Programmable melanoma-targeted radio-immunotherapy via fusogenic liposomes functionalized with multivariate-gated aptamer assemblies.

Radio-immunotherapy exploits the immunostimulatory features of ionizing radiation (IR) to enhance antitumor effects and offers emerging opportunities for treating invasive tumor indications such as melanoma. However, insufficient dose deposition and immunosuppressive microenvironment (TME) of solid tumors limit its efficacy. Here we report a programmable sequential therapeutic strategy based on multifunctional fusogenic liposomes (Lip@AUR-ACP-aptPD-L1) to overcome the intrinsic radio-immunotherapeutic resistance of solid tumors. Specifically, fusogenic liposomes are loaded with gold-containing Auranofin (AUR) and inserted with multivariate-gated aptamer assemblies (ACP) and PD-L1 aptamers in the lipid membrane, potentiating melanoma-targeted AUR delivery while transferring ACP onto cell surface through selective membrane fusion. AUR amplifies IR-induced immunogenic death of melanoma cells to release antigens and damage-associated molecular patterns such as adenosine triphosphate (ATP) for triggering adaptive antitumor immunity. AUR-sensitized radiotherapy also upregulates matrix metalloproteinase-2 (MMP-2) expression that combined with released ATP to activate ACP through an "and" logic operation-like process (AND-gate), thus triggering the in-situ release of engineered cytosine-phosphate-guanine aptamer-based immunoadjuvants (eCpG) for stimulating dendritic cell-mediated T cell priming. Furthermore, AUR inhibits tumor-intrinsic vascular endothelial growth factor signaling to suppress infiltration of immunosuppressive cells for fostering an anti-tumorigenic TME. This study offers an approach for solid tumor treatment in the clinics.

Ratiometric fluorescence determination of alkaline phosphatase activity based on carbon dots and Ce3+-crosslinked copper nanoclusters.

A new ratiometric fluorescent probe for efficient determination of ALP was developed. The probe was constructed by combining Ce3+-crosslinked copper nanoclusters (Ce3+-CuNCs) which exhibit the aggregation-induced emission (AIE) feature with carbon dots (CDs). The introduction of phosphate (Pi) induced the generation of CePO4 precipitation, resulting in significant decrease of fluorescence emission of CuNCs at 634 nm. At the same time, the fluorescence of CDs at 455 nm was obviously enhanced, thus generating ratiometric fluorescence response. Based on the fact that the hydrolysis of pyrophosphate (PPi) by ALP can produce Pi, the CD/Ce3+-CuNCs ratiometric probe was successfully used to determine ALP. A good linear relationship between the ratiometric value of F455/F634 and ALP concentrations ranging from 0.2 to 80 U·L- 1 was obtained, with a low detection limit of 0.1 U·L- 1. The ratiometric responses of the probe resulted in the visible fluorescence color change from orange red to blue with the increase of ALP concentration. The smartphone-based RGB recognition of the fluorescent sample images was used for ALP quantitative determination. A novel ratiometric fluorescent system based on Ce3+-CuNCs with AIE feature and CDs were constructed for efficient detection of ALP.

Application of color Doppler ultrasound to evaluate and analyze the risk factors of residual stenosis after vertebral artery origin stenting.

BACKGROUND: Vertebral artery origin stenting (VAOS) is the mainstream method for the treatment of vertebral artery stenosis (VAS). However, there are few studies on the risk factors analysis for residual stenosis after VAOS. PURPOSE: This study aimed to apply color Doppler ultrasound (CDU) to evaluate and analyze the risk factors of residual stenosis after VAOS. METHODS: About 178 patients with VAOS were included from 2017 to 2019 in Liuzhou worker's hospital and divided into the residual stenosis group (n = 38) and the no-residual stenosis group (n = 140). The clinical data and hemodynamics alteration before and after VAOS were collected. The univariate and multivariate logistic regression analysis was used to analyze the risk factors of residual stenosis. RESULTS: Compared with the no-residual stenosis group, the proportion of hypertension, the bending of the initial segment, and the residual stenosis length > 10 mm in the residual stenosis group were significantly higher, while the original internal diameter was significantly smaller (P < 0.05). The multivariate logistic regression analysis showed that the bending of initial segment (OR = 2.41, 95% CI: 1.32-5.45, P = 0.033), the original internal diameter (OR = 2.29, 95% CI: 1.13-5.66, P = 0.001), and the residual stenosis length > 10 mm were the risk factors of residual stenosis (OR = 2.78, 95% CI: 1.82-5.85, P = 0.044). CONCLUSION: The bending of initial segment, the original internal diameter, and the residual stenosis length > 10 mm were the risk factors of residual stenosis after VAOS.

Structurally dynamic self-healable hydrogel cooperatively inhibits intestinal inflammation and promotes mucosal repair for enhanced ulcerative colitis treatment.

Hydrogels are a class of biocompatible materials with versatile functions that have been increasing explored for the localized treatment of ulcerative colitis (UC), but various mechanical stimuli may cause premature hydrogel breakage and detachment, impeding their further clinical translation. Here we report a multifunctional mechanically-resilient self-healing hydrogel for effective UC treatment, which is synthesized through the host-guest interaction between dopamine/ß-cyclodextrin-modified hyaluronic acid (HA-CD-DA) and amantadine-modified carboxymethyl chitosan (CMCS-AD). The excessive ß-CD cavities allow the incorporation of dexamethasone (DEX), while the porous hydrogel network potentiates the encapsulation of basic fibroblast growth factor (bFGF) and L-alanyl-l-glutamine (ALG). DA moieties in HA components allow firm adhesion of the hydrogel to the ulcerative lesions after in-situ implantation, while the reversible host-guest interaction between CD and AD could enhance the persistence of hydrogel. The hydrogel demonstrated favorable biocompatibility and could continuously release DEX to induce M1-to-M2 repolarization of mucosal macrophages through inhibiting the toll-like receptor 4 (TLR4)-nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) axis. Furthermore, the co-delivered bFGF and ALG facilitates the regeneration of ulcerative mucosa and restore its barrier functions to ameliorate UC symptoms. The mechanically resilient hydrogel offers an integrative approach for UC therapy in the clinics.

Promoting sensitive colorimetric detection of hydroquinone and Hg2+ via ZIF-8 dispersion enhanced oxidase-mimicking activity of MnO2 nanozyme.

Reducing the agglomeration and improving the dispersibility in water of two-dimensional (2D) nanozymes is one of the effective ways to improve their enzyme-like activity. In this work, we propose a method by constructing zeolitic imidazolate framework-8 (ZIF-8)-dispersed 2D manganese-based nanozymes to achieve the specific regulated improvement of oxidase-mimicking activity. By in-situ growth of manganese oxides nanosheets of MnO2(1), MnO2(2) and Mn3O4 on the surface of ZIF-8, the corresponding nanocomposites of ZIF-8 @MnO2(1), ZIF-8 @MnO2(2), and ZIF-8 @Mn3O4 were prepared at room temperature. The Michaelis-Menton constant measurements indicated that ZIF-8 @MnO2(1) exhibits best substrate affinity and fastest reaction rate for 3,3',5,5'-tetramethylbenzidine (TMB). The ZIF-8 @MnO2(1)-TMB system was exploited to detection of trace hydroquinone (HQ) based on the reducibility of phenolic hydroxyl groups. In addition, by employing the fact that the cysteine (Cys) with the excellent antioxidant capacity can bind the Hg2+ based on the formation of "S-Hg2+" bonds, the ZIF-8 @MnO2(1)-TMB-Cys system was applied to detection of Hg2+ with high sensitivity and selectivity. Our findings not only provide a better understanding of the relationship between dispersion of nanozyme and enzyme-like activity, but also provide a general method for the detection of environmental pollutants using nanozymes.

Diagnostic accuracy of ultrasound-based multimodal radiomics modeling for fibrosis detection in chronic kidney disease.

OBJECTIVES: To predict kidney fibrosis in patients with chronic kidney disease using radiomics of two-dimensional ultrasound (B-mode) and Sound Touch Elastography (STE) images in combination with clinical features. METHODS: The Mindray Resona 7 ultrasonic diagnostic apparatus with SC5-1U convex array probe (bandwidth frequency of 1-5 MHz) was used to perform two-dimensional ultrasound and STE software. The severity of cortical tubulointerstitial fibrosis was divided into three grades: mild interstitial fibrosis and tubular atrophy (IFTA), fibrotic area < 25%; moderate IFTA, fibrotic area 26-50%; and severe IFTA, fibrotic area > 50%. After extracting radiomics from B-mode and STE images in these patients, we analyzed two classification schemes: mild versus moderate-to-severe IFTA, and mild-to-moderate versus severe IFTA. A nomogram was constructed based on multiple logistic regression analyses, combining clinical and radiomics. The performance of the nomogram for differentiation was evaluated using receiver operating characteristic (ROC), calibration, and decision curves. RESULTS: A total of 150 patients undergoing kidney biopsy were enrolled (mild IFTA: n = 74; moderate IFTA: n = 33; severe IFTA: n = 43) and randomized into training (n = 105) and validation cohorts (n = 45). To differentiate between mild and moderate-to-severe IFTA, a nomogram incorporating STE radiomics, albumin, and estimated glomerular filtration (eGFR) rate achieved an area under the ROC curve (AUC) of 0.91 (95% confidence interval [CI]: 0.85-0.97) and 0.85 (95% CI: 0.77-0.98) in the training and validation cohorts, respectively. Between mild-to-moderate and severe IFTA, the nomogram incorporating B-mode and STE radiomics features, age, and eGFR achieved an AUC of 0.93 (95% CI: 0.89-0.98) and 0.83 (95% CI: 0.70-0.95) in the training and validation cohorts, respectively. Finally, we performed a decision curve analysis and found that the nomogram using both radiomics and clinical features exhibited better predictability than any other model (DeLong test, p < 0.05 for the training and validation cohorts). CONCLUSION: A nomogram based on two-dimensional ultrasound and STE radiomics and clinical features served as a non-invasive tool capable of differentiating kidney fibrosis of different severities. KEY POINTS: • Radiomics calculated based on the ultrasound imaging may be used to predict the severities of kidney fibrosis. • Radiomics may be used to identify clinical features associated with the progression of tubulointerstitial fibrosis in patients with CKD. • Non-invasive ultrasound imaging-based radiomics method with accuracy aids in detecting renal fibrosis with different IFTA severities.

Removal of Per-, Poly-fluoroalkyl substances (PFASs) and multi-biosphere community dynamics in a bacteria-algae symbiotic aquatic ecosystem.

The presence of Per-, Poly-fluoroalkyl substances (PFASs) in aquatic ecosystems has drawn broad concerns in the scientific community due to their biological toxicity. However, little has been explored regarding PFASs' removal in phytoplankton-dominated environments. This study aimed to create a simulated bacteria-algae symbiotic ecosystem to observe the potential transportation of PFASs. Mass distributions showed that sand (63-2000 µm), silt & clay (0-63 µm), the phycosphere (>3 µm plankton), and the free-living biosphere (0.22-3 µm plankton) contained 19.00, 7.78, 5.73 and 2.75% PFASs in their total mass, respectively. Significant correlations were observed between carbon chain lengths and removal rates (R2 = 0.822, p < 10-4). Structural equation models revealed potential PFAS transportation pathways, such as water-phycosphere- free-living biosphere-sand-silt&clay, and water-sand-silt&clay (p < 0.05). The presence of PFASs decreased the bacterial density but increased algal density (p < 0.01) in the planktonic environment, and PFASs with longer carbon chain lengths showed a stronger enhancement in microbial community successions (p < 0.05). In algal metabolisms, chlorophyll-a and carotenoids were the key pigments that resisted reactive oxygen species caused by PFASs. PFBA (perfluorobutyric acid) (10.38-14.68%) and PFTeDA (perfluorotetradecanoic acid) (10.33-15.96%) affected bacterial metabolisms in phycosphere the most, while in the free-living biosphere was most effected by PFPeA (perfluorovaleric acid) (13.21-13.99%) and PFDoA (perfluorododecanoic acid) (10.04-10.50%). The results of this study provide new guidance measures for PFAS removal and management in aquatic environments.

Label-free electrochemical biosensor for determination of procalcitonin based on graphene-wrapped Co nanoparticles encapsulated in carbon nanobrushes coupled with AuPtCu nanodendrites.

A new label-free electrochemical immunosensor was constructed for quantitative detection of procalcitonin (PCT), by employing AuPtCu nanodendrites (AuPtCu NDs, prepared by a one-pot solvothermal method) and graphene-wrapped Co nanoparticles encapsulated in 3D N-doped carbon nanobrushes (G-Co@ NCNBs), obtained by self-catalyzed chemical vapor deposition as immune-sensing platform. Impressively, the home-made nanocomposite enlarged the highly accessible active sites and promoted the mass/electron transport, in turn showing the efficient synergistic catalysis towards H2O2 reduction, combined by greatly increasing the loading capacity of the PCT antibody (Ab). The as-constructed sensor displayed a dynamic linear range of 0.0001 ~ 100 ng mL-1 along with an ultra-low limit of detection (LOD = 0.011 pg mL-1, S/N = 3) and was further explored for determination of PCT in a diluted serum sample with acceptable results. The sensor provides some valuable guidelines for bioassay and early diagnosis of sepsis.

A label-free electrochemical immnunosensor based on signal magnification of oxygen reduction reaction catalyzed by uniform PtCo nanodendrites for highly sensitive detection of carbohydrate antigen 15-3.

Developing a highly sensitive immunoassay for tumor biomarkers is particularly important in bioanalysis and early disease diagnosis. In this work, a simple one-pot solvothermal method was developed for controllable synthesis of well-dispersed PtCo alloyed nanodendrites (PtCo NDs) by using l-carnosine as the co-structure-directing agent. The PtCo NDs had a large specific surface area and provided abundant active sites available for electrocatalytic oxygen reduction reaction (ORR). Based on the highly enhanced currents of the ORR, a novel label-free electrochemical immunosensor was fabricated for highly sensitive assay of carbohydrate antigen 15-3 (CA15-3). The sensor showed a wide linear range of 0.1-200 U mL-1 and a low limit of detection (LOD) down to 0.0114 U mL-1 (S/N = 3), in turn exploring its application to diluted human serum samples with satisfactory results. This study provides a feasible platform for monitoring other tumor markers in clinical diagnosis.

Effectiveness of contrast-enhanced ultrasound for detecting the staging and grading of bladder cancer: a systematic review and meta-analysis.

AIM: The study retrospectively analysed the accuracy of preoperative contrast-enhanced ultrasound (CEUS) in differenti-ating stage Ta-T1 or low-grade bladder cancer (BC) from stage T2 or high-grade bladder cancer. MATERIAL AND METHODS: We systematically searched the literature indexed in PubMed, Embase, and the Cochrane Library for original diagnostic articles of bladder cancer. The diagnostic accuracy of CEUS was compared with cystoscopy and/or transurethral resection of bladder tumors (TURBT). The bivariate logistic regression model was used for data pooling, couple forest plot, diagnostic odds ratio (DOR) and summary receiver operating characteristic (SROC). RESULTS: Five studies met the selection criteria; the overall number of reported bladder cancers patients were 436. The pooled-sensitivity (P-SEN), pooled-specificity (P-SPE), pooled-positive likelihood ratio (PLR+), pooled-negative likelihood ratio (PLR-), DOR, and area under the SROC curve were 94.0% (95%CI: 85%-98%), 90% (95%CI: 83%-95%), 9.5 (95%CI: 5.1-17.6), 0.06 (95%CI: 0.02-0.17), 147 (95%CI: 35-612) and 97% (95% CI: 95%-98%) respectively. CONCLUSION: CEUS reaches a high efficiency in discriminating Ta-T1 or low-grade bladder cancer from stage T2 or high-grade bladder cancer. It can be a promising method in patients to distinguish T staging and grading of bladder cancer because of its high sensitivity, specificity and diagnostic accuracy.

Discovery of ß-arrestin-biased ß2-adrenoceptor agonists from 2-amino-2-phenylethanol derivatives.

ß-Arrestins are a small family of proteins important for signal transduction at G protein-coupled receptors (GPCRs). ß-Arrestins are involved in the desensitization of GPCRs. Recently, biased ligands possessing different efficacies in activating the G protein- versus the ß-arrestin-dependent signals downstream of a single GPCR have emerged, which can be used to selectively modulate GPCR signal transduction in such a way that desirable signals are enhanced to produce therapeutic effects while undesirable signals of the same GPCR are suppressed to avoid side effects. In the present study, we evaluated agonist bias for compounds developed along a drug discovery project of ß2-adrenoceptor agonists. About 150 compounds, including derivatives of fenoterol, 2-amino-1-phenylethanol and 2-amino-2-phenylethanol, were obtained or synthesized, and initially screened for their ß-adrenoceptor-mediated activities in the guinea pig tracheal smooth muscle relaxation assay or the cardiomyocyte contractility assay. Nineteen bioactive compounds were further assessed using both the HTRF cAMP assay and the PathHunter ß-arrestin assay. Their concentration-response data in stimulating cAMP synthesis and ß-arrestin recruitment were applied to the Black-Leff operational model for ligand bias quantitation. As a result, three compounds (L-2, L-4, and L-12) with the core structure of 5-(1-amino-2-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one were identified as a new series of ß-arrestin-biased ß2-adrenoceptor agonists, whereas salmeterol was found to be Gs-biased. These findings would facilitate the development of novel drugs for the treatment of both heart failure and asthma.

Design, synthesis and biological evaluation of 5-(2-amino-1-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one derivatives as potent ß2-adrenoceptor agonists.

A series of novel ß2-adrenoceptor agonists with a 5-(2-amino-1-hydroxyethyl)-8-hydroxyquinolin-2(1H)-one moiety was designed, synthesized and evaluated for biological activity in human embryonic kidney 293 cells and isolated guinea pig trachea. Compounds 9g and (R)-18c exhibited the most excellent ß2-adrenoceptor agonistic effects and high ß2/ß1-selectivity with EC50 values of 36 pM for 9g and 21 pM for (R)-18c. They produced potent airway smooth muscle relaxant effects with fast onset of action and long duration of action in an in vitro guinea pig trachea model of bronchodilation. These results support further development of the two compounds into drug candidates.

Synthesis and biological evaluation of ß2-adrenoceptor agonists bearing the 2-amino-2-phenylethanol scaffold.

A new series of ß2-adrenoceptor agonists bearing the 2-amino-2-phenylethanol scaffold was synthesized. Evaluation of the compounds using cell assays and an in vitro guinea pig trachea relaxation assay showed that 8-hydroxy-5-(2-hydroxy-1-((4-hydroxyphenethyl)amino)ethyl)quinolin-2(1H)-one (compound 5j) has the best pharmacological profile among all the evaluated compounds. The (S)-isomer of 5j was subsequently found to be the active enantiomer with a promising EC50 value of 1.26 nM in stimulating ß2-adrenoceptor-mediated cAMP accumulation and a substantially higher selectivity for the ß2 than for the ß1 subtype. The putative binding mode of (S)-5j revealed by molecular docking of the ß2-adrenoceptor resembles that in agonist binding. Taken together, these results showed that compound (S)-5j is a promising compound worthy of further study for the development of ß2-adrenoceptor agonists.

Synthesis, biological evaluation and molecular modeling of 2-amino-2-phenylethanol derivatives as novel ß2-adrenoceptor agonists.

A novel series of 2-amino-2-phenylethanol derivatives were developed as ß2-adrenoceptor agonists. Among them, 2-amino-3-fluoro-5-(2-hydroxy-1-(isopropylamino)ethyl)benzonitrile (compound 2f) exhibited the highest activity (EC50 = 0.25 nM) in stimulating ß2-adrenoceptor-mediated cellular cAMP production with a 763.6-fold selectivity over the ß1-adrenoceptor. The (S)-isomer of 2f was subsequently found to be 8.5-fold more active than the (R)-isomer. Molecular docking was performed to determine the putative binding modes of this new class of ß2-adrenoceptor agonists. Taken together, these data show that compound 2f is a promising lead compound worthy of further study for the development of ß2-adrenoceptor agonists.

[Clinical Assessment of Chemosensitivity Test in Xeno-free Culture of Autologous 
Malignant Effusion Cells from Patients with Advanced Lung Adenocarcinoma].

BACKGROUND: A great individual differences to chemotherapeutic effects existed in the patient with advanced lung cancer. How to choose the optimum regimens to achieve the individuation and maximum effect of chemotherapy for lung cancer is worth exploring. The study was designed to examine the effect of ex vitro chemo-sensitivity assay in xeno-free culture of autologous malignant effusion cells from patients with advanced lung adenocarcinoma. METHODS: The 50 treatment-naive patients with lung adenocarcinoma complicated with malignant pleural or pericardial effusions were enrolled. Effusions of all cases had been controlled by closed drainage and 300 mL-500 mL of which were retained under sterile condition from 25 cases (Chemo-sensitivity group). Primary malignant effusion cells were isolated from autologous effusions of the patients. Then, xeno-free culture (average 11 days) were intervened with 8 chemotherapeutic drugs commonly used in clinical practice and were determined by CCK-8 assay. Optimum regimens were selected for chemotherapy based on the results of chemosensitivity test. As a contrast, chemotherapy regimens for the other 25 patients (Control group) were on the basis of physician's clinical experience. RESULTS: After four cycles of chemotherapy, in Chemo-sensitivity group, 17 (68.0%) cases were determined for partial response (PR), 5 (20.0%) cases for stable disease (SD), and the objective response rate (ORR) was 68.0%, the disease control rate (DCR) was 88.0%. Meanwhile, in Control group, 9 (36.0%) cases were determined for PR, 7 (28.0%) cases for SD, and, the ORR was 36.0%, the DCR was 64.0%. There were significant differences between the two groups in ORR and DCR (P<0.05). To the end of follow-up, there were 21 cases of death in Chemo-sensitivity group as well as 22 cases in Control group. The mean progression-free survival (PFS) in Chemo-sensitivity group and Control group respectively were 10.0 months and 5.8 months, and the mean overall survival (OS) in the two groups were 30.2 months and 21.2 months respectively. There were also significant differences between the two groups in PFS and OS (P<0.05). Furthermore, the adverse reactions in both groups were mild and controllable. CONCLUSIONS: Xeno-free culture of autologous malignant effusion cells from patients with advanced lung adenocarcinoma and ex vitro chemo-sensitivity assay are beneficial to the rational choices of chemotherapeutic agents used in patients with lung adenocarcinoma complicated with malignant effusions, which is a worthy trial in personalized cell culture for individualized cancer therapy and further studies.

[Recent advances in study of long ß(2)-adrenoceptor agonist].

ß2-Adrenoceptor agonists are highly effective bronchodilators and are widely used in the treatment of both chronic obstructive pulmonary disease (COPD) and asthma. In the last 15 years, there has been great interest within the pharmaceutical industry in the discovery of a long ß2-adrenoceptor agonist for a mono-therapy or combination therapy. The search for new long-acting ß2-adrenoreceptor agonists (LABA's), for the treatment of asthma and COPD, has become a very active area of drug discovery. This article reviews the mechanisms, potential candidates and research advances of long ß2-adrenoceptor agonists.