Cells and signals of the leukemic microenvironment that support progression of T-cell acute lymphoblastic leukemia (T-ALL).

Current intensified chemotherapy regimens have significantly increased survival rates for pediatric patients with T-cell acute lymphoblastic leukemia (T-ALL), but these treatments can result in serious adverse effects; furthermore, patients who are resistant to chemotherapy or who relapse have inferior outcomes, together highlighting the need for improved therapeutic strategies. Despite recent advances in stratifying T-ALL into molecular subtypes with distinct driver mutations, efforts to target the tumor-intrinsic genomic alterations critical for T-ALL progression have yet to translate into more effective and less toxic therapies. Ample evidence now indicates that extrinsic factors in the leukemic microenvironment are critical for T-ALL growth, infiltration, and therapeutic resistance.

Up-regulated PLA2G10 in cancer impairs T cell infiltration to dampen immunity.

T cells are often absent from human cancer tissues during both spontaneously induced immunity and therapeutic immunotherapy, even in the presence of a functional T cell-recruiting chemokine system, suggesting the existence of T cell exclusion mechanisms that impair infiltration. Using a genome-wide in vitro screening platform, we identified a role for phospholipase A2 group 10 (PLA2G10) protein in T cell exclusion. PLA2G10 up-regulation is widespread in human cancers and is associated with poor T cell infiltration in tumor tissues.

Creating and Implementing a Community-Focused, Culturally Tailored Health Marketing Campaign to Address Menthol Cigarette Use in Los Angeles County.

Introduction: Menthol tobacco products have been marketed disproportionately to communities of color for decades.

Methods: In Los Angeles County, California, a health marketing campaign, which used glossy visuals and attractive people in appealing poses, reminiscent of tobacco marketing tactics, was created and implemented to educate smokers on the health risks of using menthol cigarettes. The campaign encouraged smokers to make a quit attempt by offering access to free or low-cost resources through the Kick It California quitline and the LAQuits website (laquits.

Integrin signaling is critical for myeloid-mediated support of T-cell acute lymphoblastic leukemia.

We previously found that T-cell acute lymphoblastic leukemia (T-ALL) requires support from tumor-associated myeloid cells, which activate Insulin Like Growth Factor 1 Receptor (IGF1R) signaling in leukemic blasts. However, IGF1 is not sufficient to sustain T-ALL in vitro, implicating additional myeloid-mediated signals in leukemia progression. Here, we find that T-ALL cells require close contact with myeloid cells to survive.

Population pharmacokinetics of molnupiravir in adults with COVID-19: Lack of clinically important exposure variation across individuals.

Effective antiviral treatments for coronavirus disease 2019 (COVID-19) are needed to reduce the morbidity and mortality associated with severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2) infection, particularly in patients with risk factors for severe disease. Molnupiravir (MK-4482, EIDD-2801) is an orally administered, ribonucleoside prodrug of β-D-N4-hydroxycytidine (NHC) with submicromolar potency against SARS-CoV-2. A population pharmacokinetic (PopPK) analysis for molnupiravir exposure was conducted using 4202 NHC plasma concentrations collected in 1207 individuals from a phase I trial in healthy participants, a phase IIa trial in non-hospitalized participants with COVID-19, a phase II trial in hospitalized participants with COVID-19, and a phase II/III trial in non-hospitalized participants with COVID-19.

Stress-induced pseudokinase TRB3 augments IL1β signaling by interacting with Flightless homolog 1.

Interleukin-1β is one of the most potent inducers of beta cell inflammation in the lead-up to type 1 diabetes. We have previously reported that IL1β-stimulated pancreatic islets from mice with genetic ablation of stress-induced pseudokinase TRB3(TRB3KO) show attenuated activation kinetics for the MAP3K MLK3 and JNK stress kinases. However, JNK signaling constitutes only a portion of the cytokine-induced inflammatory response.

Growing convergence research: Coproducing climate projections to inform proactive decisions for managing simultaneous wildfire risk.

We apply a convergence research approach to the urgent need for proactive management of long-term risk associated with wildfire in the United States. In this work we define convergence research in accordance with the US National Science Foundation-as a means of addressing a specific and compelling societal problem for which solutions require deep integration across disciplines and engagement of stakeholders. Our research team brings expertise in climate science, fire science, landscape ecology, and decision science to address the risk from simultaneous and impactful fires that compete for management resources, and leverages climate projections for decision support.

Maximizing the value of phase III trials in immuno-oncology: A checklist from the Society for Immunotherapy of Cancer (SITC).

The broad activity of agents blocking the programmed cell death protein 1 and its ligand (the PD-(L)1 axis) revolutionized oncology, offering long-term benefit to patients and even curative responses for tumors that were once associated with dismal prognosis. However, only a minority of patients experience durable clinical benefit with immune checkpoint inhibitor monotherapy in most disease settings. Spurred by preclinical and correlative studies to understand mechanisms of non-response to the PD-(L)1 antagonists and by combination studies in animal tumor models, many drug development programs were designed to combine anti-PD-(L)1 with a variety of approved and investigational chemotherapies, tumor-targeted therapies, antiangiogenic therapies, and other immunotherapies.

A Model-Based Approach to Bridging Plasma and Dried Blood Spot Concentration Data for Phase 3 Verubecestat Trials.

In-clinic venous dried blood spot (DBS) pharmacokinetic (PK) sampling was incorporated into two phase 3 studies of verubecestat for Alzheimer's disease (EPOCH [NCT01739348] and APECS [NCT01953601]), as a potential alternative to plasma PK sampling. Initially, plasma and DBS PK samples were collected concurrently to better understand the DBS-plasma verubecestat concentration relationship, with the intention of discontinuing DBS or plasma sampling following interim analysis. Following initial analyses and comparison of results with prespecified selection criteria, plasma PK sampling was discontinued; however, a stability issue resulting in generally lower DBS verubecestat concentrations with longer collection-to-assay times was subsequently discovered (associated with non-compliance in DBS sample handling), prompting reintroduction of plasma sampling.

Safety Nets Work Both Ways: The Influence of Available Paid Leave on Employee Risk Taking During the COVID-19 Pandemic.

Background: During the COVID-19 pandemic, use of symptom-screening tools to limit attendance of infected workers has been widespread. However, it remains unknown how the reliability of responses to these tools may be compromised by individual and social factors. We aimed to determine whether personal concern over lost wages impacts responses to COVID-19 symptom-screening questionnaires making them less useful in limiting person-to-person transmission.

Changes in growth performance, plasma metabolite concentrations, and myogenic gene expression in growing pigs fed a methionine-restricted diet.

: Methionine (Met) is usually the second or third limiting amino acid in swine diets and plays vital roles in promoting the growth, especially, the muscle growth of pigs. This research evaluated the effects of dietary Met restriction on the growth performance, plasma metabolite concentrations, and myogenic gene expression in growing pigs. : Eight genes in two families (myogenic regulatory factor family and myocyte enhancer factor 2 family) were selected for the analysis.

N-acylethanolamine regulation of TLR3-induced hyperthermia and neuroinflammatory gene expression: A role for PPARα.

Increasing evidence suggests that SARS-CoV-2, the virus responsible for the COVID-19 pandemic, is associated with increased risk of developing neurological or psychiatric conditions such as depression, anxiety or dementia. While the precise mechanism underlying this association is unknown, aberrant activation of toll-like receptor (TLR)3, a viral recognizing pattern recognition receptor, may play a key role. Synthetic cannabinoids and enhancing cannabinoid tone via inhibition of fatty acid amide hydrolase (FAAH) has been demonstrated to modulate TLR3-induced neuroimmune responses and associated sickness behaviour.

Increasing Endocannabinoid Tone Alters Anxiety-Like and Stress Coping Behaviour in Female Rats Prenatally Exposed to Valproic Acid.

Given the sex differences evident in the prevalence of autism, there is an increased awareness of the importance of including females in autism research to determine sexual dimorphism and sex-specific treatments. Cannabinoids and endocannabinoid modulators have been proposed as potential novel treatments for autism-related symptoms; however, few studies to date have examined if these pharmacological agents elicit sex-specific effects. The aim of the present study was to use the valproic acid (VPA) model of autism to compare the behavioural responses of male and female rats and examine the effects of increasing endocannabinoid tone on the behavioural responses of VPA-exposed female rats.

Prehabilitation Coming of Age: IMPLICATIONS FOR CARDIAC AND PULMONARY REHABILITATION.

While cardiac and pulmonary rehabilitation programs traditionally involve exercise therapy and risk management following an event (eg, myocardial infarction and stroke), or an intervention (eg, coronary artery bypass surgery and percutaneous coronary intervention), prehabilitation involves enhancing functional capacity and optimizing risk profile prior to a scheduled intervention. The concept of prehabilitation is based on the principle that patients with higher functional capabilities will better tolerate an intervention, and will have better pre- and post-surgical outcomes. In addition to improving fitness, prehabilitation has been extended to include multifactorial risk intervention prior to surgery, including psychosocial counseling, smoking cessation, diabetes control, nutrition counseling, and alcohol abstinence.

Maternal presence or absence alters nociceptive responding and cortical anandamide levels in juvenile female rats.

The influence of parental support on child pain experiences is well recognised. Accordingly, animal studies have revealed both short- and long-term effects of early life stress on nociceptive responding and neural substrates such as endocannabinoids. The endocannabinoid system plays an important role in mediating and modulating stress, social interaction, and nociception.

Population Pharmacokinetic Analysis of the Cathepsin K Inhibitor Odanacatib: Insights Into Intrinsic and Extrinsic Factor Effects on Exposure in Postmenopausal and Elderly Women.

This analysis developed a population pharmacokinetic (PK) model for odanacatib, characterized demographic and concomitant medication covariates effect, and provided odanacatib exposure estimates for subjects in phase 2/3 studies. Data from multiple phase 1 (P005, P025, and P014), phase 2b (P004 and P022), and phase 3 (Long-Term Odanacatib Fracture Trial; P018) studies were pooled to create a data set of 1280 postmenopausal women aged 45 to 91 years (102 from phase 1, 514 from phase 2b, and 664 from phase 3) who received weekly oral odanacatib doses ranging from 3 to 100 mg. A 1-compartment model with first-order absorption, dose-dependent relative bioavailability (F1), and first-order elimination best described odanacatib PK.

Army Physician Career Satisfaction Based on a Medical Corps Survey.

Introduction: It is critical the U.S. Army retains skilled physicians in the Medical Corps (MC) to ensure direct support to military operations and medical readiness.

Defining tumor resistance to PD-1 pathway blockade: recommendations from the first meeting of the SITC Immunotherapy Resistance Taskforce.

As the field of cancer immunotherapy continues to advance at a fast pace, treatment approaches and drug development are evolving rapidly to maximize patient benefit. New agents are commonly evaluated for activity in patients who had previously received a programmed death receptor 1 (PD-1)/programmed death-ligand 1 (PD-L1) inhibitor as standard of care or in an investigational study. However, because of the kinetics and patterns of response to PD-1/PD-L1 blockade, and the lack of consistency in the clinical definitions of resistance to therapy, the design of clinical trials of new agents and interpretation of results remains an important challenge.

Probody Therapeutics: An Emerging Class of Therapies Designed to Enhance On-Target Effects with Reduced Off-Tumor Toxicity for Use in Immuno-Oncology.

The deep and durable antitumor effects of antibody-based immunotherapies such as immune checkpoint inhibitors (ICIs) have revolutionized oncology and transformed the therapeutic landscape for many cancers. Several anti-programmed death receptor 1 and anti-programmed death receptor ligand 1 antibodies have been approved for use in advanced solid tumors, including melanoma, non-small cell lung cancer, bladder cancer, and other cancers. ICIs are under development across many tumor types and preliminary results are compelling.

Benefits and Risks of High-Intensity Interval Training in Patients With Coronary Artery Disease.

Exercise-based cardiac rehabilitation is integral to secondary prevention in patients with coronary artery disease. Recently, the effectiveness and "superiority" of high-intensity interval training (HIIT) is a purported time-saving alternative to "traditional" moderate-intensity continuous training (MICT) in cardiac rehabilitation. The rationale for HIIT adoption is, however, not fully substantiated in the scientific literature.

UX007 for the treatment of long chain-fatty acid oxidation disorders: Safety and efficacy in children and adults following 24weeks of treatment.

Background: Long-chain fatty acid oxidation disorders (LC-FAOD) lead to accumulation of high concentrations of potentially toxic fatty acid intermediates. Newborn screening and early intervention have reduced mortality, but most patients continue to experience frequent hospitalizations and significant morbidity despite treatment. The deficient energy state can cause serious liver, muscle, and heart disease, and may be associated with an increased risk of sudden death.

The Benefits of Merging Leadership Research and Emotions Research.

A closer merging of the literature on emotions with the research on leadership may prove advantageous to both fields. Leadership researchers will benefit by incorporating the research on emotional labor, emotional regulation, and happiness. Emotions researchers will be able to more fully consider how leadership demands influence emotional processes.