Bispecific prodrug nanoparticles circumventing multiple immune resistance mechanisms for promoting cancer immunotherapy

Cancer immunotherapy is impaired by the intrinsic and adaptive immune resistance. Herein, a bispecific prodrug nanoparticle was engineered for circumventing immune evasion of the tumor cells by targeting multiple immune resistance mechanisms. A disulfide bond-linked bispecific prodrug of NLG919 and JQ1 (namely NJ) was synthesized and self-assembled into a prodrug nanoparticle, which was subsequently coated with a photosensitizer-modified and tumor acidity-activatable diblock copolymer PHP for tumor-specific delivery of NJ. Upon tumor accumulation via passive tumor targeting, the polymeric shell was detached for facilitating intracellular uptake of the bispecific prodrug. NJ was then activated inside the tumor cells for releasing JQ1 and NLG919 via glutathione-mediated cleavage of the disulfide bond. JQ1 is a bromodomain-containing protein 4 inhibitor for abolishing interferon gamma-triggered expression of programmed death ligand 1. In contrast, NLG919 suppresses indoleamine-2,3-dioxygenase 1-mediated tryptophan consumption in the tumor microenvironment, which thus restores robust antitumor immune responses. Photodynamic therapy (PDT) was performed to elicit antitumor immunogenicity by triggering immunogenic cell death of the tumor cells. The combination of PDT and the bispecific prodrug nanoparticle might represent a novel strategy for blockading multiple immune evasion pathways and improving cancer immunotherapy.

Evaluation of correlation between left ventricular mechanical contraction synchrony and left ventricular systolic function using a novel Cadmium-Zinc-Telluride SPECT / 中华核医学与分子影像杂志

Objective:To evaluate correlation between left ventricular mechanical contraction synchrony and left ventricular systolic function by gated myocardial perfusion imaging(GMPI) using Cadmium-Zine-Telluride (CZT) SPECT.Methods:Three hundred and forty three consecutive patients( 232 males, 111 females, age (60.08±12.88) years) who underwent CZT SPECT GMPI in Shanxi Cardiovascular Hospital between January and August 2019 were retrospectively analyzed. The Emory cardiac toolbox was used to process the imaging data, and the left ventricular systolic synchrony parameters and systolic function parameters were acquired, including peak phase(PP), phase standard deviation (PSD), phase histogram bandwidth(PHB), histogram skewness(HS), histogram kurtosis(HK), and end-diastolic volume( EDV), end-systolic volume (ESV), left ventrieular ejection fraction (LVEF). All patients were divided into 4 groups: the normal group (147 cases), ischemic cardiomyopathy group (114 cases), nonischemic cardiomyopathy without left bundle branch block (LBBB) group(50 cases)and nonischemic cardiomyopathy with LBBB group(32 cases). The relationship between systolic synchrony parameters and systolic function parameters were analyzed with Pearson correlation analysis.Results:Statistic results for all patients showed that PSD and PHB were well correlated with LVEF( r values: -0.790, -0.799, both P<0.01), but PP was poorly correlated with LVEF( r=-0.194, P<0.01); HS, HK were positively correlated with LVEF( r values: 0.767, 0.676, both P<0.01); PSD, PHB were positively correlated with ESV( r values: 0.778, 0.795, both P<0.01) and EDV ( r values: 0.722, 0.732, both P<0.01); but PP was poorly correlated with ESV( r=0.145, P<0.01) and not correlated with EDV ( r=0.095, P>0.01). HS, HK were negatively correlated with EDV and ESV ( r values: -0.700 to -0.580, all P<0.01). PSD and PHB showed negatively correlation with LVEF ( r values: -0.834 to -0.492, all P<0.01), while HS, HK showed positive correlation with LVEF ( r values: 0.243-0.792, all P<0.01) in normal group, the ischemic cardiomyopathy group, the nonischemic cardiomyopathy without LBBB group and the nonischemic cardiomyopathy with LBBB group. Conclusions:The left ventricular systolic synchrony parameters provided by CZT SPECT GMPI correlate well with the left ventricular systolic function parameters, and the worse systolic function, the worse systolic synchrony. Both ischemic cardiomyopathy and non-ischemic cardiomyopathy can affect left ventricular mechanical contraction synchrony, and the effect on contraction synchrony in non-ischemic cardiomyopathy patients with LBBB is greater.

An application of cone-beam CT in the diagnosis of bone defects for chronic periodontitis / 中华口腔医学杂志

<p><b>OBJECTIVE</b>To evaluate the accuracy of cone-beam CT (CBCT) for detection of bone defects in chronic periodontitis and its consistency with periapical film, panoramic radiograph and clinical examination.</p><p><b>METHODS</b>Seventy-five patients with periodontitis were selected in the study. Each patient received clinical examination, periapical film, panoramic radiograph and CBCT examination one week after supragingival scaling. The distance from the alveolar ridge crest to enamelo-cemental junction was measured. The data were statistically analyzed.</p><p><b>RESULTS</b>A total of 1 494 teeth and 8 964 sites were included in the study. Among the three kinds of imaging methods only CBCT could detect the lip (buccal) or tongue (palatine) side of alveolar bone destruction. Compared with panoramic radiographs[mesial: (4.9±0.4) mm, distal: (4.9±0.8) mm] and periapical film [mesial: (5.1±0.6) mm, distal: (5.1±0.8) mm], CBCT [mesial: (5.5±0.4) mm, distal: (5.6±0.8) mm] showed significant differences (P < 0.01) in alveolar bone defect measurements in detecting mesial and distal alveolar bone defect. There was no significant difference between clinical probing [mesial: (5.5±0.6) mm, distal: (5.5±0.6) mm] and CBCT.</p><p><b>CONCLUSIONS</b>CBCT have the highest consistency with clinical probing in detecting the alveolar bone loss in chronic periodontitis.</p>

Value of Echocardiography for Evaluation of the Flow-dependent Epicardial Coronary Vasodilation In Vivo / 华中科技大学学报（医学）（英德文版）

To assess the value of echocardiography for detection of the flow-dependent epicardial coronary vasodilation, the changes in internal diameter of the left anterior descending coronary arteries (LAD) induced by reactive hyperemia were studied by echocardiography in 12 health anesthetized open-chest dogs. Reactive hyperemia was induced by brief occlusion of the left anterior descending coronary artery for 30 s followed by rapid release. The two- dimensional images of the left anterior descending coronary artery before and after reactive hyperemia with and without intracoronary infusion of NG-nitro-L-arginine methyl ester (L-NAME), an inhibitor of nitric oxide synthase(NOS) were investigated. The internal diameter of LAD was measured and its percent change induced by reactive hyperemia was calculated. Our results showed that the internal diameter of LAD was 2.23±0.19 mm before intracoronary infusion of L-NAME (baseline). The internal diameter of LAD significantly increased to 2.52±0.24 mm (P＜0.01) after reactive hyperemia at baseline, and the percent change in internal diameter of LAD was (13. 10±3.59) %. The internal diameter of LAD before and after reactive hyperemia under the condition of intracoronary infusion of L-NAME was not different from that before reactive hyperemia at baseline. The percent change in internal diameter of LAD was (1.07±2.97) %, and it was significantly lower than that at baseline (P＜0.001). We are led to conclude that the change in internal diameter of LAD responding to reactive hyperemia was detected sensitively by echocardiography, and this change was associated with endothelium-derived nitric oxide.

Quantitative assessment of right ventricular systolic function by the analysis of right ventricular contrast time-intensity curve / 华中科技大学学报（医学）（英德文版）

To study reliability and reliable indices of quantitative assessment of right ventricular systolic function by time-intensity curve (TIC) with right ventricular contrast, 5% sonicated human albumin was injected intravenously at a does of 0.08 ml/kg into 10 dogs at baseline status and cardiac insufficiency. Apical four-chamber view was observed for washin and washout of contrast agent from right ventricle. The parameters of TIC were obtained by curve fitting. The differences of parameters were analyzed in different states of cardiac functions. Among the parameters derived from TIC, the time constant (k) was decreased significantly with decline of cardiac function (P<0.001). But half-time of decent of peak intensity (HT) and mean-transit-time (MTT) of washout were increased significantly (P<0.001). The k was strongly related to cardiac output of right ventricle (CO) and ejection fraction (EF) of left ventricle and fractional shortening (FS) of left ventricle. Right ventricular systolic function could be assessed reliably by the parameters derived from TIC with right ventricular contrast echocardiography. The k, HT and MTT are reliable indices for quantitative assessment of right ventricular systolic function.

Quantitative assessment of right ventricular systolic function by the analysis of right ventricular contrast time-intensity curve / 华中科技大学学报（医学）（英德文版）

To study reliability and reliable indices of quantitative assessment of right ventricular systolic function by time-intensity curve (TIC) with right ventricular contrast, 5% sonicated human albumin was injected intravenously at a does of 0.08 ml/kg into 10 dogs at baseline status and cardiac insufficiency. Apical four-chamber view was observed for washin and washout of contrast agent from right ventricle. The parameters of TIC were obtained by curve fitting. The differences of parameters were analyzed in different states of cardiac functions. Among the parameters derived from TIC, the time constant (k) was decreased significantly with decline of cardiac function (P<0.001). But half-time of decent of peak intensity (HT) and mean-transit-time (MTT) of washout were increased significantly (P<0.001). The k was strongly related to cardiac output of right ventricle (CO) and ejection fraction (EF) of left ventricle and fractional shortening (FS) of left ventricle. Right ventricular systolic function could be assessed reliably by the parameters derived from TIC with right ventricular contrast echocardiography. The k, HT and MTT are reliable indices for quantitative assessment of right ventricular systolic function.

DISTRACTION OF OSTEOGENESIS AND LENGTHENING OF CRANIOFACIAL BONE-PRELIMINARY REPORT OF AN EXPERIMENTAL RESEARCH / 药物分析学报

Objective The method of bone lengthening by distraction of callus was used on dog mandible as a model to study the capability and changes of membranous bone during distraction osteogenesis. Methods 15 dogs aged 5～7 months were chosen as the subjects. The operation included a unilateral or bilateral periosteal preserving corti cotomy of mandibular bone, and an introral mini lengthening device were fixed to the buccal side of the mandible. After 7d, the mandible was lengthened lmm/d for 20d and then held in internal fixation for 7～ 140d (1 ～ 20 weeks). Results The dogs were killed at 3 times. Anthropometric measurements, X-ray examination and histological observa tion were conducted and conformed that the distracted bone had formed in the expanded zone successfully. Conclu sion The results suggested that we could use the DO technique in the area of craniofacial clinic. The strong ability of generating new bone in membranous skeleton by DO technique should be further demonstrated in the future.

Experimental study on role of endogenous endothelin in echocardiographic evaluation of flow-dependent epicardial coronary vasodilation induced by reactive hyperemia after blockade of nitric oxide formation / 中华超声影像学杂志

Objective To determine whether endogenous endothelin(ET) plays a role in the echocardiographic evaluation of the flow-dependent epicardial coronary vasodilation induced by reactive hyperemia(RH) after blockade of nitric oxide(NO) formation. Methods In six anesthetized open-chest dogs, changes in internal diameter of the left anterior descending coronary artery(LAD) induced by RH were investigated via echocardiography before intracoronary infusion of GN-nitro-L-arginine methyl ester(L-NAME), after blockade of NO formation by L-NAME, and after L-NAME plus intracoronary infusion of BQ-123, an ETA receptor blocker.Results Before intracoronary infusion of L-NAME, the diameter of LAD increased significantly from((2.24)?(0.21))mm to ((2.51)?(0.23))mm (P