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Over the last decade, epidermal growth factor receptor (EGFR)-targeted therapies have transformed the treatment landscape for patients with advanced solid tumors. Despite these advances, resistance to anti-EGFR therapies is still a significant clinical challenge. While cell-autonomous mechanisms of resistance are well-documented, they do not fully elucidate the complexity of drug resistance. Cancer-associated fibroblasts (CAFs), key mediators within the tumor microenvironment (TME), have emerged as pivotal players in cancer progression and chemoresistance. Recent evidence implicates CAFs in resistance to anti-EGFR therapies, suggesting they may undermine treatment efficacy. This review synthesizes current data, highlighting the critical role of CAFs in resistance pathogenesis and summarizing recent therapeutic strategies targeting CAFs. We underscore the challenges and advocate for the exploration of CAFs as a potential dual-targeted approach.
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Antineoplásicos , Fibroblastos Associados a Câncer , Resistencia a Medicamentos Antineoplásicos , Receptores ErbB , Neoplasias , Microambiente Tumoral , Humanos , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/metabolismo , Fibroblastos Associados a Câncer/efeitos dos fármacos , Fibroblastos Associados a Câncer/metabolismo , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Animais , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Microambiente Tumoral/efeitos dos fármacosRESUMO
Metastatic disease results from the dissemination of tumor cells beyond their organ of origin to grow in distant organs and is the primary cause of death in patients with advanced breast cancer. Preclinical murine models in which primary tumors spontaneously metastasize are valuable tools for studying metastatic progression and novel cancer treatment combinations. Here, we characterize a novel syngeneic murine breast tumor cell line that provides a model of spontaneously metastatic neu-expressing breast cancer with quicker onset of widespread metastases after orthotopic mammary implantation in immune-competent NeuN mice. The NT2.5-lung metastasis (-LM) cell line was derived from serial passaging of tumor cells that were macro-dissected from spontaneous lung metastases after orthotopic mammary implantation of parental NT2.5 cells. Within one week of NT2.5-LM implantation, metastases are observed in the lungs. Within four weeks, metastases are also observed in the bones, spleen, colon, and liver. We demonstrate that NT2.5-LM metastases are positive for NeuN-the murine equivalent of human epidermal growth factor 2 (HER2). We further demonstrate altered expression of markers of epithelial-to-mesenchymal transition (EMT), suggestive of their enhanced metastatic potential. Genomic analyses support these findings and reveal enrichment in EMT-regulating pathways. In addition, the metastases are rapidly growing, proliferative, and responsive to HER2-directed therapy. The new NT2.5-LM model provides certain advantages over the parental NT2/NT2.5 model, given its more rapid and spontaneous development of metastases. Besides investigating mechanisms of metastatic progression, this new model may be used for the rationalized development of novel therapeutic interventions and assessment of therapeutic responses.
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Preclinical murine models in which primary tumors spontaneously metastasize to distant organs are valuable tools to study metastatic progression and novel cancer treatment combinations. Here, we characterize a novel syngeneic murine breast tumor cell line, NT2.5-lung metastasis (-LM), that provides a model of spontaneously metastatic neu-expressing breast cancer with quicker onset of widespread metastases after orthotopic mammary implantation in immune-competent NeuN mice. Within one week of orthotopic implantation of NT2.5-LM in NeuN mice, distant metastases can be observed in the lungs. Within four weeks, metastases are also observed in the bones, spleen, colon, and liver. Metastases are rapidly growing, proliferative, and responsive to HER2-directed therapy. We demonstrate altered expression of markers of epithelial-to-mesenchymal transition (EMT) and enrichment in EMT-regulating pathways, suggestive of their enhanced metastatic potential. The new NT2.5-LM model provides more rapid and spontaneous development of widespread metastases. Besides investigating mechanisms of metastatic progression, this new model may be used for the rationalized development of novel therapeutic interventions and assessment of therapeutic responses targeting distant visceral metastases.
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Purpose To evaluate the quality of fully automated stereotactic body radiation therapy (SBRT) planning based on volumetric modulated arc therapy, which can reduce the reliance on historical plans and the experience of dosimetrists. Methods Fully automated re-planning was performed on twenty liver cancer patients, automated plans based on automated SBRT planning (ASP) program and manual plans were conducted and compared. One patient was randomly selected and evaluate the repeatability of ASP, ten automated and ten manual SBRT plans were generated based on the same initial optimization objectives. Then, ten SBRT plans were generated for another selected randomly patient with different initial optimization objectives to assess the reproducibility. All plans were clinically evaluated in a double-blinded manner by five experienced radiation oncologists. Results Fully automated plans provided similar planning target volume dose coverage and statistically better organ at risk sparing compared to the manual plans. Notably, automated plans achieved significant dose reduction in spinal cord, stomach, kidney, duodenum, and colon, with a median dose of D2% reduction ranging from 0.64 to 2.85 Gy. R50% and Dmean of ten rings for automated plans were significantly lower than those of manual plans. The average planning time for automated and manual plans was 59.8 ± 7.9 min vs. 127.1 ± 16.8 min (− 67.3 min). Conclusion Automated planning for SBRT, without relying on historical data, can generate comparable or even better plan quality for liver cancer compared with manual planning, along with better reproducibility, and less clinically planning time (AU)
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Humanos , Neoplasias Hepáticas/radioterapia , Neoplasias Hepáticas/cirurgia , Radiocirurgia , Radioterapia de Intensidade Modulada , Dosagem Radioterapêutica , Planejamento da Radioterapia Assistida por Computador , Reprodutibilidade dos TestesRESUMO
Liquidâliquid phase separation (LLPS) is a phenomenon driven by weak interactions between biomolecules, such as proteins and nucleic acids, that leads to the formation of distinct liquid-like condensates. Through LLPS, membraneless condensates are formed, selectively concentrating specific proteins while excluding other molecules to maintain normal cellular functions. Emerging evidence shows that cancer-related mutations cause aberrant condensate assembly, resulting in disrupted signal transduction, impaired DNA repair, and abnormal chromatin organization and eventually contributing to tumorigenesis. The objective of this review is to summarize recent advancements in understanding the potential implications of LLPS in the contexts of cancer progression and therapeutic interventions. By interfering with LLPS, it may be possible to restore normal cellular processes and inhibit tumor progression. The underlying mechanisms and potential drug targets associated with LLPS in cancer are discussed, shedding light on promising opportunities for novel therapeutic interventions.
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Carcinogênese , Transformação Celular Neoplásica , Humanos , Reparo do DNA/genética , Sistemas de Liberação de Medicamentos , MutaçãoRESUMO
PURPOSE: To evaluate the quality of fully automated stereotactic body radiation therapy (SBRT) planning based on volumetric modulated arc therapy, which can reduce the reliance on historical plans and the experience of dosimetrists. METHODS: Fully automated re-planning was performed on twenty liver cancer patients, automated plans based on automated SBRT planning (ASP) program and manual plans were conducted and compared. One patient was randomly selected and evaluate the repeatability of ASP, ten automated and ten manual SBRT plans were generated based on the same initial optimization objectives. Then, ten SBRT plans were generated for another selected randomly patient with different initial optimization objectives to assess the reproducibility. All plans were clinically evaluated in a double-blinded manner by five experienced radiation oncologists. RESULTS: Fully automated plans provided similar planning target volume dose coverage and statistically better organ at risk sparing compared to the manual plans. Notably, automated plans achieved significant dose reduction in spinal cord, stomach, kidney, duodenum, and colon, with a median dose of D2% reduction ranging from 0.64 to 2.85 Gy. R50% and Dmean of ten rings for automated plans were significantly lower than those of manual plans. The average planning time for automated and manual plans was 59.8 ± 7.9 min vs. 127.1 ± 16.8 min (- 67.3 min). CONCLUSION: Automated planning for SBRT, without relying on historical data, can generate comparable or even better plan quality for liver cancer compared with manual planning, along with better reproducibility, and less clinically planning time.
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Neoplasias Hepáticas , Radiocirurgia , Radioterapia de Intensidade Modulada , Humanos , Reprodutibilidade dos Testes , Planejamento da Radioterapia Assistida por Computador , Dosagem Radioterapêutica , Neoplasias Hepáticas/diagnóstico por imagem , Neoplasias Hepáticas/radioterapia , Órgãos em RiscoRESUMO
PURPOSE: The aim of this review is to discuss previous studies on the function of stem cells in radiation-induced damage, and the factors affecting these processes, in the hope of improving our understanding of the different stem cells and the communication networks surrounding them. This is essential for the development of effective stem cell-based therapies to regenerate or replace normal tissues damaged by radiation. CONCLUSION: In salivary glands, senescence-associated cytokines and inflammation-associated cells have a greater effect on stem cells. In the intestinal glands, Paneth cells strongly affect stem cell-mediated tissue regeneration after radiation treatment. In the pancreas, ß-cells as well as protein C receptor positive (Procr) cells are expected to be key cells in the treatment of diabetes. In the bone marrow, a variety of cytokines such as CXC-chemokine ligand 12 (CXCL12) and stem cell factor (SCF), contribute to the functional recovery of hematopoietic stem cells after irradiation.
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Medula Óssea , Células-Tronco Hematopoéticas , Células-Tronco Hematopoéticas/fisiologia , Medula Óssea/efeitos da radiação , Glândulas Salivares/efeitos da radiação , Citocinas/metabolismoRESUMO
BACKGROUND: The current COVID-19 pandemic and the previous SARS/MERS outbreaks of 2003 and 2012 have resulted in a series of major global public health crises. We argue that in the interest of developing effective and safe vaccines and drugs and to better understand coronaviruses and associated disease mechenisms it is necessary to integrate the large and exponentially growing body of heterogeneous coronavirus data. Ontologies play an important role in standard-based knowledge and data representation, integration, sharing, and analysis. Accordingly, we initiated the development of the community-based Coronavirus Infectious Disease Ontology (CIDO) in early 2020. RESULTS: As an Open Biomedical Ontology (OBO) library ontology, CIDO is open source and interoperable with other existing OBO ontologies. CIDO is aligned with the Basic Formal Ontology and Viral Infectious Disease Ontology. CIDO has imported terms from over 30 OBO ontologies. For example, CIDO imports all SARS-CoV-2 protein terms from the Protein Ontology, COVID-19-related phenotype terms from the Human Phenotype Ontology, and over 100 COVID-19 terms for vaccines (both authorized and in clinical trial) from the Vaccine Ontology. CIDO systematically represents variants of SARS-CoV-2 viruses and over 300 amino acid substitutions therein, along with over 300 diagnostic kits and methods. CIDO also describes hundreds of host-coronavirus protein-protein interactions (PPIs) and the drugs that target proteins in these PPIs. CIDO has been used to model COVID-19 related phenomena in areas such as epidemiology. The scope of CIDO was evaluated by visual analysis supported by a summarization network method. CIDO has been used in various applications such as term standardization, inference, natural language processing (NLP) and clinical data integration. We have applied the amino acid variant knowledge present in CIDO to analyze differences between SARS-CoV-2 Delta and Omicron variants. CIDO's integrative host-coronavirus PPIs and drug-target knowledge has also been used to support drug repurposing for COVID-19 treatment. CONCLUSION: CIDO represents entities and relations in the domain of coronavirus diseases with a special focus on COVID-19. It supports shared knowledge representation, data and metadata standardization and integration, and has been used in a range of applications.
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COVID-19 , Doenças Transmissíveis , Coronavirus , Vacinas , Humanos , SARS-CoV-2 , Pandemias , Aminoácidos , Tratamento Farmacológico da COVID-19RESUMO
COVID-19 often manifests with different outcomes in different patients, highlighting the complexity of the host-pathogen interactions involved in manifestations of the disease at the molecular and cellular levels. In this paper, we propose a set of postulates and a framework for systematically understanding complex molecular host-pathogen interaction networks. Specifically, we first propose four host-pathogen interaction (HPI) postulates as the basis for understanding molecular and cellular host-pathogen interactions and their relations to disease outcomes. These four postulates cover the evolutionary dispositions involved in HPIs, the dynamic nature of HPI outcomes, roles that HPI components may occupy leading to such outcomes, and HPI checkpoints that are critical for specific disease outcomes. Based on these postulates, an HPI Postulate and Ontology (HPIPO) framework is proposed to apply interoperable ontologies to systematically model and represent various granular details and knowledge within the scope of the HPI postulates, in a way that will support AI-ready data standardization, sharing, integration, and analysis. As a demonstration, the HPI postulates and the HPIPO framework were applied to study COVID-19 with the Coronavirus Infectious Disease Ontology (CIDO), leading to a novel approach to rational design of drug/vaccine cocktails aimed at interrupting processes occurring at critical host-coronavirus interaction checkpoints. Furthermore, the host-coronavirus protein-protein interactions (PPIs) relevant to COVID-19 were predicted and evaluated based on prior knowledge of curated PPIs and domain-domain interactions, and how such studies can be further explored with the HPI postulates and the HPIPO framework is discussed.
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COVID-19 , Humanos , Interações Hospedeiro-PatógenoRESUMO
Going back to Ross (1967) and Chomsky (1973), researchers have sought to understand what conditions permit long-distance dependencies in language, such as between the wh-word what and the verb bought in the sentence 'What did John think that Mary bought?'. In the present work, we attempt to understand why changing the main verb in wh-questions affects the acceptability of long-distance dependencies out of embedded clauses. In particular, it has been claimed that factive and manner-of-speaking verbs block such dependencies (e.g., 'What did John know/whisper that Mary bought?'), whereas verbs like think and believe allow them. Here we provide 3 acceptability judgment experiments of filler-gap constructions across embedded clauses to evaluate four types of accounts based on (1) discourse; (2) syntax; (3) semantics; and (4) our proposal related to verb-frame frequency. The patterns of acceptability are most simply explained by two factors: verb-frame frequency, such that dependencies with verbs that rarely take embedded clauses are less acceptable; and construction type, such that wh-questions and clefts are less acceptable than declaratives. We conclude that the low acceptability of filler-gap constructions formed by certain sentence complement verbs is due to infrequent linguistic exposure.
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Idioma , Semântica , Humanos , Julgamento , Testes de Linguagem , LinguísticaRESUMO
Our systematic literature collection and annotation identified 106 chemical drugs and 31 antibodies effective against the infection of at least one human coronavirus (including SARS-CoV, SAR-CoV-2, and MERS-CoV) in vitro or in vivo in an experimental or clinical setting. A total of 163 drug protein targets were identified, and 125 biological processes involving the drug targets were significantly enriched based on a Gene Ontology (GO) enrichment analysis. The Coronavirus Infectious Disease Ontology (CIDO) was used as an ontological platform to represent the anti-coronaviral drugs, chemical compounds, drug targets, biological processes, viruses, and the relations among these entities. In addition to new term generation, CIDO also adopted various terms from existing ontologies and developed new relations and axioms to semantically represent our annotated knowledge. The CIDO knowledgebase was systematically analyzed for scientific insights. To support rational drug design, a "Host-coronavirus interaction (HCI) checkpoint cocktail" strategy was proposed to interrupt the important checkpoints in the dynamic HCI network, and ontologies would greatly support the design process with interoperable knowledge representation and reasoning.
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Antivirais/farmacologia , Infecções por Coronavirus/tratamento farmacológico , Conjuntos de Dados como Assunto , Desenho de Fármacos , Humanos , Bases de Conhecimento , Coronavírus da Síndrome Respiratória do Oriente Médio , Coronavírus Relacionado à Síndrome Respiratória Aguda Grave , SARS-CoV-2RESUMO
The increasing usage and the persistence of polyester polyurethane (PU) generate significant sources of environmental pollution. The effective and environmental friendly bioremediation techniques for this refractory waste are in high demand. In this study, three novel PU degrading bacteria were isolated from farm soils and activated sludge. Based upon 16S ribosomal RNA gene sequence blast, their identities were determined. Particularly robust activity was observed in Pseudomonas putida; it spent 4 days to degrade 92% of Impranil DLN(TM) for supporting its growth. The optimum temperature and pH for DLN removal by P. putida were 25 °C and 8.4, respectively. The degradation and transformation of DLN investigated by Fourier transformed infrared spectroscopy show the decrease in ester functional group and the emergence of amide group. The polyurethanolytic activities were both presented in the extracellular fraction and in the cytosol. Esterase activity was detected in the cell lysate. A 45-kDa protein bearing polyurethanolytic activity was also detected in the extracellular medium. This study presented high PU degrading activity of P. putida and demonstrated its responsible enzymes during the PU degradation process, which could be applied in the bioremediation and management of plastic wastes.