Biology subjects

Kozak, K.

Publications and source records attributed to Kozak, K..

4 recordsLinked to original sources

bioRxiv2026

Topotecan Syndergizes with SP141 in the Management of Uveal Melanoma

Purpose: Uveal melanoma (UM) is a rare but aggressive intraocular malignancy originating in the uvea (choroid, iris, and ciliary body). Despite primary treatment, 50% of UM patients develop metastases to the liver, lungs, bones, and skin. Topotecan, a topoisomerase I inhibitor, and SP141, an MDM2 inhibitor, have been studied in cancers, including retinoblastoma. This study explores a combined approach with these drugs in the 92-1 UM cell line. Methods: Primary choroidal melanoma-derived 92-1 cells were treated with topotecan and SP141 individually to determine IC50 values. Cell viability and proliferation were assessed using the MTT assay and the xCELLigence real-time monitoring system. The synergistic effects were analyzed quantitatively using the Loewe Additivity and Highest Single-Agent (HSA) models. Flow cytometry was employed to analyze cell cycle distribution, while cell death and apoptosis were monitored via high-throughput, real-time quantitative analysis using the IncuCyte live-cell kinetic imaging system. Results: Both Topotecan and SP141 induced significant cell death in 92-1 cells. xCELLigence showed dose- and time-dependent inhibition of proliferation. Combining sub-IC50 concentrations of topotecan and SP141 exhibited significant synergistic effects, markedly reducing growth. Cell cycle analysis revealed that topotecan causes a dose-dependent biphasic arrest in G2 and S phases, while SP141 causes G2/M arrest, leading to cell death. Cytotoxicity assays corroborated increased cell death following combination therapy, and the Caspase 3/7 assay indicated that apoptosis is the mechanism underlying cell death. Conclusions: The multi-targeted approach combining topotecan and SP141 drugs demonstrated synergistic therapeutic effects in 92-1 cells, suggesting a potential treatment strategy for managing UM.

cancer biology↗

bioRxiv2025

Müllerian mimicry in Neotropical butterflies: One mimicry ring to bring them all, and in the jungle bind them

Understanding the mechanisms underlying species distributions and coexistence is essential to predict and prevent the impacts of global change, particularly in biodiversity hotspots. However, the effects of biotic interactions may be challenging to investigate at large spatial scales. Leveraging well-characterized Mullerian mimetic systems in Neotropical butterflies, we investigated spatial patterns of mutualistic mimetic interactions within and between two tribes of aposematic Nymphalid butterflies: the Heliconiini (Heliconiinae) and the Ithomiini (Danainae). Despite 85 My of independent evolutionary histories, many species share similar warning wing patterns across the Neotropics. In this study we show that both tribes form similar biodiversity hotspots with a high prevalence of rare species and mimetic patterns in the tropical Andes. However, we reveal a higher relative richness of heliconiine butterflies than ithomiines in the Amazon basin contrasting with the Andean concentration of ithomiine diversity. Despite this difference in broadscale diversity patterns, we also document large-scale spatial associations among phenotypically similar species within and between tribes, thereby providing new empirical evidence for Fritz Mullers historical model of mutualistic mimicry at a continental scale. Furthermore, comparative phylogenetic analyses suggest that co-mimetic species within and between tribes have converged towards similar climatic niches as a response to selection favoring co-occurrence. Our findings illustrate the strength of mutualistic interactions in shaping biodiversity patterns at continental scale and in supporting niche convergence even across millions of years of evolution. Critically, it also emphasizes the pervasive vulnerability of mimetic communities, bound by positive interactions, to disassembly induced by climate change. Significance statementMullerian mimicry is a remarkable example of convergent evolution driven by natural selection where coexisting prey species converge in their warning signal advertising their defenses to predators. Heliconiine and ithomiine butterflies found throughout Neotropical rainforests were instrumental in Fritz Mullers historical model, which provided the mechanism for such resemblance. Leveraging decades of fieldwork and museum collections, we show that species with similar color patterns present strikingly similar spatial distributions, regardless of how closely related they are. Such co-occurrence appears reinforced by the evolution of similar climatic requirements among look-alike species. Our findings emphasize the key role of mutualistic interactions in shaping large-scale patterns of biodiversity and supporting convergence in the climatic niches of species spanning across phylogenetically distant clades.

evolutionary biology↗

bioRxiv2021

Combinations of Peptides Synergistically Activate the Regenerative Capacity of Skin Cells In Vitro

OBJECTIVETo explore synergistic effects related to skin regeneration, peptides with distinct biological mechanisms of action were evaluated in combination in different skin cell lines in the presence or absence of niacinamide (Nam). Furthermore, the synergistic responses of peptide combinations on global gene expression were compared to the changes that occur with fractional laser resurfacing treatment, a gold standard approach for skin rejuvenation, to further define optimal peptide combinations. METHODSMicroarray profiling was used to characterize the biological responses of peptide combinations (+/- Nam) relative to the individual components in epidermal keratinocyte and dermal fibroblast cell lines. Cellular functional assays were utilized to confirm the synergistic effects of peptide combinations. Bioinformatics approaches were used to link the synergistic effects of peptide combinations on gene expression to the transcriptomics of the skin rejuvenation response from fractional laser treatment. RESULTSMicroarray analysis of skin cells treated with peptide combinations revealed synergistic changes in gene expression compared to individual peptide controls. Bioinformatic analysis of synergy genes in keratinocytes revealed activation of NRF2-mediated oxidative stress responses by a combination of Ac-PPYL, Pal-KTTKS, and Nam. Additional analysis revealed direct downstream transcriptional targets of NRF2/ARE exhibiting synergistic regulation by this combination of materials, which was corroborated by a cellular reporter assay. NRF2-mediated oxidative stress response pathways were also found to be activated in the transcriptomics of the early skin rejuvenation response to fractional laser treatment, suggesting the importance of this biology in the early stages of tissue repair. Additionally, a second combination of peptides (pal-KT and Ac-PPYL) was found to synergistically restore cellular ATP levels that had been depleted due to the presence of ROS, indicating an additional mechanism whereby peptide synergies may accelerate skin repair. CONCLUSIONThrough combinatorial synergy studies, we have identified additional in vitro skin repair mechanisms beyond the previously described functions of individual peptides and correlated these to the transcriptomics of the skin rejuvenation response of fractional laser treatment. These findings suggest that specific peptides can act together, via complementary and synergistic mechanisms, to holistically enhance the regenerative capacity of in vitro skin cells.

molecular biology↗

bioRxiv2016

Natural diversity of the malaria vector Anopheles gambiae

The sustainability of malaria control in Africa is threatened by rising levels of insecticide resistance, and new tools to prevent malaria transmission are urgently needed. To gain a better understanding of the mosquito populations that transmit malaria, we sequenced the genomes of 765 wild specimens of Anopheles gambiae and Anopheles coluzzii sampled from 15 locations across Africa. The data reveal high levels of genetic diversity, with over 50 million single nucleotide polymorphisms across the 230 Mbp genome. We observe complex patterns of population structure and marked variations in local population size, some of which may be due at least in part to malaria control interventions. Insecticide resistance genes show strong signatures of recent selection associated with multiple independent mutations spreading over large geographical distances and between species. The genetic variability of natural populations substantially reduces the target space for novel gene-drive strategies for mosquito control. This large dataset provides a foundation for tracking the emergence and spread of insecticide resistance and developing new vector control tools.

genomics↗