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"Lucas, Pamela W."
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Pharmacokinetics and derivation of an anticancer dosing regimen for PAC-1, a preferential small molecule activator of procaspase-3, in healthy dogs
Summary
PAC-1 is a preferential small molecule activator of procaspase-3 and has potential to become a novel and effective anticancer agent. The rational development of PAC-1 for translational oncologic applications would be advanced by coupling relevant in vitro cytotoxicity studies with pharmacokinetic investigations conducted in large mammalian models possessing similar metabolism and physiology as people. In the present study, we investigated whether concentrations and exposure durations of PAC-1 that induce cytotoxicity in lymphoma cell lines in vitro can be achievable in healthy dogs through a constant rate infusion (CRI) intravenous delivery strategy. Time- and dose-dependent procaspase-3 activation by PAC-1 with subsequent cytotoxicity was determined in a panel of B-cell lymphoma cells in vitro. The pharmacokinetics of PAC-1 administered orally or intravenously was studied in 6 healthy dogs using a crossover design. The feasibility of maintaining steady state plasma concentration of PAC-1 for 24 or 48 h that paralleled in vitro cytotoxic concentrations was investigated in 4 healthy dogs. In vitro, PAC-1 induced apoptosis in lymphoma cell lines in a time- and dose-dependent manner. The oral bioavailability of PAC-1 was relatively low and highly variable (17.8 ± 9.5%). The achievement and maintenance of predicted PAC-1 cytotoxic concentrations in normal dogs was safely attained via intravenous CRI lasting for 24 or 48 h in duration. Using the dog as a large mammalian model, PAC-1 can be safely administered as an intravenous CRI while achieving predicted in vitro cytotoxic concentrations.
Journal Article
update on diagnosing and treating primary lung tumors
In veterinary medicine, the simplest classification scheme is by general cellular morphology, which includes adenocarcinoma, squamous cell carcinoma, and anaplastic carcinoma.6,19 Primary lung carcinomas can also be organized by topographical location, inclusive of bronchial, bronchoalveolar, or alveolar carcinoma.6,10 Confusingly, some studies categorize bronchoalveolar carcinoma into a separate cellular morphologic subtype altogether.5,8,14 Although organizing primary lung tumors by topographical location is useful in people, veterinary pathologists do not recommend this classification scheme in companion animals because of the advanced stage of the disease at the time of diagnosis, which makes determining the exact topographical origin of lung tumors extremely difficult.10,19 Instead in veterinary studies, pulmonary carcinomas are generally divided into four subgroups-adenocarcinoma, squamous cell carcinoma, bronchial gland carcinoma, and alveolar cell carcinoma.4,10 Adenocarcinoma, regardless of tissue cell origin, is the most common histologic type in dogs and cats.2,4,10,12-14,16,19 In two studies, adenocarcinoma made up 74% to 77% of all primary lung tumors histologically examined.4,10 Other reports suggest adenocarcinoma is more common in people and cats and bronchoalveolar carcinoma is more common in dogs.5 Squamous cell carcinoma, which is the most common pulmonary neoplasm in people, is less common in companion animals, representing 6% and 4% of all of canine and feline lung tumors, respectively.
Journal Article
Pharmacokinetics and derivation of an anticancer dosing regimen for PAC-1 in healthy dogs
PAC-1 is a preferential small molecule activator of procaspase-3 and has potential to become a novel and effective anticancer agent. The rational development of PAC-1 for translational oncologic applications would be advanced by coupling relevant in vitro cytotoxicity studies with pharmacokinetic investigations conducted in large mammalian models possessing similar metabolism and physiology as people. In the present study, we investigated whether concentrations and exposure durations of PAC-1 that induce cytotoxicity in lymphoma cell lines in vitro can be achievable in healthy dogs through a constant rate infusion (CRI) intravenous delivery strategy. Time- and dose-dependent procaspase-3 activation by PAC-1 with subsequent cytotoxicity was determined in a panel of B-cell lymphoma cells in vitro. The pharmacokinetics of PAC-1 administered orally or intravenously was studied in 6 healthy dogs using a crossover design. The feasibility of maintaining steady state plasma concentration of PAC-1 for 24 or 48 hours that paralleled in vitro cytotoxic concentrations was investigated in 4 healthy dogs. In vitro, PAC-1 induced apoptosis in lymphoma cell lines in a time- and dose-dependent manner. The oral bioavailability of PAC-1 was relatively low and highly variable (17.8 ± 9.5%). The achievement and maintenance of predicted PAC-1 cytotoxic concentrations in normal dogs was safely attained via intravenous CRI lasting for 24 or 48 hours in duration. Using the dog as a large mammalian model, PAC-1 can be safely administered as an intravenous CRI while achieving predicted in vitro cytotoxic concentrations.
Journal Article
Child and adolescent self-report symptom measurement in pediatric oncology research: a systematic literature review
Objective Previous work in pediatric oncology has found that clinicians and parents tend to under-report the frequency and severity of treatment-related symptoms compared to child self-report. As such, there is a need to identify high-quality self-report instruments to be used in pediatrie oncology research studies. This study's objective was to conduct a systematic literature review of existing English language instruments used to measure self-reported symptoms in children and adolescents undergoing cancer treatment. Methods A comprehensive literature search was conducted in MEDLINE/PubMed, EMBASE, CINAHL, and PsycINFO to identify relevant articles published through November 10, 2016. Using pre-specified inclusion/exclusion criteria, six trained reviewers carefully screened abstracts and full-text articles for eligibility. Results There were 7738 non-duplicate articles identified in the literature search. Forty articles met our eligibility criteria, and within these articles, there were 38 self-report English symptom instruments. Most studies evaluated only cross-sectional psychometric properties, such as reliability or validity. Ten studies assessed an instrument's responsiveness or ability to detect changes in symptoms over time. Eight instruments met our criteria for use in future longitudinal pediatrie oncology studies. Conclusions This systematic review aids pediatrie oncology researchers in identifying and selecting appropriate symptom measures with strong psychometric evidence for their studies. Enhancing the child's voice in pediatrie oncology research studies allows us to better understand the impact of cancer and its treatment on the lives of children.
Journal Article
A Robust Methodology for Assessing Differential Homeolog Contributions to the Transcriptomes of Allopolyploids
Polyploidy has played a pivotal and recurring role in angiosperm evolution. Allotetraploids arise from hybridization between species and possess duplicated gene copies (homeologs) that serve redundant roles immediately after polyploidization. Although polyploidization is a major contributor to plant evolution, it remains poorly understood. We describe an analytical approach for assessing homeolog-specific expression that begins with de novo assembly of parental transcriptomes and effectively (i) reduces redundancy in de novo assemblies, (ii) identifies putative orthologs, (iii) isolates common regions between orthologs, and (iv) assesses homeolog-specific expression using a robust Bayesian Poisson-Gamma model to account for sequence bias when mapping polyploid reads back to parental references. Using this novel methodology, we examine differential homeolog contributions to the transcriptome in the recently formed allopolyploids Tragopogon mirus and T. miscellus (Compositae). Notably, we assess a larger Tragopogon gene set than previous studies of this system. Using carefully identified orthologous regions and filtering biased orthologs, we find in both allopolyploids largely balanced expression with no strong parental bias. These new methods can be used to examine homeolog expression in any tetrapolyploid system without requiring a reference genome.
Journal Article
Antibody responses and correlates of protection in the general population after two doses of the ChAdOx1 or BNT162b2 vaccines
Antibody responses are an important part of immunity after Coronavirus Disease 2019 (COVID-19) vaccination. However, antibody trajectories and the associated duration of protection after a second vaccine dose remain unclear. In this study, we investigated anti-spike IgG antibody responses and correlates of protection after second doses of ChAdOx1 or BNT162b2 vaccines for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in the United Kingdom general population. In 222,493 individuals, we found significant boosting of anti-spike IgG by the second doses of both vaccines in all ages and using different dosing intervals, including the 3-week interval for BNT162b2. After second vaccination, BNT162b2 generated higher peak levels than ChAdOX1. Older individuals and males had lower peak levels with BNT162b2 but not ChAdOx1, whereas declines were similar across ages and sexes with ChAdOX1 or BNT162b2. Prior infection significantly increased antibody peak level and half-life with both vaccines. Anti-spike IgG levels were associated with protection from infection after vaccination and, to an even greater degree, after prior infection. At least 67% protection against infection was estimated to last for 2–3 months after two ChAdOx1 doses, for 5–8 months after two BNT162b2 doses in those without prior infection and for 1–2 years for those unvaccinated after natural infection. A third booster dose might be needed, prioritized to ChAdOx1 recipients and those more clinically vulnerable.
A large study in the United Kingdom shows that virus-specific antibody levels associated with at least 67% protection against SARS-CoV-2 Delta variant infection last longer after two doses of BNT162b2 vaccine than after two doses of ChAdOx1 vaccine in previously uninfected individuals.
Journal Article
Anti-spike antibody response to natural SARS-CoV-2 infection in the general population
Understanding the trajectory, duration, and determinants of antibody responses after SARS-CoV-2 infection can inform subsequent protection and risk of reinfection, however large-scale representative studies are limited. Here we estimated antibody response after SARS-CoV-2 infection in the general population using representative data from 7,256 United Kingdom COVID-19 infection survey participants who had positive swab SARS-CoV-2 PCR tests from 26-April-2020 to 14-June-2021. A latent class model classified 24% of participants as ‘non-responders’ not developing anti-spike antibodies, who were older, had higher SARS-CoV-2 cycle threshold values during infection (i.e. lower viral burden), and less frequently reported any symptoms. Among those who seroconverted, using Bayesian linear mixed models, the estimated anti-spike IgG peak level was 7.3-fold higher than the level previously associated with 50% protection against reinfection, with higher peak levels in older participants and those of non-white ethnicity. The estimated anti-spike IgG half-life was 184 days, being longer in females and those of white ethnicity. We estimated antibody levels associated with protection against reinfection likely last 1.5-2 years on average, with levels associated with protection from severe infection present for several years. These estimates could inform planning for vaccination booster strategies.
Most people who are infected with SARS-CoV-2 seroconvert within a few weeks, but the determinants and duration of the antibody response are not known. Here, the authors characterise these features of the immune response using data from a large representative community sample of the UK population.
Journal Article
Antibody responses to SARS-CoV-2 vaccines in 45,965 adults from the general population of the United Kingdom
We report that in a cohort of 45,965 adults, who were receiving either the ChAdOx1 or the BNT162b2 SARS-CoV-2 vaccines, in those who had no prior infection with SARS-CoV-2, seroconversion rates and quantitative antibody levels after a single dose were lower in older individuals, especially in those aged >60 years. Two vaccine doses achieved high responses across all ages. Antibody levels increased more slowly and to lower levels with a single dose of ChAdOx1 compared with a single dose of BNT162b2, but waned following a single dose of BNT162b2 in older individuals. In descriptive latent class models, we identified four responder subgroups, including a ‘low responder’ group that more commonly consisted of people aged >75 years, males and individuals with long-term health conditions. Given our findings, we propose that available vaccines should be prioritized for those not previously infected and that second doses should be prioritized for individuals aged >60 years. Further data are needed to better understand the extent to which quantitative antibody responses are associated with vaccine-mediated protection.
Longitudinal tracing of antibody responses to the ChAdOx1 and the BNT162b2 COVID-19 vaccines in 45,965 adults from the United Kingdom give indications for vaccine prioritization.
Journal Article