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BackgroundDiacylglycerol kinases (DGKs) play a role in regulating the responsiveness of immune cells to activating stimuli, making them an emerging immunotherapeutic target. DGKs phosphorylate the signaling lipid diacylglycerol (DAG) to produce phosphatidic acid, thus depleting the pool of DAG that can serve as a second messenger within a cell. In T cells, DAG is rapidly generated following T cell receptor (TCR) activation, forming a gradient around the immunological synapse. DAG accumulation leads to the activation of DAG-binding proteins that are critical for T cell activation and effector function, including the Ras/ERK activating guanine nucleotide-exchange factor, RasGRP1. Blocking DGK activity can delay the metabolism of DAG, leading to enhanced downstream signaling, thus increasing the strength of T cell responses to TCR stimulation and potentially protecting against T cell exhaustion. Notably, DGKs have also been shown to regulate DAG signaling in NK cells, extending the prospective anti-tumor capacity of these targets beyond T cells.MethodsTranscript analysis and flow cytometry-based profiling were used to assess the expression of different DGK isoforms in human peripheral blood mononuclear cells (PBMCs) and isolated primary CD8 T and NK cells. Efficacy of DGK inhibition in T and NK cells was examined using CRISPR-based deletion strategies or small molecules selectively targeting DGKα and/or DGKζ isoforms in various in vitro functional assays.ResultsAnalysis of PBMCs by flow cytometry confirmed expression of both DGKα and DGKζ in CD8 T cells, in alignment with transcript data from purified CD8 T cells. T cell receptor stimulation using CD3/CD28 binding antibody complexes showed increased ERK phosphorylation, cytokine production, proliferation, and CD69 expression in T cells treated with DGKα, DGKζ, or dual DGKα/ζ-inhibitors. Additionally, CD8 T cell cytokine production increased with DGK inhibition when PBMCs were treated with HLA class I-restricted viral peptides. Similarly, NK cells expressed both DGKα and DGKζ isoforms and showed increased cytokine production upon DGK inhibitor treatment in the presence of stimuli. In both T and NK cell systems, the greatest increases in activity occurred when DGKα and DGKζ were simultaneously inhibited. High throughput screening of DGK inhibitors using the Jurkat T cell line further indicated that TCR stimulation-mediated effects on IL-2 production were more robust using dual DGKα/ζ inhibitors.ConclusionsInhibition of DGKα and DGKζ increased the activation potential of T cells and NK cells, with simultaneous inhibition of DGKα and DGKζ showing the strongest effects, based on in vitro analysis.

BackgroundTIGIT is an inhibitory receptor expressed on T and NK cell subsets that outcompetes an activating receptor, CD226, for shared ligands. The TIGIT checkpoint blockade field has focused on evaluating efficacy and elucidating mechanisms of action related to Fc-enabled antibody formats. Here, we report efficacy and pharmacology associated with clinical and mouse tool Fc-silent anti-TIGIT antibodies relative to Fc-enabled counterparts.MethodsHuman NSCLC tumor (pre-treatment stages I-IV) and mouse MC38 tumor and tumor-draining lymph node (tdLN) cell suspensions were interrogated for expression of TIGIT and associated receptors by flow cytometry. Anti-tumor efficacy and pharmacodynamic changes were assessed using tool Fc-silent or Fc-enabled anti-mouse TIGIT antibodies in the MC38 tumor model. The ability of human TIGIT-specific clinical antibodies that are Fc-silent (domvanalimab) or Fc-enabled (AB308) to promote NK-mediated antibody-dependent cell-mediated cytotoxicity (ADCC) was evaluated using an in vitro co-culture system and by measuring absolute T cell counts in longitudinal peripheral blood patient samples from Phase 1 dose escalation clinical trials NCT03628677 and NCT04772989. Anecdotal clinical outcomes in two patients from NCT03628677 receiving domvanalimab in combination with an anti-PD-1 antibody, zimberelimab, are also reported.ResultsHuman and mouse tumor-infiltrating lymphocytes express TIGIT and CD226 on regulatory T cells (Treg), CD4+ non-Treg, and on CD8+ T cells with tumor-reactive or exhausted/dysfunctional phenotypes. In mice, combining Fc-silent or Fc-enabled anti-TIGIT with anti-PD-1 antibodies resulted in enhanced tumor control, but by mechanisms that differentially shape the tumor microenvironment. Fc-silent anti-TIGIT did not deplete Treg yet promoted activation of tumor-specific precursor-exhausted CD8+ populations in the tdLN. In contrast, Fc-enabled anti-TIGIT depleted Treg in mice. Consistent with the murine system, Fc-enabled human TIGIT-specific antibody AB308 induced ADCC against TIGIT-expressing human Treg in vitro, with preferential depletion of a Helios+ Treg subset with an activated/effector phenotype. In humans, significant and stable decreases in Treg were measured in the peripheral blood of cancer patients treated with AB308. In contrast, domvanalimab did not deplete Treg in vitro, and patients treated with domvanalimab in combination with anti-PD-1 antibody zimberelimab experienced partial responses while maintaining stable peripheral Treg frequencies on treatment.ConclusionsWe demonstrate that Fc-silent anti-TIGIT antibodies potentiate activation of tumor-specific T cells and anti-tumor efficacy without depleting Treg (figure 1). These data provide critical insights related to activity of anti-TIGIT antibodies lacking Fc functionality, such as domvanalimab.Ethics ApprovalAnimal studies were performed at Arcus Biosciences in accordance with federal, state, and institutional guidelines and were approved by Arcus Biosciences’ Institutional Animal Care and Use Committee. Dissociated tumor biopsies were obtained from Discovery Life Sciences with informed written consent and according to Institutional Review Board approved guidelines in accordance with the Declaration of Helsinki. Clinical studies were performed in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. Protocols and amendments were approved by institutional review boards for each study site. All patients provided written informed consent.Abstract 475 Figure 1

My project engages with the Western archives’ problematic colonial legacies of erasure, omission, and dominant culture representation of subalterns. The multiple archives (i.e. state-sanctioned, government, and mainstream media) that detail immigration in the United States are missing Chicanx/Latinx perspectives or, worse, documenting only their death. Therefore, my thesis calls for alternative archival methodologies and ontologies that provide what we might consider a “living” engagement for the subalternized. My analysis is both interdisciplinary and multimodal, for I bring together an actually-existing archive called Esencial Colorado with Valeria Luiselli’s Lost Children Archive and Tell Me How It Ends: An Essay in 40 Questions in order to consider how labor activists, promotoras, artists, child refugees, and Chicanx/Latinx agricultural workers work to address the archive’s aforementioned issues. In my primary “texts,” I identify the “testimonio archive” that bridges alternative archival and literary engagement in the critique of the Western archive.

The Somerset Field is located within southwestern Bexar and northern Atascosa counties, in south central Texas. This portion of the northeastern Maverick Basin has not been well studied. For over 100 years, the Upper Cretaceous Olmos Formation, in the Somerset Oil Field, has been the primary target out of four separate producing zones, which are, in descending order, the Lower Escondido, o-1 and o-2 sands of the Olmos, and the Anacacho Limestone. The primary structure of the region is the graben system of the Balcones-Luling-Mexia fault system. The Luling Fault system transects the Somerset Oil Field. Data collected and analyzed includes two hundred and ninety-two electric logs and core samples from 23 wells. This data was used to construct structure contour and isopach maps and cross sections. The o-1 sand is comprised of very fine-grained to medium sand that is underlain by claystone and shale. Clay is also interbedded within the sands and the o-1 varies from moderately sorted to well sorted. Many of the original sedimentary structures have been destroyed by bioturbation, but Ophiomorpha was observed in some of the cores, and crossbeds rarely occurred. The sandstone contains foraminifera and aragonite oyster shells, as well as sulfur. The o-1 sand appears to be deltaic, with distributary mouth bars and the delta front being the underlying shales. The regional Bigfoot Unconformity does not truncate the o-1 sand, with the impermeable Escondido shales overlying the south west dipping o-1 sandstone. However, cross sections indicate that the Olmos Formation in the Somerset Field is probably misnamed and is the Escondido Formation. It should be referred to as the \"Olmos\" locally. The naming of the o-1and o-2 is retained with these findings. The cross sections also show a northeast to southwest striking graben in the northern part of the Somerset Field. Displacement is as much as 320 feet across the graben.

Alongside daily classes for members and walk-ins, Roots Yoga sets aside at least two days a month to host free classes for community members who are currently homeless or have experienced homelessness, employees who support the homeless, like case managers and social workers, and those active in addiction recovery programs.

Abby Elizabeth Schmidt's set of icons is displayed in \"Subsidized Starvation.\" | Thomas Joyce TTN Abby Elizabeth Schmidt spends 25 to 75 hours meticulously positioning hundreds to thousands of grains of rice, barley, wheat and corn kernels to formulate a single piece of art.

Purpose of study: Attention-deficit disorder (ADD) is one of the most common neurobehavioral disorders of children. It is usually first diagnosed in children and often lasts into adulthood. Children with ADD have trouble paying attention and controlling impulsive behaviors and in some cases are overly active. There is a need for a tool to assist parents and encourage task management in the morning and evening hours in the absence of medication. I propose that through design-creation and application of visual cues and messaging communication tools, ADD children can show an increase in development of attention skills through task management in the home.