Cathodic Electrochemiluminesence Microscopy for Imaging of Single Carbon Nanotube and Nucleolin at Single Tumor Cell.

Cathodic electrochemiluminesence (ECL) microscopy based on luminol analog L012 was originally established to implement the imaging of a single nanotube and nucleolin on a single tumor cell. This microscopy utilizes multiwalled carbon nanotubes (MWCNTs) as advanced coreactant accelerators to efficiently convert dissolved oxygen (O2) and H2O2 into reactive oxygen species (ROS) due to excellent electrocatalytic properties. The produced ROS could oxide L012 into an excited state of L012 leading to a bright cathodic ECL illumination, thereby promoting ECL imaging of MWCNTs at a low triggering potential. After being modified with AS1411 aptamers, MWCNTs@AS1411 probes were incubated with tumor cells for specific ECL imaging of nucleolin on the plasma membrane, which permits cathodic ECL microscopy for label-free bioassays without ECL tags. The L012-based cathodic ECL microscopy with a moderate operating potential and label-free characteristics provides a universal approach in single nanomaterial and single-cell imaging and analyses.

Escherichia coli-Based In Situ Triggerable Probe as an Amplifier for Sensitive Diagnosis and Penetrated Therapy of Cancer.

Escherichia coli (E. coli) was used for cancer therapy due to the tumor-targeting, catalytic, and surface-reducing properties. Effective diagnosis combined with treatment of cancer based on E. coli, however, was rarely demonstrated. In this study, E. coli was used to surface reduce HAuCl4 and as a carrier to modify riboflavin (Rf) and luminol (E-Au@Rf@Lum). After targeted delivery to tumor, the E-Au@Rf@Lum probe could actively emit 425 nm blue-violet chemiluminescence (CL) to achieve cell imaging for cancer diagnosis. Furthermore, this light could in situ trigger the photosensitizer (Rf) through CL resonance energy transfer, which produces reactive oxygen species (ROS) for accurate photodynamic therapy. In return, the excessive ROS enhanced the blue-violet light which was further absorbed by Rf, and ROS production was cyclically amplified. Abundant ROS broke down the dense extracellular matrix network and penetrated deep into tumors. Besides, E. coli with excellent catalytic property could decompose H2O2 to O2 to relieve tumor hypoxia for a long time and enhance the photosensitized process of Rf. By self-illumination, effective penetration, and tumor hypoxia relief, this work opens a self-amplified therapy modality to tumor.

Construction of a Single-Atom Nanozyme for Enhanced Chemodynamic Therapy and Chemotherapy.

To fulfill the demand of precision and personalized medicine, single-atom catalysts (SACs) have emerged as a frontier in biomedical fields due to enzyme-mimic catalysis. Herein, we present a biocompatible and versatile nanoagent consisting of single-atom iron-containing nanoparticles (SAF NPs), DOX and A549 cell membrane (CM). The designed porous iron-based SACs originally served as a drug-carrying nanoplatform to release DOX selectively in a tumor microenvironment (TME) for chemotherapy (CT) due to their high loading capacity (155 %) for DOX; this signifies that SACs are promising candidates for universal cargo delivery. Besides, the designed single-atom nanoagent can perform like peroxidase, which effectively triggers an in situ tumor-specific Fenton reaction to generate abundant toxic hydroxyl radicals (⋅OH) selectively in the acidic TME for chemodynamic therapy (CDT). With the combination of CDT and CT, the constructed SAF NPs@DOX@CM nanoagent demonstrates better in vivo therapeutic performance than single-pathway therapy. In the meantime, after modification with CM, SAF NPs@DOX@CM can achieve homologous binding to target tumor tissues and avoid early clearance. This study presents a type of multifunctional SACs for enhanced cancer treatment via the capacity of a drug carrier combined with the enzymatic therapies of single-atom catalytic sites.

Electrochemiluminescence-Microscopy for microRNA Imaging in Single Cancer Cell Combined with Chemotherapy-Photothermal Therapy.

In this work, a new technology using ECL as a microscopy to parallel image miRNA-21 in single cancer cell was built. Phorbol-12-myristate-13-acetate (PMA) loaded gold nanocages (Au NCs) was closed with DNA gate which could be recognized and opened by miRNA-21 in HeLa cell. PMA was then released and further induced HeLa cells to produce reactive oxygen species (ROS; including O2-•, •OH and H2O2 etc.). With H2O2 as coreactant and luminol as ECL active material, ECL imaging of intracellular miRNA-21 in single HeLa cell was obtained by EMCCD. Moreover, ROS therapy and photothermal therapy (PPT) of Au NCs@PMA probe were also motivated by in situ miRNA-21 marker instead of the external source. The combined therapy leads to dramatically enhanced ability for cancer cell killing. Au NCs@PMA probe alone could not only achieve a high sensitivity and high resolution ECL-microscopy for imaging of intracellular miRNA-21 for the first time, but also realize the integrated diagnosis like ROS induced tumor damage and photothermal-induced intelligent therapy. This multifunctional platform is believed to be capable of playing an important role in future oncotherapy by the synergistic effects between chemotherapy and photothermal therapy.

Visual Color-Switch Electrochemiluminescence Biosensing of Cancer Cell Based on Multichannel Bipolar Electrode Chip.

In this work, we developed a visual electrochemiluminescence (ECL) sensing platform based on a dual-bipolar electrode (D-BPE) array chip. The chip was composed of two arrays of BPEs and three separated arrays of reservoirs filled with buffer, Ru(bpy)3(2+)-TPrA and luminol solutions, respectively. Both BPEs served as ECL reporting platforms. By applying 6.0 V voltage, an array of orange electrochemiluminescence (ECL) signals belonging to Ru(bpy)3(2+) turned on. After adding DNAzyme and H2O2 in Ru(bpy)3(2+) and luminol reservoirs, the orange Ru(bpy)3(2+) signals decreased until vanished due to the quenching effect; meanwhile, a new array of blue ECL signals turned on because of the luminol-H2O2 ECL reaction. The designed D-BPE owns superior properties compared with the three-electrode system benefiting from the quantitative relation of bipolar systems, which greatly enhanced the ECL detection sensitivity. Meanwhile, the visual color-switch ECL and the ratiometric detecting principle made the results easier to evaluate and more accurate. Quantitative detection of HL-60 cancer cells from 320 cells/mL to 2.5 × 10(5) cells/mL with two linear ranges was achieved. The detection limit was down to 80 cells/mL. Finally, this D-BPE chip could distinguish the tumor cells from normal cells and provide a prospect for cancer diagnosis in a high-throughput, visual way.

A portable and antibody-free sandwich assay for determination of chloramphenicol in food based on a personal glucose meter.

A portable and antibody-free sandwich assay was fabricated for determination of chloramphenicol (CAP) in animal-derived food by a personal glucose meter (PGM). The sandwich-type strategy was developed on the basis of magnetic molecularly imprinted probe (m-MIP) nanoparticles and a ß-cyclodextrin/invertase-functionalized signal tag. Firstly, the m-MIPs were fabricated using polydopamine molecularly imprinted film modified Fe3O4 nanoparticles with 2,2-dichloroacetamide as a template that could capture the 2,2-dichloroacetamide segment of CAP. Secondly, ß-cyclodextrin/invertase polymer bioconjungate was synthesized as a signal tag that could recognize the nitrobenzene segment of CAP through host-guest interaction. The dual-specificity recognition model relies on the formation of a sandwich between m-MIPs, different segments of CAP, and the ß-cyclodextrin-functionalized signal tag. The sandwich-type complex formed was then subjected to detection with a PGM. The complexes can hydrolyze sucrose to glucose, which can be used for detection with a PGM through invertase. According to our experiment, the concentration of CAP was proportional to the amount of glucose formed, which could quantitatively assess the CAP with a dynamic range of 0.5-50 ng mL(-1) and a detection limit of 0.16 ng mL(-1) (signal-to-noise ratio of 3). The detection time of the assay was about 1 h, which was obviously shorter than that of competitive ELISA. More importantly, we have successfully applied this on-site assay for CAP screening in animal-derived food.

Signal-on dual-potential electrochemiluminescence based on luminol-gold bifunctional nanoparticles for telomerase detection.

Here, we report a novel type of signal-on dual-potential electrochemiluminescence (ECL) approach for telomerase detection based on bifunctionalized luminol-gold nanoparticles (L-Au NPs). In this approach, CdS nanocrystals (NCs) were first coated on glassy carbon electrode, and then thiol-modified telomerase primer was attached on CdS NCs via Cd-S bond. In the presence of telomerase and dNTPs, the primer could be extended. Telomerase primer would hybridize with its complementary DNA, and the extended part would hybridize with the capture DNA which was tagged with L-Au NPs. In the presence of coreactant H2O2, the L-Au NPs could not only enhance the ECL intensity of CdS NCs at -1.25 V (vs SCE) induced by the surface plasmon resonance (SPR) of Au NPs but also produce a new ECL signal at +0.45 V (vs SCE) that resulted from luminol in L-Au NPs. Both signals at two potentials increased with the increase of telomerase concentration. This method could be used to detect the telomerase from 100 to 9000 HL-60 cells and investigate the apoptosis of tumor cells. The ratio of the two signal increments (ΔECL(Luminol)/ΔECL(CdS NCs)), which showed a high consistency value for different numbers of cells, could be used to verify the reliability of tests. This dual-potential ECL strategy showed great promise in avoiding false positive or negative results in bioanalysis.

In situ activation of CdS electrochemiluminescence film and its application in H2S detection.

Nanocrystals (NCs) usually suffer from weak electrogenerated chemiluminescence (ECL) emissions compared with conventional luminescent reagents like Ru(bpy)3(2+). In this work, we proposed a simple in situ activation approach by dipping CdS NCs film on glass carbon electrode (CdS NCs/GCE) in an activation solution containing H2O2 and citric acid, resulting in a ~58-fold enhancement of ECL intensity in the presence of coreactant H2O2. During activation, CdS NCs were oxidized by H2O2 to smaller ones which resulted in more surface S vacancies; meanwhile, citric acid played an important role in stabilizing NCs. The ECL enhancing mechanism was investigated in detail, and the coordination of H2O2 to surface excess Cd(2+) ions (S vacancies) on the CdS NCs surface formed in activation was the main factor which could stabilize the electrogenerated radicals, resulting in an enhanced ECL. ECL from the activated CdS NCs/GCE could be quenched in Na2S solution due to the bonding of S(II) to excess Cd(2+) ions on the surface of CdS NCs. On the basis of this, we then used the activated CdS NCs/GCE as an ECL probe for the detection of Na2S which showed good performance including a wide linear range of 5 nM to 20 µM and good anti-interference ability. Moreover, this ECL probe was successfully applied for hydrogen sulfide (H2S) detection in a biological system.

Thermoresponsive and Substrate Self-Cycling Nanoenzyme System for Efficient Tumor Therapy.

Cerium oxide (CeO2-x) performs well in photothermal and catalytic properties due to its abundance of oxygen vacancies. Based on this, we designed a thermosensitive therapeutic nanoplatform to achieve continuous circular drug release in tumor. It can solve the limitation caused by insufficient substrate in the process of tumor treatment. Briefly, CeO2-x and camptothecin (CPT) were wrapped in an agarose hydrogel, which could be melted by the photothermal effect of CeO2-x. At the same time, the local temperature increase provided photothermal treatment, which could induce the apoptosis of tumor cell. After that, CPT was released to damage the DNA in tumor cells to realize chemical treatment. In addition, CPT could active nicotinamide adenine dinucleotide oxidase to react with O2 to increase the intracellular H2O2. After that, the exposed CeO2-x could catalyze H2O2 to generate cytotoxic reactive oxygen species for chemodynamic therapy. More importantly, CeO2-x could catalyze H2O2 to produce O2, which could combine with the catalytic action of CPT to construct a substrate self-cycling nanoenzyme system. Overall, this self-cycling nanoplatform released hypoxia in the tumor microenvironment and built a multimode tumor treatment, which achieved an ideal antitumor affect.

Electrochemiluminescence ratiometry: a new approach to DNA biosensing.

Inspired by dual-wavelength fluorescence ratiometric method which could reduce the influence from the environmental change, here, we present a novel dual-potential electrochemiluminescence (ECL) ratiometric sensing approach. CdS nanocrystal (NC) and luminol as two different ECL emitters are employed. ECL from CdS NCs coated on glassy carbon electrode at -1.25 V (vs SCE) could be quenched by closely contacted Pt nanoparticles (NPs) via a biological binding event, while ECL from luminol at +0.45 V (vs SCE) could be enhanced by the same Pt NPs, in the presence of their common coreactant of H2O2. Thus, the quenching of ECL from CdS NCs and the enhancement of ECL from luminol could indicate the same biological binding event. With the mp53 oncogene as a model DNA molecule, a molecular beacon (MB) containing a 20-base loop, which is complementary with the mp53 oncogene, is immobilized on CdS NCs/GCE first; Pt NPs are then captured on CdS NCs surface by DNA hybridization between the MB and mp53 oncogene labeled on Pt NPs. By measuring the ratio of ECL intensities at two excitation potentials, this approach could sensitively detect the concentration of target DNA in a wide range from 5.0 fM to 1.0 pM. The sensing scheme is general and can be utilized for many other biological binding events.

Single-Atom Nanoenzyme-Based Autoluminescence System for Cancer Cell Imaging and Mitochondrial-Targeted Therapy.

The autoluminescence nanoplatform based on a single-atom catalyst has the potential to achieve accurate tumor diagnosis and treatment. Taking advantage of this, glycyrrhetinic acid (GA) and chitosan-modified single Fe-N-C atom catalysts (SAF NPs) loaded with luminol-curcumin (Cur) were fabricated (SAF-LCCG). Once delivered to the tumor, this autoluminescence SAF-LCCG could target the mitochondria to restrain tumor metastasis and promote the production of hydrogen peroxide (H2O2). Then, SAF NPs with Fenton-like properties could actively utilize intracellular H2O2 to produce ·OH for chemodynamic therapy. After that, excess ·OH and H2O2 were transmitted to luminol to emit blue-violet chemiluminescence (CL) for cancer cell imaging. Synchronously, light was transferred to Cur to produce reactive oxygen species (ROS) which realized photodynamic therapy. Besides, Cur could be served as a chemotherapeutic drug to enhance intracellular ROS for penetrating therapy. More importantly, the massive accumulation of ROS in cancer cells can promote the CL intensity of luminol, which realized the cyclic ROS amplification. This autoluminescence nanoplatform was developed for accurate cancer cell imaging, effective inhibition of tumor metastasis, and synergistic and penetrated treatment of tumors.

Artificial intelligence system-based histogram analysis of computed tomography features to predict tumor invasiveness of ground-glass nodules.

Background: The use of an artificial intelligence (AI)-based diagnostic system can significantly aid in analyzing the histogram of pulmonary nodules. The aim of our study was to evaluate the value of computed tomography (CT) histogram indicators analyzed by AI in predicting the tumor invasiveness of ground-glass nodules (GGNs) and to determine the added value of contrast-enhanced CT (CECT) compared with nonenhanced CT (NECT) in this prediction. Methods: This study enrolled patients with persistent GGNs who underwent preoperative NECT and CECT scanning. AI-based histogram analysis was performed for pathologically confirmed GGNs, which was followed by screening invasiveness-related factors via univariable analysis. Multivariable logistic models were developed based on candidate CT histogram indicators measured on either NECT or CECT. Receiver operating characteristic (ROC) curve and precision-recall (PR) curve were used to evaluate the models' performance. Results: A total of 116 patients comprising 121 GGNs were included and divided into the precancerous lesion and adenocarcinoma groups based on invasiveness. In the AI-based histogram analysis, the mean CT value [NECT: odds ratio (OR) =1.009; 95% confidence interval (CI): 1.004-1.013; P<0.001] and solid component volume (NECT: OR =1.005; 95% CI: 1.000-1.010; P=0.032) were associated with the adenocarcinoma and used for multivariable logistic modeling. The area under ROC curve (AUC) and PR curve (AUPR) were not significantly different between the NECT model (AUC =0.765, 95% CI: 0.679-0.837; AUPR =0.907, 95% CI: 0.825-0.953) and the optimal CECT model (delayed phase: AUC =0.772, 95% CI: 0.687-0.843; AUPR =0.895, 95% CI: 0.812-0.944). No significantly different metrics were observed between the NECT and CECT models (precision: 0.707 vs. 0.742; P=0.616). Conclusions: The AI diagnostic system can help in the diagnosis of GGNs. The system displayed decent performance in GGN detection and alert to malignancy. Mean CT value and solid component volume were independent predictors of tumor invasiveness. CECT provided no additional improvement in diagnostic performance as compared with NECT.

Effects of tRNA-derived fragments and microRNAs regulatory network on pancreatic acinar intracellular trypsinogen activation.

Acute pancreatitis (AP) is a common gastrointestinal disease with substantial morbidity and mortality. Pancreatic acinar intracellular trypsinogen activation (PAITA) is an important event in the early stage of AP. The present study aimed to investigate the effects of tRNA-derived fragments (tRFs) and the microRNA regulatory network on pancreatic acinar intracellular trypsinogen activation (PAITA) and identify novel key targets in AP. Taurolithocholic acid 3-sulfate (TLC-S)-treated AR42J cells were used to establish a PAITA model. Twenty differentially expressed tRFs and 35 DE microRNAs were identified in PAITA through gene sequencing. Based on these genes, we established the tRF-mRNA and microRNA-mRNA regulatory networks by using bioinformatics methods. The networks revealed 29 hub microRNAs (e.g., Let-7 family, miR-21-3p.) and 19 hub tRFs (e.g., tRF3-Thr-AGT, i-tRF-Met-CAT) in PAITA. GO analysis showed that the functions of the two networks were similar and mainly enriched in RNA splicing, mRNA processing, and so on. tRF3-Thr-AGT, targeting Btg2, Cd44, Zbp1, etc., was significantly decreased in PAITA. Moreover, the trypsinogen activation level was increased significantly in the tRF3-Thr-AGT deficiency groups, but rescued by tRF3-Thr-AGT mimics. The results revealed that downregulated tRF3-Thr-AGT was involved in PAITA. This study provides potential novel targets for researching the underlying mechanisms of AP.

pH-programmed responsive nanoplatform for synergistic cancer therapy based on single atom catalysts.

The development of stimuli-responsive nanoplatform provides powerful tool for simultaneously enhancing the efficiency and accuracy of cancer therapies. Herein, we develop a pH-programmed responsive and synergistically theranostic nanoplatform based on CaCO3 mineralized single atom iron nanoparticles (SAF NPs). Basically, the highly active site on SAF NPs nanoagent can trigger in-situ produce toxic •OH in tumor microenvironment (TME) that kill cancer cells for Fenton-reaction-based chemodynamic therapy (CDT). The porous structure of SAF NPs can serve as delivery platforms to package and programmed release chemotherapeutic drug doxorubicin (DOX) to enhance chemotherapy (CT) efficiency. The nanoplatform was simultaneously in-situ mineralized with CaCO3 and A549 cell membrane (CM) which could avoid DOX leakage during transport in bloodstream and target homologous cancer cells. In addition, overload Ca2+ decomposed from CaCO3 triggers mitochondrial dysfunction, induces cytoskeleton collapse and oxidative stress to formulate calcium ions interference therapy (CIT). With the combination of CDT, CT and CIT, the designed multi-synergetic nanoplatform exhibits excellent biocompatibility, specificity and tunable drug release behavior, which has a broad application prospect in tumor therapy.

Single-Site Fe-N-C Atom Based Carbon Nanotubes for Mutually Promoted and Synergistic Oncotherapy.

A carbon nanotube (CNT) supported single-site Fe-N-C catalyst (CNTs/Fe-N-C) exhibited attractive properties in peroxidase (POD)-like activity and photothermal effect. Herein, we designed a therapeutic platform by wrapping doxorubicin (DOX) in mesoporous CNTs/Fe-N-C with the cell membrane (CM) of breast cancer. The ultimate nanoagent (CNTs/Fe-N-C/DOX/CM) exhibited high antitumor activity on account of its efficient catalytic ability, increased drug release rates, and significant photothermal effect. Due to the POD-like activity, CNTs/Fe-N-C could effectively catalyze hydrogen peroxide (H2O2) into cytotoxic hydroxyl radicals (•OH) for chemodynamic therapy (CDT) of the tumor. Besides, the released DOX not only merely induced the diagnosis of the tumor cells for chemotherapy (CT) but also generated H2O2 to promote CDT. Moreover, the photothermal effect of the nanoagent could use for photothermal therapy (PTT). The increasing temperature was conducive to the release of DOX from micropore into the cell, which indirectly enhanced CT and CDT effects. As an intelligent and multifunctional drug delivery platform, the present CNTs/Fe-N-C/DOX/CM nanoagent could be engineered with synergistic treatments and favorable biosafety, which provides a promising paradigm in site-specific antitumor treatment and biomedicine.

REG3A/REG3B promotes acinar to ductal metaplasia through binding to EXTL3 and activating the RAS-RAF-MEK-ERK signaling pathway.

Persistent acinar to ductal metaplasia (ADM) is a recently recognized precursor of pancreatic ductal adenocarcinoma (PDAC). Here we show that the ADM area of human pancreas tissue adjacent to PDAC expresses significantly higher levels of regenerating protein 3A (REG3A). Exogenous REG3A and its mouse homolog REG3B induce ADM in the 3D culture of primary human and murine acinar cells, respectively. Both Reg3b transgenic mice and REG3B-treated mice with caerulein-induced pancreatitis develop and sustain ADM. Two out of five Reg3b transgenic mice with caerulein-induced pancreatitis show progression from ADM to pancreatic intraepithelial neoplasia (PanIN). Both in vitro and in vivo ADM models demonstrate activation of the RAS-RAF-MEK-ERK signaling pathway. Exostosin-like glycosyltransferase 3 (EXTL3) functions as the receptor for REG3B and mediates the activation of downstream signaling proteins. Our data indicates that REG3A/REG3B promotes persistent ADM through binding to EXTL3 and activating the RAS-RAF-MEK-ERK signaling pathway. Targeting REG3A/REG3B, its receptor EXTL3, or other downstream molecules could interrupt the ADM process and prevent early PDAC carcinogenesis.

Electrochemiluminescence Biosensor for Nucleolin Imaging in a Single Tumor Cell Combined with Synergetic Therapy of Tumor.

Nucleolin, a nuclear biological multifunctional protein, plays significant roles in modulating the proliferation, survival, and apoptosis of tumor cells. Different from the traditional electrochemiluminescence (ECL) method, a new ECL biosensor was built to perform ECL imaging of nucleolin in a single HeLa cell with high sensitivity and throughput. Briefly, mesoporous silica nanoparticles (MSN) loaded with doxorubicin (DOX) and phorbol 12-myristate 13-acetate (PMA) were used as drug carriers and could be specifically opened by nucleolin in a HeLa cell. PMA then induced the HeLa cell to produce reactive oxygen species (ROS) and realized ECL imaging of nucleolin. After that, ROS could damage DNA and proteins of the tumor cell and DOX could induce the apoptosis of HeLa cells by inhibiting genetic material, nucleic acid, synthesis. HeLa cells were then efficiently killed by DOX and ROS in a synergetic pathway. Herein, a new ECL biosensor for ECL imaging of nucleolin in a single HeLa cell and synergetic tumor therapy was built.

Quantitative assessment of energy conservation and emission reduction effects of nationwide industrial symbiosis in China.

Studies on quantifying the energy conservation and emission reduction (ECER) effects of industrial symbiosis are mostly confined to micro-level industrial parks or regions, and few are on national level. Focusing on the symbiosis system formed by the iron and steel industry, the thermal power industry, the cement industry, and the social sector in China, this article aims to clarify the contribution of this nationwide industrial symbiosis system to China's total industrial ECER potential and to identify optimal symbiotic technologies that should be emphasized on from 2020 to 2030. By combining traditional bottom-up model and lifecycle material metabolism theory, this article simulates the technology structure of this symbiosis system. By clarifying the ECER mechanisms of different types of symbiotic technologies, this article evaluates the ECER effect of each symbiotic technology as well as the performance of the overall symbiosis system. The results show that: (1) this nationwide industrial symbiosis system can save 35.7 million tons of coal equivalent, and reduce 189 kt of SO2 emissions, 139 kt of NOx emissions, and 64 kt of PM emissions. These ECER effects contribute to 18-43% of China's national industrial ECER targets, which are larger than the potential of promoting energy efficiency technologies and end-of-pipe technologies in each single industry; (2) reutilizing solid wastes from the thermal power industry and the social sector as cementitious materials, as well as recovering iron and zinc from metallurgical dust are key symbiotic fields between 2020 and 2030. Three types of differentiated technology promotion suggestions are put forward.

The risk of immune-related endocrine disorders associated with anti-PD-1 inhibitors therapy for solid tumors: A systematic review and meta-analysis.

BACKGROUND: We performed a systematic review and meta-analysis to evaluate the risk of immune-related endocrine disorders associated with PD-1 inhibitors therapy for solid tumors. METHODS: An Embase and PubMed search through December 6, 2017, using the following keywords was performed: immune-related endocrine disorders, and PD-1 inhibitors, etc. The data were analyzed using R 3.4.3 (R Project) and the metafor package. Patients treated with chemotherapy alone were used as control for the purpose of comparison. RESULTS: A total of 12 clinical trials including 5577 patients were found eligible for the meta-analysis. Compared with chemotherapy, the risk ratios of all-grade endocrine disorders are 13.89, (95% CI: 5.35-36.05, p < 0.001) for nivolumab therapy, and 9.85, (95% CI: 5.65-17.17, p < 0.001) for pembrolizumab therapy. The risk of all-grade hypothyroidism and hyperthyroidism incidence was increased for nivolumab therapy (hypothyroidism: RR 10.07, 95% CI: 3.37-30.11, p < 0.001; hyperthyroidism: RR 4.29, 95% CI: 1.13-16.30, p = 0.034) and for pembrolizumab therapy (hypothyroidism: RR 7.73, 95% CI: 3.86-15.49, p < 0.001; hyperthyroidism: RR 5.09, 95% CI: 2.36-10.97, p < 0.001). There was a significant increase in the risk of grade 1-5 endocrine disorders incidence for ipilimumab-nivolumab combination therapy (versus ipilimumab, RR 3.20, 95% CI: 2.08-4.91, p < 0.001; versus nivolumab, RR 2.54, 95% CI: 1.70-3.80, p < 0.001). CONCLUSIONS: Both nivolumab and pembrolizumab therapy could result in a higher risk of all-grade immune-related endocrine disorders than chemotherapy. Nivolumab and ipilimumab combination therapy could result in an even higher risk of all-grade immune-related endocrine disorders than ipilimumab or nivolumab alone. Awareness of these side effects could guide clinicians to better manage the patients treated with anti-PD-1 inhibitors therapy for solid tumors.

Integration of intracellular telomerase monitoring by electrochemiluminescence technology and targeted cancer therapy by reactive oxygen species.

Cancer therapies based on reactive oxygen species (ROS) have emerged as promising clinical treatments. Electrochemiluminescence (ECL) technology has also attracted considerable attention in the field of clinical diagnosis. However, studies about the integration of ECL diagnosis and ROS cancer therapy are very rare. Here we introduce a novel strategy that employs ECL technology and ROS to fill the above vacancy. Briefly, an ITO electrode was electrodeposited with polyluminol-Pt NPs composite films and modified with aptamer DNA to capture HL-60 cancer cells with high specificity. After that, mesoporous silica nanoparticles (MSNs) filled with phorbol 12-myristate 13-acetate (PMA) were closed by the telomerase primer DNA (T-primer DNA) and aptamer. After aptamer on MSN@PMA recognized and combined with the HL-60 cancer cells with high specificity, T-primer DNA on MSN@PMA could be moved away from the MSN@PMA surface after extension by telomerase in the HL-60 cancer cells and PMA was released to induce the production of ROS by the HL-60 cancer cells. After that, the polyluminol-Pt NPs composite films could react with hydrogen peroxide (a major ROS) and generate an ECL signal. Thus the intracellular telomerase activity of the HL-60 cancer cells could be detected in situ. Besides, ROS could induce apoptosis in the HL-60 cancer cells with high efficacy by causing oxidative damage to the lipids, protein, and DNA. Above all, the designed platform could not only detect intracellular telomerase activity instead of that of extracted telomerase, but could also kill targeted tumors by ECL technology and ROS.