A trispecific antibody induces potent tumor-directed T-cell activation and antitumor activity by CD3/CD28 co-engagement.

Aim: A novel CD19xCD3xCD28 trispecific antibody with a tandem single-chain variable fragments (scFv) structure was developed for the treatment of B-cell malignancies. Methods: The trispecific antibody in inducing tumor-directed T-cell activation and cytotoxicity was evaluated in vitro and in vivo and compared with its bispecific counterpart BiTE-CD19xCD3 lacking a CD28-targeting domain. Results: The trispecific antibody with a co-stimulatory domain exhibited augmented T-cell activation and memory T-cell differentiation capability and it induced faster tumor cell lysis than the bispecific antibody. RNAseq analysis revealed that the trispecific antibody modulates CD3/TCR complex-derived signal and upregulates antiapoptotic factors to influence the survival of T cells. Conclusion: By CD3/CD28 co-engagement, the trispecific antibody demonstrated its advantages in T-cell immunity and potential use as a more powerful and long-lasting T-cell engager.

T-cell based immunotherapies are a type of treatment that stimulates the body's own immune system to fight cancer. They have grown in popularity in recent years and have had impressive results in cancer treatment. One type of T-cell immunotherapy is a T-cell engager antibody. This is a type of molecule that redirects the body's immune cells to recognise and kill cancer cells. In this study, we developed a new type of T-cell engager antibody to treat two types of blood and bone marrow cancer. The antibody works by joining immune cells and cancer cells close together, to help activate the immune cells for cancer killing. This new type of T-cell engager antibody worked better than previous versions. It helped the immune cells survive longer and kill cancer more effectively. This means the new antibody might be better at treating people who have these types of cancers, but more testing in humans needs to be done.

dGLYAT modulates Gadd45-mediated JNK activation and cell invasion.

BACKGROUND: Cell invasion is a crucial step of tumor metastasis, finding new regulators of which offers potential drug targets for cancer therapy. Aberrant GLYAT expression is associated with human cancers, yet its role in cancer remains unknown. This study aims to understand the function and mechanism of Drosophila GLYAT in cell invasion. RESULTS: We found that dGLYAT regulates Gadd45-mediated JNK pathway activation and cell invasion. Firstly, loss of dGLYAT suppressed scrib depletion- or Egr overexpression-induced JNK pathway activation and invasive cell migration. Secondary, mRNA-seq analysis identified Gadd45 as a potential transcriptional target of dGLYAT, as depletion of dGLYAT decreased Gadd45 mRNA level. Finally, Gadd45 knockdown suppressed scrib depletion-induced JNK pathway activation and cell invasion. CONCLUSIONS: These evidences reveal the role of dGLYAT and Gadd45 in JNK-dependent cell invasion, and provide insight for the roles of their human homologs in cancers.

CHIP modulates APP-induced autophagy-dependent pathological symptoms in Drosophila.

Dysregulation of autophagy is associated with the neurodegenerative processes in Alzheimer's disease (AD), yet it remains controversial whether autophagy is a cause or consequence of AD. We have previously expressed the full-length human APP in Drosophila and established a fly AD model that exhibits multiple AD-like symptoms. Here we report that depletion of CHIP effectively palliated APP-induced pathological symptoms, including morphological, behavioral, and cognitive defects. Mechanistically, CHIP is required for APP-induced autophagy dysfunction, which promotes Aß production via increased expression of BACE and Psn. Our findings suggest that aberrant autophagy is not only a consequence of abnormal APP activity, but also contributes to dysregulated APP metabolism and subsequent AD pathogenesis.

A new grid- and modularity-based layout algorithm for complex biological networks.

The visualization of biological networks is critically important to aid researchers in understanding complex biological systems and arouses interest in designing efficient layout algorithms to draw biological networks according to their topology structures, especially for those networks with potential modules. The algorithms of grid layout series have an advantage in generating compact layouts with overlap-free nodes compared to force-directed; however, extant grid layout algorithms have difficulty in drawing modular networks and often generate layouts of high visual complexity when applied to networks with dense or clustered connectivity structure. To specifically assist the study of modular networks, we propose a grid- and modularity-based layout algorithm (GML) that consists of three stages: network preprocessing, module layout and grid optimization. The algorithm can draw complex biological networks with or without predefined modules based on the grid layout algorithm. It also outperforms other existing grid-based algorithms in the measurement of computation performance, ratio of edge-edge/node-edge crossings, relative edge lengths, and connectivity F-measures. GML helps users to gain insight into the network global characteristics through module layout, as well as to discern network details with grid optimization. GML has been developed as a VisANT plugin (https://hscz.github.io/Biological-Network-Visualization/) and is freely available to the research community.

GLYAT regulates JNK-mediated cell death in Drosophila.

Cell death is a fundamental progress that regulates cell number, tissue homeostasis and organ size in development. The c-Jun N-terminal kinase (JNK) pathway has been evolutionarily conserved from fly to human, and plays essential roles in regulating cell death. To characterize additional genes that regulate JNK signaling, we performed a genetic screen in Drosophila and identified dGLYAT, a novel gene whose function was previously unknown, as a modulator of JNK-mediated cell death. We found that loss of dGLYAT suppressed JNK activation and cell death triggered by over-expression of Egr or Hep, or depletion of puc or lgl in development, suggesting dGLYAT regulates both ectopic and physiological functions of JNK pathway. Furthermore, we showed that loss of dGLYAT inhibits JNK-mediated ROS production, suggesting dGLYAT regulates multiple functions of JNK signaling in vivo.

Establishment of a Drosophila AD model.

Alzheimer's disease (AD) is the most common form of dementia that affects people's health greatly. Though amyloid precursor protein (APP) has been implicated in the pathogenesis of AD, the exact role of APP and its underlying mechanism in AD progression have remained largely elusive. Drosophila melanogaster has been extensively used as a model organism to study a wide range of human diseases including AD. In this protocol, we expressed full length human APP in the Drosophila nervous system and examined its effect on locomotion and choice ability. We found that expression of APP produced locomotion defects in larvae as measured by plate crawling ability assay (PCA), and in adult flies as monitored by plate cycling ability assay (CLA). In addition, expression of APP results in male courtship choice (MCC) defect, since wild-type males court preferentially toward young virgin females over old ones, while APP-expressing males failed to show this preference. This protocol enables us to screen for novel AD candidate genes as well as therapeutic compounds to ameliorate the disease.