Biology subjects

Major, T.

Publications and source records attributed to Major, T..

5 recordsLinked to original sources

bioRxiv2025

Lymphocyte damage in four differently treated prostate radiotherapy cohort

Data comparing the biological dose of radiotherapy techniques in the same patient group are scarce. Furthermore, the assessment of lymphocyte damage caused by radiotherapy can be of importance as immunotherapies are used more frequently. By applying the chromosome aberration technique, over five years prospective comparison of the biological impact of four different types of treatments for low- and intermediate-risk prostate cancer was performed (at 3, 6, 9, 12, 24, 36, 48, and 60 months, 195 patients): conventional LINAC (linear accelerator) (70-78 Gy), CyberKnife (40-37.5 Gy) teletherapy, low-dose rate brachytherapy (LDR; 145 Gy) and high-dose rate brachytherapy (HDR; 19-21 Gy). Multivariate regression analyses were performed to analyze the predictive potential of chromosome aberrations for side effects. The median follow-up was 60 months. We found that teletherapy techniques (conventional LINAC and CyberKnife therapy) caused 1.7-3.2-fold more chromosomal aberrations than brachytherapy did. At three months, 4.6-12.7% of the lymphocytes were damaged. Five years after treatment, the total aberration values of conventional LINAC and LDR brachytherapy patients were still significantly greater than those before therapy (p=0.035 for LINAC and p=0.029 for LDR BT). We found that significant regression models suggest total aberrations or aberrant cell frequency might predict side effects in addition to biological effective dose (BED) and irradiated volume (V100%) (p=0.005 for model including total aberrations, p=0.003 for aberrant cell frequency). We reported a lower biological dose and fewer side effects in brachytherapy patients. We also demonstrated that long-term lymphocyte damage was dependent on the type of radiotherapy. Novelty and impactWe analyzed radiation dose of the immune cells after four types of radiotherapy for five years. The damage of the lymphocytes can be of significance, if patients receive immunotherapy after radiotherapy in the future. We demonstrated chromosome aberrations were still present in lymphocytes years after the radiation. We found that there can be threefold difference in lymphocyte damage between therapy types. We also showed capacity of chromosome aberration technique to predict side effects.

cancer biology↗

bioRxiv2025

Wnt signaling drives stromal inflammation in inflammatory arthritis

The concept that fibroblasts are critical mediators of inflammation is an emerging paradigm. In rheumatoid arthritis (RA), they are the main producers of IL-6 as well as a host of other cytokines and chemokines. Their pathologic activation also directly causes cartilage and bone degradation. Yet, therapeutic agents specifically targeting fibroblasts are not available. Here, we find that Wnt receptors and modulators are predominantly expressed in stromal populations in the synovium. Importantly, non-canonical Wnt activation induces robust inflammatory gene expression including an abundance of cytokines and chemokines in synovial fibroblasts in vitro. Strikingly, the addition of Wnt ligands or inhibition of Wnt secretion exacerbates or reduces arthritis severity, respectively, in vivo in a murine model of inflammatory arthritis. These observations are relevant in human disease, as Wnt activation signatures are enhanced in fibroblasts derived from inflamed RA synovial tissue as well as fibroblasts across other inflammatory diseases. Together, these findings implicate Wnt signaling as a major driver of fibroblast-mediated inflammation and joint pathology. They further suggest that targeting the Wnt pathway is a therapeutically relevant approach to rheumatoid arthritis, particularly in patients who do not respond to conventional treatments and who often express fibroblast-predominant synovial phenotypes.

immunology↗

bioRxiv2024

A reliance on human habitats is key to the success of an introduced predatory reptile

Understanding the success of animals in novel environments is increasingly important as human-mediated introductions continue to move species far beyond their natural ranges. Alongside these introductions, inhabited and agricultural areas are spreading, and correspondingly most animal introductions occur in populated areas. Commensal species which can live alongside humans by making use of specific conditions, structures, or prey, have a significant advantage. Introduced mammal species often use anthropogenic features in their environment and demonstrate a higher tolerance of human disturbance, but their importance remains understudied in ectotherms. The Aesculapian snake (Zamenis longissimus) is an ectotherm which has been introduced beyond the northern extremities of its natural range. To understand their persistence, we radio-tracked snakes daily over two active seasons, including high-frequency tracking of a subset of males. We investigated snake home range size using Autocorrelated Kernel Density Estimators (AKDE). Using AKDE-weighted Habitat Selection Functions we identified preferences for habitat features in a mosaic of habitats, and we used Integrated Step Selection Functions to further explore how these features influence movement. We revealed a particular preference for buildings in male snakes, while females preferred woodland. We demonstrate that the success of this ectothermic predator is likely tied to a willingness to use human features of the landscape.

animal behavior and cognition↗

bioRxiv2023

High standing diversity masks extreme genetic erosion in a declining snake.

Average heterozygosity is frequently used as a proxy for genetic health, and to compare genetic diversity between species and populations. However, this measurement could be misleading if the distribution of heterozygosity across the genome is highly skewed. We investigated this pitfall in methodology using whole-genome sequencing of the adder (Vipera berus), a species experiencing dramatic declines in the UK. We find that mean heterozygosity in adders is notably high, exceeding that of other vertebrates typically regarded as genetically diverse. Their genome-wide distribution of heterozygosity, however, approximates a negative exponential distribution, with most genome regions showing extremely low heterozygosity. Modelling approaches show that this pattern is likely to have resulted from a recent, severe bottleneck and fragmentation most likely caused by anthropogenic activity in a previously large, interconnected adder population. Our results highlight that high standing diversity may mask severe genetic erosion when declines are recent and rapid. In such situations, whole-genome sequencing may provide the best option for genetic risk assessment and targeted conservation actions.

genomics↗

bioRxiv2020

Pleiotropic effect of ABCG2 in gout: involvement in serum urate levels and progression from hyperuricemia to gout

BackgroundThe ABCG2 Q141K (rs2231142) and rs10011796 variants associate with hyperuricaemia (HU). The effect size of ABCG2 rs2231142 on urate is [~]60% that of SLC2A9, yet the effect size on gout is greater. We tested the hypothesis that ABCG2 plays a role in the progression from HU to gout by testing for association of ABCG2 rs2231142 and rs10011796 with gout using HU controls. MethodsWe analysed 1,699 European gout cases and 14,350 normourciemic (NU) and HU controls, and 912 New Zealand (NZ) Polynesian (divided into Eastern and Western Polynesian) gout cases and 696 controls. Association testing was performed using logistic and linear regression with multivariate adjusting for confounding variables. ResultsIn Europeans and Polynesians, the ABCG2 141K (T) allele was associated with gout using HU controls (OR=1.85, P=3.8E-21 and ORmeta =1.85, P=1.3E-03, respectively). There was evidence for an effect of 141K in determining HU in European (OR=1.56, P=1.7E-18) but not in Polynesian (ORmeta=1.49, P=0.057). For SLC2A9 rs11942223, the T allele associated with gout in the presence of HU in European (OR=1.37, P=4.7E-06), however significantly weaker than ABCG2 rs2231142 141K (PHet=0.0023). In Western Polynesian and European, there was epistatic interaction between ABCG2 rs2231142 and the genetically-independent rs10011796. Combining the presence of the 141K allele with the rs10011796 CC-genotype increased gout risk, in the presence of HU, 21.5-fold in Western Polynesian (P=0.009) and 2.6-fold in European (P=9.9E-06). The 141K allele positively associated with flare frequency in Polynesian (Pmeta =2.5E-03). ConclusionThese data are consistent with a role for ABCG2 141K in gout in the presence of established HU.

genetics↗