Coinhibition

Microglia, the parenchymal brain macrophages of the central nervous system, have emerged as critical players in brain development and homeostasis. The immune functions of these cells, however, remain less well defined. We investigated contributions of microglia in a relapsing-remitting multiple sclerosis paradigm, experimental autoimmune encephalitis in C57BL/6 x SJL F1 mice. Fate mapping-assisted translatome profiling during the relapsing-remitting disease course revealed the potential of microglia to interact with T cells through antigen presentation, costimulation and coinhibition...

Extending literature on youth coping and stress physiology, this two-wave longitudinal study examined independent and interactive roles of youth coping with daily stressors (i.e., peer, academic) and cardiac autonomic functioning in subsequent social and academic adjustment across the transition to middle school. Our sample consisted of 100 typically developing youth (10-12 years old at Time 1, 53 boys, 43% ethnic minorities) who reported on their coping strategies in response to peer and academic stress...

Systemic lupus erythematosus is a complex autoimmune disorder mostly mediated by B-cells in which costimulatory signals are involved. This immune dysregulation can cause tissue damage and inflammation of the kidney, resulting in lupus nephritis and chronic renal failure. Given the previous experience reported with CTLA4-Ig as well as recent understanding of the PD-1 pathway in this setting, our group was encouraged to evaluate, in the NZBWF1 model, a human fusion recombinant protein (Hybri) with two domains: CTLA4, blocking the CD28-CD80 costimulatory pathway, and PD-L2, exacerbating the PD-1-PD-L2 coinhibitory pathway...

Coinhibition of TIGIT (T cell immunoreceptor with Ig and ITIM domains) and PD-1/PD-L1 (PD-1/L1) may improve response rates compared with monotherapy PD-1/L1 blockade in checkpoint naive non-small cell lung cancer with PD-L1 expression >50%. TIGIT mAbs with an effector-competent Fc can induce myeloid cell activation, and some have demonstrated effector T cell depletion, which carries a clinical liability of unknown significance. TIGIT Ab blockade translates to antitumor activity by enabling PVR signaling through CD226 (DNAM-1), which can be directly inhibited by PD-1...

Despite recent advances in the management and treatment of esophageal squamous cell carcinoma (ESCC), the prognosis remains extremely poor, and current nonsurgical treatment options are limited. To identify new therapeutic targets, we screened a curated library of epigenetic compounds using a panel of cancer cell lines and found that coinhibiting the histone demethylase LSD1 and the histone methyltransferase G9a potently suppresses cell growth; similar results were obtained by knocking down both LSD1 and G9a expression...

We investigated whether parasympathetic and sympathetic nervous system responses to social-evaluative threat at age 14 were related to the number of substances used between ages 14 and 16 among Mexican-origin adolescents (N=243; 70.4% had never used substances by 14). Participants completed the Trier Social Stress Test, while cardiac measures of parasympathetic and sympathetic nervous system activity were measured continuously using respiratory sinus arrhythmia (RSA) and pre-ejection period (PEP), respectively...

Background: Molecular features have been included in the categorization of gliomas because they may be excellent predictors of tumor prognosis. Lower-grade glioma (LGGs, which comprise grade 2 and grade 3 gliomas) patients have a wide variety of outcomes. The goal of this research is to investigate a pyroptosis-based long noncoding RNA (lncRNA) profile and see whether it can be used to predict LGG prognosis. Methods: The Genotype-Tissue Expression (GTEx) and Cancer Genome Atlas (TCGA) datasets were utilized to get RNA data and clinical information for this research...

The Integrity model proposes that the adaptive immune response defends, protects, and keeps vigilance over the unity of an organism. These functions conceptually rely on three signals that can explain them. All signals have a dual character. The signal-1 is the recognition of antigen or peptide/MHC ligand. The signal-2 comprises either help and costimulation or suppression and coinhibition. Lastly, the signal-3 signals tissues' condition, state or integrity. A part overlaps with the Danger-associated molecular patterns, and the other part should be detected by putative cell-surface molecules, intracellular factors or epigenetic events...

Background: Hepatocellular carcinoma (HCC) is a high mortality malignant tumor with genetic and phenotypic heterogeneity, making predicting prognosis challenging. Meanwhile, the inflammatory response is an indispensable player in the tumorigenesis process and regulates the tumor microenvironment, which can affect the prognosis of tumor patients. Methods: Using HCC samples in the TCGA-LIHC dataset, we explored lncRNA expression profiles associated with the inflammatory response...

Autoimmune diseases are characterized by dysfunctional immune systems that misrecognize self as non-self and cause tissue destruction. Several cell types have been implicated in triggering and sustaining disease. Due to a strong association of major histocompatibility complex II (MHC-II) proteins with various autoimmune diseases, CD4+ T lymphocytes have been thoroughly investigated for their roles in dictating disease course. CD4+ T cell activation is a coordinated process that requires three distinct signals: Signal 1, which is mediated by antigen recognition on MHC-II molecules; Signal 2, which boosts signal 1 in a costimulatory manner; and Signal 3, which helps to differentiate the activated cells into functionally relevant subsets...

This study examined autonomic profiles in preschoolers (N = 278, age = 4.7 years) and their relations to self-regulation outcomes concurrently and one year later, in kindergarten. Children's sympathetic (preejection period [PEP]) and parasympathetic activity (respiratory sinus arrythmia [RSA]) were measured at rest and during cognitive and emotional tasks. Three self-regulatory competencies were assessed: executive functions, emotion regulation and behavioral regulation. Executive functioning was measured at ages 4 and 5 using laboratory tasks designed to assess updating/working memory, inhibitory control, and cognitive flexibility...

Costimulatory and coinhibitory mechanisms appear to be involved throughout immune responses to control their specificity and level. Many mechanisms operate; therefore, various theoretical models should be considered complementary rather than competing. One such coinhibitory model, pictured in 1971, involves the crosslinking of antigen receptors with inhibitory Fc receptors by antigen/antibody complexes. This model was prompted by observations that the Fc portion of antibody was required for potent suppression of immune responses by antibody...

Background: Osteosarcoma is the most prevalent bone cancer that affects young adults and adolescents. It is the most frequent malignancy of the bone. In spite of the fact that complete surgical resection and chemotherapy have increased the overall survival of osteosarcoma patients considerably, the prognosis remains dismal in patients with recurring and/or metastasized osteosarcoma. Thus, finding predictive biomarkers representing osteosarcoma's biological variability may result in more effective treatment for osteosarcoma patients...

The most common kind of kidney cancer with poor prognosis is clear cell renal cell carcinoma (ccRCC). Pyroptosis is shown to be an inflammatory type of programmed cell death in recent years. In this research, we utilized pyroptosis-related differentially expressed lncRNAs in ccRCC to develop a predictive multi-lncRNA signature. We uncovered 14 lncRNAs with different expression patterns that were linked to ccRCC prognosis. Kaplan-Meier analysis identified a signature of high-risk lncRNAs related to poor prognosis for ccRCC...

Oncogenic KRAS drives cancer growth by activating diverse signaling networks, not all of which have been fully delineated. We set out to establish a system-wide profile of the KRAS-regulated kinase signaling network (kinome) in KRAS-mutant pancreatic ductal adenocarcinoma (PDAC). We knocked down KRAS expression in a panel of six cell lines and then applied multiplexed inhibitor bead/MS to monitor changes in kinase activity and/or expression. We hypothesized that depletion of KRAS would result in downregulation of kinases required for KRAS-mediated transformation and in upregulation of other kinases that could potentially compensate for the deleterious consequences of the loss of KRAS...

Introduction: MET amplification is a frequently observed mechanism of resistance to osimertinib, and coinhibition strategy of MET and EGFR revealed promising results in recent clinical trials. Nevertheless, acquired resistance mechanisms to combined EGFR and MET inhibition are poorly understood. In this study, we investigated the mechanisms of acquired resistance to osimertinib and savolitinib by using pretreatment and post-treatment tissue analysis. Methods: Whole-exome sequencing was performed in EGFR -mutant, MET -amplified patients who received osimertinib and savolitinib using tissues obtained both before and after therapy...

Reactive aggression is posited to occur as a result of hypersensitivity to threat, whereas fearlessness may drive proactive aggression. This study aimed to test if physiological fear reactivity differentially relates to self-report reactive and proactive aggression using immersive virtual reality fear (VR) induction. We collected subjective fear ratings and sympathetic (SNS; skin conductance) and parasympathetic (PNS; respiratory sinus arrhythmia) nervous system reactivity during an interactive VR horror video...

Immune checkpoint molecules, also known as cosignaling molecules, are pivotal cell-surface molecules that control immune cell responses by either promoting (costimulatory molecules) or inhibiting (coinhibitory molecules) a signal. These molecules have been studied for many years. The application of immune checkpoint drugs in the clinic provides hope for cancer patients. Recently, the poliovirus receptor (PVR)-like protein cosignaling network, which involves several immune checkpoint receptors, i.e., DNAM-1 (DNAX accessory molecule-1, CD226), TIGIT (T-cell immunoglobulin (Ig) and immunoreceptor tyrosine-based inhibitory motif (ITIM)), CD96 (T cell activation, increased late expression (TACLILE)), and CD112R (PVRIG), which interact with their ligands CD155 (PVR/Necl-5), CD112 (PVRL2/nectin-2), CD111 (PVRL1/nectin-1), CD113 (PVRL3/nectin-3), and Nectin4, was discovered...

Background: Designing combination drugs for malignant cancers has been restricted due to the scarcity of synergy-medicated targets, while some natural compounds have demonstrated potential to enhance anticancer effects. Methods: We here explored the feasibility of probing synergy-mediated targets by Berberine (BER) and Evodiamine (EVO) in hepatocellular carcinoma (HCC). Using the genomics-derived HCC signaling networks of compound treatment, NF-κB and c-JUN were inferred as key responding elements with transcriptional activity coinhibited during the synergistic cytotoxicity induction in BEL-7402 cells...

The B7 family ligand HERV-H LTR-associating protein 2 (HHLA2) is an attractive target for cancer immunotherapy because of its coinhibitory function, overexpression in human cancers, and association with poor prognoses. However, the knowledge of the HHLA2 pathway is incomplete. HHLA2 has an established positive receptor transmembrane and immunoglobulin (Ig) domain containing 2 (TMIGD2) but a poorly characterized negative receptor human killer cell Ig-like receptor, three Ig domains, and long cytoplasmic tail (KIR3DL3)...