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Utility of multicellular spheroids for investigating mechanisms of chemoresistance in triple-negative breast cancer
(MDPI, 2025-08) Ncube, Keith Ntokozo; Van den Bout, Iman; Willers, Clarissa; Gouws, Chrisna; Cordier, Werner; werner.cordier@up.ac.za
Chemoresistance is a major challenge in the treatment of triple-negative breast cancer (TNBC). Multicellular spheroids are an attractive platform for investigating chemoresistance in TNBC, as they replicate the cues of the tumour microenvironment in vivo. We conducted a comprehensive literature search to summarise the multifactorial and interlinked mechanisms driving chemoresistance in TNBC spheroids. These mechanisms include spatial heterogeneity, hypoxia, extracellular matrix remodelling, tumour–stroma crosstalk, drug efflux, apoptotic resistance, and cancer stem cell signalling. Strategies for overcoming chemoresistance in TNBC spheroids include nanocarrier systems to overcome spatial diffusion limitations, pathway inhibition, and targeting tumour–microenvironment interactions. Despite their advantages, some spheroid models face challenges such as low reproducibility, a lack of heterogeneity, variability in size and shape, limited vascularisation, and constraints in long-term culture. Advanced culturing platforms such as clinostat bioreactors allow for extended culture periods, enabling mature spheroid drug testing. Furthermore, advanced analytical techniques provide spatially resolved spheroid data. These multifactorial and interlinked mechanisms reflect the tumour microenvironment in vivo that spheroids recapitulate, rendering them valuable models for studying chemoresistance. The incorporation of stromal components and advanced analytical workflows will enhance the utility and translational relevance of spheroids as reliable preclinical models for drug discovery in TNBC.
Induction of cell death and regulation of autocrine vitamin D metabolism in cervical cancer by physiological and GI20 doses of 25-Hydroxycholecalciferol
(MDPI, 2025-04) Zhou, Esther V.M.; Bhoora, Sachin; Pillay, Tahir S.; Punchoo, Rivak; tahir.pillay@up.ac.za
Vitamin D and its metabolites exert anti-cancer properties in various cancers; however, their effects on cervical cancer remain largely unexplored. To investigate this gap, we exposed HeLa adenocarcinoma cervical cells to physiological and the growth inhibition 20% (GI20) concentration of 25-hydroxycholecalciferol, the precursor hormone of active 1,25-dihydroxycholecalciferol. We then assessed its impact on cell health, and the expression of the genes and proteins involved in the activation and catabolism of vitamin D at the cellular level by autocrine vitamin D metabolism via the vitamin D metabolizing system (VDMS). Cell health was evaluated by crystal violet and alamarBlue assays, while cell cycle progression and apoptotic cell death markers were assessed by flow cytometry. Gross morphology and ultrastructure were observed using brightfield microscopy and transmission electron microscopy. Gene and protein analyses of the autocrine VDMS were assessed using reverse transcription polymerase chain reaction and Western blot, respectively. Our findings reveal that 25(OH)D3 inhibits cell growth and induces apoptosis in HeLa cervical cells in a dose-dependent manner through the autocrine upregulation of CYP27B1 and VDR. These autocrine effects most likely promote the bioactivation of 25(OH)D3 and intracellular signaling of pro-apoptotic genomic pathways by liganded VDR. Furthermore, the upregulation of CYP24A1 at GI20 treatment likely increases the catabolism of 25(OH)D3 and 1,25(OH)2D3, and therefore may mitigate the anti-cancer action of the high-treatment dose. In summary, 25(OH)D3 holds immense potential as a complementary therapeutic treatment for cervical cancer.
Genetic variants associated with suspected neonatal hypoxic ischaemic Encephalopathy : a study in a South African context
(MDPI, 2025-03) Foden, Caroline J.; Durant, Kevin; Mellet, Juanita; Joubert, Fourie; Van Rensburg, Jeanne; Masemola, Mogomane Yvonne Khomotso; Velaphi, Sithembiso C.; Nakwa, Firdose L.; Horn, Alan R.; Pillay, Shakti; Kali, Gugu; Coetzee, Melantha; Ballot, Daynia E.; Kalua, Thumbiko; Babbo, Carina; Pepper, Michael Sean; NESHIE Working Group; michael.pepper@up.ac.za
Neonatal encephalopathy suspected to be due to hypoxic ischaemic encephalopathy (NESHIE) carries the risk of death or severe disability (cognitive defects and cerebral palsy). Previous genetic studies on NESHIE have predominantly focused on exomes or targeted genes. The objective of this study was to identify genetic variants associated with moderate–severe NESHIE through whole-genome, unbiased analysis. Variant filtering and prioritization were performed, followed by association testing both on a case–control basis and to compare the grades of severity and/or progression. Association testing on neonates with NESHIE (N = 172) and ancestry-matched controls (N = 288) produced 71 significant genetic variants (false discovery rate corrected p-value < 6.2 × 10−4), all located in non-coding regions and not previously implicated in NESHIE. Disease-associated variants in non-coding regions are considered to affect regulatory functions, possibly by modifying gene expression, promoters, enhancers, or DNA structure. The most significant variant was at position 6:162010973 in the Parkin RBR E3 ubiquitin protein ligase (PRKN) intron. Intronic variants were also identified in genes involved in inflammatory processes (SLCO3A1), DNA repair (ZGRF1), synaptogenesis (CNTN5), haematopoiesis (ASXL2), and the transcriptional response to hypoxia (PADI4). Ten variants were associated with a higher severity or lack of improvement in NESHIE, including one in ADAMTS3, which encodes a procollagen amino protease with a role in angiogenesis and lymphangiogenesis. This analysis represents one of the first efforts to analyze whole-genome data to investigate the genetic complexity of NESHIE in diverse ethnolinguistic groups of African origin and provides direction for further study.
An investigation of the relationship between long bone measurements and stature : implications for estimating skeletal stature in subadults
(Springer, 2025-01) Chu, Elaine Y.; Stull, Kyra Elizabeth
The present study introduces new regression formulae that address several challenges of current subadult stature estimation methods by 1) using a large, contemporary, cross-sectional sample of subadult skeletal remains; 2) generating regression models using both lengths and breadths; 3) utilizing both linear and nonlinear regression models to accommodate the nonlinear shape of long bone growth; and 4) providing usable prediction intervals for estimating stature. Eighteen long bone measurements, stature, and age were collected from computed tomography images for a sample of individuals (n = 990) between birth and 20 years from the United States. The bivariate relationship between long bone measurements and stature was modeled using linear and nonlinear methods on an 80% training sample and evaluated on a 20% testing sample. Equations were generated using pooled-sex samples. Goodness of fit was evaluated using Kolmogorov–Smirnov tests and mean absolute deviation (MAD). Accuracy and precision were quantified using percent testing accuracy and Bland–Altman plots. In total, 38 stature estimation equations were created and evaluated, all achieving testing accuracies greater than 90%. Nonlinear models generated better fits compared to linear counterparts and generally produced smaller MAD (3.65 – 15.90cm). Length models generally performed better than breadth models, and a mixture of linear and nonlinear methods resulted in highest testing accuracies. Model performance was not biased by sex, age, or measurement type. A freely available, online graphical user interface is provided for immediate use of the models by practitioners in forensic anthropology and will be expanded to include bioarchaeological contexts in the future.
Population affinity estimation in forensic anthropology : a South African perspective
(Springer, 2025-09) Mbonani, Thandolwethu Mbali; L'Abbe, Ericka Noelle; Chen, Ding-Geng (Din); Ridel, Alison Fany, Ridel, Alison Fany; u18059385@tuks.co.za
Forensic anthropologists face the complex task of estimating population affinity from skeletal remains, a process that involves inferring culturally constructed “social race” from biological tissues, a challenge further complicated by the nuanced distinction between population affinity and “race”. The difficulty in making these estimations arises from the complex interplay between social constructs of race, skeletal morphology, and geographic origin. These factors are further influenced by elements such as assortative mating and institutional racism in regions such as South Africa and the United States. The interaction between cultural factors and biological traits raises the question of whether the challenges in estimating population affinity are inevitable or due to a limited understanding of human variation. To address this knowledge gap, this paper presents a review of population affinity estimation in forensic anthropology, with a focus on the South African context. It provides foundational background and historical insights, explores the medico-legal significance of population affinity, and critically evaluates both traditional and emerging estimation methods. By highlighting regional challenges and recent advancements, this review aims to enhance understanding and contribute to ongoing debates in the field.