Precisely Activating cGAS-STING Pathway with a Novel Peptide-Based Nanoagonist to Potentiate Immune Checkpoint Blockade Cancer Immunotherapy.

As an essential intracellular immune activation pathway, the cGAS-STING pathway has attracted broad attention in cancer treatment. However, low bioavailability, nonspecificity, and adverse effects of small molecule STING agonists severely limit their therapeutic efficacy and in vivo application. In this study, a peptide-based STING agonist is first proposed, and KLA is screened out to activate the cGAS-STING pathway by promoting mitochondrial DNA (mtDNA) leakage. To precisely activate the cGAS-STING pathway and block the PD-1/PD-L1 pathway, a multi-stimuli activatable peptide nanodrug (MAPN) is developed for the effective delivery of KLA and PD-L1 antagonist peptide (CVR). With rational design, MAPN achieved the site-specific release of KLA and CVR in response to multiple endogenous stimuli, simultaneously activating the cGAS-STING pathway and blocking PD-1/PD-L1 pathway, ultimately initiating robust and durable T cell anti-tumor immunity with a tumor growth inhibition rate of 78% and extending the median survival time of B16F10 tumor-bearing mice to 40 days. Overall, antimicrobial peptides, which can promote mtDNA leakage through damaging mitochondrial membranes, may be potential alternatives for small molecule STING agonists and giving a new insight for the design of novel STING agonists. Furthermore, MAPN presents a universal delivery platform for the effective synergy of multiple peptides.

Changes of left atrial morphology and function evaluated with four-dimensional automated left atrial quantification echocardiography in patients with coronary slow flow phenomenon and preserved left ventricular ejection fraction.

BACKGROUND: Coronary slow flow phenomenon (CSFP) can cause left ventricular diastolic dysfunction (LVDD). In multiple studies, the left atrial (LA) strain has been reported to be an excellent parameter for assessing LVDD. The 4-dimensional automated LA quantification (4D Auto LAQ) dedicated to the LA was recently available. Our study aimed to evaluate subclinical changes in LA morphology and function with 4D Auto LAQ in patients with CSFP and preserved left ventricular ejection fraction (LVEF). METHODS: Forty-eight patients with CSFP confirmed with coronary angiography and 46 age and gender-matched controls with normal coronary flow were enrolled. The thrombolysis in myocardial infarction frame count (TFC) method was used to record coronary blood flow velocities for each major coronary artery. LA volume, LA longitudinal and circumferential strains during each of the three LA phases (reservoir, conduit, and contraction), LA total emptying fraction (LATEF), LA active emptying fraction (LAAEF), and LA passive emptying fraction (LAPEF) were quantified with 4D Auto LAQ analysis. RESULTS: Compared with controls, LA longitudinal reservoir strain (LASr), LA longitudinal strain during the conduit phase (LAScd), LA contraction strain (LASct), LA conduit circumferential strain (LAScd-c), LATEF, LAPEF decreased significantly in individuals with CSFP. Of the 4D- LAQ parameters, only LASr [odds ratio (OR): 0.773, P < 0.001] and LATEF [OR: 0.762, P < 0.001] were associated with CSFP in multivariate analysis. A LASr ≤23.00% can differentiate CSFP from controls [sensitivity, 66.7%; specificity, 93.5%; area under the curve (AUC), 0.823; P < 0.001]. A LASr of ≤19.00% could predict the elevation of LV filling pressure in the CSFP cohort [sensitivity, 76.9%; specificity, 74.3%; area under the curve (AUC), 0.792; P < 0.001]. LASr was the only index to demonstrate significant changes compared to controls in single-vessel CSFP. Compared to the right coronary artery (RCA) and left circumflex (LCX), TFC of the left anterior descending (LAD) artery was the only independent variable of LASr (Standardized Coefficients: -0.386, P = 0.037). CONCLUSIONS: Impairment of LA reservoir function reflected by changes in LASr and LATEF can be seen in patients with CSFP. LASr could predict the elevation of LV filling pressure in CSFP individuals. LASr is more sensitive than LATEF in detecting LA reservoir dysfunction in single-vessel CSFP. CSFP in LAD exerts a more prominent influence on LASr than RCA or LCX.

Remodeling Tumor Immunogenicity with Dual-Activatable Binary CRISPR Nanomedicine for Cancer Immunotherapy.

The specific recognition of cancer cells by the body's immune system is an essential step in initiating antitumor immunity. However, the decreased expression of major histocompatibility complex class I (MHC-1) and overexpression of programmed death ligand 1 (PD-L1) causes insufficient tumor-associated antigens presentation and inactivation of T cells, which accounts for poor immunogenicity. To remodel tumor immunogenicity, herein, a dual-activatable binary CRISPR nanomedicine (DBCN) that can efficiently deliver a CRISPR system into tumor tissues and specifically control its activation is reported. This DBCN is made of a thioketal-cross-linked polyplex core and an acid-detachable polymer shell, which can maintain stability during blood circulation, while detaching a polymer shell to facilitate the cellular internalization of the CRISPR system after entering tumor tissues and ultimately activating gene editing under exogenous laser irradiation, thereby maximizing the therapeutic benefits and reducing potential safety concerns. With the collaborative application of multiple CRISPR systems, DBCN efficiently corrects both dysregulation of MHC-1 and PD-L1 expression in tumors, thus initiating robust T cell-dependent antitumor immune responses to inhibit malignant tumor growth, metastasis, and recurrence. Given the increasing abundance of CRISPR toolkits, this research provides an appealing therapeutic strategy and a universal delivery platform to develop more advanced CRISPR-based cancer treatments.

Left atrial reservoir strain is an outstanding predictor of adverse cardiovascular outcomes in patients undergoing maintenance hemodialysis: Assessment via three-dimensional speckle tracking echocardiography.

BACKGROUND: There is a paucity of literature focusing left atrium (LA) in patients undergoing maintenance hemodialysis (MHD). HYPOTHESIS: We used three-dimensional speckle tracking echocardiography (3DSTE) to evaluate LA in MHD patients and to explore its predictive value for adverse outcomes. METHODS: Echocardiography was performed on 130 consecutively enrolled MHD patients without previous cardiac diseases. Conventional and 3DSTE parameters of LA were obtained. The MHD cohort was then followed and the end point was major adverse cardiovascular events (MACEs). LA strain indices, including reservoir strain (LASr), conduit strain (LAScd), and contractile strain (LASct), were measured and compared between patients with and without MACEs. RESULTS: Patients were prospectively followed up for a median of 40.5 (interquartile range: 26.3-48.0) months. During follow-up, 43 patients met the end point. These patients had larger LA size and reduced LA strains (LA maximal volume indexed: 45.1 ± 11.9 vs. 33.8 ± 6.9ml/m2 ; LASr: 20.2 ± 3.5 vs. 27.2 ± 3.3%; LAScd: -12.3 ± 5.2 vs. -14.5±4.0%; LASct: -8.0 ± 4.2 vs. -13.2 ± 3.7%; all p<.05), compared with those without MACEs. Multivariable regression analysis showed LASr was the strongest predictor of MACEs (hazard ratio, 0.69; 95% confidence interval, 0.54-0.89; p=.004). Univarite Kaplan-Meier analysis revealed the incidence of MACEs in the impaired LASr (<24.2%) group was significantly higher than in the normal LASr group (log rank p<.001). CONCLUSIONS: LASr derived from 3DSTE is an independent predictor of MACEs and cardiac death in MHD patients, superior to LV parameters and LA volume indices.

Left atrial dysfunction in patients with obstructive sleep apnea: a combined assessment by speckle tracking and real-time three-dimensional echocardiography.

BACKGROUND: At present, little research concerning the assessment of left atrial (LA) dysfunction in patients with obstructive sleep apnea (OSA) using a combined assessment by speckle tracking (STE) and real-time three-dimensional echocardiography (RT3DE) is available. The objective of this study was to evaluate the LA volume and function by STE and RT3DE in patients with OSA. METHODS: In our cohort study, ninety-two OSA patients and 50 healthy individuals were enrolled. According to the apnea hypopnea index (AHI), patients (AHI >15/h) classified as having moderate and severe OSA were included. The patients were divided into 2 subgroups according to the left ventricular mass index (LVMI): the left ventricular hypertrophy (LVH) group in which patients had LVH (n=30), and the nonLVH group in which patients did not have LVH (n=62). All subjects underwent LA function assessment by conventional techniques and the combination of STE and RT3DE. RESULTS: OSA patients showed impaired LA global longitudinal strain during early diastole (LA S-E) and systole (LA S-S) but increased LA global longitudinal strain during late diastole (LA S-A) compared with controls (all P<0.05). In addition, OSA patients with LVH had lower LA S-S and LA S-E than patients without LVH (all P<0.05). With regard to parameters obtained from RT3DE, indexed LA maximum, minimum, and preatrial contraction volumes (LAVi-max, LAVi-min, LAVi-preA) and the LA active emptying fraction (LAAEF) were significantly higher, whereas the LA passive emptying fraction (LVPEF) was significantly lower in OSA patients in comparison with controls (all P<0.05). The LA total emptying fraction (LVTEF) and the LA expansion index were significantly lower in OSA patients with LVH than in controls (all P<0.05). Additionally, OSA patients with LVH had higher LAVi-min, LAVi-preA and LAAEVi but lower LAPEF than patients without LVH (all P<0.05). CONCLUSIONS: OSA is associated with LA remodeling and dysfunction that occurs in the subclinical stage before the development of LVH and left ventricular diastolic dysfunction, and it will be further aggravated along with the development of LVH and OSA severity. The process can be detected with a detailed evaluation of active and passive functions of the LA using the STE and RT3DE method.

Synthesis of Poly(acyclic orthoester)s: Acid-Sensitive Biomaterials for Enhancing Immune Responses of Protein Vaccine.

While poly(acyclic orthoester)s (PAOEs) have many appealing features for drug delivery, their application is significantly hindered by a lack of facile synthetic methods. Reported here is a simple method for synthesizing acyclic diketene acetal monomers from diols and vinyl ether, and their polymerization with a diol to first synthesize PAOEs. The PAOEs rapidly hydrolyze at lysosomal pH. With the help of a cationic lipid, ovalbumin, a model vaccine antigen was efficiently loaded into PAOEs nanoparticles using a double emulsion method. These nanoparticles efficiently delivered ovalbumin into the cytosol of dendritic cells and demonstrated enhanced antigen presentation over poly(lactic-co-glycolic acid) (PLGA) nanoparticles. PAOEs are promising vehicles for intracellular delivery of biopharmaceuticals and could increase the utility of poly(orthoesters) in biomedical research.

Evaluation of left atrial volume and function in patients with coronary slow flow phenomenon using real-time three-dimensional echocardiography.

This study aimed to evaluate the left atrial (LA) volume and phasic functions using real-time three-dimensional echocardiography (RT3DE) in coronary slow flow phenomenon (CSFP) patients with preserved left ventricular ejection fraction (LVEF). 56 patients with CSFP (36 males, 20 females) and 48 controls with normal coronary flow (27 males, 21 females) were prospectively enrolled. Comprehensive transthoracic echocardiographic examination and RT3DE for the assessment of LA dynamics were performed in all participants. LA maximum, minimum, and pre-atrial contraction volumes (LAV-max, LAV-min, and LAV-preA) were obtained for every subject. Conventional echocardiographic parameters, except for isovolumetric relaxation time and transmitral deceleration time, did not differ in two groups. RT3DE demonstrated higher LAV-max, LAV-min, LAV-preA, indexed LAV-max (LAVi-max), LA total emptying volume, and LA active emptying volume and fraction for CSFP patients compared with controls (all P < 0.05). In addition, LA total emptying fraction and LA passive emptying fraction were found to be lower in CSFP patients than in controls (all P < 0.05). Moreover, there were positive correlations between mean thrombolysis in myocardial infarction frame count values and LAV-max, LAV-min, LAV-preA, LAVi-max, and LA total and active emptying volumes. CSFP was associated with enlarged LA volumes, impaired LA reservoir and conduit function and enhanced contractile function. Evaluation of LA dynamics using RT3DE could facilitate recognition of subtle myocardial alterations related with CSFP.

Early Assessment of Left Ventricular Function by Layer-Specific Strain and Its Relationship to Pulsatile Arterial Load in Patients with Coronary Slow Flow.

Previous studies reported a controversial left ventricular (LV) function impairment and pathophysiology in patients with coronary slow flow (CSF). Greater arterial load has been shown to increase aortic impedance and endothelial shear stress, potentially affecting coronary anatomy and function. We investigated LV systolic function by a new layer-specific strain technology and assessed the association between pulsatile arterial load and contractility.A total of 70 patients with CSF and 50 controls with normal coronary angiography were included in the study. Layer-specific longitudinal and circumferential strains were assessed from endocardium, mid-myocardium, and epicardium (global longitudinal strain (GLS)-endo, GLS-mid, GLS-epi and GCS-endo, GCS-mid, GCS-epi) by two-dimensional speckle tracking imaging (2D-STI). Pulsatile arterial load was estimated by indexed arterial compliance (ACI). Layer-specific GLS showed a decreasing gradient from the endocardium to the epicardium in both the controls and CSF group. GLS-endo and GLS-mid in the CSF group were significantly lower than the control group (all P < 0.05). Layer-specific longitudinal strain showed a good correlation with the number of affected coronary arteries (all P < 0.05) and the mean thrombolysis in the myocardial infarction frame count (TFC) (all P < 0.05). ACI was lower in patients with CSF (P = 0.005), and ACI was correlated negatively with layer-specific GLS (all P < 0.05).Layer-specific evaluation of the LV provides an understanding of the layer-specific properties of the LV wall and the possible process of the LV impairment in patients with CSF. Greater pulsatile arterial load, as manifested by a lower ACI, is coupled with worse LV longitudinal function in patients with CSF.

Subclinical myocardial dysfunction in coronary slow flow phenomenon: Identification by speckle tracking echocardiography.

OBJECTIVE: This study aimed to determine whether STE could help detect subclinical myocardial dysfunction in patients with CSFP. METHODS: Sixty patients with CSFP confirmed by CAG and 51 controls with normal coronary flow were prospectively enrolled. Coronary angiographic data and conventional and speckle tracking echocardiographic parameters of the LV and RV were obtained for every subject. RESULTS: Compared with controls, CSFP patients presented with higher BMI and TG levels, but lower HDL-C levels. Conventional echocardiographic parameters of biventricular systolic and diastolic function did not differ between the two groups (all P > 0.05). The GLS of the LV and RV was significantly impaired in CSFP patients compared with that in controls (-19.03% vs -21.42%, P < 0.001 and -19.72% vs -22.96%, P = 0.001, respectively). The myocardial impairment pattern of CSFP patients was homogenous in the RV and heterogeneous in the LV, where only endo- and mid-myocardial layers were affected. LV-GLS and RV-GLS were found to be well correlated with mTFC and HDL-C in CSFP groups (r = 0.463 vs r = 0.439; r = -0.569 vs r = -0.552, all P < 0.05). ROC curve analysis demonstrated that LV-GLS-endo had the highest AUC (0.867, P < 0.001) for predicting subclinical myocardial impairment in CSFP patients. CONCLUSIONS: Subclinical myocardial systolic dysfunction occurs in both ventricles, and GLS could be an effective method to detect early-stage myocardial impairment in patients with CSFP.