CD13-Mediated Pegylated Carboxymethyl Chitosan-Capped Mesoporous Silica Nanoparticles for Enhancing the Therapeutic Efficacy of Hepatocellular Carcinoma.

Liver cancer, especially hepatocellular carcinoma, is an important cause of cancer-related death, and its incidence is increasing worldwide. Nano drug delivery systems have shown great promise in the treatment of cancers. In order to improve their therapeutic efficacy, it is very important to realize the high accumulation and effective release of drugs at the tumor site. In this manuscript, using doxorubicin (DOX) as a model drug, CD13-targeted mesoporous silica nanoparticles coated with NGR-peptide-modified pegylated carboxymethyl chitosan were constructed (DOX/MSN-CPN). DOX/MSN-CPN comprises a spherical shape with an obvious capping structure and a particle size of 125.01 ± 1.52 nm. With a decrease in pH, DOX/MSN-CPN showed responsive desorption from DOX/MSN-CPN and pH-responsive release of DOX was observed. Meanwhile, DOX/MSN-CPN could be efficiently absorbed through NGR-mediated internalization in vitro and could efficiently deliver DOX to tumor tissues with long accumulation times in vivo, suggesting good active targeting properties. Moreover, significant tumor inhibition has been observed in antitumor studies in vivo. This study provides a strategy of utilizing DOX/MSN-CPN as a nano-platform for drug delivery, which has superb therapeutic efficacy and safety for the treatment of hepatocellular carcinoma both in vivo and in vitro.

Artificial Assembled Macrophage Co-Deliver Black Phosphorus Quantum Dot and CDK4/6 Inhibitor for Colorectal Cancer Triple-Therapy.

In recent years, therapeutic strategies based on macrophages have been inspiringly developed, but due to the high intricacy and immunosuppression of the tumor microenvironment, the widespread use of these strategies still faces significant challenges. Herein, an artificial assembled macrophage concept (AB@LM) was presented to imitate the main antitumor abilities of macrophages of tumor targeting, promoting the antitumor immunity, and direct tumor-killing effects. The artificial assembled macrophage (AB@LM) was prepared through an extrusion method, which is to fuse the macrophage membrane with abemaciclib and black phosphorus quantum dot (BPQD)-loaded liposomes. AB@LM showed good stability and tumor targeting ability with the help of macrophage membrane. Furthermore, AB@LM reversed the immunosuppressive tumor microenvironment by inhibiting regulatory T cells (Tregs) and stimulating the maturation of antigen-presenting cells to activate the antitumor immune response through triggering an immunogenic cell death effect. More importantly, in the colorectal tumor model in vivo, a strong cooperative therapeutic effect of photo/chemo/immunotherapy was observed with high tumor inhibition rate (95.3 ± 2.05%). In conclusion, AB@LM exhibits excellent antitumor efficacy by intelligently mimicking the abilities of macrophages. A promising therapeutic strategy for tumor treatment based on imitating macrophages was provided in this study.

Depleting Tumor Infiltrating B Cells to Boost Antitumor Immunity with Tumor Immune-Microenvironment Reshaped Hybrid Nanocage.

Tumor infiltrating B cells (TIBs)-dependent immunotherapy has emerged as a promising method for tumor treatment. Depleting TIBs to boost antitumor immunity is a highly desirable yet challenging approach to TIBs-dependent immunotherapy. Herein, a tumor immune-microenvironment reshaped hybrid nanocage CPN-NLI/MLD coloaded with the Bruton's tyrosine kinase inhibitor ibrutinib, and cytotoxic drug docetaxel was developed for stepwise targeting TIBs and tumor cells, respectively. The tumor microenvironment responsive CPN-NLI/MLD promoted charge reversal and size reduction under acidic conditions (pH < 6.5). The accumulation of CPN-NLI/MLD in tumor tissues was achieved through CD13 targeting, and cellular uptake was increased due to the differ-targeting delivery. Targeting of docetaxel to tumor cells was achieved by the interaction of α-MSH modified on inner docetaxel-particle MLD and melanocortin-1 receptor on the surface of tumor cells. Targeting of ibrutinib to TIBs was achieved by the interaction of Neu5Ac modified on inner ibrutinib-particle NLI and CD22 on the surface of TIBs. The boosted antitumor immunity was achieved mainly by the inhibition of Bruton's tyrosine kinase activation mediated by ibrutinib, which reduced the proportion of TIBs, enhanced infiltration of CD8+ and CD4+ T cells, increased the secretion of immunogenic cytokines including IL-2 and IFN-γ, and inhibited the proliferation of regulatory T cells and secretion of immunosuppressive cytokines including IL-10, IL-4, and TGF-ß. Furthermore, CPN-NLI/MLD improved the antitumor efficiency of chemoimmunotherapy by reshaping tumor immune-microenvironment by TIBs depletion. Taken together, CPN-NLI/MLD represents a promising method for effective tumor treatment and combination therapy by TIBs-dependent immunotherapy.

High-Performance and Radiation-Hardened Solution-Processed ZrLaO Gate Dielectrics for Large-Area Applications.

Radiation hardness is important for electronics operating in harsh radiation environments such as outer space and nuclear energy industries. In this work, radiation-hardened solution-processed ZrLaO thin films are demonstrated. The radiation effects on solution-processed ZrLaO thin films and InOx/ZrLaO thin-film transistors (TFTs) were systemically investigated. The Zr0.9La0.1Oy thin films demonstrated excellent radiation hardness with negligible roughness, composition, electrical property, and bias-stress stability degradation after radiation exposure. The metal-oxide-semiconductor capacitors (MOSCAPs) based on Zr0.9La0.1Oy gate dielectrics exhibited an ultralow flat band-voltage (VFB) sensitivity of 0.11 mV/krad and 0.19 mV/krad under low dose and high dose gamma irradiation conditions, respectively. The low dose condition had a 103 krad (SiO2) total dose and a 0.12 rad/s low dose rate, whereas the high dose condition had a 580 krad total dose and a 278 rad/s high dose rate. Furthermore, InOx/Zr0.9La0.1Oy thin-film transistors (TFTs) exhibited a large Ion/Ioff of 2 × 106, a small subthreshold swing (SS) of 0.11 V/dec, a small interface trap density (Dit) of 1 × 1012 cm-2, and a 0.16 V threshold shift (ΔVTH) under 3600 s positive bias-stress (PBS). InOx/Zr0.9La0.1Oy TFT-based resistor-loaded inverters demonstrated complete swing behavior, a static output gain of 13.3 under 4 V VDD, and an ∼9% radiation-induced degradation. Through separate investigation of the radiation-induced degradation on the semiconductor layer and dielectric layer of TFTs, it was found that radiation exposure mainly generated oxygen vacancies (Vo) and increased electron concentration among gate oxide. Nevertheless, the radiation-induced TFT instability was mainly related to the semiconductor layer degradation, which could be possibly suppressed by back-channel passivation. The demonstrated results indicate that solution-processed ZrLaO is a high-potential candidate for large-area electronics and circuits applied in harsh radiation environments. In addition, the detailed investigation of radiation-induced degradation on solution-processed high-k dielectrics in this work provided clear inspiration for developing novel flexible rad-hard dielectrics.

Manipulation of TAMs functions to facilitate the immune therapy effects of immune checkpoint antibodies.

Immune checkpoint antibodies have emerged as novel therapeutics, while many patients are refractory. Researchers had identified tumor-associated macrophages (TAMs) is the pivotal factor involved in immune resistance and that manipulation of TAMs functions would improve the immunotherapies effectively. NF-κB pathway was one of the master regulators in TAMs manipulation. Inhibition of NF-κB pathway could achieve both re-polarization M2 TAMs and downregulation the expression of programmed cell death protein 1 (PD-1) ligand 1 (PD-L1) on TAMs to improve the effect of immunotherapies. Here, IMD-0354, inhibitor of NF-κB pathway was loaded in mannose modified lipid nanoparticles (M-IMD-LNP). Then, PD-1 antibody and M-IMD-LNP were co-loaded in matrix metalloproteinase 2 (MMP2) responsive and tumor target nanogels (P/ML-NNG). P/ML-NNG could co-deliver drugs to tumor site, disintegrated by MMP2 and release drugs to different targets. Evaluation of PD-1 expression, inhibition of NF-κB pathway, expression of PD-L1 on M2 TAMs and M2 TAMs re-polarization demonstrated that P/ML-NNG could block the PD-1/PD-L1 and NF-κB pathways simultaneously. Evaluation of CD4 + T cells, CD8 + T cells, Tregs, cytokines and antitumor immunity confirmed that IMD-0354 could improve the immunotherapies effectively. Those results provided forceful references for tumor immunetherapy.

High-Specific Isolation and Instant Observation of Circulating Tumour Cell from HCC Patients via Glypican-3 Immunomagnetic Fluorescent Nanodevice.

PURPOSE: Specific targeting receptors for efficiently capturing and applicable nanodevice for separating and instant observing of circulating tumour cells (CTC) are critical for early diagnosis of cancer. However, the existing CTC detection system based on epithelial cell adhesion molecule (EpCAM) was seriously limited by low expression and poor specificity of targeting receptors, and not instant observation in clinical application. METHODS: Herein, an alternative glypican-3 (GPC3)-based immunomagnetic fluorescent system (C6/MMSN-GPC3) for high-specific isolation and instant observation of CTC from hepatocellular carcinoma (HCC) patients' peripheral blood was developed. The high-specific HCC targeting receptor, GPC3, was employed for improving the sensitivity and accuracy in CTC detection. GPC3 monoclonal antibody (mAb) was linked to immunomagnetic mesoporous silica for specific targeting capture and separate CTC, and fluorescent molecule coumarin-6 (C6) was loaded for instant detection of CTC. RESULTS: The cell recovery (%) of C6/MMSN-GPC3 increased in 106 HL-60 cells (from 49.7% to 83.0%) and in whole blood (from 42% to 80.3%) compared with MACS® Beads. In clinical samples, the C6/MMSN-GPC3 could capture more CTC in the 13 cases of HCC patients and the capture efficiency was improved by 83.3%-350%. Meanwhile, the capture process of C6/MMSN-GPC3 was harmless, facilitating for the subsequent culture. Significantly, the C6/MMSN-GPC3 achieved the high-specific isolation and instant observation of CTC from HCC patients' blood samples, and successfully separated CTC from one patient with early stage of HCC (Stage I) and one post-surgery patient, further indicating the potential ability of C6/MMSN-GPC3 for HCC early diagnosis and prognosis evaluation. CONCLUSION: Our study provides a feasible glypican-3 (GPC3)-based immunomagnetic fluorescent system (C6/MMSN-GPC3) for high-specific isolation and instant observation of HCC CTC.

Charge and Size Dual Switchable Nanocage for Novel Triple-Interlocked Combination Therapy Pattern.

Combination therapy is a current hot topic in cancer treatment. Multiple synergistic effects elicited by combined drugs are essential in improving antitumor activity. Herein, a pH-triggered charge and size dual switchable nanocage co-loaded with abemaciclib and IMD-0354 (PA/PI-ND) is reported, exhibiting a novel triple-interlocked combination of chemotherapy, immunotherapy, and chemoimmunotherapy. The charge reversal polymer NGR-poly(ethylene glycol)-poly(l-lysine)-dimethylmaleic anhydride (NGR-PEG-PLL-DMA, ND) in PA/PI-ND promotes the pH-triggered charge reversal from negative to positive and size reduction from about 180 to 10 nm in an acidic tumor microenvironment, which greatly enhances cellular uptake and tumor tissue deep penetration. With the PA/PI-ND triple-interlocked combination therapy, the chemotherapeutic effect is enhanced by the action of abemaciclib to induce cell cycle arrest in the G1 phase, together with the reduction in cyclin D levels caused by IMD-0354. The dual anti-tumor promoting immunotherapy is achieved by abemaciclib selectively inhibiting the proliferation of regulatory T cells (Tregs) and by IMD-0354 promoting tumor-associated macrophage (TAM) repolarization from an M2 to M1 phenotype. Furthermore, PA/PI-ND has improved anti-tumor efficiency resulting from the third synergistic effect provided by chemoimmunotherapy. Taken together, PA/PI-ND is a promising strategy to guide the design of future drug delivery carriers and cancer combination therapy.

Controlled attenuation parameter for the detection of steatosis severity in chronic liver disease: a meta-analysis of diagnostic accuracy.

BACKGROUND AND AIM: Controlled attenuation parameter (CAP) is a novel ultrasound-based elastography method for detection of steatosis severity. This meta-analysis aimed to assess the performance of CAP. METHODS: PubMed, the Cochrane Library, and the Web of Knowledge were searched to find studies, published in English, relating to accuracy evaluations of CAP for detecting stage 1 (S1), stage 2 (S2), or stage 3 (S3) hepatic steatosis which was diagnosed by liver biopsy. Sensitivities, specificities, and hierarchical summary receiver operating characteristic (HSROC) curves were used to examine CAP performance. The clinical utility of CAP was also evaluated. RESULTS: Nine studies, with 11 cohorts were analyzed. The summary sensitivities and specificities values were 0.78 (95% confidence interval [CI], 0.69-0.84) and 0.79 (95% CI, 0.68-0.86) for ≥ S1, 0.85 (95% CI, 0.74-0.92) and 0.79 (95% CI, 0.71-0.85) for ≥ S2, and 0.83 (95% CI, 0.76-0.89) and 0.79 (95% CI, 0.68-0.87) for ≥ S3. The HSROCs were 0.85 (95% CI, 0.81-88) for ≥ S1, 0.88 (95% CI, 0.85-0.91) for ≥ S2, and 0.87 (95% CI, 0.84-0.90) for ≥ S3. Following a "positive" measurement (over the threshold value) for ≥ S1, ≥ S2, and ≥ S3, the corresponding post-test probabilities for the presence of steatosis (pretest probability was 50%) were 78%, 80% and 80%, respectively; if the values were below these thresholds ("negative" results), the post-test probabilities were 22%, 16%, and 17%, respectively. CONCLUSIONS: CAP has good sensitivity and specificity for detecting hepatic steatosis; however, based on a meta-analysis, CAP was limited in their accuracy of steatosis, which precluded widespread use in clinical practice.

Hepatitis B surface antigen inhibits MICA and MICB expression via induction of cellular miRNAs in hepatocellular carcinoma cells.

Hepatitis B surface antigen (HBsAg) seropositivity is an important risk factor for hepatocellular carcinoma (HCC), and HBsAg-transgenic mice have been reported to spontaneously develop HCC. The major histocompatibility complex class I-related molecules A and B (MICA and MICB) are NKG2D ligands that play important roles in tumor immune surveillance. In the present study, we found that HBsAg overexpression in HepG2 cells led to upregulation of 133 and downregulation of 9 microRNAs (miRNAs). Interestingly, several HBsAg-induced miRNAs repressed the expression of MICA and MICB via targeting their 3'-untranslated regions. In addition, the expression of MICA and MICB was significantly reduced upon HBsAg overexpression, which was partially restored by inhibiting the activities of HBsAg-induced miRNAs. Moreover, HBsAg-overexpressing HCC cells exhibited reduced sensitivity to natural killer cell-mediated cytolysis. Taken together, our data suggest that HBsAg supresses the expression of MICA and MICB via induction of cellular miRNAs, thereby preventing NKG2D-mediated elimination of HCC cells.

Performance of shear wave elastography for differentiation of benign and malignant solid breast masses.

OBJECTIVES: To perform a meta-analysis assessing the ability of shear wave elastography (SWE) to identify malignant breast masses. METHODS: PubMed, the Cochrane Library, and the ISI Web of Knowledge were searched for studies evaluating the accuracy of SWE for identifying malignant breast masses. The diagnostic accuracy of SWE was evaluated according to sensitivity, specificity, and hierarchical summary receiver operating characteristic (HSROC) curves. An analysis was also performed according to the SWE mode used: supersonic shear imaging (SSI) and the acoustic radiation force impulse (ARFI) technique. The clinical utility of SWE for identifying malignant breast masses was evaluated using analysis of Fagan plot. RESULTS: A total of 9 studies, including 1888 women and 2000 breast masses, were analyzed. Summary sensitivities and specificities were 0.91 (95% confidence interval [CI], 0.88-0.94) and 0.82 (95% CI, 0.75-0.87) by SSI and 0.89 (95% CI, 0.81-0.94) and 0.91 (95% CI, 0.84-0.95) by ARFI, respectively. The HSROCs for SSI and ARFI were 0.92 (95% CI, 0.90-0.94) and 0.96 (95% CI, 0.93-0.97), respectively. SSI and ARFI were both very informative, with probabilities of 83% and 91%, respectively, for correctly differentiating between benign and malignant breast masses following a "positive" measurement (over the threshold value) and probabilities of disease as low as 10% and 11%, respectively, following a "negative" measurement (below the threshold value) when the pre-test probability was 50%. CONCLUSIONS: SWE could be used as a good identification tool for the classification of breast masses.

Meta-analysis of the association between a polymorphism in microRNA-196a2 and susceptibility to colorectal cancer.

BACKGROUND/AIMS: To accurately evaluate the impact of the C/T polymorphism in microRNA (miRNA)-196a2 on the colorectal cancer (CRC) risk, by meta-analysis. METHODS: An electronic search for articles was conducted in PubMed, EMBASE, ISI Web of Science, and the Cochrane Library. The pooled odds ratio (OR) and its 95% confidence interval (CI) were used to assess the association through meta-analysis. RESULTS: 5 studies were used for analysis. The results showed a significant association between the miRNA-196a2 C/T polymorphism and CRC risk in the genetic models (C vs. T: OR = 1.168, 95% CI = 1.106-1.282, p = 0.001; CC vs. TT: OR = 1.368, 95% CI = 1.132-1.654, p = 0.001; TC/CC vs. TT: OR = 1.206, 95% = CI 1.035-1.405, p = 0.016; CC vs. TC/TT: OR = 1.254, 95% CI = 1.077-1.461, p = 0.004), with the exception of the TC-versus-TT model (TC vs. TT: OR = 1.130, 95% CI = 0.961-1.329, p = 0.138). In a subgroup analysis based on ethnicity, we identified a significant overrepresentation of the polymorphism in individuals of Asian ethnicity. CONCLUSION: This meta-analysis indicates a significant association between the miRNA-196a2 polymorphism and CRC risk.