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The combination of checkpoint blockade with focused ultrasound (FUS) physical therapy can enhance antitumor immune response by improving the precision and efficiency of immunotherapy. However, one of the major disadvantages of conventional FUS treatment is the small lesion size, which prolongs treatment duration. We constructed a focused acoustic vortex (FAV) system with a hollow cylindrical focal region, which exhibited a larger focal region compared to conventional FUS of the same frequency. We developed an all-in-one synergistic therapy against metastatic breast cancer based on integrated FAV double combination sequence-regulated phase-transformation nanodroplets (CPDA@PFH) with checkpoint blockade immunotherapy. A single treatment with FAV + CPDA@PFH resulted in 2.25-fold higher inhibition of tumor growth compared to that with FUS + CPDA@PFH. In addition, FAV-regulated CPDA@PFH combined with ICB induced a systemic immune response that not only inhibited the growth of primary (98.41% inhibition rate) and distal (80.71%) 4T1 tumors but also reduced the progression of lung metastasis. In addition, the synergistic therapy achieved long-term immune memory that effectively prevented tumor growth and improved the survival time of mice. The long-term survival rate of 4T1 tumor-bearing mice treated with FAV + CPDA@PFH + Anti-PD-L1 was 57.14% on day 60 after treatment. Our study is a proof-of-concept of cascade-amplified synergistic tumor therapeutics based on ultrasonic-hyperthermia, cavitation, sonodynamic therapy (SDT), and checkpoint blockade immunotherapy through FAV-regulated CPDA@PFH phase-transformation nanodroplets.

The design of a biomimetic sonosensitizer, opening the blood–brain barrier by focused ultrasound and synergistic therapy via noninvasive sonodynamic therapy and ferroptosis.

The dCas9-based CRISPR interference (CRISPRi) system efficiently silences genes without causing detectable off-target activity, thus showing great potential for the treatment of cancer at the transcriptional level. However, due to the large size of the commonly used CRISPRi system, effective delivery of the system has been a challenge that hinders its application in the clinic. Herein, a combination of pH-responsive lipid-polymer hybrid nanoparticles (PLPNs) and ultrasound-mediated microbubble destruction (UMMD) is used for the delivery of the CRISPRi system. The core-shell structure of PLPNs can effectively be loaded with the CRISPRi plasmid, increases the time spent in the circulating in vivo, and "actively target" cancer cells. Moreover, the combination of PLPNs with UMMD achieves a higher cellular uptake of the CRISPRi plasmid in vitro and retention in vivo. Furthermore, when PLPNs loaded with a CRISPRi plasmid that targets microRNA-10b (miR-10b) are used in combination with UMMD, it results in the effective repression of miR-10b in breast cancer, simultaneous disturbance of multiple cell migration and invasion-related signaling pathways, and a significant inhibition of lung metastasis. Thus, the established system presents a versatile, highly efficient, and safe strategy for delivery of the CRISPRi system both in vitro and in vivo. This article is protected by copyright. All rights reserved.

Ti-3.5Al-3.5V-0.5Fe-0.6Mo-0.5Cr alloy is a new superplastic titanium alloy The alloy was deformed by plane strain compression at 820°C~880°C, 0.16 s−1~8 s−1, which can provide reference for obtaining homogeneous microstructure during the rolling process. The results show that the flow stress of the alloy has a negative correlation with the deformation temperature and a positive correlation with the strain rate. The flow softening behavior of alloy is greatly influenced by deformation temperature. The fraction and the length of α lamellar increase with the decrease of temperature, and the flow-softening phenomenon of the alloy is more obvious. The homogeneity of microstructure and the recrystallization ratio of α lamellae increase with the increase of deformation temperature and the decrease of strain rate. The alloy can obtain homogeneous microstructure at 850°C, 0.16 s−1, and 880°C, 0.16 s−1~1.6 s−1 deformation conditions.

The Marine Insurance Act 2015 (UK) marked the start of a contemporary period for insurance law because the Act improved the regime for the duty of good faith by transitioning to the duty of fair presentation from traditional doctrines of utmost good faith in the Marine Insurance Act 1906 in the UK. While the obligation of utmost good faith made up the firm cornerstone of insurance law in the past, it has not been an extensive and all-encompassing duty because the nature of uberrimae fidei in insurance contracts has already changed lately. This essay introduces briefly the evolution of uberrimae fidei in marine insurance law and analyses the nature and its dilemma. By comparing the relationship between good faith and the utmost good faith, upon further analysis, the reason why the obligation needs current reform is the downturn of international trade from the macro-level perspective. Moreover, from the micro-level perspective, legal requirements between the subjective state of the insured and the duty of the “fair presentation” are radically different. All in all, though the utmost good faith laid a solid foundation on insurance law, the “fair presentation” in the 2015 Act is more obviously applicable to counterpoise the benefits of the insurer and the insured, which is regarded as insurance relationships’ fresh core. Therefore, nowadays this reform is a success on a fair and reasonable legal basis, and it reduces insurance obligations of the insured traditionally to boost the prosperity of the marine insurance business currently.

The visualization of the treatment process in situ could facilitate to accurately monitor cancer photothermal therapy (PTT), and dramatically decrease the risk of thermal damage to normal cells and tissues, which represents a major challenge for cancer precision therapy. Herein, we prepare theranostic nanoprobes (NPs) for Forster resonance energy transfer (FRET)-based dual-modal imaging-guided cancer PTT, and clear visualization of the therapeutic process. The FRET-based theranostic NPs exhibit high FRET efficiency (88.2%), good colloidal stability, and tumor-targeting ability. Tumor tissue and surrounding blood vessels are visualized clearly by FRET-based NIR fluorescence imaging with a high signal-to-background ratio (14.5) and photoacoustic imaging with an excellent resolution at 24 h post injection of NPs. Under the guidance of dual-modal imaging, the NPs-induced photothermal effect selectively destructs cancer cells, simultaneously decreasing the FRET efficiency and leading to fluorescence and photoacoustic signal changes. The sensitive self-feedback process enables the in situ visualization of therapeutic process and precision guidance of in vivo cancer PTT. A high therapeutic efficacy and minimum side effects are achieved in C6 tumor-bearing nude mice, holding great promise for precision therapy and cancer theranostics.

Liposome nanomedicine has been successfully applied for cancer chemotherapy in patients. However, in general, the therapeutic efficacy is confined by its limited accumulation and penetration in solid tumors. Here, we established a biomimetic strategy for the preparation of highly penetrative liposome nanomedicine for enhanced chemotherapeutic efficacy. By applying this unique type of nanomedicine, membrane proteins on the cancer cells are used as highly penetrative targeting ligands. Biomimetic liposomes are highly stable, exhibiting a superior in vitro homologous targeting ability, and a 2.25-fold deeper penetration in 3D tumor spheroids when compared to conventional liposome nanomedicine. The fluorescence/photoacoustic dual-modal imaging approach demonstrated enhanced tumor accumulation and improved tumor penetration of the biomimetic liposome in C6 glioma tumor-bearing nude mice. Following the intravenous administration of biomimetic liposome nanomedicine, the tumor inhibition rate reached up to 93.3%, which was significantly higher when compared to that of conventional liposome nanomedicine (69.3%). Moreover, histopathological analyses demonstrated that biomimetic liposome nanomedicine has limited side effects. Therefore, these results suggested that a cancer cell membrane-based biomimetic strategy may provide a breakthrough approach for enhancing drug penetration and improving treatment efficacy, holding a great promise for further clinical studies.

Active-targeted cancer imaging and therapy of glioma has attracted much attention in theranostic nanomedicine. As a promising tumor-targeting ligand, holo-transferrin (holo-Tf) has been applied for enhancing delivery of nanotheranostics. However, holo-Tf-based nanoassemblies for active targeting mediated multimodal imaging and therapeutics have not been previously reported. Here, we develop a one-step method for the preparation of holo-Tf-indocyanine green (holo-Tf-ICG) nanoassemblies for fluorescence (FL) and photoacoustic (PA) dual-modal imaging and photothermal therapy (PTT) of glioma. The nanoassemblies are formed by hydrophobic interaction and hydrogen bonds between holo-Tf and ICG, which exhibit excellent active tumor-targeting and high biocompability. The brain tumor with highly expressed Tf receptor can be clearly observed with holo-Tf-ICG nanoassemblies base on FL and PA dual-modal imaging in subcutaneous and orthotopic glioma models. Under the near-infrared laser irradiation, the holo-Tf-ICG nanoassemblies accumulated in tumor regions can efficiently convert laser energy into hyperthermia for tumor ablation. The novel theranostic nanoplatform holds great promise for precision diagnosis and treatment of glioma.

Correction for ‘Highly penetrative liposome nanomedicine generated by a biomimetic strategy for enhanced cancer chemotherapy’ by Yali Jia et al., Biomater. Sci., 2018, 6, 1546–1555, DOI: 10.1039/C8BM00256H.

The visualization of the treatment process in situ could facilitate to accurately monitor cancer photothermal therapy (PTT), and dramatically decrease the risk of thermal damage to normal cells and tissues, which represents a major challenge for cancer precision therapy. Herein, we prepare theranostic nanoprobes (NPs) for Förster resonance energy transfer (FRET)-based dual-modal imaging-guided cancer PTT, and clear visualization of the therapeutic process. The FRET-based theranostic NPs exhibit high FRET efficiency (88.2%), good colloidal stability, and tumor-targeting ability. Tumor tissue and surrounding blood vessels are visualized clearly by FRET-based NIR fluorescence imaging with a high signal-to-background ratio (14.5) and photoacoustic imaging with an excellent resolution at 24 h post injection of NPs. Under the guidance of dual-modal imaging, the NPs-induced photothermal effect selectively destructs cancer cells, simultaneously decreasing the FRET efficiency and leading to fluorescence and photoacoustic signal changes. The sensitive self-feedback process enables the in situ visualization of therapeutic process and precision guidance of in vivo cancer PTT. A high therapeutic efficacy and minimum side effects are achieved in C6 tumor-bearing nude mice, holding great promise for precision therapy and cancer theranostics.

MicroRNA-148a (miR-148a) has been reported to be deregulated in different tumor types, whereas the biological function of miR-148a in renal cell carcinoma (RCC) largely remains unexplored. In the present study we investigated the clinical significance, biological effects, and the underlying molecular mechanisms of miR-148 in RCC. Here, we showed that miR-148a was significantly downregulated in RCC tissues and cell lines. Low expression of miR-148a in RCC tissues was associated with large tumor size, advanced TNM stage, and lymph node metastasis. Functional assays revealed that overexpression of miR-148a significantly inhibited RCC cell proliferation, colony formation, migration and invasion in vitro and suppressed RCC xenograft tumor growth in vivo. In addition, using quantitative RT-PCR (qRT-PCR), western blot analysis and luciferase reporter assays, AKT2 was confirmed to be a direct target of miR-148a. AKT2 expression was upregulated, and was negatively correlated with miR-148a expression in RCC tissues (r=-0.641, P

Cement slurry and cement-water glass slurry are the most widely applied for soil grouting reinforcement project. The viscosity change of cement slurry is negligible during grouting period and presumed to be time-independent while the viscosity of cement-water glass slurry increases with time quickly and is presumed to be time-dependent. Due to the significantly rheology differences between them, the grouting quality and the increasing characteristics of grouting parameters may be different, such as grouting pressure, grouting surrounding rock pressure, i.e., the change of surrounding rock pressure deduced by grouting pressure. Those are main factors for grouting design. In this paper, a large-scale 3D grouting simulation device was developed to simulate the surrounding curtain grouting for a tunnel. Two series of surrounding curtain grouting experiments under different geo-stress of 100 kPa, 150 kPa and 200 kPa were performed. The overload test on tunnel was performed to evaluate grouting effect of all surrounding curtain grouting experiments. In the present results, before 240 seconds, the grouting pressure increases slowly for both slurries; after 240 seconds the increase rate of grouting pressure for cement-water glass slurry increases quickly while that for cement slurry remains roughly constant. The increasing trend of grouting pressure for cement-water glass is similar to its viscosity. The setting time of cement-water glass slurry obtained from laboratory test is less than that in practical grouting where grout slurry solidifies in soil. The grouting effect of cement-water glass slurry is better than that of cement slurry and the grouting quality decreases with initial pressure.