Structure-Guided Discovery of PD-1/PD-L1 Interaction Inhibitors: Peptide Design, Screening, and Optimization via Computation-Aided Phage Display Engineering.

Cancer immunotherapy harnesses the immune system to combat tumors and has emerged as a major cancer treatment modality. The PD-1/PD-L1 immune checkpoint modulates interactions between tumor cells and T cells and has been extensively targeted in cancer immunotherapy. However, the monoclonal antibodies known to target this immune checkpoint have considerable side effects, and novel PD-1/PD-L1 inhibitors are therefore required. Herein, a peptide inhibitor to disrupt PD-1/PD-L1 interactions was designed through structure-driven phage display engineering coupled to computational modification and optimization. BetaPb, a novel peptide library constructed by using the known structure of PD-1/PD-L, was used to develop inhibitors against the immune checkpoint, and specific peptides with high affinity toward PD-1 were screened through enzyme-linked immunosorbent assays, homogeneous time-resolved fluorescence, and biolayer interferometry. A potential inhibitor, B8, was preliminarily screened through biopanning. The binding affinity of B8 toward PD-1 was confirmed through computation-aided optimization. Assessment of B8 variants (B8.1, B8.2, B8.3, B8.4, and B8.5) demonstrated their attenuation of PD-1/PD-L1 interactions. B8.4 exhibited the strongest attenuation efficiency at a half-maximal effective concentration of 0.1 µM and the strongest binding affinity to PD-1 (equilibrium dissociation constant = 0.1 µM). B8.4 outperformed the known PD-1/PD-L1 interaction inhibitor PL120131 in disrupting PD-1/PD-L1 interactions, revealing that B8.4 has remarkable potential for modification to yield an antitumor agent. This study provides valuable information for the future development of peptide-based drugs, therapeutics, and immunotherapies for cancer.

Pilot testing the augmentech body position sensor on the morbidly obese patient.

The Augmentech Body Position Sensor (ABPS), a device for monitoring patient repositioning, was tested for use in morbidly obese patients. Specific aims were to: determine whether there was correspondence between data on patient turning and repositioning from the ABPS and data gathered through human observation; determine whether the ABPS is an acceptable instrument for measuring body movements in morbidly obese patients in terms of ease of use, comfort and ability to stay in place. A descriptive study was conducted. Data from the ABPS recording patients' body positions were compared with data from videotapes taken of the same patients during the same time period. The sleep center of a tertiary care facility in the southeastern United States was used. Ten participants with BMI ≥30 were selected from patients referred to the sleep center for polysomnography. Positioning the device on the patient's thigh, data were collected from midnight until discharge. Videotapes taken of the same patient during the same time period were examined for changes in body position over time. There was a strong correspondence between the videotaped data and the ABPS data. The device was comfortable and not irritating to the patient. The APBS can be a useful measure for determining changes in body position but further study should be undertaken to test other sites for placement.

An encyclopedia of mouse DNA elements (Mouse ENCODE).

To complement the human Encyclopedia of DNA Elements (ENCODE) project and to enable a broad range of mouse genomics efforts, the Mouse ENCODE Consortium is applying the same experimental pipelines developed for human ENCODE to annotate the mouse genome.

Resveratrol inhibits migration and invasion of human breast-cancer cells.

Metastasis is the primary cause of death from breast cancer. Cell migration and invasion play important roles in neoplastic metastasis. The insulin-like growth factor (IGF-1) stimulates cell migration through activation of PI-3K/Akt signaling pathway. IGF-1 induces the tumorigenicity of many types of cancer cells and is critical for metastatic cell spread in estrogen receptor (ER)-negative breast-cancer cells. Matrix metalloproteinase-2 (MMP-2) is a key enzyme in the degradation of extracellular matrices and its expression has been dysregulated in breast cancer invasion and metastasis. Resveratrol exhibited potential anticarcinogenic activities in several studies. However, the inhibitory effects of resveratrol on the expression of MMP-2, migration and invasion of breast-cancer cell have not been demonstrated yet. In the present study, we investigated the anti-invasive mechanism of resveratrol in human breast cancer MDA-MB 435cells. Here, we showed that IGF-1 is a potent stimulant of the migration of ER-negative human breast-cancer cells. Resveratrol could inhibit IGF-1-mediated cell migration of MDA-MB 435 in vitro. The inhibitory effect of resveratrol was mediated in part through the suppression of the activation of PI-3K/Akt signaling pathway. Furthermore, IGF-1-mediated expression of MMP-2 was significantly inhibited by resveratrol in concomitance with alteration of cell invasion.