Objectives: Bispecific antibodies targeting CD47 and PD-L1 (CD47 × PD-L1 BisAb) demonstrate efficacy against a range of solid cancers. While dual blockade negates anti-CD47-mediated toxicity, the effect of combined innate and adaptive immune activation on protective tumor-resident CD8 T cells has yet to be fully elucidated.
Methods: CD8 T cell populations were tracked upon CD47 × PD-L1 BisAb treatment in an orthotopic model of murine breast cancer where anti-tumor immunity is mediated by CD8 T cells.
Objective: To determine if universal access to care for military beneficiaries improves timing of presentation to prenatal care (PNC) in adolescent and young adult (AYA) pregnancies, improving maternal and neonatal outcomes.
Study Design: Retrospective descriptive cohort study, which assessed PNC initiation in eligible military beneficiaries: dependent daughters, active-duty women, and active-duty spouses aged 13 to 26 between January 2015 and December 2019, and subsequent adverse maternal and neonatal outcomes.
Results: The cohort included 4,557 eligible pregnancies and 4,044 mothers aged 13 to 26.
Enhancer of Zeste Homolog 2 (EZH2) inhibitors (EZH2i) are approved to treat certain cancer types. Previous studies have suggested the potential to combine EZH2i with immune checkpoint blockade targeting coinhibitory receptors like PD-(L)1 and CTLA-4, but whether it can also enhance the activity of agents targeting costimulatory receptors is not known. Here, we explore the combination between EZH2i and an agonist antibody targeting the T cell costimulatory receptor 4-1BB (α4-1BB).
View Article and Find Full Text PDFProtein arginine methyltransferase 5 (PRMT5) overexpression in hematologic and solid tumors methylates arginine residues on cellular proteins involved in important cancer functions including cell-cycle regulation, mRNA splicing, cell differentiation, cell signaling, and apoptosis. PRMT5 methyltransferase function has been linked with high rates of tumor cell proliferation and decreased overall survival, and PRMT5 inhibitors are currently being explored as an approach for targeting cancer-specific dependencies due to PRMT5 catalytic function. Here, we describe the discovery of potent and selective S-adenosylmethionine (SAM) competitive PRMT5 inhibitors, with and characterization of clinical candidate PF-06939999.
View Article and Find Full Text PDFProgrammed cell death pathways eliminate infected cells and regulate infection-associated inflammation during pathogen invasion. Cytomegaloviruses encode several distinct suppressors that block intrinsic apoptosis, extrinsic apoptosis, and necroptosis, pathways that impact pathogenesis of this ubiquitous herpesvirus. Here, we expanded the understanding of three cell autonomous suppression mechanisms on which murine cytomegalovirus relies: (i) M38.
View Article and Find Full Text PDFResearch has identified treatment-responsive and treatment-resistant subtypes of automatically maintained self-injurious behavior (ASIB) based on patterns of responding in the functional analysis (FA) reflecting its sensitivity to disruption by alternative reinforcement, and the presence of self-restraint. Rooker et al. (2019) unexpectedly observed reductions in treatment-resistant self-injury while participants performed an operant task.
View Article and Find Full Text PDFPurpose: Magnetic resonance guided focused ultrasound (MRgFUS) treatment of tumors uses inter-sonication delays to allow heat to dissipate from the skin and other near-field tissues. Despite inter-sonication delays, treatment of tumors close to the skin risks skin burns. This work has designed and evaluated an open-source, conformable, skin-cooling system for body MRgFUS treatments to reduce skin burns and enable ablation closer to the skin.
View Article and Find Full Text PDFHomogeneous cationic gold(i) catalysis emerged as a preferred avenue for the activation of alkenes and alkynes towards reactions with weak nucleophiles, especially in cyclization reactions. Here we report an intramolecular carboalkoxylation reaction of electron-rich benzyl ethers of 2-ethynylaryl phenols catalysed by a digold(i)-NHC complex. The reaction proceeds efficiently with low catalyst loading and the resulting 2,3-disubstituted benzofurans form in moderate to good yields.
View Article and Find Full Text PDFDevelopment of antagonistic mAbs that specifically target the immune checkpoint receptor, programmed cell death protein-1 (PD-1), is of great interest for cancer immunotherapy. Here, we report the biophysical characteristics and nonclinical antagonistic activities of sasanlimab (PF-06801591), a humanized anti-PD-1 antibody of IgG4 isotype. We show that sasanlimab binds selectively and with similar high potency to human and cynomolgus monkey PD-1 receptor and blocks its interaction with PD-L1 and PD-L2, with no detectable Fc-dependent effector function.
View Article and Find Full Text PDFCompeting stimulus assessments (CSAs) are designed to identify stimuli that, when made freely available, reduce problem behavior. Although CSAs have demonstrated utility, identifying competing stimuli can be difficult for some individuals. The current study describes outcomes from an augmented CSA (A-CSA) for 6 consecutively encountered cases with treatment-resistant subtypes of automatically maintained problem behavior.
View Article and Find Full Text PDFReceptor-interacting protein kinase 1 (RIPK1) regulates cell fate and proinflammatory signaling downstream of multiple innate immune pathways, including those initiated by TNF-α, TLR ligands, and IFNs. Genetic ablation of results in perinatal lethality arising from both RIPK3-mediated necroptosis and FADD/caspase-8-driven apoptosis. IFNs are thought to contribute to the lethality of -deficient mice by activating inopportune cell death during parturition, but how IFNs activate cell death in the absence of RIPK1 is not understood.
View Article and Find Full Text PDFPurpose: Treating uterine fibroids with less invasive therapies such as magnetic resonance-guided focused ultrasound (MRgFUS) is an attractive alternative to surgery. Treatment planning can improve MRgFUS procedures and reduce treatment times, but the tissue properties that currently inform treatment planning tools are not adequate. This study aims to develop an ex vivo uterine fibroid model that can emulate the in vivo environment allowing for characterization of the uterus and fibroid MR, acoustic, and thermal tissue properties while maintaining viability for the necessary postsurgical histopathological assessments.
View Article and Find Full Text PDFNatural products and their derivatives continue to be wellsprings of nascent therapeutic potential. However, many laboratories have limited resources for biological evaluation, leaving their previously isolated or synthesized compounds largely or completely untested. To address this issue, the Canvass library of natural products was assembled, in collaboration with academic and industry researchers, for quantitative high-throughput screening (qHTS) across a diverse set of cell-based and biochemical assays.
View Article and Find Full Text PDFBenzo[b]thiophene heterocycles are important components of many important small molecule pharmaceuticals and drug candidates as well as organic semiconducting materials. Many methods have been developed for the construction of a benzo[b]thiophene core via cyclization reaction of alkynes. Although few catalytic reactions were disclosed, most methods rely on stoichiometric activation of alkynes.
View Article and Find Full Text PDFIn focused ultrasound (FUS) thermal ablation of diseased tissue, acoustic beam and thermal simulations enable treatment planning and optimization. In this study, a treatment-planning methodology that uses the hybrid angular spectrum (HAS) method and the Pennes' bioheat equation (PBHE) is experimentally validated in homogeneous tissue-mimicking phantoms. Simulated three-dimensional temperature profiles are compared to volumetric MR thermometry imaging (MRTI) of FUS sonications in the phantoms, whose acoustic and thermal properties are independently measured.
View Article and Find Full Text PDFTumors use indoleamine 2,3-dioxygenase-1 (IDO1) as a major mechanism to induce an immunosuppressive microenvironment. IDO1 expression is upregulated in many cancers and considered to be a resistance mechanism to immune checkpoint therapies. IDO1 is induced in response to inflammatory stimuli such as IFNγ and promotes immune tolerance by depleting tryptophan and producing tryptophan catabolites, including kynurenine, in the tumor microenvironment.
View Article and Find Full Text PDFPurpose: To construct a predictive model that describes how the duration and symmetry of a k-space-weighted image contrast (KWIC) window affects the temporal resolution of differently sized ultrasound foci when using a pseudo-golden angle stack-of-stars acquisition.
Methods: We performed a modulation analysis of proton resonance frequency temperature measurements to create the temporal modulation transfer function for KWIC windows of different symmetry and temporal duration. We reconstructed simulated ultrasound heating trajectories and stack-of-stars k-space data as well as experimental phantom data using the same trajectories.
Some individuals diagnosed with intellectual and developmental disabilities engage in automatically reinforced self-injurious behavior (SIB). For these individuals, identifying effective treatments may be difficult due to the nature of the reinforcement contingency. The purpose of this study was to review the literature on the treatment of automatically reinforced SIB to determine commonalities in procedures that produced effective and ineffective treatment outcomes, as well as historical trends in the treatment of this class of SIB.
View Article and Find Full Text PDFPurpose: This study validates that phase aberrations in breast magnetic resonance-guided focussed ultrasound (MRgFUS) therapies can be corrected in a clinically relevant time frame to generate more intense, smaller and more spatially accurate foci.
Materials And Methods: Hybrid angular spectrum (HAS) ultrasound calculations in an magnetic resonance imaging (MRI)-based tissue model, were used to compute phase aberration corrections for improved experimental MRgFUS heating in four heterogeneous breast-mimicking phantoms (n = 18 total locations). Magnetic resonance(MR) temperature imaging was used to evaluate the maximum temperature rise, focus volume and focus accuracy for uncorrected and phase aberration-corrected sonications.
Concomitant hepatocyte apoptosis and regeneration is a hallmark of chronic liver diseases (CLDs) predisposing to hepatocellular carcinoma (HCC). Here, we mechanistically link caspase-8-dependent apoptosis to HCC development via proliferation- and replication-associated DNA damage. Proliferation-associated replication stress, DNA damage, and genetic instability are detectable in CLDs before any neoplastic changes occur.
View Article and Find Full Text PDFMany pathogens deliver virulence factors or effectors into host cells in order to evade host defenses and establish infection. Although such effector proteins disrupt critical cellular signaling pathways, they also trigger specific antipathogen responses, a process termed "effector-triggered immunity." The Gram-negative bacterial pathogen inactivates critical proteins of the NF-κB and MAPK signaling cascade, thereby blocking inflammatory cytokine production but also inducing apoptosis.
View Article and Find Full Text PDFIn addition to promoting cell death and senescence, p53 also has important cellular survival functions. A mutant p53, lacking a proline-rich domain (p53), that is deficient in controlling both cell death and cell cycle arrest, was employed to determine the biological means by which p53 mediates survival upon DNA damage. While p53 and p53 cells were equally resistant to many DNA damaging agents, p53 cells showed an exquisite resistance to high doses of the alkylating agent Diazald (N-Methyl-N-(p-tolylsulfonyl)nitrosamide), as compared to cells completely deficient for p53 function.
View Article and Find Full Text PDFPurpose: This study investigates the feasibility of non-invasively determining thermal diffusivity (α) and the Pennes perfusion parameter (w) from pre-clinical and clinical magnetic resonance-guided focussed ultrasound (MRgFUS) temperature data.
Materials And Methods: Pre-clinical MRgFUS experiments were performed in rabbit muscle (N = 3, 28 sonications) using three-dimensional MR thermometry. Eight sonications were made in a clinical QA phantom with two-dimensional thermometry.
Objectives: The goal of this study was to develop and evaluate a tool to measure the complexity and intensity of psychotropic medication interventions, behavioral interventions, and issues related to crisis management for challenging behavior using a standardized rating form.
Method: The Treatment Intensity Rating Form (TIRF) is a 10-item scale with three categories: pharmacological interventions, behavior supports, and protective equipment. In a retrospective review we examined the final treatment recommendations for 74 individuals with self-injurious behavior (SIB) based on psychiatric and behavioral notes and reports.