Mark Nicholas Wass

Background: The Critical Assessment of Functional Annotation (CAFA) is a community effort held to understand the field of computational protein function prediction. Every three years, since 2010, the organizers initiate an experiment to collect function predictions on a large set of proteins and then evaluate the performance of predicting methods on a subset of proteins that have accumulated experimental annotations between the submission deadline and the evaluation time. CAFA provides an independent and rigorous assessment of the current state of the art, thus leveling the playing field, highlighting successes, revealing bottlenecks, and offering a forum for the exchange of ideas in protein science. Here, we report the results of the fourth CAFA experiment (CAFA4). Results: CAFA4 featured the participation of 148 methods from 70 research groups on a total of 46,205 unique proteins over a 5-year annotation accumulation phase, the longest in any CAFA. In a comparison across CAFA2-CAFA4 methods, the prediction of Gene Ontology (GO) terms has clearly improved across all three GO aspects and traditional evaluation settings. While not achieving the first rank, several CAFA2 and CAFA3 methods featured in the top ten methods in many evaluations, suggesting that earlier methods still hold relevance. The performance is weaker in the newly introduced “partial knowledge” evaluation category (proteins with experimental annotations before submission deadline that gained additional annotations in the same GO aspect during the annotation accumulation phase), highlighting the need for a new class of methods. The rankings of the methods were stable over the years in traditional evaluation settings, but less so in the new partial knowledge evaluation. Overall, the field continues to progress with some influx of new participants. Sustained efforts will be necessary to substantially advance it.

Here, we introduce novel sublines of the EGFR‐mutant non‐small cell lung cancer (NSCLC) cell lines HCC827 and HCC4006 adapted to the EGFR kinase inhibitors gefitinib (HCC827 ^r GEFI ^{2μ m} , HCC4006 ^r GEFI ^{1μ m} ), erlotinib (HCC827 ^r ERLO ^{2μ m} , HCC4006 ^r ERLO ^{1μ m} ) and afatinib (HCC827 ^r AFA ^{50n m} , HCC4006 ^r AFA ^{100n m} ). All sublines displayed resistance to gefitinib, erlotinib, afatinib and the third‐generation EGFR kinase inhibitor osimertinib that overcomes T790M‐mediated resistance. HCC4006 ^r ERLO ^{1μ m} displayed a spindle‐like morphology in agreement with previous findings that had detected epithelial–mesenchymal transition (EMT) in its precursor cell line HCC4006 ^r ERLO ^{0.5μ m} . EMT had also been reported for the HCC4006 ^r GEFI ^{1μ m} precursor cell line HCC4006 ^r GEFI ^{0.5μ m} and for HCC4006 ^r AFA ^{100n m} , but the morphologies of HCC4006 ^r GEFI ^{1μ m} or HCC4006 ^r AFA ^{100n m} did not support this, suggesting plasticity in EMT regulation during the drug adaptation process and in established resistant cell lines. Accordingly, HCC4006 ^r ERLO ^{1μ m} displayed resistance to MEK and AKT inhibitors in contrast to its precursor HCC4006 ^r ERLO ^{0.5μ m} . We also detected metabolic plasticity, that is a temporary Warburg metabolism, in HCC4006 and HCC827 ^r GEFI ^{2μ m} . Response profiles to cytotoxic anticancer drugs, kinase inhibitors and HDAC inhibitors resulted in complex patterns that were specific for each individual subline, indicating individual resistance phenotypes. All resistant sublines remained sensitive or displayed collateral sensitivity to at least one of the investigated drugs. In conclusion, the comparison of EGFR kinase‐resistant NSCLC sublines with their precursor cell lines that had been previously characterised at a lower resistance level and metabolic investigations indicated phenotypic plasticity during the resistance formation process and in established cell lines. This plasticity may contribute to the well‐known variability in cell line phenotypes observed between different laboratories and in intra‐laboratory experiments.

The first ISCB LGBTQI+ Symposium, held during Pride Month in 2024, marked a significant milestone for the International Society for Computational Biology (ISCB) community to promote diversity. This event aimed to provide a safe and supportive space for LGBTQI+ members of the society to share their experiences, address unique challenges in Bioinformatics and Computational Biology, and foster strategies for creating an equitable environment within ISCB. Through keynote presentations, short talks, and a roundtable discussion, participants explored topics such as minority stress, visibility, and the impact of role models. The symposium was rooted in a recognition of the historical and ongoing marginalization faced by LGBTQI+ individuals and sought to challenge systemic barriers while emphasizing the importance of community and representation. This article details the journey behind organizing the symposium, including overcoming the challenges of ensuring inclusivity and privacy, and highlights the profound impact of role models and collective action in advancing LGBTQI+ equity in science.

Here, we introduce sublines of the EGFR-mutant non-small cell lung cancer (NSCLC) cell lines HCC827 and HCC4006 adapted to the EGFR kinase inhibitors gefitinib (HCC827 ^r GEFI ^2µM , HCC4006 ^r GEFI ^1µM ), erlotinib (HCC827 ^r ERLO ^2µM , HCC4006 ^r ERLO ^1µM ), and afatinib (HCC827 ^r AFA ^50nM , HCC4006 ^r AFA ^100nM ). All sublines displayed resistance to gefitinib, erlotinib, afatinib, and the third-generation EGFR kinase inhibitor osimertinib that overcomes T790M-mediated resistance. HCC4006 ^r ERLO ^1µM displayed a spindle-like morphology in agreement with previous findings that had detected epithelial-mesenchymal-transition (EMT) in its precursor cell line HCC4006 ^r ERLO ^0.5µM . EMT had also been reported for the HCC4006 ^r GEFI ^1µM precursor cell line HCC4006 ^r GEFI ^0.5µM and for HCC4006 ^r AFA ^100nM , but the morphologies of HCC4006 ^r GEFI ^1µM or HCC4006 ^r AFA ^100nM did not support this, suggesting plasticity in EMT regulation during the drug adaptation process and in established resistant cell lines. Accordingly, HCC4006 ^r ERLO ^1µM displayed resistance to MEK and AKT inhibitors in contrast to its precursor HCC4006 ^r ERLO ^0.5µM . We also detected metabolic plasticity, i.e., a temporary Warburg metabolism, in HCC4006 and HCC827 ^r GEFI ^2µM . Response profiles to cytotoxic anti-cancer drugs, kinase inhibitors, and HDAC inhibitors resulted in complex patterns that were specific for each individual subline without obvious overlaps, indicating individual resistance phenotypes. All resistant sublines remained sensitive or displayed collateral sensitivity to at least one of the investigated drugs. In conclusion, the comparison of EGFR kinase-resistant NSCLC sublines with their precursor cell lines that had been previously characterised at a lower resistance level and metabolic investigations indicated phenotypic plasticity during the resistance formation process and in established cell lines. This plasticity may contribute to the well-known variability in cell line phenotypes observed between different laboratories and in intra-laboratory experiments.

Background: Here, we introduce a novel set of triple-negative breast cancer (TNBC) cell lines consisting of MDA-MB-468, HCC38, and HCC1806 and their sublines adapted to cisplatin, doxorubicin, eribulin, paclitaxel, gemcitabine, or 5-fluorouracil. Methods: The cell lines were characterized by whole exome sequencing and the determination of drug-response profiles. Moreover, genes harbouring resistance-associated mutations were investigated using TCGA data for potential clinical relevance. Result: Sequencing combined with TCGA-derived patient data resulted in the identification of 682 biomarker candidates in the pan-cancer analysis. Thirty-five genes were considered the most promising candidates because they harboured resistance-associated variants in at least two resistant sublines, and their expression correlated with TNBC patient survival. Exome sequencing and response profiles to cytotoxic drugs and DNA damage response inhibitors identified revealed remarkably little overlap between the resistant sublines, suggesting that each resistance formation process follows a unique route. All of the drug-resistant TNBC sublines remained sensitive or even displayed collateral sensitivity to a range of tested compounds. Cross-resistance levels were lowest for the CHK2 inhibitor CCT241533, the PLK1 inhibitor SBE13, and the RAD51 recombinase inhibitor B02, suggesting that CHK2, PLK1, and RAD51 are potential drug targets for therapy-refractory TNBC. Conclusions: We present novel preclinical models of acquired drug resistance in TNBC and many novel candidate biomarkers for further investigation. The finding that each cancer cell line adaptation process follows an unpredictable route reflects recent findings on cancer cell evolution in patients, supporting the relevance of drug-adapted cancer cell lines as preclinical models of acquired resistance.

The antiviral drugs tecovirimat, brincidofovir, and cidofovir are considered for mpox (monkeypox) treatment despite a lack of clinical evidence. Moreover, their use is affected by toxic side-effects (brincidofovir, cidofovir), limited availability (tecovirimat), and potentially by resistance formation. Hence, additional, readily available drugs are needed. Here, therapeutic concentrations of nitroxoline, a hydroxyquinoline antibiotic with a favourable safety profile in humans, inhibited the replication of 12 mpox virus isolates from the current outbreak in primary cultures of human keratinocytes and fibroblasts and a skin explant model by interference with host cell signalling. Tecovirimat, but not nitroxoline, treatment resulted in rapid resistance development. Nitroxoline remained effective against the tecovirimat-resistant strain and increased the anti-mpox virus activity of tecovirimat and brincidofovir. Moreover, nitroxoline inhibited bacterial and viral pathogens that are often co-transmitted with mpox. In conclusion, nitroxoline is a repurposing candidate for the treatment of mpox due to both antiviral and antimicrobial activity.

The COVID-19 pandemic and the associated prevention measures did not only impact on the transmission of COVID-19 but also on the spread of other infectious diseases in an unprecedented natural experiment. Here, we analysed the transmission patterns of 22 different infectious diseases during the COVID-19 pandemic in England. Our results show that the COVID-19 prevention measures generally reduced the spread of pathogens that are transmitted via the air and the faecal-oral route. Moreover, the COVID-19 prevention measures resulted in the sustained suppression of vaccine-preventable infectious diseases also after the removal of restrictions, while non-vaccine preventable diseases displayed a rapid rebound. Despite concerns that a lack of exposure to common pathogens may affect population immunity and result in large outbreaks by various pathogens post-COVID-19, only four of the 22 investigated diseases and disease groups displayed higher post-than pre-pandemic levels without an obvious causative relationship. Notably, this included chickenpox for which an effective vaccine is available but not used in the UK, which provides strong evidence supporting the inclusion of the chickenpox vaccination into the routine vaccination schedule in the UK. In conclusion, our findings provide unique, novel insights into the impact of non-pharmaceutical interventions on the spread of a broad range of infectious diseases.