Biology subjects

Horak, P.

Publications and source records attributed to Horak, P..

10 recordsLinked to original sources

bioRxiv2026

TOPAS: phosphoproteome data analysis and decision support platform for molecular tumor boards

The molecular tumor board (MTB) is central to precision oncology, providing personalized treatment recommendations based on molecular profiles of patient tumors. Genomics is instrumental for MTBs but often fails to identify clinically actionable targets, a gap that phosphoproteomics can fill. We present the tumor proteome activity status (TOPAS) platform, an end-to-end analysis pipeline that converts terabytes of phosphoproteomic data into patient-specific reports for MTB discussions, focusing on clinically relevant signaling linked to oncogenic mechanisms and therapeutic targets. Designed to scale with growing cohorts, the platform integrates data from 1,998 tumor samples to support patient- and cohort-level hypothesis generation. A web portal handles quality control, calculates TOPAS scores, identifies tumor antigens and immune checkpoints, and offers interactive analyses of differential protein abundance and outlier detection. The TOPAS platform is open source, addresses a critical unmet need and facilitates broader adoption of phosphoproteomics in precision oncology in the future.

bioinformatics↗

bioRxiv2026

Prospective pan-cancer phosphoproteomics at clinical scale extends therapeutic options in precision oncology

Genomics-guided precision oncology has improved survival in cancer entities with actionable mutations but cannot capture oncogenic signaling that manifests at the protein level. Here, we report a prospective, real-world pan-cancer study profiling proteomes and phosphoproteomes of 1,998 tumor samples from adults and children with rare or advanced cancers enrolled in the German precision oncology programs DKFZ/NCT/DKTK MASTER, CATCH and INFORM and their molecular tumor boards (MTBs). We developed tumor proteome activity status (TOPAS) scores for 46 clinically relevant kinases, an immune activity score capturing antigen presentation and T-cell activation and identified therapeutically targetable cell-surface proteins for 94% of patients. These readouts enhance MTB recommendations by exposing actionable non-genomic kinase activity, refining interpretation of oncogenic genome alterations, and highlighting cell-surface treatment options. Three proof-of-concept analyses indicate clinical utility including kinase activity-stratified pazopanib response in sarcoma, immune activity score-tracked checkpoint-inhibitor outcomes pan-cancer, and a phosphoproteomic biomarker distinguishing EGFR-inhibitor response in chordoma.

cancer biology↗

bioRxiv2026

Hierarchical classification of hematologic malignancies using epigenetic and genetic information

Molecular testing in hematology requires different assays for disease subgroup identification, risk stratification and selection of appropriate treatment regimens. Yet, molecular tests are not necessarily standardized between diagnostic laboratories, resulting in varying turnaround times and potentially divergent results. To resolve this issue and enable single-assay molecular testing, we have developed a hierarchical classification framework that combines epigenetic and genetic data from whole genome nanopore sequencing (WGNS) with machine learning to determine disease entities, epigenetic subgroups (epitypes) and genetic aberrations in hematopoietic neoplasms. We curated DNA methylation data from 5,420 samples and trained a classifier allowing entity-level diagnostics featuring 21 conditions, including healthy controls, acute and chronic myeloid and lymphoid neoplasms. This classifier was subsequently combined with entity-specific epitype classifiers predicting 44 therapeutically or prognostically relevant states, followed by integration of genetic data. Benchmarking of the combined (epi-)genetic testing strategy using WGNS confirmed high accuracy in the detection of diagnostic groups and risk stratification, and identified diagnosis-defining molecular alterations that were not reported by standard-of-care work-up.

cancer biology↗

bioRxiv2026

Genetic Architecture of Reproduction and Longevity in Historical Dutch Cohorts

Life-history theory predicts genetic trade-offs between reproduction and survival, often invoked to explain ageing through antagonistic pleiotropy, but evidence in humans is mixed. We analysed a historical Dutch genealogical dataset (birth cohorts 1850-1915) to estimate pedigree-based heritabilities and genetic correlations among lifespan, offspring number, and ages at first and last birth (AFB and ALB). Bayesian animal models were fitted by sex in samples surviving beyond ages 45 and 13, with year of birth modelled by a natural spline. Lifespan heritability was approximately 0.19-0.23. Reproductive-trait heritabilities varied by sex and were generally higher in men. Cross-sex genetic correlations were substantial. Genetic correlations between offspring number and lifespan were weakly negative in women (-0.10), near zero in men aged 45+, and weakly positive in men aged 13+. AFB was positively genetically correlated with lifespan, especially in the 13+ sample. Offspring number was strongly genetically correlated with earlier AFB and later ALB, while AFB and ALB shared positive genetic covariance. Phenotypic associations changed little after adjustment for birth year, province, and urban/rural marriage location. Overall, results provide little support for a strong additive genetic fertility-longevity trade-off and instead highlight shared genetic influences on reproductive timing and viability

evolutionary biology↗

bioRxiv2026

Alternative lengthening of telomeres stratifies complex karyotype sarcomas into distinct genomic and transcriptomic states

Complex karyotype sarcomas (CKS) are heterogeneous mesenchymal malignancies that typically lack recurrent actionable oncogenic drivers and remain therapeutically challenging. Loss of ATRX is a recurrent feature of CKS and defines a particularly high-risk subgroup. ATRX loss is also associated with activation of the alternative lengthening of telomeres (ALT) pathway, and ALT-positive sarcomas have been linked to poor clinical outcomes. However, the molecular underpinnings underlying ALT-status-dependent differences in CKS, as well as the therapeutic vulnerabilities associated with ALT, remain poorly defined. By integrating C-circle-based ALT detection across 776 sarcoma samples with multi-modal sequencing of five CKS subtypes, we find that ALT activity is associated with enriched hallmarks of genomic instability. ALT-positive transcriptomes are dominated by a coordinated DNA damage response and mitotic program, in contrast to oncogenic signaling pathways that drive TERT activation in ALT-negative tumors. Long-read sequencing reveals telomere repeat clusters and telomere-mediated healing at structural breakpoints in ALT-positive tumors. These events also occur on extrachromosomal DNA (ecDNA), linking ALT activity to ecDNA biology. Together, our findings position ALT status as an important stratifying feature of CKS and identify ALT-associated transcriptional programs as potential therapeutic targets.

cancer biology↗

bioRxiv2026

Systematic functional drug testing in patient-derived models reveals ex vivo sensitivities associated with clinical outcome in rare solid tumors

Rare cancers are individually uncommon but collectively represent a substantial share of cancer burden, with limited systemic treatment options for many entities. Molecular profiling identifies targetable alterations, but actionable findings are limited and responses can vary despite a matched target. This motivates complementary approaches that directly assess tumor drug response. Here, we establish a biopsy-compatible ex vivo drug sensitivity testing platform optimized for low input and reproducibility. Patient-derived material was tested either directly or following ex vivo expansion. Functional profiling was performed within clinically relevant timelines across models from 126 patients with rare advanced solid tumors. Drug responses were consistent between model types. In most samples, we identified at least one potentially active compound, supporting feasibility at biopsy-scale. High in vitro sensitivity was associated with clinical benefit and progression-free survival. These findings support functional drug sensitivity testing as a complementary component in precision oncology for adults with rare cancers. Statement of SignificanceThis study presents a biopsy-compatible drug sensitivity testing platform for phenotype-based therapy stratification in rare cancers. It identifies actionable ex vivo drug responses and shows associations with clinical outcome in patients treated with screened therapies. These findings support functional testing as a complementary additional layer of stratification for therapeutic prioritization.

cancer biology↗

bioRxiv2026

Genetic influences on educational outcomes during and after the Soviet era: Revisiting evidence from Estonia

The origins of individual differences in socioeconomic outcomes, including educational attainment and occupational status, reflect a combination of genetic and environmental factors whose relative contributions may differ across historical contexts. Previous research suggested a doubling of the relative role of genetics in explaining variation in these traits in independent Estonia compared with the Soviet era. Using the Estonian Biobank, now tenfold larger than at the time of the original study, we aimed to replicate and extend these findings. We found converging evidence that the relative contribution of genetic factors to educational attainment, but not to occupational status, was higher in the post-Soviet era, although the differences were smaller than previously reported and varied across analytical approaches. However, analyses using narrower birth cohorts revealed a more complex pattern, with the relative genetic contribution to educational attainment decreasing gradually across successive cohorts. Thus, while the Soviet-to-post-Soviet transition was associated with an increase in the relative role of genetic factors in explaining individual differences in educational attainment, it represents only one component of the broader historical changes that have shaped genetic associations with educational attainment in Estonia over the last century.

genetics↗

bioRxiv2021

Differential proteomic analysis of laser-microdissected penetration glands of avian schistosome cercariae with a focus on proteins involved in host invasion

Schistosome invasive stages, cercariae, leave intermediate snail hosts, penetrate the skin of definitive hosts, and transform to schistosomula migrating to final localization. During invasion, cercariae employ histolytic and other bioactive products of specialized holocrine secretory cells - postacetabular (PA) and circumacetabular (CA) penetration glands. Although several studies attempted to characterize protein composition of the in vitro induced gland secretions in Schistosoma mansoni and Schistosoma japonicum, the results were inconsistent and dependent on the method of sample collection and processing. Products of both gland types mixed during their secretion did not allow localization of identified proteins to a particular gland. Here we compared proteomes of separately isolated cercarial gland cells of the avian schistosome Trichobilharzia szidati employing laser-assisted microdissection and shotgun LC-MS/MS, thus obtaining the largest dataset so far concerning the representation and localization of cercarial penetration gland proteins. We optimized the methods of sample processing with cercarial bodies (heads) first. Alizarin-pre-stained, chemically non-fixed samples provided optimal results of MS analyses, and enabled distinguishing PA and CA glands for microdissection. Using 7.5 x 106 m3 sample volume per gland replicate, we identified 3347 peptides assigned to 792 proteins, from which 461 occurred in at least 2 of 3 replicates in either gland type (PA = 455, 40 exclusives; CA = 421, 6 exclusives; 60 proteins differed significantly in their abundance between the glands). Peptidases of 5 catalytic types accounted for ca. 8 % and 6 % of reliably identified proteins in PA and CA glands, respectively. Invadolysin, nardilysin, cathepsins B2 and L3, and elastase 2b orthologs were the major gland endopeptidases. Two cystatins and a serpin were highly abundant peptidase inhibitors in the glands. CA glands were rich in venom allergen-like proteins. The assembled total cercarial body proteome included 1631 identified proteins and revealed additional interesting factors possibly related to tissue invasion. HighlightsO_LIProteomes of two penetration gland types in schistosome cercariae greatly differ C_LIO_LIPostacetabular glands possess 40 unique proteins and are abundant in hydrolases C_LIO_LICircumacetabular glands posses 6 unique proteins and are rich in VAL proteins C_LIO_LIPeptidases make up 8 % of postacetabular and 6 % of circumacetabular gland proteins C_LIO_LICercarial elastase is unique to circumacetabular glands of Trichobilharzia szidati C_LI Note: Supplementary data associated with this article All supplementary data files can be accessed from the following link: http://www.helminthology.cz/supplementary_files.html

bioinformatics↗

bioRxiv2021

Evolution of the open-access CIViC knowledgebase is driven by the needsof the cancer variant interpretation community

CIViC (Clinical Interpretation of Variants in Cancer; civicdb.org) is a crowd-sourced, public domain knowledgebase composed of literature-derived evidence characterizing the clinical utility of cancer variants. As clinical sequencing becomes more prevalent in cancer management, the need for cancer variant interpretation has grown beyond the capability of any single institution. With nearly 300 contributors, CIViC contains peer-reviewed, published literature curated and expert-moderated into structured data units (Evidence Items) that can be accessed globally and in real time, reducing barriers to clinical variant knowledge sharing. We have extended CIViCs functionality to support emergent variant interpretation guidelines, increase interoperability with other variant resources, and promote widespread dissemination of structured curated data. To support the full breadth of variant interpretation from basic to translational, including integration of somatic and germline variant knowledge and inference of drug response, we have enabled curation of three new evidence types (predisposing, oncogenic and functional). The growing CIViC knowledgebase distributes clinically-relevant cancer variant data currently representing >2500 variants in >400 genes from >2800 publications.

genomics↗

bioRxiv2021

Antibiotic treatment increases yellowness of carotenoid feather coloration in greenfinches (Chloris chloris)

Carotenoid plumage coloration is an important signal of quality, and plays an important role in mate choice in many bird species. However, it remains unclear what mechanism makes carotenoids an honest signal. Here, we test the hypothesis that carotenoid plumage coloration might indicate gut health. Parasitic and microbial infections can affect nutrient absorption due to decreased gut surface or by altered gut microbiome. We took an advantage of a naturally occurring coinfection of parasites inhabiting the upper and lower portions of the digestive track to distinguish between the direct and indirect effects of parasites on carotenoid acquisition. Protozoan coccidian intestinal parasites are widespread in greenfinches (Chloris chloris) and the majority of greenfinches are infected in nature. Trichomonosis is an emerging disease of the upper digestive track that causes high mortality among greenfinches. We captured wild greenfinches (N=71) and administered anticoccidial medication toltrazuril (TOLTRA) to one group, antibiotic metronidazole (METRO) that is also effective for treating Trichomonas gallinea, to the second group, and third group received no medication. In the METRO group, feathers grown during the experiment had significantly higher chroma of yellow parts, but there was no effect of TOLTRA on feather chroma. These results suggest that METRO increased the efficiency of carotenoid modification or deposition to the feathers rather than nutrient acquisition, and/or freed energy resources that could be invested in coloration. Alternatively, in accordance with shared pathway hypothesis, increase in efficiency of vital cellular processes might have occurred, as many microbial metabolites can modulate mitochondrial and immune function.

ecology↗