Although the clinical development of immune checkpoint inhibitors (ICIs) therapy has ushered in a new era of anti-tumor therapy, with sustained responses and significant survival advantages observed in multiple tumors, most patients do not benefit. Therefore, more and more attention has been paid to the identification and development of predictive biomarkers for the response of ICIs, and more in-depth and comprehensive understanding has been continuously explored in recent years. Predictive markers of ICIs efficacy have been gradually explored from the expression of intermolecular interactions within tumor cells to the expression of various molecules and cells in tumor microenvironment, and been extended to the exploration of circulating and host systemic markers. With the development of high-throughput sequencing and microarray technology, a variety of biomarker strategies have been deeply explored and gradually achieved the process from the identification of single marker to the development of multifactorial synergistic predictive markers. Comprehensive predictive-models developed by integrating different types of data based on different components of tumor-host interactions is the direction of future research and will have a profound impact in the field of precision immuno-oncology. In this review, we deeply analyze the exploration course and research progress of predictive biomarkers as an adjunctive tool to tumor immunotherapy in effectively identifying the efficacy of ICIs, and discuss their future directions in achieving precision immuno-oncology.
Numerous studies have shown that acetaldehyde can can coexist in the liver during ethanol oxidation, protein covalently react with proteins in vitro under physiologiadduct formation in the presence of both of these alde-cal conditions to form both stable and unstable adhydes was studied under both in vitro and in vivo condi-ducts. [1][2][3] Because of this chemical reactivity, the cova- hyde and MDA on adduct formation has not been From the
We examined thermal hyperalgesia, excitability of dorsal root ganglion (DRG) neurons, and antinociceptive effects of N-methyl-d-aspartate (NMDA) receptor antagonists in rats with injury to different regions of DRG neurons. The central or peripheral branches of axons of DRG neurons were injured by partial dorsal rhizotomy (PDR) and chronic constriction injury of sciatic nerve (CCI), respectively, or the somata injured by chronic compression of DRG (CCD). Thermal hyperalgesia was evidenced by significantly shortened latencies of foot withdrawal to radiant heat stimulation of the plantar surface. Intracellular recordings were obtained in vitro from L(4) and/or L(5) ganglia. There are four principle findings: 1) PDR as well as CCD and CCI induced thermal hyperalgesia; 2) PDR produced significantly less severe and shorter duration hyperalgesia than CCD and CCI; 3) intrathecal administration of NMDA receptor antagonists d-2-amino-5-phosphonovaleric acid (APV) and dizocilpine maleate (MK-801) inhibited thermal hyperalgesia in PDR, CCD, and CCI rats. Pretreatment of APV and MK-801 delayed the emergence of hyperalgesia for 48-72 h, while posttreatment inhibited hyperalgesia for 24-36 h; and 4) CCD and CCI increased excitability of DRG neurons as judged by the significantly lowered threshold currents and action potential voltage thresholds and increased incidence of repetitive discharges. However, PDR did not alter the excitability of DRG neurons. These findings indicate that injury to the dorsal root, compared with injury to the peripheral nerve or DRG somata has different effects on the development of hyperalgesia. These contributions involve different changes in DRG membrane excitability, but each involves pathways (presumably in the spinal cord) that depend on NMDA receptors.
We studied the clinical usefulness of the VCS parameters (mean channels of cell volume, conductivity, and light scatter) in reactive neutrophils for predicting acute bacterial infection, which are obtained by the Coulter LH 750 hematology analyzer (Beckman Coulter, Fullerton, CA) during automated differential counts. Peripheral blood samples from 69 patients with positive blood cultures for bacteria and 35 control subjects were studied. We observed a significant increase in the mean channel of neutrophil volume (MNV) from septic patients compared with control subjects (156+/-13.5 vs 143+/-4.8; P<.001). The mean channel of neutrophil light scatter was decreased significantly in patients (140+/-10.1 vs 146+/-7.3; P=.002). An elevation of the MNV was associated with a higher WBC count and percentage of neutrophils and was present even in patients who did not have leukocytosis or neutrophilia. With a cutoff of 150 for the MNV, a specificity of 91% and sensitivity of 70% were achieved. As a quantitative, objective, and more sensitive parameter, we believe that the MNV has a potential to be an additional indicator for acute bacterial infection.
Malondialdehyde (MDA) and acetaldehyde react together with proteins in a synergistic manner and form hybrid protein adducts, designated as MAA adducts. In a previous study, a polyclonal antibody specific for MAA-protein adducts was used in an immunoassay to detect the presence of MAA adducts in livers of ethanol-fed rats. In the present study, the specific epitope recognized by the antibody was defined and the chemistry of MAA adduct formation was further characterized. When several synthetic analogs were tested for their ability to inhibit antibody binding in a competitive ELISA, the results indicated that the major determinant of antibody binding was a highly fluorescent cyclic adduct composed of two molecules of MDA and one of acetaldehyde. The structure of this adduct was shown to be a 4-methyl-1,4-dihydropyridine-3,5-dicarbaldehyde derivative of an amino group of a protein. Examination of MAA adduct formation with a variety of proteins indicated that in addition to this specific fluorescent adduct, MAA adducts were also comprised of other nonfluorescent products. The amount of fluorescent epitopes present on a given protein was the major determinant of antibody binding as assessed in a competitive ELISA, although the efficiency of inhibition of antibody binding by these fluorescent epitopes on MAA-adducted proteins varied depending upon the particular protein. However, when these MAA-adducted proteins were hydrolyzed with Pronase, the concentration of these modified proteins necessary to achieve 50% inhibition of antibody binding in a competitive ELISA fell into a much narrower range of values, indicating that protein hydrolysis equalized the accessibility of the antibody to bind the epitope on these various derivatized proteins. In summary, a cyclic fluorescent adduct of defined structure has been identified as the epitope recognized by our MAA adduct antibody. In addition to this specific adduct, MAA adducts are also comprised of other nonfluorescent products.
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