Structure-Based Design of Novel TLR7/8 Agonist Payloads Enabling an Immunomodulatory Conjugate Approach.

Dual activation of the TLR7 and TLR8 pathways leads to the production of type I interferon and proinflammatory cytokines, resulting in efficient antigen presentation by dendritic cells to promote T-cell priming and antitumor immunity. We developed a novel series of TLR7/8 dual agonists with varying ratios of TLR7 and TLR8 activity for use as payloads for an antibody-drug conjugate approach. The agonist-induced production of several cytokines in human whole blood confirmed their functional activity.

Roles of Progranulin and FRamides in Neural Versus Non-Neural Tissues on Dietary Restriction-Related Longevity and Proteostasis in .

Dietary Restriction (DR) mitigates loss of proteostasis associated with aging that underlies neurodegenerative conditions including Alzheimer's disease and related dementias. Previously, we observed increased translational efficiency of certain FMRFamide-Like neuro-Peptide () genes and the neuroprotective growth factor progranulin gene under dietary restriction in . Here, we tested the effects of , , and on lifespan and proteostasis under both standard and dietary restriction conditions.

Neuronal CBP-1 is Required for Enhanced Body Muscle Proteostasis in Response to Reduced Translation Downstream of mTOR.

Background: The ability to maintain muscle function decreases with age and loss of proteostatic function. Diet, drugs, and genetic interventions that restrict nutrients or nutrient signaling help preserve long-term muscle function and slow age-related decline. Previously, it was shown that attenuating protein synthesis downstream of the mechanistic target of rapamycin (mTOR) gradually increases expression of heat shock response (HSR) genes in a manner that correlates with increased resilience to protein unfolding stress.

Neuronal CBP-1 is required for enhanced body muscle proteostasis in response to reduced translation downstream of mTOR.

Background: The ability to maintain muscle function decreases with age and loss of proteostatic function. Diet, drugs, and genetic interventions that restrict nutrients or nutrient signaling help preserve long-term muscle function and slow age-related decline. Previously, it was shown that attenuating protein synthesis downstream of the mechanistic target of rapamycin (mTOR) gradually increases expression of heat shock response (HSR) genes in a manner that correlates with increased resilience to protein unfolding stress.

Roles of progranulin and FRamides in neural versus non-neural tissues on dietary restriction-related longevity and proteostasis in .

Dietary restriction (DR) mitigates loss of proteostasis associated with aging that underlies neurodegenerative conditions including Alzheimer's disease and related dementias. Previously, we observed increased translational efficiency of certain FMRFamide-like neuropeptide ( ) genes and the neuroprotective growth factor progranulin gene under dietary restriction in . Here, we tested the effects of , , and on lifespan and proteostasis under both standard and dietary restriction conditions.

Identification and Optimization of Small Molecule Pyrazolopyrimidine TLR7 Agonists for Applications in Immuno-oncology.

Small molecule toll-like receptor (TLR) 7 agonists have gathered considerable interest as promising therapeutic agents for applications in cancer immunotherapy. Herein, we describe the development and optimization of a series of novel TLR7 agonists through systematic structure-activity relationship studies focusing on modification of the phenylpiperidine side chain. Additional refinement of ADME properties culminated in the discovery of compound , which displayed nanomolar reporter assay activity and favorable drug-like properties.

Discovery of Novel TLR7 Agonists as Systemic Agent for Combination With aPD1 for Use in Immuno-oncology.

We have designed and developed novel and selective TLR7 agonists that exhibited potent receptor activity in a cell-based reporter assay. , these agonists significantly induced secretion of cytokines IL-6, IL-1β, IL-10, TNFa, IFNa, and IP-10 in human and mouse whole blood. Pharmacokinetic and pharmacodynamic studies in mice showed a significant secretion of IFNα and TNFα cytokines.

The integrated stress response protects against ER stress but is not required for altered translation and lifespan from dietary restriction in .

The highly conserved integrated stress response (ISR) reduces and redirects mRNA translation in response to certain forms of stress and nutrient limitation. It is activated when kinases phosphorylate a key residue in the alpha subunit of eukaryotic translation initiation factor 2 (eIF2). General Control Nonderepressible-2 (GCN2) is activated to phosphorylate eIF2α by the presence of uncharged tRNA associated with nutrient scarcity, while protein kinase R-like ER kinase-1 (PERK) is activated during the ER unfolded protein response (UPR).

Successful kinetic impact into an asteroid for planetary defence.

Although no known asteroid poses a threat to Earth for at least the next century, the catalogue of near-Earth asteroids is incomplete for objects whose impacts would produce regional devastation. Several approaches have been proposed to potentially prevent an asteroid impact with Earth by deflecting or disrupting an asteroid. A test of kinetic impact technology was identified as the highest-priority space mission related to asteroid mitigation.

Olfactory flow in the sea catfish, Ariopsis felis (L.): Origin, regulation, and resampling.

The olfactory epithelium of the sea catfish, Ariopsis felis, is found on a pinnate array of lamellae (the olfactory rosette) housed within a nasal chamber. The nasal anatomy of A. felis suggests an ability to capture external water currents.

Safety risk management for low molecular weight process-related impurities in monoclonal antibody therapeutics: Categorization, risk assessment, testing strategy, and process development with leveraging clearance potential.

Process-related impurities (PRIs) derived from manufacturing process should be minimized in final drug product. ICH Q3A provides a regulatory road map for PRIs but excludes biologic drugs like monoclonal antibodies (mAbs) that contain biological PRIs (e.g.

Changing multiple health behaviors in cancer survivors: smoking and exercise.

Research regarding cross-behavioral relationships between the cognitive mechanisms motivating health behavior change is lacking for cancer survivors. This study investigated these relationships to inform the development of multiple health behavior change (MHBC) interventions for this at-risk population. Eligible participants included cancer survivors attending an intake appointment for smoking cessation services.

Over-expression of miR-34c leads to early-life visceral fat accumulation and insulin resistance.

Overweight children and adolescents are at high risk for adult and late life obesity. This report investigates some underlying mechanisms contributing to obesity during early life in an animal model. We generated a strain of transgenic mice, cU2, overexpressing human microRNA 34c, a microRNA functionally implicated in adipogenesis.

Long-term Outcomes of Ossiculoplasty With and Without an Intact Malleus.

Objective: To compare long-term hearing outcomes following ossiculoplasty with cartilage tympanoplasty with (M) and without (M) the malleus present.

Study Design: Retrospective chart review.

Setting: Tertiary referral center.

Adverse events and safety issues associated with physical activity and exercise for adults with osteoporosis and osteopenia: A systematic review of observational studies and an updated review of interventional studies.

Objectives: We conducted a systematic review to identify adverse effects of physical activity and/or exercise for adults with osteoporosis/osteopenia. We synthesised evidence from observational studies, and updated three previously published systematic reviews.

Methods: We searched MEDLINE, EMBASE, CINAHL, Web of Science, grey literature and reference lists of relevant studies.

Evaluation of Intraoperative Testing During Cochlear Implantation From a Time and Cost Perspective: A Single-Center Experience in the United States.

Objective: To measure the time spent performing intraoperative testing during cochlear implantation (CI) and determine the impact on hospital charges.

Study Design: Prospective study.

Setting: Tertiary referral hospital.

The feasibility of early pulmonary rehabilitation and activity after COPD exacerbations: external pilot randomised controlled trial, qualitative case study and exploratory economic evaluation.

Background: Chronic obstructive pulmonary disease (COPD) affects > 3 million people in the UK. Acute exacerbations of COPD (AECOPD) are the second most common reason for emergency hospital admission in the UK. Pulmonary rehabilitation is usual care for stable COPD but there is little evidence for early pulmonary rehabilitation (EPR) following AECOPD, either in hospital or immediately post discharge.

Trends in Intraoperative Testing During Cochlear Implantation.

Objective: No consensus guidelines exist regarding intraoperative testing during cochlear implantation and wide variation in practice habits exists. The objective of this observational study was to survey otologists/neurotologists to understand practice habits and overall opinion of usefulness of intraoperative testing.

Study Design: Cross-sectional survey.

Long-term Complications and Surgical Failures After Ossiculoplasty.

Objective: To study long-term complications after ossiculoplasty.

Study Design: Case series with chart review.

Setting: Tertiary care referral center otology practice.

Comparison of Internet and Telephone Interventions for Weight Loss Among Cancer Survivors: Randomized Controlled Trial and Feasibility Study.

Background: Weight loss interventions have been successfully delivered via several modalities, but recent research has focused on more disseminable and sustainable means such as telephone- or Internet-based platforms.

Objective: The aim of this study was to compare an Internet-delivered weight loss intervention to a comparable telephone-delivered weight loss intervention.

Methods: This randomized pilot study examined the effects of 6-month telephone- and Internet-delivered social cognitive theory-based weight loss interventions among 37 cancer survivors.

Using rating of perceived exertion in assessing cardiorespiratory fitness in endometrial cancer survivors.

For cancer survivors, who also often present with co-existing health conditions, exercise testing is often performed using submaximal protocols incorporating linear heart rate response for estimating the cardiorespiratory capacity and assessing exercise tolerance. However, use of beta-blocker medications, during sub-maximal protocols based on linear HR response can be problematic. Rating of perceived exertion (RPE), which takes into account an individual's overall perception of effort, can be used as a complementary tool that does not rely solely on the heart rate response to increased workload.

The Influence of Intraoperative Testing on Surgical Decision-making During Cochlear Implantation.

Objective: To review our use of intraoperative testing during cochlear implantation (CI) and determine its impact on surgical decision-making.

Study Design: Retrospective chart review.

Setting: Tertiary referral center.