ICG-labeled PD-L1-antagonistic affibody dimer for tumor imaging and enhancement of tumor photothermal-immunotherapy.

In clinical practice, tumor-targeting diagnosis and immunotherapy against programmed death ligand 1 (PD-L1) have a significant impact. In this research, a PD-L1-antagonistic affibody dimer (ZPD-L1) was successfully prepared through Escherichia coli expression system, and conjugated with the photosensitizer of ICG via N-hydroxysuccinimide (NHS) ester to develop a novel tumor-targeting agent (ICG-ZPD-L1) for both tumor imaging diagnosis and photothermal-immunotherapy simultaneously. In vitro, ZPD-L1 could specifically bind to PD-L1-positive LLC and MC38 tumor cells, and ICG-ZPD-L1-mediated photothermal therapy (PTT) also showed excellent phototoxicity to these tumor cells. In vivo, ICG-ZPD-L1 selectively enriched into the PD-L1-positive MC38 tumor tissues, and the high-contrast optical imaging of tumors was obtained. ICG-ZPD-L1-mediated PTT exhibited a potent anti-tumor effect in vivo due to its remarkable photothermal properties. Furthermore, ICG-ZPD-L1-mediated PTT significantly induced the immunogenic cell death (ICD) of primary tumors, promoted maturation of dendritic cells (DCs), up-regulated anti-tumor immune response, enhanced immunotherapy, and superiorly inhibited the growth of metastatic tumors. In addition, ICG-ZPD-L1 showed favorable biosafety throughout the brief duration of treatment. In summary, these results suggest that ICG-ZPD-L1 is a multifunctional tumor-targeting drug integrating tumor imaging diagnosis and photothermal-immunotherapy, and has great guiding significance for the diagnosis and treatment of clinical PD-L1-positive tumor patients.

ILD-GAP combined with the monocyte ratio could be a better prognostic prediction model than ILD-GAP in patients with interstitial lung diseases.

BACKGROUND: The ILD-GAP scoring system is known to be useful in predicting prognosis in patients with interstitial lung disease (ILD). An elevated monocyte count was associated with increased risks of IPF poor prognosis. We examined whether the ILD-GAP scoring system combined with the monocyte ratio (ILD-GAPM) is superior to the conventional ILD-GAP model in predicting ILD prognosis. METHODS: In patients with ILD treated between April 2013 and April 2017, we were retrospectively assessed the relationships between baseline clinical parameters, including age, sex, Charlson Comorbidity Index score (CCIS), ILD diagnosis, blood biomarkers, pulmonary function test results, and disease outcomes. In ILD patients were included idiopathic pulmonary fibrosis (IPF), idiopathic nonspecific interstitial pneumonia (iNSIP), collagen vascular disease-related interstitial pneumonia (CVD-IP), chronic hypersensitivity pneumonitis (CHP), and unclassifiable ILD (UC-ILD). We also assessed the ability to predict prognosis was compared between the ILD-GAP and ILD-GAPM models. RESULTS: A total of 179 patients (mean age, 73 years) were assessed. All of them were taken pulmonary function test, including percentage predicted diffusion capacity for carbon monoxide. ILD patients included 56 IPF cases, 112 iNSIP and CVD-IP cases, 6 CHP cases and 5 UC-ILD cases. ILD-GAPM provided a greater area under the receiver-operating characteristic curve (0.747) than ILD-GAP (0.710) for predicting 3-year ILD-related events. Furthermore, the log-rank test showed that the Kaplan-Meier curves in ILD-GAPM were significantly different by stage (P = 0.015), but not by stage in ILD-GAP (P = 0.074). CONCLUSIONS: The ILD-GAPM model may be a more accurate predictor of prognosis for ILD patients than the ILD-GAP model.

Formation of anaerobic granular sludge (AnGS) to treat high-strength perchlorate wastewater via anaerobic baffled reactor (ABR) system: Electron transfer characteristic, bacterial community and positive feedback mechanism.

Anaerobic granular sludge (AnGS) was cultured to treat high-strength perchlorate (reaching to 4800 mg/L) wastewater by an anaerobic baffled reactor (ABR) system with five equal-volume compartments (C1-C5 compartments). Inoculated sludge completely granulated on day 104 with granule size of 0.50-0.75 mm and perchlorate removal efficiency reaching to 97% (influent perchlorate of 2000-4800 mg/L). The Cyclic voltammetry (CV) capacitance increased from 487.5, 465.8 and 407.8 µF to 576.5, 552.4, 549.6 µF in C1, C3 and C5 compartments of ABR system, respectively, suggesting the electron transfer capacity was enhanced under high-strength perchlorate stress. Meanwhile, adenosine triphosphate (ATP) value and electron transport system activity (ETSA) increased to 25.05, 22.87, 20.43 and 6.22, 4.87, 3.95 of C1, C3 and C5 compartments, respectively. The results suggested that high-strength perchlorate stress improved the microbial metabolic activity, which promoted secretion of extracellular polymeric substances (EPS). The more EPS could facilitate the formation and stability of AnGS under high-strength perchlorate stress. In addition, more reasonable metabolic division of labor in functional bacterial (Thauera and Comamonas) was beneficial to AnGS formation, which achieved high-strength perchlorate efficient removal. Finally, a positive feedback mechanism between AnGS formation and high-strength perchlorate removal was established through EPS, microbial metabolic activity and electron transfer characteristic in ABR system. However, excessive perchlorate (5800 mg/L) would exceed the treatment capacity of AnGS, which resulted in the deterioration of removal performance. This work provided an effective information for AnGS application to treat high-strength perchlorate wastewater.

Progress of non-coding RNAs in triple-negative breast cancer.

Non-coding RNAs (ncRNAs) include miRNA, lncRNA, and circRNA. NcRNAs are involved in multiple biological processes, including chromatin remodeling, signal transduction, post-transcriptional modification, cell autophagy, carbohydrate metabolism, and cell cycle regulation. Triple negative breast cancer (TNBC) is notorious for high invasiveness and metastasis, poor prognosis, and high mortality, and it is the most malignant breast cancer, while the effective targets for TNBC treatment are still lacking. NcRNAs act as oncogenes or suppressor genes, as well as promote or inhibit the occurrence and development of TNBC. Here, we reviewed some important miRNAs, lncRNAs, circRNAs, their target(s) and molecular mechanisms in TNBC. It is benefited to understand the occurrence and development of TNBC, further some ncRNAs might be potential targets for TNBC treatment.

Efficacy and safety of different ticagrelor regimens versus clopidogrel in patients with coronary artery disease: a retrospective multicenter study (SUPERIOR).

Current guidelines favor dual anti-platelet therapy with ticagrelor 90 mg BID (T90BID) over clopidogrel 75 mg QD (C75QD) in addition to aspirin for acute coronary syndrome. However, an increased risk of ticagrelor-related adverse events prompted the evaluation of low-dose regimens. This study (NCT03381742) retrospectively analyzed the data from 11 hospitals on 3,043 patients with coronary artery disease, who received C75QD, T90BID, ticagrelor 45 mg BID (T45BID), or ticagrelor 90 mg QD (T90QD). Compared with C75QD, both T45BID and T90QD showed significantly higher inhibition of platelet aggregation (P < .0001) and lower platelet-fibrin clot strength (P < .0001) induced by adenosine diphosphate. Furthermore, compared with T90BID, two low-dose regimens had a much lower minor bleeding rate and a significantly higher proportion of patients within the therapeutic window for P2Y12 receptor reactivity. There were no significant differences between T45BID and T90QD in the trough plasma concentrations of ticagrelor and its active metabolite. Similar efficacy and safety outcomes were observed in the propensity score-matched analysis. In conclusion, the low-dose ticagrelor regimen, either T45BID or T90QD, may provide a more attractive benefit-risk profile than C75QD or T90BID.

Comparison of the roles of estrogens and androgens in breast cancer and prostate cancer.

Breast cancer (BC) and prostate cancer (PC) are the second most common malignant tumors in women and men in western countries, respectively. The risks of death are 14% for BC and 9% for PC. Abnormal estrogen and androgen levels are related to carcinogenesis of the breast and prostate. Estradiol stimulates cancer development in BC. The effect of estrogen on PC is concentration-dependent, and estrogen can regulate androgen production, further affecting PC. Estrogen can also increase the risk of androgen-induced PC. Androgen has dual effects on BC via different metabolic pathways, and the role of the androgen receptor (AR) in BC also depends on cell subtype and downstream target genes. Androgen and AR can stimulate both primary PC and castration-resistant PC. Understanding the mechanisms of the effects of estrogen and androgen on BC and PC may help us to improve curative BC and PC treatment strategies.

HMGB1, TGF-ß and NF-κB are associated with chronic allograft nephropathy.

The present study aimed to investigate the association between high mobility group protein B1 (HMGB1), transforming growth factor-ß1 (TGF-ß1), nuclear factor-κB (NF-κB) and chronic allograft nephropathy (CAN) and to identify the clinical significance of HMGB1, TGF-ß1, NF-κB on patients with CAN. Between September 2012 and November 2014, 27 patients with CAN diagnosed by biopsy were enrolled in the present study and a further 30 patients that underwent nephrectomy following trauma were selected as the control group. Immunohistochemical staining with HMGB1, TGF-ß1 and NF-κB expression in the renal tissues, and western blot analysis were used to measure the relative expression of HMGB1, TGF-ß1 and NF-κB. Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to estimate the relative expression of HMGB1, TGF-ß1 and NF-κB mRNA. Statistical analysis was used to calculate the association between HMGB1, TGF-ß1 and NF-κB expression and CAN grade. Immunohistochemical staining demonstrated that HMGB1, TGF-ß1 and NF-κB had markedly positive expression rates in renal tubular epithelial cell cytoplasm and membranes in CAN renal tissues, and the positive rates of HMGB1, TGF-ß1 and NF-κB increased with the aggravation of CAN pathological grade (I, II and III). The results of western blot analysis indicated that the expression levels of HMGB1, TGF-ß1 and NF-κB were significantly higher in the CAN group, compared with the normal group (P<0.05), and the expression levels increased with the progression of CAN grade. A positive association among HMGB1, TGF-ß1 and NF-κB expression was identified. RT-qPCR analysis demonstrated that the expression of HMGB1, TGF-ß1 and NF-κB mRNA in the CAN group was significantly higher than in the normal group (P<0.05), and the relative expression level of HMGB1, TGF-ß1 and NF-κB mRNA not only increased with the aggravation of CAN grade, but was also positively associated with the expression of HMGB1, TGF-ß1 and NF-κB, respectively. The abnormal expression of HMGB1, TGF-ß1 and NF-κB is therefore, an important manifestation of CAN and the expression of HMGB1, TGF-ß1 and NF-κB mRNA in the renal tissues are significantly associated with CAN pathological progression. HMGB1, TGF-ß1 and NF-κB may form a signaling pathway that leads to the occurrence of CAN, which induces renal interstitial fibrosis.

Chronic obstructive sleep apnea promotes aortic remodeling in canines through miR-145/Smad3 signaling pathway.

Obstructive sleep apnea (OSA) is a causal pathogenetic factor of many cardiovascular diseases, however, its role in aortic diseases remains unknown. Therefore, this study was performed to explore the potential effects and pathophysiological mechanisms of chronic OSA on aortic remodeling in a canine model. After chronic OSA, the morphological changes of ascending aorta were characterized by thinner cells with pycnotic nuclei and swollen mitochondria, and obvious hyperplasia of collagenous fiber in the matrix. Both the apoptotic ratio and collagen volume fraction were significantly increased in ascending aorta of chronic OSA canines. Besides, aortic sympathetic nerve sprouting increased significantly in chronic OSA group. Meanwhile, protein expression of TGF-ß1, Smad3, collagenI, apoptosis-inducing factor (AIF), tyrosine hydroxylase (TH) and growth associated protein-43 (GAP43) was upregulated after chronic OSA. Additionally, chronic OSA also strikingly increased pro-inflammatory factors like tumor necrosis factor α (TNF-α), NOD-like receptor 3 (NLRP3), NF-κB-p65 and oxidative stress factors like xanthine oxidase (XOD), malondialdehyde (MDA) while declined superoxide dismutase (SOD) activity. Furthermore, suppressed miR-145 and subsequently increased Smad3 expression were found obviously in vascular smooth muscle cells (VSMCs) treated by hypoxia. Luciferase reporter assays confirmed that Smad3 was one of the targets of miR-145. In conclusion, OSA could exacerbate aortic remodeling by aortic fibrosis, apoptosis and sympathetic nerve sprouting. miR-145/Smad3 signaling pathway might promote aortic remodeling during OSA. These findings provide novel information of chronic OSA-induced vascular dysfunction.

One-quarter standard-dose ticagrelor better than standard-dose clopidogrel in Chinese patients with stable coronary artery disease: A randomized, single-blind, crossover clinical study.

BACKGROUND: Ticagrelor has been demonstrated to provide a more rapid and powerful inhibition of platelet aggregation compared with clopidogrel in coronary artery disease (CAD) patients. In our previous study, we found that half-dose ticagrelor produced similar inhibitory effects on platelet aggregation as standard-dose ticagrelor and exerted significantly stronger effects than clopidogrel in Chinese patients with non-ST-elevation ACS. Therefore, we performed this study to observe the efficacy of one-quarter standard-dose ticagrelor in comparison to standard-dose clopidogrel in Chinese patients with stable CAD. METHODS: In a randomized, single-blind, crossover trial, 30 patients with stable CAD were randomized to one-quarter standard-dose ticagrelor (22.5mg BID for 7days) or standard-dose clopidogrel (75mg QD for 7days). Following a 2-week washout period, patients switched regimens. Light transmission aggregometry (LTA) and VerifyNow assay were used to measure platelet function. RESULTS: The platelet aggregation rate (PAgR) was obviously lower with ticagrelor than clopidogrel (17.70%±12.67% versus 27.63%±13.10%, P<0.05). The % inhibition levels in the ticagrelor group exhibited significantly greater than that in the clopidogrel group (65.33%±21.31% versus 36.23%±23.01%, P<0.01). PRU values in the ticagrelor group were dramatically lower than that in the clopidogrel group (87.03±51.38 versus 163.77±58.66, P<0.01). High-platelet reactivity (HPR) (≥208 PRU) was 0% with ticagrelor and 16.67% with clopidogrel. CONCLUSIONS: One-quarter standard-dose ticagrelor provided greater degree of platelet inhibition than standard-dose clopidogrel in Chinese patients with stable CAD.

Geraniol improves endothelial function by inhibiting NOX-2 derived oxidative stress in high fat diet fed mice.

Endothelial dysfunction occurs in obese patients and high-fat diet (HFD) fed experimental animals. While geraniol has been reported to ameliorate inflammation and oxidative stress, inhibit tumor cell proliferation, and improve atherosclerosis, its direct effect on endothelial function remains uncharacterized. The present study therefore investigated the effect of geraniol on endothelial function in HFD mice and its underlying mechanisms. C57 BL/6 mice were fed an HFD (n = 40) or a normal diet (n = 20) for 8 weeks. HFD fed mice then were randomized to intraperitoneal treatment with geraniol (n = 20) or vehicle (n = 20) for another 6 weeks. Acetylcholine (Ach)-induced endothelial dependent vasorelaxation was measured on wire myography; reactive oxygen species (ROS) generation was assessed by fluorescence imaging, and NADPH oxidases (NOXs) and adhesive molecules VCAM-1 and ICAM-1 protein expression by western blotting. Geraniol improved endothelial function in HFD fed mice, as evidenced by its: 1. restoring endothelial dependent vasorelaxation induced by Ach, and reversing increased VCAM-1 and ICAM-1 expression; 2. attenuating HFD induced increased serum TBARS and aortic ROS generation; and 3. downregulating aortic NOX-2 expression in both HFD fed mice and in palmitic acid treated endothelial cells. Geraniol therefore protects against endothelial dysfunction induced by HFD through reducing NOX-2 associated ROS generation.

[Pathogenesis of rat mesangial proliferative glomerulonephritis induced by anti-Thy1 antibody].

OBJECTIVE: To probe into the pathogenesis of rat mesangial proliferative glomerulonephritis (MsPGN) induced by anti-Thy1 antibody. METHODS: Anti-Thy1 serum was produced, and then intravenously injected into Wistar rats for establishing an experimental model of MsPGN. The control group received intravenous injection of normal saline. Urinary volume and urinary protein were examined every other day. The IL-1, IL-6 and TNF contents of serum were detected by radioimmunoassay. Pathologic morphology of renal section was observed with micrscope and BI2000 Image Analysis System. The rats of model group were killed on the 1st, 3rd, 5th and 7th days. RESULTS: No significant difference was seen between the model group and control group in regard to the volume of urine and in-take water (P > 0.05). The levels of urinary protein, IL-1, IL-6 and TNF in model group were significantly higher than those in control group at all time points (P < 0.001-0.005). Glomerular mesangium cells and matrix in the model group were obviously proliferative, compared with those in control group. CONCLUSION: It is suggested that cytokine plays an important role in the onset of MsPGN.