Glycyrrhizin for treatment of CRS caused by CAR T-cell therapy: A pharmacological perspective

Chimeric antigen receptor T (CAR T)-cell therapy promises to revolutionize the management of hematologic malignancies and possibly other tumors. However, the main side effect of cytokine release syndrome (CRS) is a great challenge for its clinical application. Currently, treatment of CRS caused by CAR T-cell therapy is limited to tocilizumab (TCZ) and corticosteroids in clinical guidelines. However, the theoretical risks of these two agents may curb clinicians’ enthusiasm for their application, and the optimal treatment is still debated. CAR T-cell therapy induced-CRS treatment is a current research focus. Glycyrrhizin, which has diverse pharmacological effects, good tolerance, and affordability, is an ideal therapeutic alternative for CRS. It can also overcome the shortcoming of TCZ and corticosteroids. In this brief article, we discuss the therapeutic potential of glycyrrhizin for treating CRS caused by CAR T-cell therapy from the perspective of its pharmacological action

DualVD: An Adaptive Dual Encoding Model for Deep Visual Understanding in Visual Dialogue

Different from Visual Question Answering task that requires to answer only one question about an image, Visual Dialogue involves multiple questions which cover a broad range of visual content that could be related to any objects, relationships or semantics. The key challenge in Visual Dialogue task is thus to learn a more comprehensive and semantic-rich image representation which may have adaptive attentions on the image for variant questions. In this research, we propose a novel model to depict an image from both visual and semantic perspectives. Specifically, the visual view helps capture the appearance-level information, including objects and their relationships, while the semantic view enables the agent to understand high-level visual semantics from the whole image to the local regions. Futhermore, on top of such multi-view image features, we propose a feature selection framework which is able to adaptively capture question-relevant information hierarchically in fine-grained level. The proposed method achieved state-of-the-art results on benchmark Visual Dialogue datasets. More importantly, we can tell which modality (visual or semantic) has more contribution in answering the current question by visualizing the gate values. It gives us insights in understanding of human cognition in Visual Dialogue.Comment: Accepted by the Thirty-Fourth AAAI Conference on Artificial Intelligence (AAAI-2020

Genome Editing of Pik3cd Impedes Abnormal Retinal Angiogenesis

Abnormal angiogenesis is associated with myriad human diseases including proliferative diabetic retinopathy. Signaling transduction via phosphoinositide 3-kinases (PI3Ks) plays a critical role in angiogenesis. Herein, we showed that p110δ, the catalytic subunit of PI3Kδ, was highly expressed in pathological retinal vascular endothelial cells (ECs) in a mouse model of oxygen-induced retinopathy (OIR) and in fibrovascular membranes from patients with proliferative diabetic retinopathy. To explore novel intervention with PI3Kδ expression, we developed a recombinant dual adeno-associated viral (rAAV) system for delivering CRISPR/Cas9 in which Streptococcus pyogenes (Sp) Cas9 expression was driven by an endothelial specific promoter of intercellular adhesion molecule 2 (pICAM2) to edit genomic Pik3cd, the gene encoding p110δ. We then demonstrated that infection of cultured mouse vascular endothelial cells with the dual rAAV1s of rAAV1-pICAM2-SpCas9 and rAAV1-SpGuide targeting genomic Pik3cd resulted in 80% DNA insertion/deletion in the locus of genomic Pik3cd and 70% depletion of p110δ expression. Furthermore, we showed that in the mouse model of OIR editing retinal Pik3cd with the dual rAAV1s resulted in not only a significant decrease in p110δ expression, and Akt activation, but also a dramatic reduction in pathological retinal angiogenesis. These findings reveal that Pik3cd editing is a novel approach to treating abnormal retinal angiogenesis

Correction to: Genome Editing of Pik3cd Impedes Abnormal Retinal Angiogenesis, by Wu et al. Hum Gene Ther 2023;34(1-2):30-41; doi: 10.1089/hum.2022.079

In the January 2023 issue of Human Gene Therapy (vol. 34, no. 1-2; 30–41), the article titled Genome Editing of Pik3cd Impedes Abnormal Retinal Angiogenesis, by Wu et al. requires correction. The author byline originally appeared with the 13th author's name incorrectly published as GuomingZhao Wenyi Wu,1,2,3 Gaoen Ma,4 Hui Qi,5 Lijun Dong,5 Fang Chen,6 Yun Wang,5 Xingxing Mao,5 Xiaoqing Guo,2,3 Jing Cui,7 Joanne Aiko Matsubara,7 Bart Vanhaesebroeck,8 Xiaohe Yan,5Guoming Zhao,5 Shaochong Zhang,5,* and Hetian Lei 5,* The correct spelling of the author's name is GuomingZhang The online version of the article has been corrected to reflect this. The authors apologize for the error

Functional roles of two novel P450 genes in the adaptability of Conogethes punctiferalis to three commonly used pesticides

Introduction: Insect cytochrome P450 (CYP450) genes play important roles in the detoxification and metabolism of xenobiotics, such as plant allelochemicals, mycotoxins and pesticides. The polyphagous Conogethes punctiferalis is a serious economic pest of fruit trees and agricultural crops, and it shows high adaptability to different living environments.Methods: The two novel P450 genes CYP6CV1 and CYP6AB51 were identified and characterized. Quantitative real-time PCR (qRT-PCR) technology was used to study the expression patterns of the two target genes in different larval developmental stages and tissues of C. punctiferalis. Furthermore, RNA interference (RNAi) technology was used to study the potential functions of the two P450 genes by treating RNAi-silenced larvae with three commonly used pesticides.Results: The CYP6CV1 and CYP6AB51 genes were expressed throughout various C. punctiferalis larval stages and in different tissues. Their expression levels increased along with larval development, and expression levels of the two target genes in the midgut were significantly higher than in other tissues. The toxicity bioassay results showed that the LC50 values of chlorantraniliprole, emamectin benzoate and lambda-cyhalothrin on C. punctiferalis larvae were 0.2028 μg/g, 0.0683 μg/g and 0.6110 mg/L, respectively. After treating with different concentrations of chlorantraniliprole, emamectin benzoate and lambda-cyhalothrin (LC10, LC30, LC50), independently, the relative expressions of the two genes CYP6CV1 and CYP6AB51 were significantly induced. After the dsRNA injection, the expression profiles of the two CYP genes were reduced 72.91% and 70.94%, respectively, and the mortality rates of the larvae significantly increased when treated with the three insecticides independently at LC10 values.Discussion: In the summary, after interfering with the CYP6CV1 and CYP6AB51 in C. punctiferalis, respectively, the sensitivity of C. punctiferalis to chlorantraniliprole, emamectin benzoate and lambda-cyhalothrin was significantly increased, indicating that the two CYP6 genes were responsible for the adaptability of C. punctiferalis to the three chemical insecticides in C. punctiferalis. The results from this study demonstrated that CYP6CV1 and CYP6AB51 in C. punctiferalis play crucial roles in the detoxification of chlorantraniliprole, emamectin benzoate and lambda-cyhalothrin

What you don't know... can't hurt you? A natural field experiment on relative performance feedback in higher education

This paper studies the effect of providing feedback to college students on their position in the grade distribution by using a natural field experiment. This information was updated every six months during a three-year period. We find that greater grades transparency decreases educational performance, as measured by the number of examinations passed and grade point average (GPA). However, self-reported satisfaction, as measured by surveys conducted after feedback is provided but before students take their examinations, increases. We provide a theoretical framework to understand these results, focusing on the role of prior beliefs and using out-of-trial surveys to test the model. In the absence of treatment, a majority of students underestimate their position in the grade distribution, suggesting that the updated information is “good news” for many students. Moreover, the negative effect on performance is driven by those students who underestimate their position in the absence of feedback. Students who overestimate initially their position, if anything, respond positively. The performance effects are short lived—by the time students graduate, they have similar accumulated GPA and graduation rates

Amplified EPOR/JAK2 Genes Define a Unique Subtype of Acute Erythroid Leukemia

ゲノム解析から急性赤白血病の変異プロファイルと治療標的を解明 --特定の遺伝子変異群の組み合わせと、特徴となる遺伝子の増幅が鍵--. 京都大学プレスリリース. 2022-08-05.Acute erythroid leukemia (AEL) is a unique subtype of acute myeloid leukemia characterized by prominent erythroid proliferation whose molecular basis is poorly understood. To elucidate the underlying mechanism of erythroid proliferation, we analyzed 121 AEL using whole-genome/exome and/or targeted-capture sequencing, together with transcriptome analysis of 21 AEL samples. Combining publicly available sequencing data, we found a high frequency of gains/amplifications involving EPOR/JAK2 in TP53-mutated cases, particularly those having >80% erythroblasts designated as pure erythroid leukemia (10/13). These cases were frequently accompanied by gains/amplifications of ERG/ETS2 and associated with a very poor prognosis, even compared with other TP53-mutated AEL. In addition to activation of the STAT5 pathway, a common feature across all AEL cases, these AEL cases exhibited enhanced cell proliferation and heme metabolism and often showed high sensitivity to ruxolitinib in vitro and in xenograft models, highlighting a potential role of JAK2 inhibition in therapeutics of AEL

A Four-Order Linear Recurrence Formula Involving the Quartic Gauss Sums and One Kind Two-Term Exponential Sums

The main purpose of this paper is using the analytic method and the properties of the classical Gauss sums to study the computational problem of one kind hybrid power mean involving the quartic Gauss sums and two-term exponential sums and give an interesting four-order linear recurrence formula for it. As an application, we can obtain all values of this kind hybrid power mean with mathematica software