Biology subjects

Holt, C. A.

Publications and source records attributed to Holt, C. A..

4 recordsLinked to original sources

bioRxiv2024

Tirzepatide attenuates mammary tumor progression in diet-induced obese mice

Obesity, an established risk and progression factor for at least 13 cancer types, is highly prevalent globally, and effective strategies to mitigate the burden of obesity-related cancer are urgently needed. We investigated whether tirzepatide, a widely used incretin-mimetic drug that induces substantial weight loss, offers anticancer benefits. Across 3 tumor models, we demonstrate that chronic tirzepatide treatment reverses diet-induced increases in body weight and fat mass, systemic metabolic perturbations, and tumor growth. We also showed that the anticancer activity of tirzepatide does not involve direct effects on the neoplastic cells used, which lack incretin receptor expression. The anticancer actions of tirzepatide require the reversal of both the metabolic dysregulation and hyporesponsiveness of CD8+ tumor infiltrating lymphocytes evident in obesity. Our findings establish tirzepatide as a promising compound for intercepting obesity-related cancers.

cancer biology↗

bioRxiv2021

Linking habitat and population dynamics to inform conservation benchmarks for data-limited salmon stocks

Management of data-limited populations is a key challenge to the sustainability of fisheries around the world. For example, sockeye salmon (Oncorhynchus nerka) spawn and rear in many remote coastal watersheds of British Columbia (BC), Canada, making population assessment a challenge. Estimating conservation and management targets for these populations is particularly relevant given their importance to First Nations and commercial fisheries. Most sockeye salmon have obligate lake-rearing as juveniles, and total abundance is typically limited by production in rearing lakes. Although methods have been developed to estimate population capacity based on nursery lake photosynthetic rate (PR) and lake area or volume, they have not yet been widely incorporated into stock-recruit analyses. We tested the value of combining lake-based capacity estimates with traditional stock-recruit based approaches to assess population status using a hierarchical-Bayesian stock-recruit model for 70 populations across coastal BC. This analysis revealed regional variation in sockeye population productivity (Ricker ), with coastal stocks exhibiting lower mean productivity than those in interior watersheds. Using moderately-informative PR estimates of capacity as priors reduced model uncertainty, with a more than five-fold reduction in credible interval width for estimates of conservation benchmarks (e.g. SMAX - spawner abundance at carrying capacity). We estimated that almost half of these remote sockeye stocks are below one commonly applied conservation benchmarks (SMSY), despite substantial reductions in fishing pressure in recent decades. Thus, habitat-based capacity estimates can dramatically reduce scientific uncertainty in model estimates of management targets that underpin sustainable sockeye fisheries. More generally, our analysis reveals opportunities to integrate spatial analyses of habitat characteristics with population models to inform conservation and management of exploited species where population data are limited.

ecology↗

bioRxiv2019

Evaluating the consequences of common assumptions in run reconstructions on Pacific-salmon biological status assessments

Information on biological status is essential for designing, implementing, and evaluating management strategies and recovery plans for threatened or exploited species. However, the data required to quantify status are often limited, and it is important to understand how assessments of status may be biased by assumptions in data analysis. For Pacific salmon, biological status assessments based on spawner abundances and spawner-recruitment (SR) analyses often involve "run reconstructions" that impute missing spawner data, expand observed spawner abundance to account for unmonitored streams, assign catch to individual stocks, and quantify age-at-return. Using a stochastic simulation approach, we quantified how common assumptions in run reconstructions biased assessments of biological status based on spawner abundance. We found that status assessments were robust to most common assumptions in run reconstructions, even in the face of declining monitoring coverage, but that overestimating catch tended to increase rates of status misclassification. Our results lend confidence to biological status assessments based on spawner abundances and SR analyses, even in the face of incomplete data.

ecology↗

bioRxiv2018

Which osteoarthritic gait features recover following Total Knee Replacement surgery?

BackgroundGait analysis can be used to measure variations in joint function in patients with knee osteoarthritis (OA), and is useful when observing longitudinal biomechanical changes following Total Knee Replacement (TKR) surgery. The Cardiff Classifier is an objective classification tool applied previously to examine the extent of biomechanical recovery following TKR. In this study, it is further developed to reveal the salient features that contribute to recovery towards healthy function.\n\nMethodsGait analysis was performed on 30 patients before and after TKR surgery, and 30 healthy controls. Median TKR follow-up time was 13 months. The combined application of principal component analysis (PCA) and the Cardiff Classifier defined 18 biomechanical features that discriminated OA from healthy gait. Statistical analysis tested whether these features were affected by TKR surgery and, if so, whether they recovered to values found for the controls.\n\nResultsThe Cardiff Classifier successfully discriminated between OA and healthy gait in all 60 cases. Of the 18 discriminatory features, only six (33%) were significantly affected by surgery, including features in all three planes of the ground reaction force (p<0.001), ankle dorsiflexion moment (p<0.001), hip adduction moment (p=0.003), and transverse hip angle (p=0.007). All but two (89%) of these features remained significantly different to those of the control group after surgery.\n\nConclusionsThis approach was able to discriminate gait biomechanics associated with knee OA. The ground reaction force provided the strongest discriminatory features. Despite increased gait velocity and improvements in self-reported pain and function, which would normally be clinical indicators of recovery, the majority of features were not affected by TKR surgery. This TKR cohort retained pre-operative gait patterns; reduced sagittal hip and knee moments, decreased knee flexion, increased hip flexion, and reduced hip adduction. The changes that were associated with surgery were predominantly found at the ankle and hip, rather than at the knee.

bioengineering↗