Publications by authors named "J Nicole Hamblin"

86 Publications

Exploring PI3Kδ Molecular Pathways in Stable COPD and Following an Acute Exacerbation, Two Randomized Controlled Trials.

Int J Chron Obstruct Pulmon Dis 2021 3;16:1621-1636. Epub 2021 Jun 3.

Refractory Respiratory Inflammation Discovery Performance Unit, GlaxoSmithKline, Stevenage, UK.

Background: Inhibition of phosphoinositide 3-kinase δ (PI3Kδ) exerts corrective effects on the dysregulated migration characteristics of neutrophils isolated from patients with chronic obstructive pulmonary disease (COPD).

Objective: To develop novel, induced sputum endpoints to demonstrate changes in neutrophil phenotype in the lung by administering nemiralisib, a potent and selective inhaled PI3Kδ inhibitor, to patients with stable COPD or patients with acute exacerbation (AE) of COPD.

Methods: In two randomized, double-blind, placebo-controlled clinical trials patients with A) stable COPD (N=28, randomized 3:1) or B) AECOPD (N=44, randomized 1:1) received treatment with inhaled nemiralisib (1mg). Endpoints included induced sputum at various time points before and during treatment for the measurement of transcriptomics (primary endpoint), inflammatory mediators, functional respiratory imaging (FRI), and spirometry.

Results: In stable COPD patients, the use of nemiralisib was associated with alterations in sputum neutrophil transcriptomics suggestive of an improvement in migration phenotype; however, the same nemiralisib-evoked effects were not observed in AECOPD. Inhibition of sputum inflammatory mediators was also observed in stable but not AECOPD patients. In contrast, a placebo-corrected improvement in forced expiratory volume in 1 sec of 136 mL (95% Credible Intervals -46, 315mL) with a probability that the true treatment ratio was >0% (Pr(θ>0)) of 93% was observed in AECOPD. However, FRI endpoints remained unchanged.

Conclusion: We provide evidence for nemiralisib-evoked changes in neutrophil migration phenotype in stable COPD but not AECOPD, despite improving lung function in the latter group. We conclude that induced sputum can be used for measuring evidence of alteration of neutrophil phenotype in stable patients, and our study provides a data set of the sputum transcriptomic changes during recovery from AECOPD.
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http://dx.doi.org/10.2147/COPD.S309303DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184158PMC
June 2021

An Inhaled PI3Kδ Inhibitor Improves Recovery in Acutely Exacerbating COPD Patients: A Randomized Trial.

Int J Chron Obstruct Pulmon Dis 2021 3;16:1607-1619. Epub 2021 Jun 3.

Refractory Respiratory Inflammation Discovery Performance Unit, GlaxoSmithKline, Stevenage, UK.

Purpose: This study evaluated the safety and efficacy of inhaled nemiralisib, a phosphoinositide 3-kinase δ (PI3Kδ) inhibitor, in patients with an acute exacerbation of chronic obstructive pulmonary disease (COPD).

Methods: In this double-blind, placebo-controlled study, 126 patients (40-80 years with a post-bronchodilator forced expiratory volume in 1 sec (FEV) ≤80% of predicted (previously documented)) were randomized 1:1 to once daily inhaled nemiralisib (1 mg) or placebo for 84 days, added to standard of care. The primary endpoint was specific imaging airway volume (siVaw) after 28 treatment days and was analyzed using a Bayesian repeated measures model (clintrials.gov: NCT02294734).

Results: A total of 126 patients were randomized to treatment; 55 on active treatment and 49 on placebo completed the study. When comparing nemiralisib and placebo-treated patients, an 18% placebo-corrected increase from baseline in distal siVaw (95% credible intervals (Cr I) (-1%, 42%)) was observed on Day 28. The probability that the true treatment ratio was >0% (Pr(θ>0)) was 96%, suggestive of a real treatment effect. Improvements were observed across all lung lobes. Patients treated with nemiralisib experienced a 107.3 mL improvement in posterior median FEV (change from baseline, 95% Cr I (-2.1, 215.5)) at day 84, compared with placebo. Adverse events were reported by 41 patients on placebo and 49 on nemiralisib, the most common being post-inhalation cough on nemiralisib (35%) vs placebo (3%).

Conclusion: These data show that addition of nemiralisib to usual care delivers more effective recovery from an acute exacerbation and improves lung function parameters including siVaw and FEV. Although post-inhalation cough was identified, nemiralisib was otherwise well tolerated, providing a promising novel therapy for this acutely ill patient group.
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http://dx.doi.org/10.2147/COPD.S309129DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8184151PMC
June 2021

Connecting to the Living History of Radiation Exposure.

J Hist Biol 2021 04 20;54(1):1-6. Epub 2021 Apr 20.

School of History, Philosophy, and Religion, Oregon State University, Ballard Extension Hall 330B, 2591 SW Campus Way, Corvallis, OR, 97331, USA.

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http://dx.doi.org/10.1007/s10739-021-09634-9DOI Listing
April 2021

Increased diagnostic yield of routine multiplex PCR compared to clinician requested testing for detection of Trichomonas vaginalis.

Pathology 2021 Feb 6;53(2):257-263. Epub 2020 Oct 6.

Department of Microbiology, Monash Pathology, Clayton, Vic, Australia; Monash Infectious Diseases, Monash Health, Clayton, Vic, Australia; Faculty of Medicine Nursing and Health Sciences, Monash University, Clayton, Vic, Australia.

Trichomonas vaginalis (TV) infection is the leading cause of non-viral sexually transmitted infection (STI) globally and is endemic in rural and remote Australia. However, current accurate prevalence data for TV in urban Australia are scarce as TV is not a notifiable infection outside of the Northern Territory (NT). This study evaluated Australian guidelines for TV testing and determined TV prevalence among patients at a large urban public hospital in Melbourne, Australia. A retrospective analysis of genitourinary samples screened for STIs by multiplex polymerase chain reaction (MPCR) between May 2017 and April 2019 was performed. A total of 7155 results (5064 females) were included in the analysis. A prevalence for TV of 1.7% (n=123) was found, which was higher than Neisseria gonorrhoeae (1.4%, n=103) but less than Chlamydia trachomatis (5%, n=358). The highest rate of TV (3%) was found in females aged 30-44 years (n = 48). Routine MPCR improved TV detection almost six-fold compared with clinician request based testing. Current targeted testing guidelines for TV were inadequate for case finding in an urban setting, and clinical request among symptomatic patients was rare. MPCR testing provides a comprehensive testing strategy for curable STI, and removes the need for clinical suspicion of TV. Implementation of MPCR for STI screening can improve TV detection in populations not normally suspected to be at risk and therefore potentially reduce disease transmission or complications associated with undiagnosed infection.
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http://dx.doi.org/10.1016/j.pathol.2020.07.008DOI Listing
February 2021

Leveraging an Open Science Drug Discovery Model to Develop CNS-Penetrant ALK2 Inhibitors for the Treatment of Diffuse Intrinsic Pontine Glioma.

J Med Chem 2020 09 26;63(17):10061-10085. Epub 2020 Aug 26.

Drug Discovery Program, Ontario Institute for Cancer Research, 661 University Avenue, MaRS Centre, West Tower, Toronto, Ontario M5G 0A3, Canada.

There are currently no effective chemotherapeutic drugs approved for the treatment of diffuse intrinsic pontine glioma (DIPG), an aggressive pediatric cancer resident in the pons region of the brainstem. Radiation therapy is beneficial but not curative, with the condition being uniformly fatal. Analysis of the genomic landscape surrounding DIPG has revealed that activin receptor-like kinase-2 (ALK2) constitutes a potential target for therapeutic intervention given its dysregulation in the disease. We adopted an open science approach to develop a series of potent, selective, orally bioavailable, and brain-penetrant ALK2 inhibitors based on the lead compound . Modest structural changes to the C-3, C-4, and C-5 position substituents of the core pyridine ring afforded compounds , , and , each with a superior potency, selectivity, and/or blood-brain barrier (BBB) penetration profile. Robust pharmacokinetic (PK) properties and tolerability mark these inhibitors as advanced preclinical compounds suitable for further development and evaluation in orthotopic models of DIPG.
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http://dx.doi.org/10.1021/acs.jmedchem.0c01199DOI Listing
September 2020
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