1D CrB40 belong to nonmagnetic metals. The 3D Cr3B40 network is a magnetic metal. This work presents the viable possibility of assembling Mn&B40 metalloborospherenes into stable functional nanomaterials via effective transition-metal intercalations with potential applications in electronic and spintronic devices.