A novel dual mechanism-of-action bispecific PD-1-IL-2v armed by a "ßγ-only" interleukin-2 variant.

Introduction: Interleukin-2 (IL-2) is one of the first cytokines to be discovered as an immune agonist for cancer immunotherapy. Biased IL-2 variants had been discovered to eliminate Treg activation or enhance the tumor specific T cell cytotoxicity. However, all the biased IL-2 variants pose the risk to overstimulate immune response at a low-dose range. Here, we introduce a novel dual-MOA bispecific PD-1-IL-2v molecule with great anti-tumor efficacy in a high dosed manner. Methods: The novel IL-2 variant was designed by structural truncation and shuffling. The single armed bispecific PD-1-IL-2v molecule and IL-2v were studied by immune cell activations in vitro and in vivo and anti-tumor efficacy in mouse model. Results and discussion: The IL-2 variant in this bispecific antibody only binds to IL-2Rßγ complex in a fast-on/off manner without α, ß or γ single receptor binding. This IL-2v mildly activates T and NK cells without over stimulation, meanwhile it diminishes Treg activation compared to the wild type IL-2. This unique bispecific molecule with "ßγ-only" IL-2v can not only "in-cis" stimulate and expand CD8 T and NK cells moderately without Treg activation, but also block the PD-1/L1 interaction at a similar dose range with monoclonal antibody.

Do radioiodine-avid lymph nodes from differentiated thyroid cancer on the initial posttherapy scan need repeated 131I therapy?

Background: Residual/recurrent lymph node metastase (LNM) is often found after differentiated thyroid cancer (DTC) surgery. This study aimed to investigate whether patients complicated with radioiodine-avid (131I+) lymph nodes from DTC on the initial posttherapy scan (PTS) need repeated 131I therapy. Methods: From June 2013 to August 2022, DTC patients with 131I+ lymph nodes on the initial PTS who received at least two cycles of 131I therapy were retrospectively enrolled. They were divided into a complete response (CR) group and an incomplete response (IR) group according to their response to the initial 131I therapy based on the 2015 American Thyroid Association (ATA) guidelines. Results: A total of 170 DTC patients with 131I+ lymph nodes on the initial PTS were included; 42/170 (24.7%) patients were classified into the CR group and 128/170 (75.9%) were classified into the IR group according to their response to the initial 131I therapy. None of the 42 CR patients had disease progression at the subsequent follow-up, and 37/170 (21.8%) IR patients improved after repeated therapy. Univariate analysis showed that N stage (P=0.002), stimulated thyroglobulin (sTg) level before initial 131I therapy (P<0.001), LNM size (P<0.001), number of total residual/recurrent LNM (P=0.021), radioiodine-nonavid (131I-) LNM (P=0.002) and ultrasound features (P<0.001) were related to the initial treatment response. On multivariate analysis, sTg level (OR=1.186, P<0.001) and LNM size (OR=1.533, P=0.004) were independent risk factors for IR after initial 131I therapy. The optimal sTg level and LNM size cutoff value for predicting the treatment response after initial 131I therapy were 18.2 µg/l and 5mm. Conclusion: This study suggested that approximately one-quarter of patients with 131I+ lymph nodes on initial PTS, especially those with N0 or N1a stage, lower sTg level, smaller LNM size, ≤2 residual/recurrent LNMs, negative ultrasound features and no 131I- LNM, remain stable after one cycle of 131I therapy and do not need repeated therapy.

Comparison of 2D-QCA, 3D-QCA and coronary angiography derived FFR in predicting myocardial ischemia assessed by CZT-SPECT MPI.

BACKGROUND: Angiography derived fractional flow reserve (angio-FFR) has been proposed. This study aimed to assess its diagnostic performance with cadmium-zinc-telluride single emission computed tomography (CZT-SPECT) as reference. METHODS AND RESULTS: Patients underwent CZT-SPECT within 3 months of coronary angiography were included. Angio-FFR computation was performed using computational fluid dynamics. Percent diameter (%DS) and area stenosis (%AS) were measured by quantitative coronary angiography. Myocardial ischemia was defined as a summed difference score ≥ 2 in a vascular territory. Angio-FFR ≤ 0.80 was considered abnormal. 282 coronary arteries in 131 patients were analyzed. Overall accuracy of angio-FFR to detect ischemia on CZT-SPECT was 90.43%, with a sensitivity of 62.50% and a specificity of 98.62%. The diagnostic performance (= area under ROC = AUC) of angio-FFR [AUC = 0.91, 95% confidence intervals (CI) 0.86-0.95] was similar as those of %DS (AUC = 0.88, 95% CI 0.84-0.93, p = 0.326) and %AS (AUC = 0.88, 95% CI 0.84-0.93 p = 0.241) by 3D-QCA, but significantly higher than those of %DS (AUC = 0.59, 95% CI 0.51-0.67, p < 0.001) and %AS (AUC = 0.59, 95% CI 0.51-0.67, p < 0.001) by 2D-QCA. However, in vessels with 50-70% stenoses, AUC of angio-FFR was significantly higher than those of %DS (0.80 vs. 0.47, p < 0.001) and %AS (0.80 vs. 0.46, p < 0.001) by 3D-QCA and %DS (0.80 vs. 0.66, p = 0.036) and %AS (0.80 vs. 0.66, p = 0.034) by 2D-QCA. CONCLUSION: Angio-FFR had a high accuracy in predicting myocardial ischemia assessed by CZT-SPECT, which is similar as 3D-QCA but significantly higher than 2D-QCA. While in intermediate lesions, angio-FFR is better than 3D-QCA and 2D-QCA in assessing myocardial ischemia.

Potential of enhancing the phytoremediation efficiency of Solanum nigrum L. by earthworms.

Contamination of the soil by Cadmium (Cd) is emerged as a critical environmental problem in China due to current urbanization and industrial activities that hinder the sustainable future development of agriculture. In this study, a system combined by earthworm and Solanum nigrum L. (S. nigurm) was designed for remediation of Cadmium from contaminated soils. The present study revealed that application of earthworm enhanced the biomass of S. nigrum by 61.71%, maxim; the Cd concentrations in the aboveground part of S. nigrum enhanced 35.8% when 50 g earthworm was added into each pot; the addition of earthworm also have some effect on the bio-concentration factor (BF) of S. nigrum while no effect was detected on the bio-transfer factor (TF). In addition, considering the accumulation of Cd by earthworm, the total amount of Cd extracted by the combined system enhanced 57.7% at least and 264.6% at the most, compared to the Cd extraction amount of S. nigrum alone. Generally, according to this study, the earthworm-S. nigrum system has the potential to be used for the remediation of Cd contaminated soils.

A two-year field study of phytoremediation using Solanum nigrum L. in China.

A two-year in-situ phytoremediation trial was launched in Shenyang Zhangshi (Sewage) Irrigation Area (SZIA). The phytoremediation efficiency of Solanum nigrum L. was determined, by both monitoring the change of soil Cadmium level in the upper 20 cm of soil, and calculating the plant uptake of soil Cd. After two years experimental, by monitoring the soil Cd concentrations, The Cd concentrations decreased on average from 2.75 mg kg(-1)to 2.45 mg kg(-1) in the first year and from 2.33 mg kg(-1) to 1.53 mg kg(-1) in the second year, amounting to a decrease by a factor of 10.6% in the first year and 12% in the second year. After two years phytoremediation by S. nigrum, Cd concentrations of the seven experimental plots with S. nigrum growth decreased from 2.75 mg kg(-1) to 1.53 mg kg(-1), a decrease by a factor of 24.9%. And the soil Cd concentration decreased only 2.1% and 1.7% in the bared experimental plot. And the calculating of Cd uptake by S. nigrum shown that, the plants uptake 4.46% and 5.18% of the total soil Cd in 2008 and 2009, while the soil Cd concentrations decreased by a factor of 10.6% in 2008 and 12.1% in 2009.

Potential of Gibberellic Acid 3 (GA3) for Enhancing the Phytoremediation Efficiency of Solanum nigrum L.

A microcosm experiment with artificially contaminated soils was conducted in a greenhouse to evaluate the effect of gibberellic acid 3 (GA3) on phytoremediation efficiency of Solanum nigrum L. The GA3 was applied at three different concentrations (10, 100, 1000 mg L(-1)) to S. nigrum. Results indicated that GA3 can significantly (p < 0.05) increase the biomass of S. nigrum by 56 % at 1000 mg L(-1). Concurrently, GA3 application increased Cd concentrations in the shoot of S. nigrum by 16 %. The combined effects resulted in an increase in the amount of Cd extracted by a single plant by up to 124 %. Therefore, it is possible to use GA3 to promote the Cd phytoremediation efficiency of S. nigrum.

Crystallization and preliminary X-ray study of the deaminase AmnE from Pseudomonas sp. AP-3.

The amnE gene from Pseudomonas sp. AP-3 has been verified as encoding a deaminase with 142 amino-acid residues. In order to change the substrate specificity via structure-based protein engineering, the amnE gene, after gene-code optimization, was chemically synthesized and cloned into the expression vector pET-28a. The protein was expressed in Escherichia coli BL21 (DE3) and purified by Ni(2+)-chelating affinity chromatography. Diffraction-quality crystals were obtained using the hanging-drop vapour-diffusion method and diffracted to a resolution of 2.09 Å. The crystals belonged to the orthorhombic space group C2221, with unit-cell parameters a = 63.23, b = 88.93, c = 137.83 Å.