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.

Ni/Photoredox-Catalyzed C(sp)-C(sp) Cross-Coupling of Alkyl Pinacolboronates and (Hetero)Aryl Bromides.

Utilizing quinoline as a mild, catalytic additive, broadly applicable conditions for the Ni/photoredox-catalyzed C(sp)-C(sp) cross-coupling of (hetero)aryl bromides and alkyl pinacolboronate esters were developed, which can be applied to both batch and flow reactions. In addition to primary benzylic nucleophiles, both stabilized and nonstabilized secondary alkyl boronic esters are effective coupling partners. Density functional theory calculations suggest that alkyl radical generation occurs from an alkyl-B(pin)-quinoline complex, which may proceed via an energy transfer process.

Digital Interventions to Save Lives From the Opioid Crisis Prior and During the SARS COVID-19 Pandemic: A Scoping Review of Australian and Canadian Experiences.

Background: The potential for digital initiatives for opioid harm reduction is boundless. Synthesized evidence on current interventions and their efficacy are emerging. This scoping review is an effort to aggregate Canadian and Australian digital health initiatives used to prevent opioid-related deaths and minimize harm, prior to and particularly during the pandemic of SARs-COVID-19, when the crisis escalated.

Long-Acting Tumor-Activated Prodrug of a TGFβR Inhibitor.

Inhibition of TGFβ signaling in concert with a checkpoint blockade has been shown to provide improved and durable antitumor immune response in mouse models. However, on-target adverse cardiovascular effects have limited the clinical use of TGFβ receptor (TGFβR) inhibitors in cancer therapy. To restrict the activity of TGFβR inhibitors to tumor tissues and thereby widen the therapeutic index, a series of tumor-activated prodrugs of a selective small molecule TGFβR1 inhibitor were prepared by appending to a serine protease substrate and a half-life extension fatty acid carbon chain.

Microscale purification in support of high-throughput medicinal chemistry.

In recent years, successful assay miniaturization has enabled the exploration of synthesis scale reduction in pharmaceutical discovery. Miniaturization of pharmaceutical synthesis and purification allows a reduction in material consumption and shortens timelines, which ultimately reduces the cost per experiment without compromising data quality. Isolating and purifying the compounds of interest is a key step in the library synthesis process.

Pharmacokinetics and Toxicity Evaluation of a PLGA and Chitosan-Based Micro-Implant for Sustained Release of Methotrexate in Rabbit Vitreous.

The present research investigates the pharmacokinetics and toxicity of a chitosan (CS) and poly(lactic-co-glycolic) acid (PLGA)-based methotrexate (MTX) intravitreal micro-implant in normal rabbit eyes. PLGA and CS-based micro-implants containing 400 µg of MTX were surgically inserted in the vitreous of twenty-four New Zealand rabbits using minimally invasive procedures. The PLGA-coated CS-MTX micro-implant and the placebo micro-implant were inserted in the right eye and in the left eye, respectively, of each rabbit.

Enabling Nurse-Patient Communication With a Mobile App: Controlled Pretest-Posttest Study With Nurses and Non-English-Speaking Patients.

Background: There is growing concern regarding the implications of miscommunication in health care settings, the results of which can have serious detrimental impacts on patient safety and health outcomes. Effective communication between nurses and patients is integral in the delivery of timely, competent, and safe care. In a hospital environment where care is delivered 24 hours a day, interpreters are not always available.

Retrospective analysis of lameness localisation in Western Performance Horses: A ten-year review.

Background: Similar to other high-level athletic disciplines, the western performance horse experiences a variety of orthopaedic conditions as a result of rigorous sport-specific physical demands. While musculoskeletal injury rates have been quantified in other equine disciplines, these data are lacking for the western performance athlete.

Objectives: To identify the most common anatomical regions of lameness in western performance horses being evaluated at the nation's largest sanctioned shows over a 10-year study period.

Sensory-Discriminative Three-Dimensional Body Pain Mobile App Measures Versus Traditional Pain Measurement With a Visual Analog Scale: Validation Study.

Background: To quantify pain severity in patients and the efficacy treatments, researchers and clinicians apply tools such as the traditional visual analog scale (VAS) that leads to inaccurate interpretation of the main sensory pain.

Objective: This study aimed to validate the pain measurements of a neuroscience-based 3D body pain mobile app called GeoPain.

Methods: Patients with temporomandibular disorder (TMD) were assessed using GeoPain measures in comparison to VAS and positive and negative affect schedule (PANAS), pain and mood scales, respectively.

The effect of surgical pain severity, preoperative opioid use and patient characteristics on postoperative opioid prescriptions and refills in orthopedic surgery.

Background: Excessive opioid prescriptions after orthopedic surgery are common. The purpose of this study was to examine the association between surgical severity, preoperative opioid use and patient characteristics with postoperative opioid prescriptions and refills.

Methods: Seventy-nine patients undergoing orthopedic surgeries were reviewed.

Prospective randomized comparison of platelet rich plasma to extracorporeal shockwave therapy for treatment of proximal suspensory pain in western performance horses.

Proximal suspensory desmitis (PSD) is a frequent cause of lameness in the performance horse. Extracorporeal shockwave therapy (EST) and platelet rich plasma (PRP) have become common treatments for PSD yet clinical data on efficacy is limited. The main objective of this randomized, prospective clinical study was to compare long-term effectiveness of EST and PRP in Western performance horses.

Discovery of 4-Azaindole Inhibitors of TGFβRI as Immuno-oncology Agents.

The multifunctional cytokine TGFβ plays a central role in regulating antitumor immunity. It has been postulated that inhibition of TGFβ signaling in concert with checkpoint blockade will provide improved and durable immune response against tumors. Herein, we describe a novel series of 4-azaindole TGFβ receptor kinase inhibitors with excellent selectivity for TGFβ receptor 1 kinase.

CALD Assist-Nursing: Improving communication in the absence of interpreters.

Aims And Objectives: To develop a communication app to support nursing staff during the provision of standard care of patients from non-English-speaking backgrounds (NESBs), when an interpreter is not available. This paper reports on the user needs analysis phase that informed the development, content and functionality of the app.

Background: In 2014 we developed CALD Assist, a communication app to support patient interactions with allied health clinicians when interpreters are not present.

Improved design and characterization of PLGA/PLA-coated Chitosan based micro-implants for controlled release of hydrophilic drugs.

Repetitive intravitreal injections of Methotrexate (MTX), a hydrophilic chemotherapeutic drug, are currently used to treat selected vitreoretinal (VR) diseases, such as intraocular lymphoma. To avoid complications associated with the rapid release of MTX from the injections, a Polylactic acid (PLA) and Chitosan (CS)-based MTX micro-implant prototype was fabricated in an earlier study, which showed a sustained therapeutic release rate of 0.2-2.

Macrocyclic pyrrolobenzodiazepine dimers as antibody-drug conjugate payloads.

Macrocyclic pyrrolobenzodiazepine dimers were designed and evaluated for use as antibody-drug conjugate payloads. Initial structure-activity exploration established that macrocyclization could increase the potency of PBD dimers compared with non-macrocyclic analogs. Further optimization overcame activity-limiting solubility issues, leading to compounds with highly potent (picomolar) activity against several cancer cell lines.

Investigation of an optimal cell lysis method for the study of the zinc metalloproteome of Histoplasma capsulatum.

This work sought to assess optimal extraction conditions in the study of the metalloproteome of the dimorphic fungus Histoplasma capsulatum. One of the body's responses to H. capsulatum infection is sequestration of zinc within host macrophage (MØ), as reported by Vignesh et al.

Studies of Azetidin-2-one as a Reactive Enolate Synthon of β-Alanine for Condensations with Aldehydes and Ketones.

Studies describe formation of the lithium enolate of N-(4-methoxybenzyloxy)azetidin-2-one (1) and characterization of representative aldol reactions with aldehydes and ketones. Diastereoselectivity features the production of anti-aldol adducts from α,β-unsaturated ketones and α-branched aliphatic aldehydes. The stereoselectivity is rationalized via closed, six-membered transition-state arrangements leading to the formation of Felkin-Anh and anti-Felkin products.

HcZrt2, a zinc responsive gene, is indispensable for the survival of Histoplasma capsulatum in vivo.

Histoplasma capsulatum (Hc) exists in the soil and is capable of adapting to the shift in environment during infection to ensure survival. Yeast encounter a restrictive host environment low in nutrients such as zinc. In this study we functionally analyzed a putative zinc regulated transporter, HcZrt2, in zinc limiting conditions by complementation of HcZrt2 and gene knockdown through RNA interference (RNAi).

Utility of the Neurobehavioral Symptom Inventory As an Outcome Measure: A VA TBI Model Systems Study.

Objective: To examine the utility of the Neurobehavioral Symptom Inventory (NSI)-a measure of postconcussion symptoms used within the Veterans Health Administration-as an index of rehabilitation outcome.

Setting: Veterans Administration Polytrauma Rehabilitation Centers Traumatic Brain Injury (TBI) Model Systems program.

Participants: A total of 159 Veterans (14% with mild TBI; 86% with moderate-severe TBI).

High-Definition and Non-invasive Brain Modulation of Pain and Motor Dysfunction in Chronic TMD.

Background: Temporomandibular disorders (TMD) have a high prevalence and in many patients pain and masticatory dysfunction persist despite a range of treatments. Non-invasive brain neuromodulatory methods, namely transcranial direct current stimulation (tDCS), can provide relatively long-lasting pain relief in chronic pain patients.

Objective: To define the neuromodulatory effect of five daily 2x2 motor cortex high-definition tDCS (HD-tDCS) sessions on clinical pain and motor measures in chronic TMD patients.

Biodegradable chitosan and polylactic acid-based intraocular micro-implant for sustained release of methotrexate into vitreous: analysis of pharmacokinetics and toxicity in rabbit eyes.

Purpose: The purpose of this study was to evaluate the pharmacokinetics and toxicity of a chitosan (CS) and polylactic acid (PLA) based methotrexate (MTX) intravitreal micro-implant in an animal model using rabbit eyes.

Methods: CS- and PLA-based micro-implants containing 400 μg of MTX were fabricated using lyophilization and dip-coating techniques. The micro-implants were surgically implanted in the vitreous of eight New Zealand rabbits employing minimally invasive technique.