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Science (New York, N.Y.) Oct 2018Programmed cell death protein-1 (PD-1) and programmed cell death ligand-1 (PD-L1) checkpoint blockade immunotherapy elicits durable antitumor effects in multiple...
Programmed cell death protein-1 (PD-1) and programmed cell death ligand-1 (PD-L1) checkpoint blockade immunotherapy elicits durable antitumor effects in multiple cancers, yet not all patients respond. We report the evaluation of >300 patient samples across 22 tumor types from four KEYNOTE clinical trials. Tumor mutational burden (TMB) and a T cell-inflamed gene expression profile (GEP) exhibited joint predictive utility in identifying responders and nonresponders to the PD-1 antibody pembrolizumab. TMB and GEP were independently predictive of response and demonstrated low correlation, suggesting that they capture distinct features of neoantigenicity and T cell activation. Analysis of The Cancer Genome Atlas database showed TMB and GEP to have a low correlation, and analysis by joint stratification revealed biomarker-defined patterns of targetable-resistance biology. These biomarkers may have utility in clinical trial design by guiding rational selection of anti-PD-1 monotherapy and combination immunotherapy regimens.
Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; Biomarkers, Tumor; Cell Cycle Checkpoints; Genetic Markers; Humans; Immunotherapy; Inflammation; Molecular Targeted Therapy; Mutation; Neoplasms; Programmed Cell Death 1 Receptor; T-Lymphocytes; Transcriptome; Tumor Burden
PubMed: 30309915
DOI: 10.1126/science.aar3593 -
Immunological Reviews Jan 2023C3 is the central effector molecule of the complement system, mediating its multiple functions through different binding sites and their corresponding receptors. We will... (Review)
Review
C3 is the central effector molecule of the complement system, mediating its multiple functions through different binding sites and their corresponding receptors. We will introduce the C3 forms (native C3, C3 [H O], and intracellular C3), the C3 fragments C3a, C3b, iC3b, and C3dg/C3d, and the C3 expression sites. To highlight the important role that C3 plays in human biological processes, we will give an overview of the diseases linked to C3 deficiency and to uncontrolled C3 activation. Next, we will present a structural description of C3 activation and of the C3 fragments generated by complement regulation. We will proceed by describing the C3a interaction with the anaphylatoxin receptor, followed by the interactions of opsonins (C3b, iC3b, and C3dg/C3d) with complement receptors, divided into two groups: receptors bearing complement regulatory functions and the effector receptors without complement regulatory activity. We outline the molecular architecture of the receptors, their binding sites on the C3 activation fragments, the cells expressing them, the diversity of their functions, and recent advances. With this review, we aim to give an up-to-date analysis of the processes triggered by C3 activation fragments on different cell types in health and disease contexts.
Topics: Humans; Complement C3; Complement C3b; Receptors, Complement; Binding Sites; Complement Activation
PubMed: 36271889
DOI: 10.1111/imr.13147 -
Journal of the International Society of... Oct 2020Despite a substantial body of research, no clear best practice guidelines exist for the assessment of hydration in athletes. Body water is stored in and shifted between... (Review)
Review
BACKGROUND
Despite a substantial body of research, no clear best practice guidelines exist for the assessment of hydration in athletes. Body water is stored in and shifted between different sites throughout the body complicating hydration assessment. This review seeks to highlight the unique strengths and limitations of various hydration assessment methods described in the literature as well as providing best practice guidelines.
MAIN BODY
There is a plethora of methods that range in validity and reliability, including complicated and invasive methods (i.e. neutron activation analysis and stable isotope dilution), to moderately invasive blood, urine and salivary variables, progressing to non-invasive metrics such as tear osmolality, body mass, bioimpedance analysis, and sensation of thirst. Any single assessment of hydration status is problematic. Instead, the recommended approach is to use a combination, which have complementary strengths, which increase accuracy and validity. If methods such as salivary variables, urine colour, vital signs and sensation of thirst are utilised in isolation, great care must be taken due to their lack of sensitivity, reliability and/or accuracy. Detailed assessments such as neutron activation and stable isotope dilution analysis are highly accurate but expensive, with significant time delays due to data analysis providing little potential for immediate action. While alternative variables such as hormonal and electrolyte concentration, bioimpedance and tear osmolality require further research to determine their validity and reliability before inclusion into any test battery.
CONCLUSION
To improve best practice additional comprehensive research is required to further the scientific understanding of evaluating hydration status.
Topics: Absorptiometry, Photon; Blood Physiological Phenomena; Body Mass Index; Body Water; Dehydration; Drinking; Electric Impedance; Hematocrit; Hormones; Humans; Neutron Activation Analysis; Osmolar Concentration; Saliva; Serum; Sodium; Sports; Tears; Thirst; Urinalysis; Vital Signs
PubMed: 33126891
DOI: 10.1186/s12970-020-00381-6 -
BMB Reports Dec 2014Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing. Integrins also function as signal transducing receptors... (Review)
Review
Integrin-mediated cell adhesion is important for development, immune responses, hemostasis and wound healing. Integrins also function as signal transducing receptors that can control intracellular pathways that regulate cell survival, proliferation, and cell fate. Conversely, cells can modulate the affinity of integrins for their ligands a process operationally defined as integrin activation. Analysis of activation of integrins has now provided a detailed molecular understanding of this unique form of "inside-out" signal transduction and revealed new paradigms of how transmembrane domains (TMD) can transmit long range allosteric changes in transmembrane proteins. Here, we will review how talin and mediates integrin activation and how the integrin TMD can transmit these inside out signals.
Topics: Allosteric Regulation; Cell Adhesion; Humans; Integrins; Protein Binding; Protein Structure, Tertiary; Talin
PubMed: 25388208
DOI: 10.5483/bmbrep.2014.47.12.241 -
Blood Advances Apr 2020Human natural killer (NK) cells in peripheral blood perform many functions, and classification of specific subsets has been a longstanding goal. We report single-cell...
Human natural killer (NK) cells in peripheral blood perform many functions, and classification of specific subsets has been a longstanding goal. We report single-cell RNA sequencing of NK cells, comparing gene expression in unstimulated and interleukin (IL)-2-activated cells from healthy cytomegalovirus (CMV)-negative donors. Three NK cell subsets resembled well-described populations; CD56brightCD16-, CD56dimCD16+CD57-, and CD56dimCD16+CD57+. CD56dimCD16+CD57- cells subdivided to include a population with higher chemokine mRNA and increased frequency of killer-cell immunoglobulin-like receptor expression. Three novel human blood NK cell populations were identified: a population of type I interferon-responding NK cells that were CD56neg; a population exhibiting a cytokine-induced memory-like phenotype, including increased granzyme B mRNA in response to IL-2; and finally, a small population, with low ribosomal expression, downregulation of oxidative phosphorylation, and high levels of immediate early response genes indicative of cellular activation. Analysis of CMV+ donors established that CMV altered the proportion of NK cells in each subset, especially an increase in adaptive NK cells, as well as gene regulation within each subset. Together, these data establish an unexpected diversity in blood NK cells and provide a new framework for analyzing NK cell responses in health and disease.
Topics: Cytomegalovirus; Cytomegalovirus Infections; Humans; Killer Cells, Natural; Receptors, KIR; Sequence Analysis, RNA
PubMed: 32271902
DOI: 10.1182/bloodadvances.2019000699 -
Journal of Advanced Research Feb 2023Increasing evidence demonstrates that the activation states and diverse spectrum of macrophage subtypes display dynamic heterogeneity in the tumor microenvironment,...
Integrated immunogenomic analysis of single-cell and bulk tissue transcriptome profiling unravels a macrophage activation paradigm associated with immunologically and clinically distinct behaviors in ovarian cancer.
INTRODUCTION
Increasing evidence demonstrates that the activation states and diverse spectrum of macrophage subtypes display dynamic heterogeneity in the tumor microenvironment, which plays a critical role in a variety of cancer types.
OBJECTIVES
To investigate the heterogeneity and the homeostasis of different macrophage subtypes, as well as their effect on biological and clinical manifestations of ovarian cancer (OV).
METHOD
Integrated immunogenomic analysis of single-cell and bulk tissuetranscriptome profiling was performed to systematically investigate the association between macrophage activation and prognostic and therapeutic efficacy. Consensus clustering analysis was used to define novel macrophage subtypes. An artificial neural network was used to simulate the dynamic activation of macrophages.
RESULTS
The pan-cohort results suggested that high relative infiltration abundance of M0 and M1 macrophages was associated with improved outcome and therapeutic efficacy. However, it was the opposite for M2 macrophages. Unsupervised consensus clustering analysis revealed two OV subgroups characterized by a balance between M0, M1 and M2 macrophages with distinct clinical and immunological behaviors. Finally, a macrophage polarization-derived artificial neural network model was proposed to serve as a robust prognostic factor and predictive biomarker for therapeutic efficacy, which was validated in different independent patient cohorts.
CONCLUSION
The present study provides a new understanding of macrophage heterogeneity and its association with OV prognosis and underlines the future clinical potential of a macrophage activation model for tumor prevention and treatment.
Topics: Humans; Female; Macrophage Activation; Macrophages; Transcriptome; Gene Expression Profiling; Ovarian Neoplasms; Tumor Microenvironment
PubMed: 36725186
DOI: 10.1016/j.jare.2022.04.006 -
Cell Reports Sep 2020Single-nucleus RNA sequencing (snRNA-seq) is used as an alternative to single-cell RNA-seq, as it allows transcriptomic profiling of frozen tissue. However, it is...
Single-nucleus RNA sequencing (snRNA-seq) is used as an alternative to single-cell RNA-seq, as it allows transcriptomic profiling of frozen tissue. However, it is unclear whether snRNA-seq is able to detect cellular state in human tissue. Indeed, snRNA-seq analyses of human brain samples have failed to detect a consistent microglial activation signature in Alzheimer's disease. Our comparison of microglia from single cells and single nuclei of four human subjects reveals that, although most genes show similar relative abundances in cells and nuclei, a small population of genes (∼1%) is depleted in nuclei compared to whole cells. This population is enriched for genes previously implicated in microglial activation, including APOE, CST3, SPP1, and CD74, comprising 18% of previously identified microglial-disease-associated genes. Given the low sensitivity of snRNA-seq to detect many activation genes, we conclude that snRNA-seq is not suited for detecting cellular activation in microglia in human disease.
Topics: Gene Expression Profiling; Humans; Microglia; Sequence Analysis, RNA; Single-Cell Analysis
PubMed: 32997994
DOI: 10.1016/j.celrep.2020.108189 -
Frontiers in Immunology 2019T-regulatory cells (Tregs) represent a unique subpopulation of helper T-cells by maintaining immune equilibrium using various mechanisms. The role of T-cell receptors... (Review)
Review
T-regulatory cells (Tregs) represent a unique subpopulation of helper T-cells by maintaining immune equilibrium using various mechanisms. The role of T-cell receptors (TCR) in providing homeostasis and activation of conventional T-cells is well-known; however, for Tregs, this area is understudied. In the last two decades, evidence has accumulated to confirm the importance of the TCR in Treg homeostasis and antigen-specific immune response regulation. In this review, we describe the current view of Treg subset heterogeneity, homeostasis and function in the context of TCR involvement. Recent studies of the TCR repertoire of Tregs, combined with single-cell gene expression analysis, revealed the importance of TCR specificity in shaping Treg phenotype diversity, their functions and homeostatic maintenance in various tissues. We propose that Tregs, like conventional T-helper cells, act to a great extent in an antigen-specific manner, which is provided by a specific distribution of Tregs in niches.
Topics: Animals; Homeostasis; Humans; Lymphocyte Activation; Receptors, Antigen, T-Cell; T-Lymphocytes, Regulatory
PubMed: 31993063
DOI: 10.3389/fimmu.2019.03100 -
Scientific Data Dec 2023The UCLA Cosmochemistry Database was initiated as part of a data-rescue and -storage project aimed at archiving a variety of cosmochemical data acquired at University of...
The UCLA Cosmochemistry Database was initiated as part of a data-rescue and -storage project aimed at archiving a variety of cosmochemical data acquired at University of California, Los Angeles (UCLA). The data collection includes elemental compositions of extraterrestrial materials analyzed by UCLA cosmochemists over the last five decades. The analytical techniques include atomic absorption spectrometry (AAS) and neutron activation analysis (NAA) at UCLA. The data collection is stored on the Astromaterials Data System (Astromat). We provide both interactive tables and downloadable datasheets for users to access all data. The UCLA Cosmochemistry Database archives cosmochemical data that are essential tools for increasing our understanding of the nature and origin of extraterrestrial materials. Future studies can reference the data collection in the examination, analysis, and classification of newly acquired extraterrestrial samples.
PubMed: 38062064
DOI: 10.1038/s41597-023-02807-7 -
Molecular Cancer Feb 2022Unlike autosomal tumor suppressors, X-linked tumor suppressors can be inactivated by a single hit due to X-chromosome inactivation (XCI). Here, we argue that targeted...
BACKGROUND
Unlike autosomal tumor suppressors, X-linked tumor suppressors can be inactivated by a single hit due to X-chromosome inactivation (XCI). Here, we argue that targeted reactivation of the non-mutated allele from XCI offers a potential therapy for female breast cancers.
METHODS
Towards this goal, we developed a dual CRISPR interference and activation (CRISPRi/a) approach for simultaneously silencing and reactivating multiple X-linked genes using two orthogonal, nuclease-deficient CRISPR/Cas9 (dCas9) proteins.
RESULTS
Using Streptococcus pyogenes dCas9-KRAB for silencing XIST and Staphylococcus aureus dCas9-VPR for activating FOXP3, we achieved CRISPR activation of FOXP3 in various cell lines of human female breast cancers. In human breast cancer HCC202 cells, which express a synonymous heterozygous mutation in the coding region of FOXP3, simultaneous silencing of XIST from XCI led to enhanced and prolonged FOXP3 activation. Also, reactivation of endogenous FOXP3 in breast cancer cells by CRISPRi/a inhibited tumor growth in vitro and in vivo. We further optimized CRISPRa by fusing dCas9 to the demethylase TET1 and observed enhanced FOXP3 activation. Analysis of the conserved CpG-rich region of FOXP3 intron 1 confirmed that CRISPRi/a-mediated simultaneous FOXP3 activation and XIST silencing were accompanied by elevated H4 acetylation, including H4K5ac, H4K8ac, and H4K16ac, and H3K4me3 and lower DNA methylation. This indicates that CRISPRi/a targeting to XIST and FOXP3 loci alters their transcription and their nearby epigenetic modifications.
CONCLUSIONS
The simultaneous activation and repression of the X-linked, endogenous FOXP3 and XIST from XCI offers a useful research tool and a potential therapeutic for female breast cancers.
Topics: Breast Neoplasms; Cell Line; DNA Methylation; Female; Forkhead Transcription Factors; Genes, X-Linked; Humans; Mixed Function Oxygenases; Proto-Oncogene Proteins
PubMed: 35130925
DOI: 10.1186/s12943-021-01472-x