An engineered IL-21 with half-life extension enhances anti-tumor immunity as a monotherapy or in combination with PD-1 or TIGIT blockade.

Interleukin-21 (IL-21) has exhibited anti-tumor activity in preclinical and clinical studies; however, its modest efficacy and short half-time has limited its therapeutic utility as a monotherapy. Therefore, we engineered a fusion protein (IL-21-αHSA) in which a nanobody targeting human serum albumin (HSA) was fused to the C-terminus of rhIL-21. The αHSA nanobody displayed broad species cross-reactivity and bound to a HSA epitope that does not overlap with the FcRn binding site, thus providing a strategic design for half-life extension. The IL-21-αHSA fusion protein showed increased stability compared to rhIL-21, while retaining its bioactivity in a liquid solution for at least 6 months. Moreover, IL-21-αHSA showed a dramatically extended half-life and prolonged exposure in cynomolgus monkeys, with the t1/2 and AUC nearly 10 and 50 times greater than that of rhIL-21, respectively. Furthermore, IL-21-αHSA displayed enhanced anti-tumor efficacy in two syngeneic mouse models. Notably, IL-21-αHSA increased the anti-tumor effect of programmed cell death protein 1 (PD-1) and T cell immunoglobulin and ITIM domain (TIGIT) blockades when used in combination, with a protection against tumor rechallenge, suggesting the formation of long-term anti-tumor memory response. KEGG analysis identified significantly enriched pathways associated with anti-tumor immune response, with increased expression of genes associated with CD8+ T and NK cell cytotoxicity. Overall, these data support further clinical evaluation of IL-21-αHSA as a monotherapy or in combination with immune checkpoint blockades.

Epigenetic regulation of putative tumor suppressor TGFBI in human leukemias.

BACKGROUND: Both in vitro and in vivo data have demonstrated the TGFBI gene functions as a putative tumor suppressor and is frequently downregulated in human tumors of different histological types. The hypermethylation of the TGFBI promoter, as one of the main regulatory mechanisms, is associated with TGFBI silencing. In this study, we used a methylation-specific PCR (MSP) method to evaluate the methylation status of the TGFBI promoter in human leukemias. METHODS: Real-time RT-PCR and methylation-specific PCR approaches were performed to define the TGFBI expression and promoter methylation in human leukemia cell lines and clinical samples. Genomic DNA was isolated from peripheral blood mononuclear cells from leukemia patients, bisulfite-converted, and analyzed by the MSP method. RESULTS: Hypermethylation of the TGFBI promoter occurred in leukemia cell lines and demethylation treatment reexpressed TGFBI at a substantially increased level in most of leukemia cell lines tested. Furthermore, a much higher level of CpG island methylation and a significantly lower TGFBI expression were also identified in clinical leukemia samples. CONCLUSION: The results suggest an important role of promoter methylation in regulating TGFBI expression in leukemia, which provides a useful diagnostic marker for clinical management of human leukemias.

[Endoscopic ligation in treatment of advanced schistosomiasis patients with esophageal variceal bleeding: a report of 68 cases].

OBJECTIVE: To evaluate the therapeutic effect of endoscopic ligation in the treatment of advanced schistosomiasis patients with esophageal variceal bleeding. METHODS: A total of 130 advanced schistosomiasis patients with esophageal varices rupture and bleeding were divided into a ligation group (68 cases) and a control group (64 cases), and the patients of ligation group were treated with the emergency endoscopic ligation, and the patients of control group received the routine therapy. The rebleeding rate, hemostatic success rate, and varicose veins red color sign were observed. RESULTS: In the ligation group, the rebleeding rate was 10.3% and the positive rate of varicose veins red color sign was 8.8%, which were better than those in the control group (both P values <0.01). CONCLUSION: Endoscopic ligation is an effective therapy for esophageal variceal bleeding.

Genetic algorithms for route discovery.

Packet routing in networks requires knowledge about available paths, which can be either acquired dynamically while the traffic is being forwarded, or statically (in advance) based on prior information of a network's topology. This paper describes an experimental investigation of path discovery using genetic algorithms (GAs). We start with the quality-of-service (QoS)-driven routing protocol called "cognitive packet network" (CPN), which uses smart packets (SPs) to dynamically select routes in a distributed autonomic manner based on a user's QoS requirements. We extend it by introducing a GA at the source routers, which modifies and filters the paths discovered by the CPN. The GA can combine the paths that were previously discovered to create new untested but valid source-to-destination paths, which are then selected on the basis of their "fitness." We present an implementation of this approach, where the GA runs in background mode so as not to overload the ingress routers. Measurements conducted on a network test bed indicate that when the background-traffic load of the network is light to medium, the GA can result in improved QoS. When the background-traffic load is high, it appears that the use of the GA may be detrimental to the QoS experienced by users as compared to CPN routing because the GA uses less timely state information in its decision making.