Recent innovations in nanomaterials inspire abundant novel tumor-targeting CRISPR-based gene therapies. However, the therapeutic efficiency of traditional targeted nanotherapeutic strategies is limited by that the biomarkers vary in a spatiotemporal-dependent manner with tumor progression. Here, we propose a self-amplifying logic-gated gene editing strategy for gene/H₂O₂-mediated/starvation multimodal cancer therapy. In this approach, a hypoxia-degradable covalent-organic framework (COF) is synthesized to coat a-ZIF-8 in which glucose oxidase (GOx) and CRISPR system are packaged. To intensify intracellular redox dyshomeostasis, DNAzymes which can cleave catalase mRNA are loaded as well. When the nanosystem gets into the tumor, the weakly acidic and hypoxic microenvironment degrades the ZIF-8@COF to activate GOx, which amplifies intracellular H⁺ and hypoxia, accelerating the nanocarrier degradation to guarantee available CRISPR plasmid and GOx release in target cells. These tandem reactions deplete glucose and oxygen, leading to logic-gated-triggered gene editing as well as synergistic gene/H₂O₂-mediated/starvation therapy. Overall, this approach highlights the biocomputing-based CRISPR delivery and underscores the great potential of precise cancer therapy.

[This corrects the article DOI: 10.1016/j.apsb.2022.06.016.].

New drug discovery is under growing pressure to satisfy the demand from a wide range of domains, especially from the pharmaceutical industry and healthcare services. Assessment of drug efficacy and safety prior to human clinical trials is a crucial part of drug development, which deserves greater emphasis to reduce the cost and time in drug discovery. Recent advances in microfabrication and tissue engineering have given rise to organ-on-a-chip, an in vitro model capable of recapitulating human organ functions in vivo and providing insight into disease pathophysiology, which offers a potential alternative to animal models for more efficient pre-clinical screening of drug candidates. In this review, we first give a snapshot of general considerations for organ-on-a-chip device design. Then, we comprehensively review the recent advances in organ-on-a-chip for drug screening. Finally, we summarize some key challenges of the progress in this field and discuss future prospects of organ-on-a-chip development. Overall, this review highlights the new avenue that organ-on-a-chip opens for drug development, therapeutic innovation, and precision medicine.

Objective:To investigate the safety and dose of 4D template (real-time adjustable angle template) in the treatment of advanced malignant tumors with 125I seeds. Methods:98 patients with advanced malignant tumors admitted to Department of Thoracic Surgery of Shaanxi Provincial Tumor Hospital were treated with 4D template-navigated radioactive 125I seed implantation from June 2018 to December 2019. Preoperative TPS plan, intraoperative optimization, postoperative verification of immediate dose and postoperative evaluation of implantation dose were performed. The treatment results were observed. Results:All 98 patients completed the seed implantation. The implantation dose of GTV of implantation site receiving external irradiation was (12 489±414) cGy and the dose of no external irradiation was (15 036±514) cGy. V 100% was 84.7%-94.1%, and 88.2%-93.7%. The implantation dose of CTV was (7 450±621) cGy, and (9 080±761) cGy. The quality of dose implantation was evaluated as: excellent in 89 cases (91%, 89/98), good in 7 cases (7%, 7/98), fair in 2 cases (2%, 2/98), and poor in 0 case, respectively. The symptom relief rate of patients with pain was 92%(36/39). The 1-and 2-year local control rates were 61%, 36% and 82%, 54% in patients treated with and without external irradiation, respectively. The difference was statistically significant ( P=0.02). The incidence rates of pneumothorax and hemoptysis were 19%(9/48) and 10%(5/48). No corresponding complications were observed in other parts of the patients. Conclusion:4D template-assisted 125I seed therapy is safe and effective for malignant tumors, and intraoperative adjustment of needle angle and dose optimization can realize the precise control of implantation dose.

Objective:To provide a new morning check method for the output dose stability of the multileaf collimator (MLC) of the CyberKnife M6 (CK-M6) system.Methods:The CT images of a verification phantom with a size of 20 cm × 20 cm × 10 cm were transmitted into the Precision Treatment Plan ning System (ver. 1.1.1.1). The high-precision alignment between the accelerator output front and the fixed position of the phantom surface was achieved using the fiducial tracking method. A 10 cm × 10 cm radiation field was formed by the MLC and a DailyCheck plan with an output of 200 MU was designed. The repeatability, sensitivity, and accuracy of the DailyCheck plan were measured, and the CK-M6 system was continuously tested for one month using the artificial fixed method and the DailyCheck plan designed in this study. Results:The average and the standard deviation of 10 repeated measurements by the DailyCheck plan were 492.28 pC and 0.09, respectively, indicating good stability. There was a linear correlation between the measured values and the output dose, with a correlation coefficient of R2 > 0.999. Moreover, there was a position deviation of 2 mm between the phantom and the accelerator output front, and the result ant effect on the measured values was equivalent to a dose deviation caused by an output of 1.24 MU. The result from the continuous measurement of both the artificial fixed method and the DailyCheck plan fell within permissible limits, showing high consistency. Conclusions:The DailyCheck plan established through the fiducial tracking of a verification phantom can achieve the convenient, quick, and accurate daily detection of the output dose stability of the MLC of CK-M6. Therefore, this method can be widely applied in the clinical quality control of the CK-M6 system.

Near-infrared (NIR)-light-triggered nanomedicine, including photodynamic therapy (PDT) and photothermal therapy (PTT), is growing an attractive approach for cancer therapy due to its high spatiotemporal controllability and minimal invasion, but the tumor eradication is limited by the intrinsic anti-stress response of tumor cells. Herein, we fabricate a tumor-microenvironment responsive CRISPR nanoplatform based on oxygen-deficient titania (TiO_2-x ) for mild NIR-phototherapy. In tumor microenvironment, the overexpressed hyaluronidase (HAase) and glutathione (GSH) can readily destroy hyaluronic acid (HA) and disulfide bond and releases the Cas9/sgRNA from TiO_2-x to target the stress alleviating regulators, i.e., nuclear factor E2-related factor 2 (NRF2) and heat shock protein 90α (HSP90α), thereby reducing the stress tolerance of tumor cells. Under subsequent NIR light illumination, the TiO_2-x demonstrates a higher anticancer effect both in vitro and in vivo. This strategy not only provides a promising modality to kills cancer cells in a minimal side-effects manner by interrupting anti-stress pathways but also proposes a general approach to achieve controllable gene editing in tumor region without unwanted genetic mutation in normal environments.

Stereotactic body radiation therapy (SBRT) is a high-precision radiotherapy technology that provides high-dose and high-precision radiotherapy through less fractional irradiation. SBRT can significantly improve local control and survival rates in patients with hepatocellular carcinoma (HCC). SBRT can also be an effective and safe bridging therapy for patients awaiting liver transplantation. Moreover, recent studies have reported the potential effects of the combination of SBRT and immune checkpoint inhibitors. This article reviews the safety and efficacy of SBRT in the treatment of HCC, in anticipation of the future application of SBRT in combination with immunotherapy.

Objective To evaluate the safety and effectiveness of ultra-hypofractionated stereotactic body radiotherapy in the treatment of prostate cancer.Methods A total of 26 patients with prostate cancer treated with Cyber-Knife from May 2010 to May 2018 were analyzed retrospectively.The median age of the patients was 69 years old (range,57 to 87).Ultra-hypofractionated radiotherapy was delivered in five fractions of 7.0-7.5 Gy for a total dose of 35.0-37.5 Gy.Androgen deprivation therapy (ADT) was administered in combination with the Cyber-Knife.The primary endpoints were radiation toxicity,PSA-response,local control and symptom alleviation,while the secondary endpoints were progression-free survival and overall survival.Results No graded ≥ 3 acute and late radiation toxicities occurred during follow-up.The acute toxicity of Grades 1 and 2 was 38.4％ and 19.2％,while the late toxicity of Grades 1 and 2 was 30.8％ and 3.8％,respectively.At a median follow-up of 22.44 months,for patients with localized stage,PSA level was decreased significantly after radiotherapy (Z =2.900,2.794,2.510,2.090,P＜0.05).However,there was no statistically significant difference for the metastatic group (P＞ 0.05).Conclusions Ultra-hypofractionated stereotactic body radiotherapy is a safe and effective treatment for patients with prostate cancer.

Objective: To compare the dosimetrics of the plan target volume (PTV) and organs at risk (OARs) between two treatment planning approaches for patients with multiple brain metastases from non-small cell lung cancer on CyberKnife. Methods: 20 patients with multiple metastases from lung carcinoma were reviewed and analyzed, who had been treated by CyberKnife from December 2017 to December 2018. The CyberKnife stereotactic radiotherapy plans of the 20 cases were re-planed with single plan for multiple lesions and multiple plans per lesion. The dosimetry differences of PTV and OARs isodose disribution, conformity index (CI), total beam counts and total monitor units (MUs) were compared in the two types of plans. Results: The two types of plans could satisfy over 95% PTV coverage of the prescription dose. The maximum and mean dose of normal brain adjacent to the PTV were reduced in multiple plan approach effectively. Moreover, the maximum and mean dose of OARs (brainstem) dropped by 1.62% and 5.57% (t=1.09, P<0.01) respectively. The number of treatment nodes and total MU declined by 4.63% (t=1.87, P<0.01)and 1.06% in multiple plan approach, which could significantly shorten the clinical treatment time. The differences in CI index between these two types of plans was of no statistical significance. Conclusions For patients with multiple brain metastases of similar diameter and volume from non-small cell lung cancer to be treated on CyberKnife, multiple plans per lesion could not only reduce dose to normal brain tissue and OARs, but also improve the treatment efficiency.

We aimed to obtain the recombinant aminopeptidase encoded by Listeria monocytogenes (L. monocytogenes) gene lmo1711, and characterized the enzyme. First, the amino acid sequences of Lmo1711 from L. monocytogenes EGD-e and its homologues in other microbial species were aligned and the putative active sites were analyzed. The putative model of Lmo1711 was constructed through the SWISS-MODEL Workspace. Then, the plasmid pET30a-Lmo1711 was constructed and transformed into E. coli for expression of the recombinant Lmo1711. The his-tagged soluble protein was purified using the nickel-chelated affinity column chromatography. With the amino acid-p-nitroaniline as the substrate, Lmo1711 hydrolyzed the substrate to free p-nitroaniline monomers, whose absorbance measured at 405 nm reflected the aminopeptidase activity. The specificity of Lmo1711 to substrates was then examined by changing various substrates, and the effect of metal ions on the catalytic efficiency of this enzyme was further determined. Based on the bioinformatics data, Lmo1711 is a member of the M29 family aminopeptidases, containing a highly conserved catalytic motif (Glu-Glu-His-Tyr-His-Asp) with typical structure arrangements of the peptidase family. The recombinant Lmo1711 with a size of about 49.3 kDa exhibited aminopeptidase activity and had a selectivity to the substrates, with the highest degree of affinity for leucine-p-nitroaniline. Interestingly, the enzymatic activity of Lmo1711 can be activated by Cd²⁺, Zn²⁺, and is strongly stimulated by Co²⁺. We here, for the first time demonstrate that L. monocytogenes lmo1711 encodes a cobalt-activated aminopeptidase of M29 family.