Immuno-PET Imaging of 89Zr Labeled Anti-PD-L1 Domain Antibody.

Recently, various immuno-PET tracers based on monoclonal antibodies (mAbs), engineered scaffold proteins, and peptides were developed to target either programmed cell death protein 1 (PD-1) or programmed cell death ligand 1 (PD-L1), showing promise in assessment of immune checkpoints. We sought to develop an immunotherapeutic agent based PET probe that enables real-time assessment of PD-L1 expression and evaluation of antibody drug biodistribution to select eligible candidates for anti-PD-1/PD-L1 immunotherapies. KN035, a 79.6 kDa size anti-PD-L1 domain antibody under analysis in clinical trials, was used to develop the immuno-PET probe, 89Zr-Df-KN035. Immuno-PET studies were performed to monitor PD-L1 levels in nude mice bearing LN229 xenografts with positive expression for PD-L1, and to evaluate the whole-body biodistribution in healthy non-human primates (NHPs). LN229 xenografts were markedly visualized from 24 h after injection of 89Zr-Df-KN035, with elevated accumulation persisting for up to 120 h. Tumor radioactivity was notably reduced in the presence of excess KN035. Mouse ex vivo biodistribution studies performed at 24 and 120 h revealed tumor-to-muscle ratios as high as 5.64 ± 0.65 and 7.70 ± 1.37, respectively. In the NHP model, PET imaging demonstrated low background. The liver and kidney showed moderate accumulation with the highest SUVmean value of 1.15 ± 0.15 and 2.13 ± 0.10 at 72 h, respectively. The spleen, lymph nodes, and salivary glands were also slightly visualized. In conclusion, 89Zr-Df-KN035, a novel anti-PD-L1 domain antibody-based probe, shows the feasibility of noninvasive in vivo evaluation of PD-L1 expression. This work further provides a template for immunotherapeutic agent based imaging to evaluate human PD-L1 expression and to augment our understanding of therapeutic agent biodistribution, leading to better therapeutic strategies in the future.

Chameleon Luminophore for Erasable Encrypted and Decrypted Devices: From Dual-Channel, Programmable, Smart Sensory Lanthanide Hydrogel to Logic Devices.

With the rapid development of the data security technology, increasing attention has been paid to programmable memory materials with desirable security. However, most conventional memory devices only have a single switchable color state. In this research, a kind of pH-responsive Chameleon luminescent sensor (Lap@Eu-OFX, Lap = laponite, OFX = ofloxacin) based on lanthanide doping has been fabricated, which can realize highly contrast, dynamically controlled full-color display by changing the pH value of the solution. The advanced programmable security inks, including the green and red luminescent inks, have been prepared and used to protect confidential information. More interestingly, triethylamine and hydrochloric acid are selected as encryption and decryption reagents, which can repeatedly switch the emission color of important data. Hence, the high-tech security inks show great potential in data coding, multiencryption, and decryption under UV light. Furthermore, the designed dual-channel memory device, Lap@Eu-OFX@CS (CS = Chitosan), enables reversible synchronous switching of sol-gel and emission color when converting from acid to base conditions. This can be dynamically monitored by a subsequent logic gate system and can be converted and stored into binary values. This work provides an effective approach for the design and promising application of information encryptor, smart monitor, and circuit controllers.

Dual-Mode, Color-Tunable, Lanthanide-Doped Core-Shell Nanoarchitectures for Anti-Counterfeiting Inks and Latent Fingerprint Recognition.

With the rapid development of information in modern society, the research and development of advanced anti-counterfeiting technology is becoming more and more important to protect the security and comprehensiveness of information. Therefore, fluorescent ink as an anti-counterfeiting technology and fingerprint recognition technology as a ″human information identification card″ has attracted the attention of many research groups. Herein, dual-mode (upconversion and downconversion) lanthanide-doped luminescent nanoarchitectures were developed using Y2O3:Er3+,Yb3+ nanoparticles as a core and layered lanthanide hydroxides nanomaterials as a shell. Under the irradiation of 980 nm near-infrared light, the nanoarchitectures emitted a bright upconverted red light emission. Meanwhile, under the irradiation of 254 nm UV light, the nanoarchitectures can directly emit multicolor luminescence (from green to yellow-green, yellow, orange, and red) by changing the suitable ratios of Tb3+/Eu3+ ions. The information can only be extracted when the irradiation of two kinds of excitation light sources existed at the same time, which can improve the difficulty of illegal imitation and enhance the level of anti-counterfeiting. Furthermore, these luminescent nanoarchitectures were investigated for visual latent fingerprint recognition on various substrates with high definition, high sensitivity, and high anti-interference. These results indicated that the nanoarchitectures reported in this study may have great application prospects in information security and identity recognition.

A Ratiometric Fluorescent Nano-Probe for Rapid and Specific Detection of Tetracycline Residues Based on a Dye-Doped Functionalized Nanoscaled Metal-Organic Framework.

Tetracycline (TC) residues are harmful to the environment and human body, so it is necessary to develop a highly sensitive probe for rapid detection of tetracycline residues. In the present paper, a novel dye-doped porous metal-organic framework (UiO-66)-based multi-color fluorescent nano-probe was designed for sensitive ratiometric detection of tetracycline (TC). In this probe, dye-molecules doped UiO-66 was used as a fluorescent internal standard, and the externally grafted lanthanide Eu3+ complex was used as response signals. The fluorescence of the Eu3+ complex was selectively enhanced with increasing concentrations of TC, which was accompanied by a visual blue-to-red color switch. The nano-probe had a linear response between 0.1 and 6 µM with a lowest detection limit of 17.9 nM, which was much lower than the maximum residue limits set by the United States Food and Drug Administration (676 nM) and the European Union (225 nM). The applicability of this method in the analysis of actual samples was evaluated by the determination of TC in honey and milk samples, indicating satisfactory recovery and good reproducibility. In addition, a cost-effective paper-based probe for rapid and visual detection of TC was developed by fixing the nano-probe on filter papers. With the help of a smartphone camera to capture the fluorescence color, and chromaticity analysis software, the calculation and analysis of red (R) and blue (B) values can be realized, which has the potential for real-time visual detection of TC.

A reappraisal of CTLA-4 checkpoint blockade in cancer immunotherapy.

It is assumed that anti-CTLA-4 antibodies cause tumor rejection by blocking negative signaling from B7-CTLA-4 interactions. Surprisingly, at concentrations considerably higher than plasma levels achieved by clinically effective dosing, the anti-CTLA-4 antibody Ipilimumab blocks neither B7 trans-endocytosis by CTLA-4 nor CTLA-4 binding to immobilized or cell-associated B7. Consequently, Ipilimumab does not increase B7 on dendritic cells (DCs) from either CTLA4 gene humanized (Ctla4 h/h ) or human CD34+ stem cell-reconstituted NSG™ mice. In Ctla4 h/m mice expressing both human and mouse CTLA4 genes, anti-CTLA-4 antibodies that bind to human but not mouse CTLA-4 efficiently induce Treg depletion and Fc receptor-dependent tumor rejection. The blocking antibody L3D10 is comparable to the non-blocking Ipilimumab in causing tumor rejection. Remarkably, L3D10 progenies that lose blocking activity during humanization remain fully competent in inducing Treg depletion and tumor rejection. Anti-B7 antibodies that effectively block CD4 T cell activation and de novo CD8 T cell priming in lymphoid organs do not negatively affect the immunotherapeutic effect of Ipilimumab. Thus, clinically effective anti-CTLA-4 mAb causes tumor rejection by mechanisms that are independent of checkpoint blockade but dependent on the host Fc receptor. Our data call for a reappraisal of the CTLA-4 checkpoint blockade hypothesis and provide new insights for the next generation of safe and effective anti-CTLA-4 mAbs.

Racial/ethnic disparity in the associations of smoking status with uncontrolled hypertension subtypes among hypertensive subjects.

BACKGROUND: Racial/ethnic differences in the associations of smoking with uncontrolled blood pressure (BP) and its subtypes (isolated uncontrolled systolic BP (SBP), uncontrolled systolic-diastolic BP, and isolated uncontrolled diastolic BP (DBP)) have not been investigated among diagnosed hypertensive subjects. METHODS: A sample of 7,586 hypertensive patients aged ≥18 years were selected from the National Health and Nutrition Examination Survey 1999-2010. Race/ethnicity was classified into Hispanic, non-Hispanic white, and non-Hispanic black. Smoking was categorized as never smoking, ex-smoking, and current smoking. Uncontrolled BP was determined as SBP≥140 or DBP≥90 mm Hg. Isolated uncontrolled SBP was defined as SBP≥140 and DBP<90 mm Hg, uncontrolled SDBP as SBP≥140 and DBP≥90 mm Hg, and isolated uncontrolled DBP as SBP<140 and DBP≥90 mm Hg. Adjusted odds ratios (ORs) with 95% confidence intervals (CIs) of uncontrolled BP and its subtypes were calculated using weighted logistic regression models. RESULTS: The interaction effect of race and smoking was significant after adjustment for the full potential confounding covariates (Adjusted p = 0.0412). Compared to never smokers, current smokers were 29% less likely to have uncontrolled BP in non-Hispanic whites (OR = 0.71, 95% CI = 0.56-0.90), although the likelihood for uncontrolled BP is the same for smokers and never smokers in Hispanics and non-Hispanic blacks. Current smokers were 26% less likely than never smokers to have isolated uncontrolled SBP in non-Hispanic whites (OR = 0.74, 95% CI = 0.58-0.95). However, current smoking is associated with an increased likelihood of uncontrolled systolic-diastolic BP in non-Hispanic blacks, and current smokers in this group were 70% more likely to have uncontrolled systolic-diastolic BP than never smokers (OR = 1.70, 95% CI = 1.10-2.65). CONCLUSION: The associations between current smoking and uncontrolled BP differed over race/ethnicity. Health practitioners may need to be especially vigilant with non-Hispanic black smokers with diagnosed hypertension.