MOTIVATION:Automatic information extraction from biomedical texts requires machine learning methodology that can recognize biomedical entities, characterize inter-entity relationships, and relate extracted information to specific research topics. Large language models (LLMs) excel in general tasks but perform less reliably in the biomedical domain, where texts are characterized by extensive technical terminology and semantic variations from general literature. There is an unmet need for annotated full-text datasets that can be used to fine-tune language models for significant biomedical applications. Here, we focus on extraction of the complex relationships between genes and diseases. RESULTS:We present BioTriplex, a corpus of 100 full-length biomedical research articles (comprising 604 subsection texts) manually annotated with disease names, genes, and 21 subtypes of disease-gene relationships. We employ BioTriplex to train the LLaMA 3.1 8B language model in gene-disease relation extraction. Our fine-tuned model outperforms zero-shot and few-shot approaches, both within the LLaMA 3.1 architecture and across the larger state-of-the-art LLMs GPT-4 and Claude Sonnet 3.7, and classifies gene-disease relation types with broader scope and greater granularity than previously described. These results validate BioTriplex as a useful full-text data resource and underscore the value of specialized datasets in fine-tuning language models for important biomedical tasks. AVAILABILITY AND IMPLEMENTATION:https://github.com/PanagiotisFytas/BioTriplex.

MOTIVATION:Scientific advances build on the findings of existing research. The 2001 publication of the human genome has led to the production of huge volumes of literature exploring the context-specific functions and interactions of genes. Technology is needed to perform large-scale text mining of research papers to extract the reported actions of genes in specific experimental contexts and cell states, such as cancer, thereby facilitating the design of new therapeutic strategies. RESULTS:We present a new corpus and Text Mining methodology that can accurately identify and extract the most important details of cancer genomics experiments from biomedical texts. We build a Named Entity Recognition model that accurately extracts relevant experiment details from PubMed abstract text, and a second model that identifies the relationships between them. This system outperforms earlier models and enables the analysis of gene function in diverse and dynamically evolving experimental contexts. AVAILABILITY AND IMPLEMENTATION:Code and data are available here: https://github.com/cambridgeltl/functional-genomics-ie.

This file includes supplementary figures S1-S9: Figure S1. Immunofluorescence and western blot results showing differences in CXADR expression between EpH4, EpRas and EpXT cells. Figure S2. Western blots showing how incubatino with an AKT inhibitor, or knockdown of CXADR affects EMT markers in EpRas cells. Figure S3. Immunofluorescence images showing co-localization of CXADR with PHLPP2, PTEN and MAGI-1 in EpH4 cells. Figure S4. Results from Co-IP experiments, protein stability assays, and confuency experiments. Figure S5. Immunofluorescence staining of PHLPP2 and PTEN in the intestinal epithelium of CXADR-deficient mice. Figure S6. Kaplan-Meier curves showing how the expression of CXADR and other junction proteins correlates with overall survival in the GOBO database. Figure S7. Kaplan-Meier curves showing how the expression of MAGI1, PTEN and PHLPP2 correlates with overall survival in the GOBO database. Figure S8. Schematic diagram showing the expression of CXADR in 51 human breast cancer cells. Immunofluorescence and western blot results showing how overexpression of CXADR affects EMT markers and signalosome components in breast and lung cancer cells. Figure S9. Scatter plots showing variability in staining of MAGI-1, PTEN, PHLPP2 and E-cadherin in luminal A and basal tumors.

<p>This supplementary information includes 3 supplementary tables. Table S1. List of antibodies. Table S2. List of plasmids. Table S3. List of human tumor samples.</p>

Crystalline silica particles (CSi) are an established human carcinogen, but it is not clear how these particles cause necessary mutations. A well-established scenario includes inflammation caused by retained particles in the bronchioles, activated macrophages, and reactive oxygen species (ROS) that cause DNA damage. In previous studies, we showed that CSi in contact with the plasma membrane of human bronchial epithelium induced double strand breaks within minutes. A signaling pathway implicating the ATX-LPA axis, Rac1, NLRP3, and mitochondrial depolarization upstream of DSB formation was delineated. In this paper, we provide in vitro and in vivo evidence that this signaling pathway triggers endonuclease G (EndoG) translocation from the mitochondria to the nucleus. The DNA damage is documented as γH2AX and p53BP1 nuclear foci, strand breaks in the Comet assay, and as micronuclei. In addition, the DNA damage is induced by low doses of CSi that do not induce apoptosis. By inhibiting the ATX-LPA axis or by EndoG knockdown, we prevent EndoG translocation and DSB formation. Our data indicate that CSi in low doses induces DSBs by sub-apoptotic activation of EndoG, adding CSi to a list of carcinogens that may induce mutations via sub-apoptotic and “minority MOMP” effects. This is the first report linking the ATX-LPA axis to this type of carcinogenic effect.

Atorvastatin decreases proliferation in hepatocytes.

Overexpression of HBx protein increases pAkt level in Huh7 cells.

Autotaxin (ATX) and its product lysophosphatidic acid (LPA) have been implicated in lung fibrosis and cancer. We have studied their roles in DNA damage induced by carcinogenic crystalline silica particles (CSi). In an earlier study on bronchial epithelia, we concluded that ATX, via paracrine signaling, amplifies DNA damage. This effect was seen at 6-16 h. A succeeding study showed that CSi induced NLRP3 phosphorylation, mitochondrial depolarization, double strand breaks (DSBs), and NHEJ repair enzymes within minutes. In the current study we hypothesized a role for the ATX-LPA axis also in this rapid DNA damage. Using 16HBE human bronchial epithelial cells, we show ATX secretion at 3 min, and that ATX inhibitors (HA130 and PF8380) prevented both CSi-induced mitochondrial depolarization and DNA damage (detected by gamma H2AX and Comet assay analysis). Experiments with added LPA gave similar rapid effects as CSi. Furthermore, Rac1 was activated at 3 min, and a Rac1 inhibitor (NSC23766) prevented mitochondrial depolarization and genotoxicity. In mice the bronchial epithelia exhibited histological signs of ATX activation and signs of DSBs (53BP1 positive nuclei) minutes after a single inhalation of CSi. Our data indicate that CSi rapidly activate the ATX-LPA axis and within minutes this leads to DNA damage in bronchial epithelial cells. Thus, ATX mediates very rapid DNA damaging effects of inhaled particles. (C) 2021 The Authors. Published by Elsevier Inc.

The use of pesticides has increased during the past decades, also increasing the risk of exposure to toxic pesticides that can cause detrimental health effects in the future. This is of special concern among farmers in low-to-middle-income countries that may lack proper training in the safe use of these chemicals. To assess the situation in Bolivia a cross-sectional study in three agricultural communities was performed ( n = 297). Handling, use of personal protective equipment (PPE) and pesticide exposure were assessed by a questionnaire and measurements of urinary pesticide metabolites (UPMs). Results showed that methamidophos (65%) and paraquat (52%) were the most commonly used pesticides and that 75% of the farmers combined several pesticides while spraying. Notably, only 17% of the farmers used recommended PPEs while 84% reported to have experienced symptoms of acute pesticide poisoning after spraying. UPM measurements indicated high levels of exposure to chlorpyrifos, pyrethroids and 2,4D and that men generally were more highly exposed compared to women. Our study demonstrates that farmers who are better at following recommendations for pesticide handling and use of PPE had a significantly lower risk of having high UPM levels of most measured pesticides. Our results thus confirm the need of proper training of farmers in low-to-middle-income countries in proper protection and pesticide handling in order to reduce exposure levels and health problems.

Background: Cancer risk assessment of complex exposures, such as exposure to mixtures of polycyclic aromatic hydrocarbons (PAHs), is challenging due to the diverse biological activities of these compounds. With the help of text mining (TM), we have developed TM tools—the latest iteration of the Cancer Risk Assessment using Biomedical literature tool (CRAB3) and a Cancer Hallmarks Analytics Tool (CHAT)—that could be useful for automatic literature analyses in cancer risk assessment and research. Although CRAB3 analyses are based on carcinogenic modes of action (MOAs) and cover almost all the key characteristics of carcinogens, CHAT evaluates literature according to the hallmarks of cancer referring to the alterations in cellular behavior that characterize the cancer cell. Objectives: The objective was to evaluate the usefulness of these tools to support cancer risk assessment by performing a case study of 22 European Union and U.S. Environmental Protection Agency priority PAHs and diesel exhaust and a case study of PAH interactions with silica. Methods: We analyzed PubMed literature, comprising 57,498 references concerning priority PAHs and complex PAH mixtures, using CRAB3 and CHAT. Results: CRAB3 analyses correctly identified similarities and differences in genotoxic and nongenotoxic MOAs of the 22 priority PAHs and grouped them according to their known carcinogenic potential. CHAT had the same capacity and complemented the CRAB output when comparing, for example, benzo[a]pyrene and dibenzo[a,l]pyrene. Both CRAB3 and CHAT analyses highlighted potentially interacting mechanisms within and across complex PAH mixtures and mechanisms of possible importance for interactions with silica. Conclusion: These data suggest that our TM approach can be useful in the hazard identification of PAHs and mixtures including PAHs. The tools can assist in grouping chemicals and identifying similarities and differences in carcinogenic MOAs and their interactions. https://doi.org/10.1289/EHP6702

Background Respirable crystalline silica causes lung carcinomas and many thousand future cancer cases are expected in e.g. Europe. Critical questions are how silica causes genotoxicity in the respiratory epithelium and if new cases can be avoided by lowered permissible exposure levels. In this study we investigate early DNA damaging effects of low doses of silica particles in respiratory epithelial cells in vitro and in vivo in an effort to understand low-dose carcinogenic effects of silica particles. Results We find DNA damage accumulation already after 5–10 min exposure to low doses (5 μg/cm 2 ) of silica particles (Min-U-Sil 5) in vitro. DNA damage was documented as increased levels of γH2AX, pCHK2, by Comet assay, AIM2 induction, and by increased DNA repair (non-homologous end joining) signaling. The DNA damage response (DDR) was not related to increased ROS levels, but to a NLRP3-dependent mitochondrial depolarization. Particles in contact with the plasma membrane elicited a Ser198 phosphorylation of NLRP3, co-localization of NLRP3 to mitochondria and depolarization. FCCP, a mitochondrial uncoupler, as well as overexpressed NLRP3 mimicked the silica-induced depolarization and the DNA damage response. A single inhalation of 25 μg silica particles gave a similar rapid DDR in mouse lung. Biomarkers (CC10 and GPRC5A) indicated an involvement of respiratory epithelial cells. Conclusions Our findings demonstrate a novel mode of action (MOA) for silica-induced DNA damage and mutagenic double strand breaks in airway epithelial cells. This MOA seems independent of particle uptake and of an involvement of macrophages. Our study might help defining models for estimating exposure levels without DNA damaging effects.

Akt kinase regulates several cellular processes, among them growth, proliferation and survival, and has been correlated to neoplastic disease. We report here crosstalk between several Akt regulatory phosphatases that controls the level of the activated form (phosphorylated) of Akt and affects tumor cell aggressiveness. In prostate cancer cell lines, we observed that transient transfection of PTEN decreased the endogenous level of PHLPPs and in contrast, the transient transfection of PHLPPs decreased the endogenous level of PTEN. Furthermore, silencing of PTEN by siRNA resulted in increased PHLPP levels. This phenomenon was not seen in non-transformed cells or in prostate stem cells. This crosstalk promoted cancer cell invasion and was controlled by epigenetically regulated processes where activation of miRs (miR-190 and miR214), the polycomb group of proteins and DNA methylation were involved. The purinergic P2X4 receptor, which has been shown to have a role in wound healing, was identified to be the mediator of this crosstalk. We also studied prostate stem cells and found this crosstalk in the TGFβ1-activated epithelial-mesenchymal transition (EMT). The crosstalk seemed to be a natural part of EMT. In summary, we identify a crosstalk between Akt phosphatases which is not present in non-transformed prostate cells but occurs in cancer cells and stem cells transformed by TGFβ-1. This crosstalk is important for cellular invasion. Background: Phosphatases regulate the Akt oncogene. Results: Crosstalk between Akt phosphatases in prostate cancer cells and in TGF-β1 activated stem cells but not in non-transformed cells. Conclusion: This back-up mechanism facilitates invasive migration of prostate stem and cancer cells. Significance: Characterization of Akt regulation may lead to a better understanding of tumor development and to novel strategies for treatment.

Abstract Tight junctions (TJ) act as hubs for intracellular signaling pathways controlling epithelial cell fate and function. Deregulation of TJ is a hallmark of epithelial–mesenchymal transition (EMT), which contributes to carcinoma progression and metastasis. However, the signaling mechanisms linking TJ to the induction of EMT are not understood. Here, we identify a TJ-based signalosome, which controls AKT signaling and EMT in breast cancer. The coxsackie and adenovirus receptor (CXADR), a TJ protein with an essential yet uncharacterized role in organogenesis and tissue homeostasis, was identified as a key component of the signalosome. CXADR regulated the stability and function of the phosphatases and AKT inhibitors PTEN and PHLPP2. Loss of CXADR led to hyperactivation of AKT and sensitized cells to TGFβ1–induced EMT. Conversely, restoration of CXADR stabilized PHLPP2 and PTEN, inhibited AKT, and promoted epithelial differentiation. Loss of CXADR in luminal A breast cancer correlated with loss of PHLPP2 and PTEN and poor prognosis. These results show that CXADR promotes the formation of an AKT-inhibitory signalosome at TJ and regulates epithelial–mesenchymal plasticity in breast cancer cells. Moreover, loss of CXADR might be used as a prognostic marker in luminal breast cancer. Significance: The tight junction protein CXADR controls epithelial-mesenchymal plasticity in breast cancer by stabilizing the AKT regulators PTEN and PHLPP2.

Juniper (Juniperus communis L.) is a northern coniferous plant generally used as a spice and for nutritional purposes in foods and drinks. It was previously reported that juniper extract (JE) affects p53 activity, cellular stress, and gene expression induced cell death in human neuroblastoma cells. Therefore, the effects of juniper on p53 and Akt signaling was examined further in A549 lung, 22RV1 and DU145 prostate, and HepG2 liver cancer cells using Western blot, confocal microscopy, and MTT analysis. We found that juniper simultaneously decreased cell viability, activated the p53 pathway, and inactivated the PI3K/Akt pathway. The p53 activation was associated with increased nuclear p53 level. Akt was dephosphorylated, and its inactivation was associated with increased levels of PHLPP1 and PHLPP2 phosphatases. Parallel increases of PARP suggest that JE decreased cell viability by activating cell death. In addition, JE potentiated the effects of gemcitabine and 5-fluorouracil anticancer drugs. Thus, JE can activate cell death in different cancer cell lines through p53 and Akt pathways.

BACKGROUND:VerbNet, an extensive computational verb lexicon for English, has proved useful for supporting a wide range of Natural Language Processing tasks requiring information about the behaviour and meaning of verbs. Biomedical text processing and mining could benefit from a similar resource. We take the first step towards the development of BioVerbNet: A VerbNet specifically aimed at describing verbs in the area of biomedicine. Because VerbNet-style classification is extremely time consuming, we start from a small manual classification of biomedical verbs and apply a state-of-the-art neural representation model, specifically developed for class-based optimization, to expand the classification with new verbs, using all the PubMed abstracts and the full articles in the PubMed Central Open Access subset as data.RESULTS:Direct evaluation of the resulting classification against BioSimVerb (verb similarity judgement data in biomedicine) shows promising results when representation learning is performed using verb class-based contexts. Human validation by linguists and biologists reveals that the automatically expanded classification is highly accurate. Including novel, valid member verbs and classes, our method can be used to facilitate cost-effective development of BioVerbNet.CONCLUSION:This work constitutes the first effort on applying a state-of-the-art architecture for neural representation learning to biomedical verb classification. While we discuss future optimization of the method, our promising results suggest that the automatic classification released with this article can be used to readily support application tasks in biomedicine.

TPS 792: Occupational health 2, Exhibition Hall, Ground floor, August 27, 2019, 3:00 PM - 4:30 PM Pesticides are well-known chemicals that can increase the risk to develop cancer by induction of DNA damage and oxidative stress, especially in populations with chronic exposure. Bolivian farmers have been increasing their use of pesticides during the last decades to increase their production and economy. Chronic exposure to these chemicals, their combined effects and genetic polymorphisms can increase the risk of genotoxic damage, mutagenicity and development of chronic diseases. A cross-sectional study in 297 volunteers from three different Bolivian agricultural communities was conducted. Exposure and handling of pesticides were assessed by a questionnaire and urinary pesticide metabolite analysis. Genotoxic effects were evaluated in collected blood samples by Micronucleus and Comet assay. Frequency of glutathione transferase (GST) null genotypes (GSTM1 and GSTT1) was determined to evaluate the impact on DNA damage levels. The results showed that only 17% of the farmers used recommended protection equipment. In agreement, they were highly exposed to chlorpyrifos, pyrethroids and 2,4-D, and men generally more highly compared to women. Higher frequency of micronuclei (MN) was found in women compared to men (4.52 vs 3.55, p<0.05). Farmers active >8 years had higher frequency of MN compared to farmers active <8 years (4.23 vs 2.94, p<0.05). Surprisingly, a null GST genotype (GSTM1 and GSTT1: 84% and 24% null, respectively) was associated with lower levels of DNA damage. High levels of exposure to tebuconazole, 2,4-D or cyfluthrin was associated with high levels of DNA strand breaks (p<0.05-0.01). After adjustment for confounding factors (e.g. gender, age, GST genotype), a significant increased risk of DNA strand breaks was found for exposure to 2,4-D (OR=1.9, CI=1.0-3.8, p=0.049). In conclusion, agricultural Bolivian population, especially men are highly exposed to mixtures of pesticides causing genotoxic effects in lymphocytes and which constitutes an increased risk of developing cancer in the future.

MOTIVATION:The overwhelming size and rapid growth of the biomedical literature make it impossible for scientists to read all studies related to their work, potentially leading to missed connections and wasted time and resources. Literature-based discovery (LBD) aims to alleviate these issues by identifying implicit links between disjoint parts of the literature. While LBD has been studied in depth since its introduction three decades ago, there has been limited work making use of recent advances in biomedical text processing methods in LBD. RESULTS:We present LION LBD, a literature-based discovery system that enables researchers to navigate published information and supports hypothesis generation and testing. The system is built with a particular focus on the molecular biology of cancer using state-of-the-art machine learning and natural language processing methods, including named entity recognition and grounding to domain ontologies covering a wide range of entity types and a novel approach to detecting references to the hallmarks of cancer in text. LION LBD implements a broad selection of co-occurrence based metrics for analyzing the strength of entity associations, and its design allows real-time search to discover indirect associations between entities in a database of tens of millions of publications while preserving the ability of users to explore each mention in its original context in the literature. Evaluations of the system demonstrate its ability to identify undiscovered links and rank relevant concepts highly among potential connections. AVAILABILITY AND IMPLEMENTATION:The LION LBD system is available via a web-based user interface and a programmable API, and all components of the system are made available under open licenses from the project home page http://lbd.lionproject.net. SUPPLEMENTARY INFORMATION:Supplementary data are available at Bioinformatics online.

During the past decades, farmers in low to middle -income countries have increased their use of pesticides, and thereby the risk of being exposed to potentially genotoxic chemicals that can cause adverse health effects. Here, the aim was to investigate the con-elation between exposure to pesticides and genotoxic damage in a Bolivian agricultural population. Genoloxic effects were assessed in peripheral blood samples by comet and micronucleus (MN) assays, and exposure levels by measurements of 10 urinary pesticide metabolites. Genetic susceptibility was assessed by determination of null frequency of GSTM1 and GSTT1 genotypes. The results showed higher MN frequency in women and farmers active ?S years compared W their counterpart (P< 0.05). In addition, age, GST genotype, alcohol consumption, and type of water source influenced levels of genotoxic damage. Individuals with high exposure to Lebuconazole, 2,4-D, or cyfluthrin displayed increased levels of genotoxic damage (P< 0.05-0.001). Logistic regression was conducted to evaluate associations between pesticide exposure and risk of genotoxic damage. After adjustment for confounders, a significant increased risk of DNA strand breaks was found for high exposure to 2,4-D, odds ratio (OR) 1.99 (P < 0.05). In contrast, high exposure to pyrethroids was associated with a reduced risk of DNA strand breaks, OR 0.49 (P < 0.05). It was also found that high exposure to certain mixtures of pesticides (containing mainly 2,4-D or cyfluthrin) was significantly associated with increased level and risk of genotoxic damage (P < 0.05). In conclusion, our data show that high exposure levels to some pesticides is associated with an increased risk of genotoxic damage among Bolivian fariTters, suggesting that their use should be better controlled or limited. (C) 2019 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

Transforming growth factor beta (TGFβ) is multifunctional cytokine that is involved in the coordination and regulation of many cellular homeostatic processes. Compromised TGFβ activity has been attributed to promotion of human cancers. Recent studies have identified a role for TGFβ in response to radiation-induced DNA damage, suggesting a link between TGFβ and the DNA damage response with implications for cancer development. In this study, the effects of TGFβ on promoting the repair of bulky DNA damage, through modulation of nucleotide excision repair (NER), were investigated. We show that treatment of cells with exogenous TGFβ leads to enhanced repair of DNA damage formed by polycyclic aromatic hydrocarbons and ultraviolet-C radiation; similarly, cells with constitutively activated endogenous TGFβ signaling show comparable responses. This effect of TGFβ is independent of the cell cycle. The response to TGFβ is decreased in cells that have compromised TGFβ signaling through RNA interference of Smad4 and is decreased in NER-deficient cells and cells with compromised NER through RNA interference of excision repair cross-complementing group 1 (ERCC1). Increased interaction and nuclear localization of ERCC1/xeroderma pigmentosum (XP) F and ERCC1/XPA proteins is observed after TGFβ treatment. Our study represents the first experimental evidence of a role for TGFβ in the repair of bulky DNA damage resulting from promotion of the interaction and localization of repair protein complexes involved in the incision step of NER.