ABSTRACT
Cyclophosphamide plus fludarabine (C/F) are currently used to improve the expansion and effectiveness of adoptive cell therapy (ACT). However, these chemotherapeutics cause pan-leukopenia and adverse events, suggesting that safer and more effective conditioning treatments are needed to improve ACT outcomes. Previously, we reported that varlilumab, a CD27-targeting antibody, mediates Treg -preferential T cell depletion, CD8-T cell dominant costimulation, and systemic immune activation in hCD27 transgenic mice and cancer patients. We reasoned that the activities induced by varlilumab may provide an effective conditioning regimen for ACT. Varlilumab pretreatment of hCD27 +/+mCD27 - /- mice resulted in prominent proliferation of transferred T cells isolated from wild-type mice. These studies uncovered a critical role for CD27 signaling for the expansion of transferred T cells, as transfer of T cells from CD27 deficient mice or treatment with a CD70 blocking antibody greatly reduced their proliferation. In this model, varlilumab depletes endogenous hCD27+/+ T cells and blocks their subsequent access to CD70, allowing for more CD70 costimulation available to the mCD27 +/+ transferred T cells. CD27-targeted depletion led to a greater expansion of transferred T cells compared to C/F conditioning and resulted in longer median survival and more cures than C/F conditioning in the E.G7 tumor model receiving OT-I cell therapy. We propose that translation of this work could be achieved through engineering of T cells for ACT to abrogate varlilumab binding but preserve CD70 ligation. Thus, varlilumab could be an option to chemotherapy as a conditioning regimen for ACT.
Subject(s)
Adoptive Transfer , Antibodies, Monoclonal, Humanized/pharmacology , Antibodies, Monoclonal/chemistry , Neoplasms/therapy , T-Lymphocytes/cytology , Tumor Necrosis Factor Receptor Superfamily, Member 7/chemistry , Animals , CD27 Ligand/immunology , CD4-Positive T-Lymphocytes/cytology , CD8-Positive T-Lymphocytes/cytology , Cell Line, Tumor , Cell Proliferation , Immune System , Immunotherapy , Lymphocyte Activation/immunology , Mice , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Neoplasms/metabolism , Signal Transduction , Transplantation Conditioning , Treatment OutcomeABSTRACT
BACKGROUND: Mast cells (MC) are powerful inflammatory immune sentinel cells that drive numerous allergic, inflammatory, and pruritic disorders when activated. MC-targeted therapies are approved in several disorders, yet many patients have limited benefit suggesting the need for approaches that more broadly inhibit MC activity. MCs require the KIT receptor and its ligand stem cell factor (SCF) for differentiation, maturation, and survival. Here we describe CDX-0159, an anti-KIT monoclonal antibody that potently suppresses MCs in human healthy volunteers. METHODS: CDX-0159-mediated KIT inhibition was tested in vitro using KIT-expressing immortalized cells and primary human mast cells. CDX-0159 safety and pharmacokinetics were evaluated in a 13-week good laboratory practice (GLP)-compliant cynomolgus macaque study. A single ascending dose (0.3, 1, 3, and 9 mg/kg), double-blinded placebo-controlled phase 1a human healthy volunteer study (n = 32) was conducted to evaluate the safety, pharmacokinetics, and pharmacodynamics of CDX-0159. RESULTS: CDX-0159 inhibits SCF-dependent KIT activation in vitro. Fc modifications in CDX-0159 led to elimination of effector function and reduced serum clearance. In cynomolgus macaques, multiple high doses were safely administered without a significant impact on hematology, a potential concern for KIT inhibitors. A single dose of CDX-0159 in healthy human subjects was generally well tolerated and demonstrated long antibody exposure. Importantly, CDX-0159 led to dose-dependent, profound suppression of plasma tryptase, a MC-specific protease associated with tissue MC burden, indicative of systemic MC suppression or ablation. CONCLUSION: CDX-0159 administration leads to systemic mast cell ablation and may represent a safe and novel approach to treat mast cell-driven disorders.
Subject(s)
Antibodies, Monoclonal , Mast Cells , Proto-Oncogene Proteins c-kit , Antibodies, Monoclonal/adverse effects , Antibodies, Monoclonal/pharmacology , Healthy Volunteers , Humans , Mast Cells/drug effects , Proto-Oncogene Proteins c-kit/antagonists & inhibitors , Stem Cell FactorABSTRACT
Pyoverdines (PVDs) are a class of siderophores produced mostly by members of the genus Pseudomonas. Their primary function is to accumulate, mobilize, and transport iron necessary for cell metabolism. Moreover, PVDs also play a crucial role in microbes' survival by mediating biofilm formation and virulence. In this review, we reorganize the information produced in recent years regarding PVDs biosynthesis and pathogenic mechanisms, since PVDs are extremely valuable compounds. Additionally, we summarize the therapeutic applications deriving from the PVDs' use and focus on their role as therapeutic target themselves. We assess the current biotechnological applications of different sectors and evaluate the state-of-the-art technology relating to the use of synthetic biology tools for pathway engineering. Finally, we review the most recent methods and techniques capable of identifying such molecules in complex matrices for drug-discovery purposes.
Subject(s)
Oligopeptides , Siderophores , Iron/metabolism , Oligopeptides/metabolism , Pseudomonas/metabolism , Pseudomonas aeruginosa/metabolism , Siderophores/metabolismABSTRACT
Children with hearing loss often attend inclusive preschool classrooms aimed at improving their spoken language skills. Although preschool classrooms are fertile environments for vocal interaction with peers, little is known about the dyadic processes that influence children's speech to one another and foster their language abilities and how these processes may vary in children with hearing loss. We used new objective measurement approaches to identify and quantify children's vocalizations during social contact, as determined by children's proximity and mutual orientation. The contributions of peer vocalizations to children's future vocalizations and language abilities were examined in oral language inclusion classrooms containing children with hearing loss who use hearing aids or cochlear implants and their typically hearing peers. Across over 600 hours of recorded vocal interactions of twenty-nine 2.5-3.5 year olds (16 girls) in three cohorts of children in a classroom, we found that vocalizations from each peer on a given observation predicted a child's vocalizations to that same peer on the subsequent observation. Children who produced more vocalizations to their peers had higher receptive and expressive language abilities, as measured by a standardized end-of-year language assessment. In fact, vocalizations from peers had an indirect association with end-of-year language abilities as mediated by children's vocalizations to peers. These findings did not vary as a function of hearing status. Overall, then, the results demonstrate the importance of dyadic peer vocal interactions for children's language use and abilities.
ABSTRACT
CD27 is a costimulatory molecule that provides a complementary target to the PD-1/PD-L1 checkpoint axis on T cells. Combining a CD27 agonist antibody with PD-1/PD-L1 blockade has shown synergistic antitumor activity in preclinical models, which led to clinical studies of the combination in cancer patients. We theorized that coupling CD27 costimulation with PD-1/PD-L1 blockade in a bispecific antibody (BsAb) may provide greater immune activating properties than combining the individual mAbs due to enhanced CD27 activation by cross-linking through PD-L1 and Fc receptors. To test this approach, we developed CDX-527, a tetravalent PD-L1xCD27 IgG1-scFv BsAb. CDX-527 potently inhibits PD-1 signaling and induces CD27-mediated T cell costimulation through PD-L1 cross-linking. In mixed lymphocyte reaction assays, CDX-527 is more potent than the combination of the parental antibodies, suggesting that cross-linking through both Fc receptors and PD-L1 results in enhanced CD27 agonist activity. CDX-527 was shown to mediate effector function against tumor cells overexpressing either CD27 or PD-L1. In human CD27 transgenic mice, we observed that antigen-specific T cell responses to a vaccine are greatly enhanced with a surrogate PD-L1xCD27 BsAb. Furthermore, the BsAb exhibits greater antitumor activity than the combination of the parental antibodies in a syngeneic lymphoma model. A pilot study of CDX-527 in cynomolgus macaques confirmed a mAb-like pharmacokinetic profile without noted toxicities. These studies demonstrate that CDX-527 effectively combines PD-1 blockade and CD27 costimulation into one molecule that is more potent than combination of the parental antibodies providing the rationale to advance this BsAb toward clinical studies in cancer patients.
Subject(s)
Antibodies, Bispecific/pharmacology , Antibody Formation , Immunotherapy/methods , Lymphoma, B-Cell/therapy , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Tumor Necrosis Factor Receptor Superfamily, Member 7/antagonists & inhibitors , Animals , Antibodies, Bispecific/chemistry , Humans , Lymphoma, B-Cell/immunology , Lymphoma, B-Cell/metabolism , Lymphoma, B-Cell/pathology , Macaca fascicularis , Male , Mice , Mice, TransgenicABSTRACT
Limitations of immunotherapy include poorly functioning events early in the immune response cycle, such as efficient antigen presentation and T cell priming. CD40 signaling in dendritic cells leads to upregulation of cell surface costimulatory and MHC molecules and the generation of cytokines, which promotes effective priming of CD8+ effector T cells while minimizing T cell anergy and the generation of regulatory T cells. This naturally occurs through interaction with CD40 ligand (CD40L) expressed on CD4+ T-helper cells. CD40 signaling can also be achieved using specific antibodies, leading to several agonist CD40 antibodies entering clinical development. Our approach to select a CD40 agonist antibody was to define a balanced profile between sufficiently strong immune stimulation and the untoward effects of systemic immune activation. CDX-1140 is a human IgG2 antibody that activates DCs and B cells and drives NFkB stimulation in a CD40-expressing reporter cell line. These activities are Fc-independent and are maintained using an F(ab')2 fragment of the antibody. CDX-1140 binds outside of the CD40L binding site, and addition of recombinant CD40L greatly enhances DC and B activation by CDX-1140, suggesting that CDX-1140 may act synergistically with naturally expressed CD40L. CDX-1140 also has both direct and immune-mediated anti-tumor activity in xenograft models. CDX-1140 does not promote cytokine production in whole blood assays and has good pharmacodynamic and safety profiles in cynomolgus macaques. These data support the potential of CDX-1140 as part of a cancer therapy regimen, and a phase 1 trial has recently commenced.
Subject(s)
Antibodies, Monoclonal/pharmacology , CD40 Antigens/agonists , Immunotherapy/methods , Neoplasms/therapy , Animals , Antibodies, Monoclonal/immunology , CD40 Antigens/immunology , CD40 Antigens/metabolism , CD40 Ligand/immunology , CD40 Ligand/metabolism , CHO Cells , Cell Line, Tumor , Cricetinae , Cricetulus , HEK293 Cells , Humans , Macaca fascicularis , Mice, SCID , Mice, Transgenic , Neoplasms/immunology , Neoplasms/metabolism , Signal Transduction/drug effects , Signal Transduction/immunology , T-Lymphocytes/immunology , T-Lymphocytes/metabolism , Xenograft Model Antitumor AssaysABSTRACT
CD27, a member of the TNFR superfamily, is constitutively expressed in most T cells and plays crucial roles in T cell effector functions. The costimulation and antitumor activity of CD27 agonistic Abs have been well documented in mouse models. Clinical testing of a human IgG1 anti-CD27 Ab, varlilumab (clone 1F5), is ongoing in cancer patients. In this study, we set out to further understand CD27 as an immunomodulatory target and to address the mechanism of antitumor efficacy using different IgG isotypes of 1F5 in human CD27-transgenic mice. 1F5mIgG1, the only isotype engaging inhibitory FcγRIIB expressed in B cells, elicited the most potent and broad immune response, but terminal differentiation, exhaustion, and apoptosis in the activated effector T cells were inevitable. Accordingly, this isotype was the most effective in eradicating BCL1 lymphoma but had limited efficacy in s.c. tumors. Conversely, 1F5mIgG2a, which interacts with cells expressing activating FcγRs, led to moderate immune activation, as well as to prominent reduction in the number and suppressive activity of regulatory T cells. These combined mechanisms imparted potent antitumor activity to 1F5mIgG2a, particularly against the s.c. tumors. 1F5hIgG1, varlilumab, showed balanced agonistic activity that was prominent at lower doses and depleting activity that was greater at higher doses. 1F5hIgG1 had good antitumor activity in all tumor models tested. Thus, both agonist and depleting properties contribute to the antitumor efficacy of CD27-targeted immunotherapy, and modulation of these activities in patients may be achieved by varying the dose and regimen.
Subject(s)
Antibodies, Monoclonal/therapeutic use , Antineoplastic Agents, Immunological/therapeutic use , Lymphocyte Depletion , Neoplasms, Experimental/drug therapy , T-Lymphocytes, Regulatory/immunology , Tumor Necrosis Factor Receptor Superfamily, Member 7/immunology , Animals , Antibodies, Monoclonal/immunology , Antibodies, Monoclonal, Humanized , Antineoplastic Agents, Immunological/immunology , Apoptosis , CD27 Ligand/immunology , Drug Screening Assays, Antitumor , Female , Humans , Immunoglobulin Isotypes/immunology , Immunoglobulin Isotypes/therapeutic use , Immunologic Memory , Immunotherapy , Lymphoma, B-Cell/drug therapy , Mice , Mice, Inbred BALB C , Mice, Transgenic , Mutation, Missense , Receptors, IgG/immunology , Receptors, IgG/metabolism , Specific Pathogen-Free Organisms , Tumor Microenvironment , Tumor Necrosis Factor Receptor Superfamily, Member 7/agonists , Tumor Necrosis Factor Receptor Superfamily, Member 7/antagonists & inhibitorsABSTRACT
Microalgae play a major role as primary producers in aquatic ecosystems. Cell signalling regulates their interactions with the environment and other organisms, yet this process in phytoplankton is poorly defined. Using the marine planktonic diatom Pseudo-nitzschia multistriata, we investigated the cell response to cues released during sexual reproduction, an event that demands strong regulatory mechanisms and impacts on population dynamics. We sequenced the genome of P. multistriata and performed phylogenomic and transcriptomic analyses, which allowed the definition of gene gains and losses, horizontal gene transfers, conservation and evolutionary rate of sex-related genes. We also identified a small number of conserved noncoding elements. Sexual reproduction impacted on cell cycle progression and induced an asymmetric response of the opposite mating types. G protein-coupled receptors and cyclic guanosine monophosphate (cGMP) are implicated in the response to sexual cues, which overall entails a modulation of cell cycle, meiosis-related and nutrient transporter genes, suggesting a fine control of nutrient uptake even under nutrient-replete conditions. The controllable life cycle and the genome sequence of P. multistriata allow the reconstruction of changes occurring in diatoms in a key phase of their life cycle, providing hints on the evolution and putative function of their genes and empowering studies on sexual reproduction.
Subject(s)
Biological Evolution , Diatoms/physiology , Biological Transport/genetics , Cell Cycle , Diatoms/genetics , Gene Expression Regulation, Developmental , Phylogeny , Population Dynamics , Reproduction/genetics , Signal TransductionABSTRACT
The CD70/CD27 pathway plays a significant role in the control of immunity and tolerance, and previous studies demonstrated that targeting murine CD27 (mCD27) with agonist mAbs can mediate antitumor efficacy. We sought to exploit the potential of this pathway for immunotherapy by developing 1F5, a fully human IgG1 mAb to human CD27 (hCD27) with agonist activity. We developed transgenic mice expressing hCD27 under control of its native promoter for in vivo testing of the Ab. The expression and regulation of hCD27 in hCD27-transgenic (hCD27-Tg) mice were consistent with the understood biology of CD27 in humans. In vitro, 1F5 effectively induced proliferation and cytokine production from hCD27-Tg-derived T cells when combined with TCR stimulation. Administration of 1F5 to hCD27-Tg mice enhanced Ag-specific CD8(+) T cell responses to protein vaccination comparably to an agonist anti-mCD27 mAb. In syngeneic mouse tumor models, 1F5 showed potent antitumor efficacy and induction of protective immunity, which was dependent on CD4(+) and CD8(+) T cells. The requirement of FcR engagement for the agonistic and antitumor activities of 1F5 was demonstrated using an aglycosylated version of the 1F5 mAb. These data with regard to the targeting of hCD27 are consistent with previous reports on targeting mCD27 and provide a rationale for the clinical development of the 1F5 mAb, for which studies in advanced cancer patients have been initiated under the name CDX-1127.
Subject(s)
Antibodies, Monoclonal/immunology , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Neoplasms/therapy , Tumor Necrosis Factor Receptor Superfamily, Member 7/immunology , Animals , Cell Proliferation , Humans , Immunoglobulin G/immunology , Immunotherapy , Lymphocyte Activation , Mice , Mice, Inbred BALB C , Mice, Inbred C3H , Mice, Inbred C57BL , Mice, Transgenic , Neoplasms/immunology , Receptors, Antigen, T-Cell/immunology , Tumor Necrosis Factor Receptor Superfamily, Member 7/agonists , Tumor Necrosis Factor Receptor Superfamily, Member 7/geneticsABSTRACT
Understanding the genetic structure of populations and the processes responsible for its spatial and temporal dynamics is vital for assessing species' adaptability and survival in changing environments. We investigate the genetic fingerprinting of blooming populations of the marine diatom Pseudo-nitzschia multistriata in the Gulf of Naples (Mediterranean Sea) from 2008 to 2020. Strains were genotyped using microsatellite fingerprinting and natural samples were also analysed with Microsatellite Pool-seq Barcoding based on Illumina sequencing of microsatellite loci. Both approaches revealed a clonal expansion event in 2013 and a more stable genetic structure during 2017-2020 compared to previous years. The identification of a mating type (MT) determination gene allowed to assign MT to strains isolated over the years. MTs were generally at equilibrium with two notable exceptions, including the clonal bloom of 2013. The populations exhibited linkage equilibrium in most blooms, indicating that sexual reproduction leads to genetic homogenization. Our findings show that P. multistriata blooms exhibit a dynamic genetic and demographic composition over time, most probably determined by deeper-layer cell inocula. Occasional clonal expansions and MT imbalances can potentially affect the persistence and ecological success of planktonic diatoms.
Subject(s)
Diatoms , Diatoms/genetics , Plankton/genetics , Reproduction/genetics , Cell Communication , Genetic StructuresABSTRACT
Immunization of cancer patients with vaccines containing full-length tumor Ags aims to elicit specific Abs and both CD4(+) and CD8(+) T cells. Vaccination with protein Ags, however, often elicits only CD4(+) T cell responses without inducing Ag-specific CD8(+) T cells, as exogenous protein is primarily presented to CD4(+) T cells. Recent data revealed that Ab-mediated targeting of protein Ags to cell surface receptors on dendritic cells could enhance the induction of both CD4(+) and CD8(+) T cells. We investigated in this study if these observations were applicable to NY-ESO-1, a cancer-testis Ag widely used in clinical cancer vaccine trials. We generated two novel targeting proteins consisting of the full-length NY-ESO-1 fused to the C terminus of two human mAbs against the human mannose receptor and DEC-205, both internalizing molecules expressed on APC. These targeting proteins were evaluated for their ability to activate NY-ESO-1-specific human CD4(+) and CD8(+) T cells in vitro. Both targeted NY-ESO-1 proteins rapidly bound to their respective targets on APC. Whereas nontargeted and Ab-targeted NY-ESO-1 proteins similarly activated CD4(+) T cells, cross-presentation to CD8(+) T cells was only efficiently induced by targeted NY-ESO-1. In addition, both mannose receptor and DEC-205 targeting elicited specific CD4(+) and CD8(+) T cells from PBLs of cancer patients. Receptor-specific delivery of NY-ESO-1 to APC appears to be a promising vaccination strategy to efficiently generate integrated and broad Ag-specific immune responses against NY-ESO-1 in cancer patients.
Subject(s)
Antigens, CD/metabolism , Antigens, Neoplasm/immunology , CD4-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/immunology , Lectins, C-Type/metabolism , Mannose-Binding Lectins/metabolism , Membrane Proteins/immunology , Receptors, Cell Surface/metabolism , Amino Acid Sequence , Antigen-Presenting Cells/immunology , Antigen-Presenting Cells/metabolism , Antigens, CD/genetics , Antigens, CD/immunology , Antigens, Neoplasm/genetics , Antigens, Neoplasm/metabolism , CD4-Positive T-Lymphocytes/metabolism , CD8-Positive T-Lymphocytes/metabolism , Cell Line , Clone Cells , Cross-Priming/genetics , Cross-Priming/immunology , Cytotoxicity Tests, Immunologic , Dendritic Cells/immunology , Dendritic Cells/metabolism , Humans , Lectins, C-Type/genetics , Lectins, C-Type/immunology , Mannose Receptor , Mannose-Binding Lectins/genetics , Mannose-Binding Lectins/immunology , Membrane Proteins/genetics , Membrane Proteins/metabolism , Minor Histocompatibility Antigens , Molecular Sequence Data , Protein Binding/immunology , Receptors, Cell Surface/genetics , Receptors, Cell Surface/immunology , Recombinant Fusion Proteins/genetics , Recombinant Fusion Proteins/immunology , Recombinant Fusion Proteins/metabolismABSTRACT
Metals are essential in our daily lives and have a finite supply, being simultaneously contaminants of concern. The current carbon emissions and environmental impact of mining are untenable. We need to reclaim metals sustainably from secondary resources, like waste. Biotechnology can be applied in metal recovery from waste streams like fly ashes and bottom ashes of municipal solid waste incineration (MSWI). They represent substantial substance flows, with roughly 46 million tons of MSWI ashes produced annually globally, equivalent in elemental richness to low-grade ores for metal recovery. Next-generation methods for resource recovery, as in particular bioleaching, give the opportunity to recover critical materials and metals, appropriately purified for noble applications, in waste treatment chains inspired by circular economy thinking. In this critical review, we can identify three main lines of discussion: (1) MSWI material characterization and related environmental issues; (2) currently available processes for recycling and metal recovery; and (3) microbially assisted processes for potential recycling and metal recovery. Research trends are chiefly oriented to the potential exploitation of bioprocesses in the industry. Biotechnology for resource recovery shows increasing effectiveness especially downstream the production chains, i.e., in the waste management sector. Therefore, this critical discussion will help assessing the industrial potential of biotechnology for urban mining of municipal, post-combustion waste.
Subject(s)
Metals, Heavy , Refuse Disposal , Waste Management , Solid Waste/analysis , Incineration , Waste Management/methods , Metals , Coal Ash , Carbon , Metals, Heavy/analysisABSTRACT
Homophily, the tendency for individuals to preferentially interact with others similar to themselves is typically documented via self-report and, for children, adult report. Few studies have investigated homophily directly using objective measures of social movement. We quantified homophily in children with developmental disabilities (DD) and typical development (TD) using objective measures of position/orientation in preschool inclusion classrooms, designed to promote interaction between these groups of children. Objective measurements were collected using ultra-wideband radio-frequency tracking to determine social approach and social contact, measures of social movement and interaction. Observations of 77 preschoolers (47 with DD, and 30 TD) were conducted in eight inclusion classrooms on a total of 26 days. We compared DD and TD groups with respect to how children approached and shared time in social contact with peers using mixed-effects models. Children in concordant dyads (DD-DD and TD-TD) both moved toward each other at higher velocities and spent greater time in social contact than discordant dyads (DD-TD), evidencing homophily. DD-DD dyads spent less time in social contact than TD-TD dyads but were comparable to TD-TD dyads in their social approach velocities. Children's preference for similar peers appears to be a pervasive feature of their naturalistic interactions.
Subject(s)
Child Development , Developmental Disabilities , Adult , Humans , Child , Child, PreschoolABSTRACT
Protein vaccines for T-cell immunity are not being prioritized because of poor immunogenicity. To overcome this hurdle, proteins are being targeted to maturing dendritic cells (DCs) within monoclonal antibodies (mAbs) to DC receptors. To extend the concept to humans, we immunized human immunoglobulin-expressing mice with human DEC205 (hDEC205) extracellular domain. 3D6 and 3G9 mAbs were selected for high-affinity binding to hDEC205. In addition, CD11c promoter hDEC205 transgenic mice were generated, and 3G9 was selectively targeted to DCs in these animals. When mAb heavy chain was engineered to express HIV Gag p24, the fusion mAb induced interferon-γ- and interleukin-2-producing CD4(+) T cells in hDEC205 transgenic mice, if polynocinic polycytidylic acid was coadministered as an adjuvant. The T-cell response was broad, recognizing at least 3 Gag peptides, and high titers of anti-human immunoglobulin G antibody were made. Anti-hDEC205 also improved the cross-presentation of Gag to primed CD8(+) T cells from HIV-infected individuals. In all tests, 3D6 and 3G9 targeting greatly enhanced immunization relative to nonbinding control mAb. These results provide preclinical evidence that in vivo hDEC205 targeting increases the efficiency with which proteins elicit specific immunity, setting the stage for proof-of-concept studies of these new protein vaccines in human subjects.
Subject(s)
Antigens, CD/immunology , Dendritic Cells/immunology , Dendritic Cells/virology , HIV Core Protein p24/immunology , HIV-1/immunology , Lectins, C-Type/immunology , Receptors, Cell Surface/immunology , AIDS Vaccines/genetics , AIDS Vaccines/immunology , Animals , Antibodies, Monoclonal , Antigens, CD/genetics , Base Sequence , Cross-Priming , DNA Primers/genetics , HIV Core Protein p24/genetics , HIV-1/genetics , Humans , Immunity, Cellular , Immunity, Humoral , Lectins, C-Type/genetics , Mice , Mice, Inbred C57BL , Mice, Transgenic , Minor Histocompatibility Antigens , Receptors, Cell Surface/genetics , Recombinant Proteins/genetics , Recombinant Proteins/immunology , Simian Immunodeficiency Virus/genetics , Simian Immunodeficiency Virus/immunology , Vaccines, Subunit/genetics , Vaccines, Subunit/immunologyABSTRACT
Children's preschool experiences have consequences for development. However, it is not clear how children's real-time interactions with peers affect their language development; nor is it clear whether these processes differ between children with autism spectrum disorder (ASD) and two other groups of children, those with general developmental delays (DD) and typically developing (TD) children. We used objective measures of movement and vocalizations to quantify children's real-time dyadic vocal interactions and quantify classroom social networks. Participants included 56 preschoolers (22 female; M = 50.14 months) in five inclusive classrooms for children with ASD or DD and their TD peers. Each class was observed monthly on two to five occasions. Overall, children vocalized more to peers who had vocalized more to them in the previous observation. These dyadic vocalization patterns were associated with group differences in social network analyses. Modularity, the cohesiveness of group ties, was lower among children with ASD than it was among TD children or children with DD. Individually, children with ASD exhibited lower total levels of vocalizations with peers (lower degree centrality) than TD children and children with DD. In an exploratory analysis with a subset of the participants, children's degree centrality was strongly associated with their end-of-year assessed language abilities, even when accounting for mean differences between groups. Findings highlight the impact peers and social networks play in real-time language use and in the developing language abilities of children with ASD in inclusion classrooms. LAY SUMMARY: This study objectively measured associations between children's peer vocal interactions and assessed language abilities in inclusion classrooms for children with autism spectrum disorder (ASD) and their peers. All children benefited from peers talking to them, but children with ASD were less central to classroom speech networks than were typically developing children. Children's centrality to social speech networks, regardless of ASD status, was associated with assessed language abilities.
Subject(s)
Autism Spectrum Disorder , Autistic Disorder , Aptitude , Child , Child, Preschool , Female , Humans , Language , Language DevelopmentABSTRACT
Everyday language use, including the pronouns people choose when speaking to romantic partners, may reflect underlying aspects of relationship functioning and may have important implications for understanding couple conflict and dating aggression more generally. The current study measured couples' hour-to-hour "we," "I," and "you" speech in daily life and examined symmetry in pronoun use, or the extent to which partners mirror each other in the frequency of the pronouns they use. First, we examined associations between symmetry in pronoun use and overall levels of dating aggression. Second, we investigated whether aggressive couples evidence patterns of pronoun use distinct from nonaggressive couples when they become annoyed with each other. Multilevel models showed that symmetry in "we" speech and symmetry in "I" speech each were related to lower levels of dating aggression. In addition, symmetry in couples' "you" speech increased during hours of annoyance, but only among those couples reporting high levels of aggression in their relationships. These results demonstrate how everyday language use relates to couples' general tendencies toward aggression and how such patterns are linked to ongoing fluctuations in the emotional tone of the relationship. The discussion focuses on implications for intervention and the use of novel ambulatory assessment methods for capturing couple processes in real-life contexts. (PsycInfo Database Record (c) 2021 APA, all rights reserved).
Subject(s)
Aggression/psychology , Interpersonal Relations , Language , Sexual Partners/psychology , Adult , Female , Humans , MaleABSTRACT
This study is an exploration of engagement in outpatient medical care, medication utilization, and barriers to treatment utilization among 24 predominantly low-income, ethnic minority adults who were admitted to an urban hospital for HIV-related illnesses. A semi-structured interview was administered during the sample's hospital stay to explore patterns of service use and identify barriers to care. The majority of the sample was connected to an outpatient provider and satisfied with the care they received; however, most missed treatment appointments and skipped medication dosages. Health and treatment-related barriers, competing demands, and co-occurring mental health symptoms and illicit substance use were identified as barriers to care. Multiple obstacles indigenous to the individual, their treatment, and the environment prevented consistent treatment use among an economically disadvantaged ethnic minority sample: Implications and future directions in engaging vulnerable populations into health care for HIV are discussed.
Subject(s)
HIV Infections/psychology , HIV Infections/therapy , Health Behavior , Health Services Accessibility , Patient Compliance/psychology , Adult , Black or African American/psychology , Ambulatory Care/statistics & numerical data , Comorbidity , Female , HIV Infections/ethnology , Health Behavior/ethnology , Hispanic or Latino/psychology , Humans , Interviews as Topic , Male , Middle Aged , New York City/epidemiology , Patient Compliance/ethnology , Poverty , Substance-Related Disorders/epidemiology , Urban PopulationABSTRACT
PURPOSE: Rindopepimut is a vaccine targeting the tumor-specific EGF driver mutation, EGFRvIII. The ReACT study investigated whether the addition of rindopepimut to standard bevacizumab improved outcome for patients with relapsed, EGFRvIII-positive glioblastoma. PATIENTS AND METHODS: In this double-blind, randomized, phase II study (NCT01498328) conducted at 26 hospitals in the United States, bevacizumab-naïve patients with recurrent EGFRvIII-positive glioblastoma were randomized to receive rindopepimut or a control injection of keyhole limpet hemocyanin, each concurrent with bevacizumab. The primary endpoint was 6-month progression-free survival (PFS6) by central review with a one-sided significance of 0.2. RESULTS: Between May 2012 and 2014, 73 patients were randomized (36 rindopepimut, 37 control). Rindopepimut toxicity included transient, low-grade local reactions. As primary endpoint, PFS6 was 28% (10/36) for rindopepimut compared with 16% (6/37) for control (P = 0.12, one-sided). Secondary and exploratory endpoints also favored the rindopepimut group including a statistically significant survival advantage [HR, 0.53; 95% confidence interval (CI), 0.32-0.88; two-sided log-rank P = 0.01], a higher ORR [30% (9/30) vs. 18% (6/34; P = 0.38)], median duration of response [7.8 months (95% CI, 3.5-22.2) vs. 5.6 (95% CI, 3.7-7.4)], and ability to discontinue steroids for ≥6 months [33% (6/18) vs. 0% (0/19)]. Eighty percent of rindopepimut-treated patients achieved robust anti-EGFRvIII titers (≥1:12,800), which were associated with prolonged survival (HR = 0.17; 95% CI, 0.07-0.45; P < 0.0001). CONCLUSIONS: Our randomized trial supports the potential for targeted immunotherapy among patients with GBM, but the therapeutic benefit requires validation due to the small sample size and potential heterogeneity of bevacizumab response among recurrent patients with GBM.See related commentary by Wick and Wagener, p. 1535.
Subject(s)
Brain Neoplasms , Glioblastoma , Bevacizumab , Cancer Vaccines , Double-Blind Method , ErbB Receptors , Humans , Neoplasm Recurrence, Local , Patients , Vaccines, SubunitABSTRACT
Generating responses to tumor antigens poses a challenge for immunotherapy. This phase II trial (NCT02129075) tested fms-like tyrosine kinase 3 (Flt3) ligand pre-treatment enhancement of responses to dendritic cell (DC)-targeting vaccines. We evaluated a regimen of Flt3L (CDX-301) to increase DCs and other antigen-presenting cells, poly-ICLC (TLR3 agonist that activates DCs) and a vaccine comprising anti-DEC-205-NY-ESO-1, a fusion antibody targeting CD205, linked to NY-ESO-1. High-risk melanoma patients were randomized to vaccine, with and without CDX-301. The end point was immune response to NY-ESO-1. Flt3L increased peripheral monocytes and conventional DCs (cDCs), including cross-presenting cDC1 and cDC2 and plasmacytoid DCs. Significant increases in humoral and T-cell responses and activation of DCs, natural killer cells and T cells were elicited. Transcriptional analyses revealed gene signatures associated with CDX-301 induction of an early, durable immune response. This study reveals in vivo effects of Flt3L on innate immune cells in the setting of vaccination, leading to an immunogenic vaccine regimen.
Subject(s)
Cancer Vaccines , Melanoma , Dendritic Cells , Humans , Immunity , Membrane Proteins , fms-Like Tyrosine Kinase 3ABSTRACT
Genetic diversity is what selection acts on, thus shaping the adaptive potential of populations. We studied micro-evolutionary patterns of the key planktonic diatom Pseudo-nitzschia multistriata at a long-term sampling site over 2 consecutive years by genotyping isolates with 22 microsatellite markers. We show that both sex and vegetative growth interplay in shaping intraspecific diversity. We document a brief but massive demographic and clonal expansion driven by strains of the same mating type. The analysis of an extended data set (6 years) indicates that the genetic fingerprint of P. multistriata changed over time with a nonlinear pattern, with intermittent periods of weak and strong diversification related to the temporary predominance of clonal expansions over sexual recombination. These dynamics, rarely documented for phytoplankton, contribute to the understanding of bloom formation and of the mechanisms that drive microevolution in diatoms.