Yi Xiao

Antigen-escape relapse has emerged as a major challenge for long-term disease control after CD19-directed therapies, to which dual-targeting of CD19 and CD22 has been proposed as a potential solution. From March 2016 through January 2018, we conducted a pilot study in 89 patients who had refractory/relapsed B-cell malignancies, to evaluate the efficacy and safety of sequential infusion of anti-CD19 and anti-CD22, a cocktail of 2 single-specific, third-generation chimeric antigen receptor-engineered (CAR19/22) T cells. Among the 51 patients with acute lymphoblastic leukemia, the minimal residual disease-negative response rate was 96.0% (95% confidence interval [CI], 86.3-99.5). With a median follow-up of 16.7 months (range, 1.3-33.3), the median progression-free survival (PFS) was 13.6 months (95% CI, 6.5 to not reached [NR]), and the median overall survival (OS) was 31.0 months (95% CI, 10.6-NR). Among the 38 patients with non-Hodgkin lymphoma, the overall response rate was 72.2% (95% CI, 54.8-85.8), with a complete response rate of 50.0% (95% CI, 32.9-67.1). With a median follow-up of 14.4 months (range, 0.4-27.4), the median PFS was 9.9 months (95% CI, 3.3-NR), and the median OS was 18.0 months (95% CI, 6.1-NR). Antigen-loss relapse occurred in 1 patient during follow-up. High-grade cytokine release syndrome and neurotoxicity occurred in 22.4% and 1.12% patients, respectively. In all except 1, these effects were reversible. Our results indicated that sequential infusion of CAR19/22 T cell was safe and efficacious and may have reduced the rate of antigen-escape relapse in B-cell malignancies. This trial was registered at www.chictr.org.cn as #ChiCTR-OPN-16008526.

Currently, a variety of elastomers with a self-healing capacity and reprocessability have been developed by dynamic chemistry to extend the service life, increase the reliability of polymeric materials, and reduce the waste. However, it is still a large challenge to seek an appropriate dynamic interaction that may perfectly match the general performance of the target polymeric materials such as polyurethane. Herein, we report a poly(thiourethane-urethane) (PTUU–Nx) elastomer containing dynamic thiourethane bonds prepared via a thiol–isocyanate click reaction, which is stable at room temperature, healable at moderate temperature, and reprocessable at high temperature. Importantly, it exhibits a mechanical strength similar to the polyurethane because of a very similar structure. The dynamic feature of PTUU–Nx is demonstrated theoretically and experimentally to originate from the exchange of thiourethane bonds via the reversible generation of isocyanates and thiols. Most importantly, the thiourethane bond possesses a much lower bond dissociation energy than the urethane bond, which not only makes PTUU–Nx elastomers easier to be reprocessed but also endows them with a desirable self-healing ability under moderate conditions. In addition, the optimized sample PTUU–N2 is utilized to fabricate a conductive device by coating Ag glue on the elastomer surface and inserting the coated elastomer into a circuit, which displays a high self-healing efficiency, as the material recovers to its original mechanical property and conductivity. Therefore, these results not only indicate that the PTUU–Nx elastomers have considerable potential for applications in intelligent electronic devices but also provide new ideas for developing new self-healing materials by applying the adaptable dynamic bond to the target polymers.

Myocardial infarction (MI) is the leading cause of morbidity and mortality in the world. The infarcted heart displays typical cell death cascades characterized by a loss of cells and fibrotic scarring in the myocardium. Cardiac hypertrophy and fibrosis largely contribute to ventricular wall thickening and stiffening, altogether defining an adverse cardiac remodeling that ultimately leads to impaired cardiac function and subsequent heart failure. Finding a strategy to promote therapeutic, instead of detrimental, cardiac remodeling may pose as a potent MI treatment. Accumulating evidence shows that microRNAs (miRNAs) may play an essential role in cardiovascular diseases. In particular, microRNA-133a (miR-133a) is one of the most abundant miRNAs in the heart. Multiple studies have demonstrated that miR-133a participates in the early pathology of MI, as well as in subsequent cardiac remodeling. In this review, we summarize recent research progress highlighting the regulatory effects of miR-133a in ischemic myocardial diseases, such as inhibiting angiogenesis, apoptosis, fibrosis, hypertrophy, and inflammation, while promoting therapeutic cardiac remodeling. The goal is to elicit a critical discussion on the translational direction of miRNA-mediated treatments towards a safe and effective MI therapy.

BACKGROUND: We conducted a systematic review and meta-analysis to clarify the incidence and risk of cardiotoxicity associated with bortezomib in cancer patients. METHODS: Databases from PubMed, Web of Science and abstracts presented at ASCO meeting up to July 31, 2013 were searched to identify relevant studies. Eligible studies included prospective phase II and III trials evaluating bortezomib in cancer patients with adequate data on cardiotoxicity. Statistical analyses were conducted to calculate the summary incidence, odds ratio (OR) and 95% confidence intervals (CIs) by using either random effects or fixed effect models according to the heterogeneity of included studies. RESULTS: A total of 5718 patients with a variety of malignancies from 25 clinical trials were included in our analysis. The incidence of all-grade and high-grade cardiotoxicity associated with bortezomib was 3.8% (95%CI: 2.6-5.6%) and 2.3% (1.6-3.5%), with a mortality of 3.0% (1.4-6.5%). Patients treated with bortezomib did not significantly increase the risk of all-grade (OR 1.15, 95%CI: 0.82-1.62, p=0.41) and high-grade (OR 1.13, 95%CI: 0.58-2.24, p=0.72) cardiotoxicity compared with patients treated with control medication. Sub-group analysis showed that the incidence of cardiotoxicity varied with tumor types, treatment regimens and phases of trials. No evidence of publication bias was observed. CONCLUSIONS: The use of bortezomib does not significantly increase the risk of cardiotoxicity compared to control patients. Further studies are recommended to investigate this association and risk differences among different tumor types, treatment regimens and phases of trials.