[Stapled anoplin peptide combined with photothermal therapy enhances oncolytic immunotherapy of triple-negative breast cancer].

This study constructed a nano-drug delivery system, A3@GMH, by co-delivering the stapled anoplin peptide(Ano-3, A3) with the light-harvesting material graphene oxide(GO), and evaluated its oncolytic immunotherapy effect on triple-negative breast cancer(TNBC). A3@GMH was prepared using an emulsion template method and its physicochemical properties were characterized. The in vivo and in vitro photothermal conversion abilities of A3@GMH were investigated using an infrared thermal imager. The oncoly-tic activity of A3@GMH against TNBC 4T1 cells was evaluated through cell counting kit-8(CCK-8), lactate dehydrogenase(LDH) release, live/dead cell staining, and super-resolution microscopy. The targeting properties of A3@GMH on 4T1 cells were assessed using a high-content imaging system and flow cytometry. In vitro and in vivo studies were conducted to investigate the antitumor mechanism of A3@GMH in combination with photothermal therapy(PTT) through inducing immunogenic cell death(ICD) in 4T1 cells. The results showed that the prepared A3@GMH exhibited distinct mesoporous and coated structures with an average particle size of(308.9±7.5) nm and a surface potential of(-6.79±0.58) mV. The encapsulation efficiency and drug loading of A3 were 23.9%±0.6% and 20.5%±0.5%, respectively. A3@GMH demonstrated excellent photothermal conversion ability and biological safety. A3@GMH actively mediated oncolytic features such as 4T1 cell lysis and LDH release, as well as ICD effects, and showed enhanced in vitro antitumor activity when combined with PTT. In vivo, A3@GMH efficiently induced ICD effects with two rounds of PTT, activated the host's antitumor immune response, and effectively suppressed tumor growth in 4T1 tumor-bearing mice, achieving an 88.9% tumor inhibition rate with no apparent toxic side effects. This study suggests that the combination of stapled anoplin peptide and PTT significantly enhances the oncolytic immunotherapy for TNBC and provides a basis for the innovative application of anti-tumor peptides derived from TCM in TNBC treatment.

Right ventricular diastolic dysfunction and failure: a review.

Right ventricular diastolic dysfunction and failure (RVDDF) has been increasingly identified in patients with cardiovascular diseases, including heart failure and other diseases with cardiac involvement. It is unknown whether RVDDF exists as a distinct clinical entity; however, its presence and degree have been shown to be a sensitive marker of end-organ dysfunction related to multiple disease processes including systemic hypertension, pulmonary hypertension, heart failure, and endocrine disease. In this manuscript, we review issues pertaining to RVDDF including anatomic features of the right ventricle, physiologic measurements, RVDDF diagnosis, underlying mechanisms, clinical impact, and clinical management. Several unique features of RVDDF are also discussed.

Preoperative Liver Stiffness is Associated With Hospital Length of Stay After Cardiac Surgery.

OBJECTIVES: Risk assessment models for cardiac surgery do not account for the degrees of liver dysfunction. Ultrasound shear-wave elastography measures liver stiffness (LSM), a quantitative measurement related to fibrosis, congestion, and inflammation. The authors hypothesized that preoperative liver stiffness would be associated with hospital length of stay after cardiac surgery. DESIGN: Prospective observational study. SETTING: University hospital, single center. PARTICIPANTS: One hundred five adult patients undergoing nonemergent cardiac surgery. INTERVENTIONS: Preoperative liver stiffness measured by ultrasound elastography. MEASUREMENTS AND MAIN RESULTS: The associations were analyzed using linear mixed models, with adjustments for preoperative variables, duration of cardiopulmonary bypass, and type of surgery. Median liver stiffness was 6.4 kPa (range, 4.1-18.6 kPa). The median length of hospital stay was 6 days (range, 3-18 d). Each unit increase in liver stiffness, treated as a continuous variable, was associated with an increase of 0.32 ± 0.10 days in the hospital (p = 0.002). When treated as a categorical variable (<6 kPa, 6-9.4 kPa, and ≥9.5 kPa), LSM ≥9.5 kPa v LSM <6 kPa was associated strongly with an increase in hospital length of stay of 3.25 ± 0.87 days (p = 0.0003). CONCLUSIONS: A preoperative LSM ≥9.5 kPa was associated with a significantly longer postoperative hospital length of stay. This association appeared independent of preoperative comorbidities commonly associated with coronary disease. Preoperative liver stiffness is a novel risk metric that is associated with the postoperative hospital length of stay after cardiac surgery.

Acetate, a Short-Chain Fatty Acid, Acutely Lowers Heart Rate and Cardiac Contractility Along with Blood Pressure.

Short-chain fatty acids (SCFAs) are metabolites produced almost exclusively by the gut microbiota and are an essential mechanism by which gut microbes influence host physiology. Given that SCFAs induce vasodilation, we hypothesized that they might have additional cardiovascular effects. In this study, novel mechanisms of SCFA action were uncovered by examining the acute effects of SCFAs on cardiovascular physiology in vivo and ex vivo. Acute delivery of SCFAs in conscious radiotelemetry-implanted mice results in a simultaneous decrease in both mean arterial pressure and heart rate (HR). Inhibition of sympathetic tone by the selective ß-1 adrenergic receptor antagonist atenolol blocks the acute drop in HR seen with acetate administration, yet the decrease in mean arterial pressure persists. Treatment with tyramine, an indirect sympathomimetic, also blocks the acetate-induced acute drop in HR. Langendorff preparations show that acetate lowers HR only after long-term exposure and at a smaller magnitude than seen in vivo. Pressure-volume loops after acetate injection show a decrease in load-independent measures of cardiac contractility. Isolated trabecular muscle preparations also show a reduction in force generation upon SCFA treatment, though only at supraphysiological concentrations. These experiments demonstrate a direct cardiac component of the SCFA cardiovascular response. These data show that acetate affects blood pressure and cardiac function through parallel mechanisms and establish a role for SCFAs in modulating sympathetic tone and cardiac contractility, further advancing our understanding of the role of SCFAs in blood pressure regulation. SIGNIFICANCE STATEMENT: Acetate, a short-chain fatty acid, acutely lowers heart rate (HR) as well as mean arterial pressure in vivo in radiotelemetry-implanted mice. Acetate is acting in a sympatholytic manner on HR and exerts negative inotropic effects in vivo. This work has implications for potential short-chain fatty acid therapeutics as well as gut dysbiosis-related disease states.

The Effect of the No Pain Labor & Delivery-Global Health Initiative on Cesarean Delivery and Neonatal Outcomes in China: An Interrupted Time-Series Analysis.

BACKGROUND: The proportion of live births by cesarean delivery (CD) in China is significant, with some, particularly rural, provinces reporting up to 62.5%. The No Pain Labor & Delivery-Global Health Initiative (NPLD-GHI) was established to improve obstetric and neonatal outcomes in China, including through a reduction of CD through educational efforts. The purpose of this study was to determine whether a reduction in CD at a rural Chinese hospital occurred after NPLD-GHI. We hypothesized that a reduction in CD trend would be observed. METHODS: The NPLD-GHI program visited the Weixian Renmin Hospital, Hebei Province, China, from June 15 to 21, 2014. The educational intervention included problem-based learning, bedside teaching, simulation drill training, and multidisciplinary debriefings. An interrupted time-series analysis using segmented logistic regression models was performed on data collected between June 1, 2013 and May 31, 2015 to assess whether the level and/or trend over time in the proportion of CD births would decline after the program intervention. The primary outcome was monthly proportion of CD births. Secondary outcomes included neonatal intensive care unit (NICU) admissions and extended NICU length of stay, neonatal antibiotic and intubation use, and labor epidural analgesia use. RESULTS: Following NPLD-GHI, there was a level decrease in CD with an estimated odds ratio (95% confidence interval [CI]) of 0.87 (0.78-0.98), P = .017, with odds (95% CI) of monthly CD reduction an estimated 3% (1-5; P < .001), more in the post- versus preintervention periods. For labor epidural analgesia, there was a level increase (estimated odds ratio [95% CI] of 1.76 [1.48-2.09]; P < .001) and a slope decrease (estimated odds ratio [95% CI] of 0.94 [0.92-0.97]; P < .001). NICU admissions did not have a level change (estimated odds ratio [95% CI] of 0.99 [0.87-1.12]; P = .835), but the odds (95% CI) of monthly reduction in NICU admission was estimated 9% (7-11; P < .001), greater in post- versus preintervention. Neonatal intubation level and slope changes were not statistically significant. For neonatal antibiotic administration, while the level change was not statistically significant, there was a decrease in the slope with an odds (95% CI) of monthly reduction estimated 6% (3-9; P < .001), greater post- versus preintervention. CONCLUSIONS: In a large, rural Chinese hospital, live births by CD were lower following NPLD-GHI and associated with increased use of labor epidural analgesia. We also found decreasing NICU admissions. International-based educational programs can significantly alter practices associated with maternal and neonatal outcomes.

Anesthetic Agents Isoflurane and Propofol Decrease Maximal Ca2+-Activated Force and Thus Contractility in the Failing Myocardium.

In the normal heart, frequently used anesthetics such as isoflurane and propofol can reduce inotropy. However, the impact of these agents on the failing myocardium is unclear. Here, we examined whether and how isoflurane and propofol influence cardiac contractility in intact cardiac muscles from rats treated with monocrotaline to induce heart failure. We measured force and intracellular Ca2+ ([Ca2 +]i) in trabeculae from the right ventricles of the rats in the absence or presence of propofol or isoflurane. At low to moderate concentrations, both propofol and isoflurane dose-dependently depressed cardiac force generation in failing trabeculae without altering [Ca2+]i At high doses, propofol (but not isoflurane) also decreased amplitude of [Ca2+]i transients. During steady-state activation, both propofol and isoflurane impaired maximal Ca2+-activated force (Fmax) while increasing the amount of [Ca2+]i required for 50% of maximal activation (Ca50). These events occurred without apparent change in the Hill coefficient, suggesting no impairment of cooperativity. Exposing these same muscles to the anesthetics after fiber skinning resulted in a similar decrement in Fmax and rise in Ca50 but no change in the myofibrillar ATPase-Ca2+ relationship. Thus, our study demonstrates that challenging the failing myocardium with commonly used anesthetic agents such as propofol and isoflurane leads to reduced force development as a result of lowered myofilament responsiveness to Ca2+ SIGNIFICANCE STATEMENT: Commonly used anesthetics such as isoflurane and propofol can impair myocardial contractility in subjects with heart failure by lowering myofilament responsiveness to Ca2+. High doses of propofol can also reduce the overall amplitude of the intracellular Ca2+ transient. These findings may have important implications for the safety and quality of intra- and perioperative care of patients with heart failure and other cardiac disorders.

Fropofol decreases force development in cardiac muscle.

Supranormal contractile properties are frequently associated with cardiac diseases. Anesthetic agents, including propofol, can depress myocardial contraction. We tested the hypothesis that fropofol, a propofol derivative, reduces force development in cardiac muscles via inhibition of cross-bridge cycling and may therefore have therapeutic potential. Force and intracellular Ca2+ concentration ([Ca2+]i) transients of rat trabecular muscles were determined. Myofilament ATPase, actin-activated myosin ATPase, and velocity of actin filaments propelled by myosin were also measured. Fropofol dose dependently decreased force without altering [Ca2+]i in normal and pressure-induced hypertrophied-hypercontractile muscles. Similarly, fropofol depressed maximum Ca2+-activated force ( Fmax) and increased the [Ca2+]i required for 50% of Fmax (Ca50) at steady state without affecting the Hill coefficient in both intact and skinned cardiac fibers. The drug also depressed cardiac myofibrillar and actin-activated myosin ATPase activity. In vitro actin sliding velocity was significantly reduced when fropofol was introduced during rigor binding of cross-bridges. The data suggest that the depressing effects of fropofol on cardiac contractility are likely to be related to direct targeting of actomyosin interactions. From a clinical standpoint, these findings are particularly significant, given that fropofol is a nonanesthetic small molecule that decreases myocardial contractility specifically and thus may be useful in the treatment of hypercontractile cardiac disorders.-Ren, X., Schmidt, W., Huang, Y., Lu, H., Liu, W., Bu, W., Eckenhoff, R., Cammarato, A., Gao, W. D. Fropofol decreases force development in cardiac muscle.

The Genetic and Molecular Bases for Hypertrophic Cardiomyopathy: The Role for Calcium Sensitization.

Hypertrophic cardiomyopathy (HCM) affects millions of people around the world as one of the most common genetic heart disorders and leads to cardiac ischemia, heart failure, dysfunction of other organ systems, and increased risk for sudden unexpected cardiac deaths. HCM can be caused by single-point mutations, insertion or deletion mutations, or truncation of cardiac myofilament proteins. The molecular mechanism that leads to disease progression and presentation is still poorly understood, despite decades of investigations. However, recent research has made dramatic advances in the understanding of HCM disease development. Studies have shown that increased calcium sensitivity is a universal feature in HCM. At the molecular level, increased crossbridge force (or power) generation resulting in hypercontractility is the prominent feature. Thus, calcium sensitization/hypercontractility is emerging as the primary stimulus for HCM disease development and phenotypic expression. Cross-bridge inhibition has been shown to halt HCM presentation, and myofilament desensitization appears to reduce lethal arrhythmias in animal models of HCM. These advances in basic research will continue to deepen the knowledge of HCM pathogenesis and are beginning to revolutionize the management of HCM.

Molecular mechanism of anesthetic-induced depression of myocardial contraction.

Isoflurane and propofol are known to depress cardiac contraction, but the molecular mechanisms involved are not known. In this study, we determined whether decreasing myofilament Ca(2+) responsiveness underlies anesthesia-induced depression of contraction and uncovered the molecular targets of isoflurane and propofol. Force and intracellular Ca(2+) ([Ca(2+)]i) were measured in rat trabeculae superfused with Krebs-Henseleit solution, with or without propofol or isoflurane. Photoaffinity labeling of myofilament proteins with meta-Azi-propofol (AziPm) and Azi-isoflurane (Azi-iso) and molecular docking were also used. Both propofol and isoflurane dose dependently depressed force from low doses (propofol, 27 ± 6 µM; isoflurane, 1.0 ± 0.1%) to moderate doses (propofol, 87 ± 4 µM; isoflurane, 3.0 ± 0.25%), without significant alteration [Ca(2+)]i During steady-state activations in both intact and skinned preparations, propofol and isoflurane depressed maximum Ca(2+)-activated force and increased the [Ca(2+)]i required for 50% of activation. Myofibrils photolabeled with AziPm and Azi-iso identified myosin, actin, and myosin light chain as targets of the anesthetics. Several adducted residues in those proteins were located in conformationally sensitive regions that underlie contractile function. Thus, propofol and isoflurane decrease force development by directly depressing myofilament Ca(2+) responsiveness and have binding sites in key regions for contraction in both actin and myosin.-Meng, T., Bu, W., Ren, X., Chen, X., Yu, J., Eckenhoff, R. G., Gao, W. D. Molecular mechanism of anesthetic-induced depression of myocardial contraction.

Restoring redox balance enhances contractility in heart trabeculae from type 2 diabetic rats exposed to high glucose.

Hearts from type 2 diabetic (T2DM) subjects are chronically subjected to hyperglycemia and hyperlipidemia, both thought to contribute to oxidizing conditions and contractile dysfunction. How redox alterations and contractility interrelate, ultimately diminishing T2DM heart function, remains poorly understood. Herein we tested whether the fatty acid palmitate (Palm), in addition to its energetic contribution, rescues function by improving redox [glutathione (GSH), NAD(P)H, less oxidative stress] in T2DM rat heart trabeculae subjected to high glucose. Using cardiac trabeculae from Zucker Diabetic Fatty (ZDF) rats, we assessed the impact of low glucose (EG) and high glucose (HG), in absence or presence of Palm or insulin, on force development, energetics, and redox responses. We found that in EG ZDF and lean trabeculae displayed similar contractile work, yield of contractile work (Ycw), representing the ratio of force time integral over rate of O2 consumption. Conversely, HG had a negative impact on Ycw, whereas Palm, but not insulin, completely prevented contractile loss. This effect was associated with higher GSH, less oxidative stress, and augmented matrix GSH/thioredoxin (Trx) in ZDF mitochondria. Restoration of myocardial redox with GSH ethyl ester also rescued ZDF contractile function in HG, independently from Palm. These results support the idea that maintained redox balance, via increased GSH and Trx antioxidant activities to resist oxidative stress, is an essential protective response of the diabetic heart to keep contractile function.

Effect of isoflurane on myocardial energetic and oxidative stress in cardiac muscle from Zucker diabetic fatty rat.

The effect of inhalational anesthetics on myocardial contraction and energetics in type 2 diabetes mellitus is unknown. We investigated the effect of isoflurane (ISO) on force and intracellular Ca(2+) transient (iCa), myocardial oxygen consumption (MVo(2)), and energetics/redox behavior in trabecular muscles from Zucker diabetic fatty (ZDF) rats. At baseline, force and corresponding iCa were lower in ZDF trabeculae than in controls. ISO decreased force in both groups in a dose-dependent manner. ISO did not affect iCa amplitude in controls, but ISO > 1.5% significantly reduced iCa amplitude in ZDF trabeculae. ISO-induced force depression fully recovered as a result of increased iCa when external Ca(2+) was raised in controls. However, both force and iCa remained low in ZDF muscle at elevated external Ca(2+). In controls, force, iCa, and MVo(2) increased when stimulation frequency was increased from 0.5 to 1.5 Hz. ZDF muscles, however, exhibited blunted responses in force and iCa and decreased MVo(2). Oxidative stress levels were unchanged in control muscles but increased significantly in ZDF muscles after exposure to ISO. Finally, the depressive effect of ISO was prevented by 4-hydroxy-2,2,6,6-tetramethylpiperidine-N-oxyl (Tempol) in ZDF muscles. These findings suggest that ISO dose-dependently attenuates force in control and ZDF muscles with differential effect on iCa. The mechanism of force depression by ISO in controls is mainly decreased myofilament Ca(2+) sensitivity, whereas in ZDF muscles the ISO-induced decrease in contraction is due to worsening oxidative stress, which inhibits iCa and force development.

Nitroxyl-mediated disulfide bond formation between cardiac myofilament cysteines enhances contractile function.

RATIONALE: In the myocardium, redox/cysteine modification of proteins regulating Ca(2+) cycling can affect contraction and may have therapeutic value. Nitroxyl (HNO), the one-electron-reduced form of nitric oxide, enhances cardiac function in a manner that suggests reversible cysteine modifications of the contractile machinery. OBJECTIVE: To determine the effects of HNO modification in cardiac myofilament proteins. METHODS AND RESULTS: The HNO-donor, 1-nitrosocyclohexyl acetate, was found to act directly on the myofilament proteins, increasing maximum force (F(max)) and reducing the concentration of Ca(2+) for 50% activation (Ca(50)) in intact and skinned cardiac muscles. The effects of 1-nitrosocyclohexyl acetate are reversible by reducing agents and distinct from those of another HNO donor, Angeli salt, which was previously reported to increase F(max) without affecting Ca50. Using a new mass spectrometry capture technique based on the biotin switch assay, we identified and characterized the formation by HNO of a disulfide-linked actin-tropomyosin and myosin heavy chain-myosin light chain 1. Comparison of the 1-nitrosocyclohexyl acetate and Angeli salt effects with the modifications induced by each donor indicated the actin-tropomyosin and myosin heavy chain-myosin light chain 1 interactions independently correlated with increased Ca(2+) sensitivity and force generation, respectively. CONCLUSIONS: HNO exerts a direct effect on cardiac myofilament proteins increasing myofilament Ca(2+) responsiveness by promoting disulfide bond formation between critical cysteine residues. These findings indicate a novel, redox-based modulation of the contractile apparatus, which positively impacts myocardial function, providing further mechanistic insight for HNO as a therapeutic agent.

One size does not fit all: Perioperative management of patients with heart failure with preserved ejection fraction.

Heart failure with preserved ejection fraction (HFpEF) is recognized as an important risk factor for perioperative complications. However, anesthesia management of HFpEF patients remains a considerable challenge without clear guidance. HFpEF is heterogeneous in its pathophysiological processes, diverse clinical presentations, adverse remodeling of cardiovascular and other organs, and clinical outcomes. It is difficult to manage the disease with one fixed approach because of this. This review phenotypes HFpEF patients by combining their clinical features and anesthesia care issues. Five phenotypes of HFpEF patients are identified: A, O, P, C, and Y. The clinical features, anesthesia implications, and anesthesia management for each phenotype are highlighted and discussed. Such an approach to HFpEF patients in the operating room could deliver safe, high-quality perioperative care.

The Impact of Silent Liver Disease on Hospital Length of Stay Following Isolated Coronary Artery Bypass Grafting Surgery.

Objectives: Risk assessment models for cardiac surgery do not distinguish between degrees of liver dysfunction. We have previously shown that preoperative liver stiffness is associated with hospital length of stay following cardiac surgery. The authors hypothesized that a liver stiffness measurement (LSM) ≥ 9.5 kPa would rule out a short hospital length of stay (LOS < 6 days) following isolated coronary artery bypass grafting (CABG) surgery. Methods: A prospective observational study of one hundred sixty-four adult patients undergoing non-emergent isolated CABG surgery at a single university hospital center. Preoperative liver stiffness measured by ultrasound elastography was obtained for each participant. Multivariate logistic regression models were used to assess the adjusted relationship between LSM and a short hospital stay. Results: We performed multivariate logistic regression models using short hospital LOS (<6 days) as the dependent variable. Independent variables included LSM (< 9.5 kPa, ≥ 9.5 kPa), age, sex, STS predicted morbidity and mortality, and baseline hemoglobin. After adjusting for included variables, LSM ≥ 9.5 kPa was associated with lower odds of early discharge as compared to LSM < 9.5 kPa (OR: 0.22, 95% CI: 0.06-0.84, p = 0.03). The ROC curve and resulting AUC of 0.76 (95% CI: 0.68-0.83) suggest the final multivariate model provides good discriminatory performance when predicting early discharge. Conclusions: A preoperative LSM ≥ 9.5 kPa ruled out a short length of stay in nearly 80% of patients when compared to patients with a LSM < 9.5 kPa. Preoperative liver stiffness may be a useful metric to incorporate into preoperative risk stratification.

SLIT2 inhibits cell migration in colorectal cancer through the AKT-GSK3ß signaling pathway.

PURPOSE: Colorectal cancer is a common malignancy and one of the major causes of cancer-related deaths worldwide. Similar to other human cancers, tumor metastasis is the biggest obstacle in the clinical treatment of colorectal cancer. In this study, we explored the functional role of SLIT2 in colon tumor metastasis and the relevant molecular mechanisms. METHODS: Immunohistochemistry, Western blotting, and quantitative reverse transcription-polymerase chain reaction were used to measure SLIT2 expression in colorectal tumor tissues in the presence or absence of metastasis. Wound-healing assays, Transwell assays, Western blotting, and immunofluorescence assays were used to examine the effects of SLIT2 on SW480 and NCM460 cell migration and the epithelial-to-mesenchymal transition (EMT). An AKT inhibitor was introduced to examine the mechanism underlying SLIT2-mediated suppression of NCM460 cell migration. RESULTS: Higher SLIT2 expression was detected in metastasis-positive tumor tissues, and this upregulation was beneficial for the overall survival of patients with colorectal cancer. Either the addition of purified SLIT2 or overexpression of SLIT2 inhibited SW480 cell migration, whereas the depletion of SLIT2 with shRNA enhanced the migratory ability of NCM460 cells. Meanwhile, SLIT2 depletion also induced ß-catenin accumulation and altered the expression levels of several molecules related to EMT in NCM460 cells. AKT inhibition abrogated the effects of SLIT2 depletion on EMT and migration in NCM460 cells. CONCLUSIONS: SLIT2 suppresses colon tumor metastasis, and it exerts its suppressive activity against colorectal cancer metastasis by restraining AKT signaling and EMT, thus making it a potential clinical prognosis marker in colorectal cancer.

Human Resistin Induces Cardiac Dysfunction in Pulmonary Hypertension.

Background Cardiac failure is the primary cause of death in most patients with pulmonary arterial hypertension (PH). As pleiotropic cytokines, human resistin (Hresistin) and its rodent homolog, resistin-like molecule α, are mechanistically critical to pulmonary vascular remodeling in PH. However, it is still unclear whether activation of these resistin-like molecules can directly cause PH-associated cardiac dysfunction and remodeling. Methods and Results In this study, we detected Hresistin protein in right ventricular (RV) tissue of patients with PH and elevated resistin-like molecule expression in RV tissues of rodents with RV hypertrophy and failure. In a humanized mouse model, cardiac-specific Hresistin overexpression was sufficient to cause cardiac dysfunction and remodeling. Dilated hearts exhibited reduced force development and decreased intracellular Ca2+ transients. In the RV tissues overexpressing Hresistin, the impaired contractility was associated with the suppression of protein kinase A and AMP-activated protein kinase. Mechanistically, Hresistin activation triggered the inflammation mediated by signaling of the key damage-associated molecular pattern molecule high-mobility group box 1, and subsequently induced pro-proliferative Ki67 in RV tissues of the transgenic mice. Intriguingly, an anti-Hresistin human antibody that we generated protected the myocardium from hypertrophy and failure in the rodent PH models. Conclusions Our data indicate that Hresistin is expressed in heart tissues and plays a role in the development of RV dysfunction and maladaptive remodeling through its immunoregulatory activities. Targeting this signaling to modulate cardiac inflammation may offer a promising strategy to treat PH-associated RV hypertrophy and failure in humans.

Nanotechnology-based photo-immunotherapy: a new hope for inhibition of melanoma growth and metastasis.

Melanoma is the most aggressive form of skin cancer and there is a need for the development of effective anti-melanoma therapies as it shows high metastatic ability and low response rate. In addition, it has been identified that traditional phototherapy could trigger immunogenic cell death (ICD) to activate antitumor immune response, which could not only effectively arrest primary tumour growth, but also exhibit superior effects in terms of anti-metastasis, anti-recurrence for metastatic melanoma treatment. However, the limited tumour accumulation of photosensitizers/photothermal agents and immunosuppressive tumour microenvironment severely weaken the immune effects. The application of nanotechnology facilitates a higher accumulation of photosensitizers/photothermal agents at the tumour site, which can thus improve the antitumor effects of photo-immunotherapy (PIT). In this review, we summarise the basic principles of nanotechnology-based PIT and highlight novel nanotechnologies that are expected to enhance the antitumor immune response for improved therapeutic efficacy.

A Four-Stepwise Electrocardiographic Algorithm for Differentiation of Ventricular Arrhythmias Originated from Left Ventricular Outflow Tract.

Several electrocardiographic algorithms have been proposed to identify the site of origin for the ventricular arrhythmias (VAs) from the left ventricular outflow tract (LVOT) versus right ventricular outflow tract. However, the electrocardiographic criteria for distinguishing VAs originated from the different sites of LVOT is lacking. We aimed to develop a simple and efficient ECG algorithm to differentiate LVOT VAs originated from the aortic root, AMC and LV summit. We analyzed 12-lead ECG characteristics of 68 consecutive patients who underwent successful radiofrequency catheter ablation of symptomatic VAs from LVOT. Patients were divided into RCC (right coronary cusp) group (n = 8), the L-RCC (the junction between the LCC and RCC) group (n = 21), the LCC (left coronary cusp) group (n = 24), the aortomitral continuity (AMC) group (n = 9) and the LV summit group (n = 6) according to the final ablation sites. Measurements with the highest diagnostic performance were modeled into a 4-stepwise algorithm to discriminate LVOT VAs. The performance of this novel algorithm was prospectively tested in a validation cohort of 43 consecutive patients undergoing LVOT VAs ablation. Based on the accuracy of AUC, a 4-stepwise ECG algorithm was developed. First, the QS duration in aVL > 134 ms was used to distinguish VAs from AMC, LV summit and VAs from aortic root (80% sensitivity and 76% specificity). Second, the R duration in II > 155 ms was used to differentiate VAs from LV summit and VAs from AMC (67% sensitivity and 56% specificity). Third, the ratio of III/II < 0.9 was used to discriminate VAs from RCC and VAs from LCC, L-RCC (82% sensitivity and 63% specificity). Fourth, the QS duration of aVR > 130 ms was used to discern VAs from LCC and VAs from L-RCC (75% sensitivity and 62% specificity). In the prospective evaluation, our 4-stepwise ECG algorithm exhibited a good predictive value. We have developed a novel and simple 4-stepwise ECG algorithm with good predictive value to discriminate the AVs from different sites of LVOT.

Selected Transesophageal Echocardiographic Parameters of Left Ventricular Diastolic Function Predict Length of Stay Following Coronary Artery Bypass Graft-A Prospective Observational Study.

(1) Importance: Abnormal left ventricular (LV) diastolic function, with or without a diagnosis of heart failure, is a common finding that can be easily diagnosed by intra-operative transesophageal echocardiography (TEE). The association of diastolic function with duration of hospital stay after coronary artery bypass (CAB) is unknown. (2) Objective: To determine if selected TEE parameters of diastolic dysfunction are associated with length of hospital stay after coronary artery bypass surgery (CAB). (3) Design: Prospective observational study. (4) Setting: A single tertiary academic medical center. (5) Participants: Patients with normal systolic function undergoing isolated CAB from September 2017 through June 2018. (6) Exposures: LV function during diastole, as assessed by intra-operative TEE prior to coronary revascularization. (7) Main Outcomes and Measures: The primary outcome was duration of postoperative hospital stay. Secondary intermediate outcomes included common postoperative cardiac, respiratory, and renal complications. (8) Results: The study included 176 participants (mean age 65.2 ± 9.2 years, 73% male); 105 (60.2%) had LV diastolic dysfunction based on selected TEE parameters. Median time to hospital discharge was significantly longer for subjects with selected parameters of diastolic dysfunction (9.1/IQR 6.6−13.5 days) than those with normal LV diastolic function (6.5/IAR 5.3−9.7 days) (p < 0.001). The probability of hospital discharge was 34% lower (HR 0.66/95% CI 0.47−0.93) for subjects with diastolic dysfunction based on selected TEE parameters, independent of potential confounders, including a baseline diagnosis of heart failure. There was a dose−response relation between severity of diastolic dysfunction and probability of discharge. LV diastolic dysfunction based on those selected TEE parameters was also associated with postoperative cardio-respiratory complications; however, these complications did not fully account for the relation between LV diastolic dysfunction and prolonged length of hospital stay. (9) Conclusions and Relevance: In patients with normal systolic function undergoing CAB, diastolic dysfunction based on selected TEE parameters is associated with prolonged duration of postoperative hospital stay. This association cannot be explained by baseline comorbidities or common post-operative complications. The diagnosis of diastolic dysfunction can be made by TEE.

Reversal of isoflurane-induced depression of myocardial contraction by nitroxyl via myofilament sensitization to Ca2+.

Isoflurane (ISO) is known to depress cardiac contraction. Here, we hypothesized that decreasing myofilament Ca(2+) responsiveness is central to ISO-induced reduction in cardiac force development. Moreover, we also tested whether the nitroxyl (HNO) donor 1-nitrosocyclohexyl acetate (NCA), acting as a myofilament Ca(2+) sensitizer, restores force in the presence of ISO. Trabeculae from the right ventricles of LBN/F1 rats were superfused with Krebs-Henseleit solution at room temperature, and force and intracellular Ca(2+) ([Ca(2+)](i)) were measured. Steady-state activations were achieved by stimulating the muscles at 10 Hz in the presence of ryanodine. The same muscles were chemically skinned with 1% Triton X-100, and the force-Ca(2+) relation measurements were repeated. ISO depressed force in a dose-dependent manner without significantly altering [Ca(2+)](i). At 1.5%, force was reduced over 50%, whereas [Ca(2+)](i) remained unaffected. At 3%, contraction was decreased by ∼75% with [Ca(2+)](i) reduced by only 15%. During steady-state activation, 1.5% ISO depressed maximal Ca(2+)-activated force (F(max)) and increased the [Ca(2+)](i) required for 50% activation (Ca(50)) without affecting the Hill coefficient. After skinning, the same muscles showed similar decreases in F(max) and increases in Ca(50) in the presence of ISO. NCA restored force in the presence of ISO without affecting [Ca(2+)](i). These results show that 1) ISO depresses cardiac force development by decreasing myofilament Ca(2+) responsiveness, and 2) myofilament Ca(2+) sensitization by NCA can effectively restore force development without further increases in [Ca(2+)](i). The present findings have potential translational value because of the efficiency and efficacy of HNO on ISO-induced myocardial contractile dysfunction.