LAG3 (CD223) as a cancer immunotherapy target Andrews, Lawrence P.; Marciscano, Ariel E.; Drake, Charles G. ...
Immunological reviews,
March 2017, 2017-03-00, 20170301, Volume:
276, Issue:
1
Journal Article
Peer reviewed
Open access
Summary
Despite the impressive impact of CTLA4 and PD1‐PDL1‐targeted cancer immunotherapy, a large proportion of patients with many tumor types fail to respond. Consequently, the focus has shifted to ...targeting alternative inhibitory receptors (IRs) and suppressive mechanisms within the tumor microenvironment. Lymphocyte activation gene‐3 (LAG3) (CD223) is the third IR to be targeted in the clinic, consequently garnering considerable interest and scrutiny. LAG3 upregulation is required to control overt activation and prevent the onset of autoimmunity. However, persistent antigen exposure in the tumor microenvironment results in sustained LAG3 expression, contributing to a state of exhaustion manifest in impaired proliferation and cytokine production. The exact signaling mechanisms downstream of LAG3 and interplay with other IRs remain largely unknown. However, the striking synergy between LAG3 and PD1 observed in multiple settings, coupled with the contrasting intracellular cytoplasmic domain of LAG3 as compared with other IRs, highlights the potential uniqueness of LAG3. There are now four LAG3‐targeted therapies in the clinic with many more in preclinical development, emphasizing the broad interest in this IR. Given the translational relevance of LAG3 and the heightened interest in the impact of dual LAG3/PD1 targeting in the clinic, the outcome of these trials could serve as a nexus; significantly increasing or dampening enthusiasm for subsequent targets in the cancer immunotherapeutic pipeline.
•Wheat-derived Cd-stabilizing endophytic strains M14 and R27 strains were obtained.•Grain Cd content treated with BC+MR did not exceed Cd limited standard in wheat.•BC+MR showed higher ability to ...reduce Cd availability and Cd transfer than BC or MR.•BC+MR decreased soil Cd availability by affecting soil specific biomarker abundances.•BC+MR reduced Cd transfer by affecting root interior specific biomarker abundances.
In this study, two wheat-derived cadmium (Cd)-immobilizing endophytic Pseudomonas paralactis M14 and Priestia megaterium R27 were evaluated for their effects on wheat tissue Cd uptake under hydroponic conditions. Then, the impacts of the biochar (BC), M14+R27 (MR), and BC+MR treatments on wheat Cd uptake and the mechanisms involved were investigated at the jointing, heading, and mature stages of wheat plants under field-plot conditions. A hydroponic experiment showed that the MR treatment significantly decreased the above-ground tissue Cd content compared with the M14 or R27 treatment. The BC+MR treatment reduced the grain Cd content by 51.5%–67.7% and Cd translocation factor at the mature stage of wheat plants and increased the organic matter-bound Cd content by 31%–75% in the rhizosphere soils compared with the BC or MR treatment. Compared with the BC or MR treatment, the relative abundances of the biomarkers associated with Gemmatimonas, Altererythrobacter, Gammaproteobacteria, Xanthomonadaceae, Phenylobacterium, and Nocardioides in the BC+MR-treated rhizosphere microbiome decreased and negatively correlated with the organic matter-bound Cd contents. In the BC+MR-treated root interior microbiome, the relative abundance of the biomarker belonging to Exiguobacterium increased and negatively correlated with the Cd translocation factor, while the relative abundance of the biomarker belonging to Pseudonocardiaceae decreased and positively correlated with the Cd translocation factor. Our findings suggested that the BC+MR treatment reduced Cd availability and Cd transfer through affecting the abundances of these specific biomarkers in the rhizosphere soil and root interior microbiomes, leading to decreased wheat grain Cd uptake in the contaminated soil.
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VE-cadherin is a component of endothelial cell-to-cell adherens junctions, and it has a key role in the maintenance of vascular integrity. During embryo development, VE-cadherin is required for the ...organization of a stable vascular system, and in the adult it controls vascular permeability and inhibits unrestrained vascular growth. The mechanisms of action of VE-cadherin are complex and include reshaping and organization of the endothelial cell cytoskeleton and modulation of gene transcription. Here we review some of the most important pathways through which VE-cadherin modulates vascular homeostasis and discuss the emerging concepts in the overall biological role of this protein.
Analysis of circular dichroism spectra of proteins provides information about protein secondary structure. Analytical methods developed for such an analysis use structures and spectra of a set of ...reference proteins. The reference protein sets currently in use include soluble proteins with a wide range of secondary structures, and perform quite well in analyzing CD spectra of soluble proteins. The utility of soluble protein reference sets in analyzing membrane protein CD spectra, however, has been questioned in a recent study that found current reference protein sets to be inadequate for analyzing membrane proteins. We have examined the performance of reference protein sets available in the CDPro software package for analyzing CD spectra of 13 membrane proteins with available crystal structures. Our results indicate that the reference protein sets currently available for CD analysis perform reasonably well in analyzing membrane protein CD spectra, with performance indices comparable to those for soluble proteins. Soluble + membrane protein reference sets, which were constructed by combining membrane proteins with soluble protein reference sets, gave improved performance in both soluble and membrane protein CD analysis.
The cadmium contamination of soil is an alarming issue worldwide and among various mitigation strategies, nanotechnology mediated management of Cd contamination has become a well-accepted approach. ...The Cerium Oxide Nanoparticles (CeO2-NPs) are widely being explored for their novel works in Agro-Industry and Environment, including stress mitigation in crops. Very little work is reported regarding role of CeO2-NPs in management of Cd contamination in cereal crops like wheat. Present work was planned to check efficacy of CeO2-NPs in Cd stress mitigation of wheat under alkaline calcareous soil conditions. In this experiment, 4 sets of Cd contamination (Uncontaminated control-UCC, 10, 20, and 30 mg Cd per kg soil) and 5 sets of CeO2-NPs NPs (0, 200, 400, 600, and 1000 mg NP per kg soil) were applied in pots following completely randomized design (CRD) and wheat crop was grown. The growth, physiology, yield and Cd and Ce accumulation by wheat root, shoot and grain was monitored. The maximum Cd spiking level (30 mg kg−1) was found to be most toxic for plant growth. The results showed that the nanoparticles were overall beneficial for wheat growth and maximum level (1000 mg kg−1) being the most significant one under all Cd spiking sets. In Cd-30 sets, 1000 mg kg−1 NPs application resulted in decreased soil bioavailable Cd concentration (49.63% decrease compared to 30 mg kg−1 Cd spiked sets termed as Cd-30 Control), decreased Cd accumulation in all three tissues: root (58.36% decrease), shoot (52.30% decrease) and grain (55.56% decrease) while increased root dry weight (62.14%), shoot dry weight (89.32%), total grain yield (80.08%) and improved plant physiology with respect to Cd-30 control. Nanoparticles application substantially increased wheat root, shoot and grain Ce concentrations as well. The further prospects of these nanoparticles in relation to various biotic and abiotic stresses are advised to be explored.
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•CeO2-NPs have novel applications in Cd stress mitigation.•CeO2-NPs decreased bioavailable Cd in alkaline soil.•CeO2-NPs enhanced wheat tissue Ce concentration.•CeO2-NPs decreased wheat tissue Cd concentrations.
In coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, the relationship between disease severity and the host immune response is not ...fully understood. Here we performed single-cell RNA sequencing in peripheral blood samples of 5 healthy donors and 13 patients with COVID-19, including moderate, severe and convalescent cases. Through determining the transcriptional profiles of immune cells, coupled with assembled T cell receptor and B cell receptor sequences, we analyzed the functional properties of immune cells. Most cell types in patients with COVID-19 showed a strong interferon-α response and an overall acute inflammatory response. Moreover, intensive expansion of highly cytotoxic effector T cell subsets, such as CD4
effector-GNLY (granulysin), CD8
effector-GNLY and NKT CD160, was associated with convalescence in moderate patients. In severe patients, the immune landscape featured a deranged interferon response, profound immune exhaustion with skewed T cell receptor repertoire and broad T cell expansion. These findings illustrate the dynamic nature of immune responses during disease progression.
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