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PURPOSE: To explore the predictive potential of serial computed tomography (CT) radiology reports for pancreatic cancer survival using natural language processing (NLP). METHODS: Deep-transfer-learning-based NLP models were retrospectively trained and tested with serial, free-text CT reports, and survival information of consecutive patients diagnosed with pancreatic cancer in a Korean tertiary hospital was extracted. Randomly selected patients with pancreatic cancer and their serial CT reports from an independent tertiary hospital in the United States were included in the external testing data set. The concordance index (c-index) of predicted survival and actual survival, and area under the receiver operating characteristic curve (AUROC) for predicting 1-year survival were calculated. RESULTS: Between January 2004 and June 2021, 2,677 patients with 12,255 CT reports and 670 patients with 3,058 CT reports were allocated to training and internal testing data sets, respectively. ClinicalBERT (Bidirectional Encoder Representations from Transformers) model trained on the single, first CT reports showed a c-index of 0.653 and AUROC of 0.722 in predicting the overall survival of patients with pancreatic cancer. ClinicalBERT trained on up to 15 consecutive reports from the initial report showed an improved c-index of 0.811 and AUROC of 0.911. On the external testing set with 273 patients with 1,947 CT reports, the AUROC was 0.888, indicating the generalizability of our model. Further analyses showed our model's contextual interpretation beyond specific phrases. CONCLUSION: Deep-transfer-learning-based NLP model of serial CT reports can predict the survival of patients with pancreatic cancer. Clinical decisions can be supported by the developed model, with survival information extracted solely from serial radiology reports.
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Aprendizado Profundo , Processamento de Linguagem Natural , Neoplasias Pancreáticas , Tomografia Computadorizada por Raios X , Humanos , Neoplasias Pancreáticas/mortalidade , Neoplasias Pancreáticas/diagnóstico por imagem , Tomografia Computadorizada por Raios X/métodos , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Estudos Retrospectivos , Prognóstico , Curva ROCRESUMO
MOTIVATION: Molecular core structures and R-groups are essential concepts in drug development. Integration of these concepts with conventional graph pre-training approaches can promote deeper understanding in molecules. We propose MolPLA, a novel pre-training framework that employs masked graph contrastive learning in understanding the underlying decomposable parts in molecules that implicate their core structure and peripheral R-groups. Furthermore, we formulate an additional framework that grants MolPLA the ability to help chemists find replaceable R-groups in lead optimization scenarios. RESULTS: Experimental results on molecular property prediction show that MolPLA exhibits predictability comparable to current state-of-the-art models. Qualitative analysis implicate that MolPLA is capable of distinguishing core and R-group sub-structures, identifying decomposable regions in molecules and contributing to lead optimization scenarios by rationally suggesting R-group replacements given various query core templates. AVAILABILITY AND IMPLEMENTATION: The code implementation for MolPLA and its pre-trained model checkpoint is available at https://github.com/dmis-lab/MolPLA.
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Software , Aprendizado de Máquina , Estrutura Molecular , Algoritmos , Desenvolvimento de Medicamentos/métodosRESUMO
SUMMARY: Recent proprietary large language models (LLMs), such as GPT-4, have achieved a milestone in tackling diverse challenges in the biomedical domain, ranging from multiple-choice questions to long-form generations. To address challenges that still cannot be handled with the encoded knowledge of LLMs, various retrieval-augmented generation (RAG) methods have been developed by searching documents from the knowledge corpus and appending them unconditionally or selectively to the input of LLMs for generation. However, when applying existing methods to different domain-specific problems, poor generalization becomes apparent, leading to fetching incorrect documents or making inaccurate judgments. In this paper, we introduce Self-BioRAG, a framework reliable for biomedical text that specializes in generating explanations, retrieving domain-specific documents, and self-reflecting generated responses. We utilize 84k filtered biomedical instruction sets to train Self-BioRAG that can assess its generated explanations with customized reflective tokens. Our work proves that domain-specific components, such as a retriever, domain-related document corpus, and instruction sets are necessary for adhering to domain-related instructions. Using three major medical question-answering benchmark datasets, experimental results of Self-BioRAG demonstrate significant performance gains by achieving a 7.2% absolute improvement on average over the state-of-the-art open-foundation model with a parameter size of 7B or less. Similarly, Self-BioRAG outperforms RAG by 8% Rouge-1 score in generating more proficient answers on two long-form question-answering benchmarks on average. Overall, we analyze that Self-BioRAG finds the clues in the question, retrieves relevant documents if needed, and understands how to answer with information from retrieved documents and encoded knowledge as a medical expert does. We release our data and code for training our framework components and model weights (7B and 13B) to enhance capabilities in biomedical and clinical domains. AVAILABILITY AND IMPLEMENTATION: Self-BioRAG is available at https://github.com/dmis-lab/self-biorag.
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Armazenamento e Recuperação da Informação , Humanos , Armazenamento e Recuperação da Informação/métodos , Processamento de Linguagem NaturalRESUMO
Most research on forest therapy has examined the therapeutic effects of forest activity development. There has been insufficient research identifying and evaluating the forest therapy environment. This study aimed to derive a representative forest therapy environment from each of the four evaluation sites, comprising national luxury forests; Scopus, PubMed, Medline, Web of Science, RISS, and DBpia were searched, and 13 studies evaluating forest therapy environments were analyzed and synthesized. After conducting a Conformity Evaluation, one layer of items, comprising anions with low conformity scores, was excluded, and six field measurements, phytoncide, oxygen, illuminance, UV-rays, sound, and anion, were added to increase objectivity. Finally, five forest therapy environment categories and 25 detailed items were derived. Analytic Hierarchy Process-based importance was evaluated to calculate the weight between the final evaluation items. According to the site evaluations, the categories of landscape, forest air, sunlight, sound, and anions appeared, in that order. This study is significant as it developed evaluation items and rating criteria for forest therapy environments, applied these in the field, and derived representative forest therapy environments for each location. This study developed indicators, provided basic data for establishing a therapy environment management plan, and there recommendations were made for an environment suitable for visitors and customizing forest welfare and therapy services.
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Florestas , Oxigênio , ÂnionsRESUMO
Biomedical relation extraction (BioRE) is the task of automatically extracting and classifying relations between two biomedical entities in biomedical literature. Recent advances in BioRE research have largely been powered by supervised learning and large language models (LLMs). However, training of LLMs for BioRE with supervised learning requires human-annotated data, and the annotation process often accompanies challenging and expensive work. As a result, the quantity and coverage of annotated data are limiting factors for BioRE systems. In this paper, we present our system for the BioCreative VII challenge-DrugProt track, a BioRE system that leverages a language model structure and weak supervision. Our system is trained on weakly labelled data and then fine-tuned using human-labelled data. To create the weakly labelled dataset, we combined two approaches. First, we trained a model on the original dataset to predict labels on external literature, which will become a model-labelled dataset. Then, we refined the model-labelled dataset using an external knowledge base. Based on our experiment, our approach using refined weak supervision showed significant performance gain over the model trained using standard human-labelled datasets. Our final model showed outstanding performance at the BioCreative VII challenge, achieving 3rd place (this paper focuses on our participating system in the BioCreative VII challenge). Database URL: http://wonjin.info/biore-yoon-et-al-2022.
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Pesquisa Biomédica , Idioma , Humanos , Bases de Dados FactuaisRESUMO
OBJECTIVE: Applications of machine learning in healthcare are of high interest and have the potential to improve patient care. Yet, the real-world accuracy of these models in clinical practice and on different patient subpopulations remains unclear. To address these important questions, we hosted a community challenge to evaluate methods that predict healthcare outcomes. We focused on the prediction of all-cause mortality as the community challenge question. MATERIALS AND METHODS: Using a Model-to-Data framework, 345 registered participants, coalescing into 25 independent teams, spread over 3 continents and 10 countries, generated 25 accurate models all trained on a dataset of over 1.1 million patients and evaluated on patients prospectively collected over a 1-year observation of a large health system. RESULTS: The top performing team achieved a final area under the receiver operator curve of 0.947 (95% CI, 0.942-0.951) and an area under the precision-recall curve of 0.487 (95% CI, 0.458-0.499) on a prospectively collected patient cohort. DISCUSSION: Post hoc analysis after the challenge revealed that models differ in accuracy on subpopulations, delineated by race or gender, even when they are trained on the same data. CONCLUSION: This is the largest community challenge focused on the evaluation of state-of-the-art machine learning methods in a healthcare system performed to date, revealing both opportunities and pitfalls of clinical AI.
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Crowdsourcing , Medicina , Humanos , Inteligência Artificial , Aprendizado de Máquina , AlgoritmosRESUMO
MOTIVATION: Protein-ligand binding affinity prediction is a central task in drug design and development. Cross-modal attention mechanism has recently become a core component of many deep learning models due to its potential to improve model explainability. Non-covalent interactions (NCIs), one of the most critical domain knowledge in binding affinity prediction task, should be incorporated into protein-ligand attention mechanism for more explainable deep drug-target interaction models. We propose ArkDTA, a novel deep neural architecture for explainable binding affinity prediction guided by NCIs. RESULTS: Experimental results show that ArkDTA achieves predictive performance comparable to current state-of-the-art models while significantly improving model explainability. Qualitative investigation into our novel attention mechanism reveals that ArkDTA can identify potential regions for NCIs between candidate drug compounds and target proteins, as well as guiding internal operations of the model in a more interpretable and domain-aware manner. AVAILABILITY: ArkDTA is available at https://github.com/dmis-lab/ArkDTA. CONTACT: kangj@korea.ac.kr.
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Sistemas de Liberação de Medicamentos , Desenho de Fármacos , LigantesRESUMO
SUMMARY: Biomedical named entity recognition (NER) plays a crucial role in extracting information from documents in biomedical applications. However, many of these applications require NER models to operate at a document level, rather than just a sentence level. This presents a challenge, as the extension from a sentence model to a document model is not always straightforward. Despite the existence of document NER models that are able to make consistent predictions, they still fall short of meeting the expectations of researchers and practitioners in the field. To address this issue, we have undertaken an investigation into the underlying causes of inconsistent predictions. Our research has led us to believe that the use of adjectives and prepositions within entities may be contributing to low label consistency. In this article, we present our method, ConNER, to enhance a label consistency of modifiers such as adjectives and prepositions. By refining the labels of these modifiers, ConNER is able to improve representations of biomedical entities. The effectiveness of our method is demonstrated on four popular biomedical NER datasets. On three datasets, we achieve a higher F1 score than the previous state-of-the-art model. Our method shows its efficacy on two datasets, resulting in 7.5%-8.6% absolute improvements in the F1 score. Our findings suggest that our ConNER method is effective on datasets with intrinsically low label consistency. Through qualitative analysis, we demonstrate how our approach helps the NER model generate more consistent predictions. AVAILABILITY AND IMPLEMENTATION: Our code and resources are available at https://github.com/dmis-lab/ConNER/.
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Mineração de Dados , Idioma , Humanos , Mineração de Dados/métodos , PesquisadoresRESUMO
MOTIVATION: Compound-protein interaction (CPI) plays an essential role in drug discovery and is performed via expensive molecular docking simulations. Many artificial intelligence-based approaches have been proposed in this regard. Recently, two types of models have accomplished promising results in exploiting molecular information: graph convolutional neural networks that construct a learned molecular representation from a graph structure (atoms and bonds), and neural networks that can be applied to compute on descriptors or fingerprints of molecules. However, the superiority of one method over the other is yet to be determined. Modern studies have endeavored to aggregate information that is extracted from compounds and proteins to form the CPI task. Nonetheless, these approaches have used a simple concatenation to combine them, which cannot fully capture the interaction between such information. RESULTS: We propose the Perceiver CPI network, which adopts a cross-attention mechanism to improve the learning ability of the representation of drug and target interactions and exploits the rich information obtained from extended-connectivity fingerprints to improve the performance. We evaluated Perceiver CPI on three main datasets, Davis, KIBA and Metz, to compare the performance of our proposed model with that of state-of-the-art methods. The proposed method achieved satisfactory performance and exhibited significant improvements over previous approaches in all experiments. AVAILABILITY AND IMPLEMENTATION: Perceiver CPI is available at https://github.com/dmis-lab/PerceiverCPI. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
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Inteligência Artificial , Redes Neurais de Computação , Simulação de Acoplamento Molecular , Proteínas/química , Mapas de Interação de ProteínasRESUMO
Forecasting the interaction between compounds and proteins is crucial for discovering new drugs. However, previous sequence-based studies have not utilized three-dimensional (3D) information on compounds and proteins, such as atom coordinates and distance matrices, to predict binding affinity. Furthermore, numerous widely adopted computational techniques have relied on sequences of amino acid characters for protein representations. This approach may constrain the model's ability to capture meaningful biochemical features, impeding a more comprehensive understanding of the underlying proteins. Here, we propose a two-step deep learning strategy named MulinforCPI that incorporates transfer learning techniques with multi-level resolution features to overcome these limitations. Our approach leverages 3D information from both proteins and compounds and acquires a profound understanding of the atomic-level features of proteins. Besides, our research highlights the divide between first-principle and data-driven methods, offering new research prospects for compound-protein interaction tasks. We applied the proposed method to six datasets: Davis, Metz, KIBA, CASF-2016, DUD-E and BindingDB, to evaluate the effectiveness of our approach.
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Aminoácidos , Mapeamento de Interação de Proteínas , Conformação Proteica , Ligação ProteicaRESUMO
Association between exposure to periodontal bacteria and development of autoantibodies related to rheumatoid arthritis (RA) has been widely accepted; however, direct causal relationship between periodontal bacteria and rheumatoid factor (RF) is currently not fully understood. We investigated whether periodontal bacteria could affect RF status. Patients with preclinical, new-onset, or chronic RA underwent periodontal examination, and investigation of subgingival microbiome via 16S rRNA sequencing. Degree of arthritis and RF induction was examined in collagen-induced arthritis (CIA) mice that were orally inoculated with different periodontal bacteria species. Subsequently, single-cell RNA sequencing analysis of the mouse spleen cells was performed. Patients with preclinical RA showed an increased abundance of the Porphyromonadacae family in the subgingival microbiome compared to those with new-onset or chronic RA, despite comparable periodontitis severity among them. Notably, a distinct subgingival microbial community was found between patients with high-positive RF and those with negative or low-positive RF (p=0.022). Oral infections with the periodontal pathogens P. gingivalis and Treponema denticola in CIA mice similarly enhanced arthritis score, but resulted in different levels of RF induction. Genes related to B cell receptor signaling, B cell proliferation, activation, and differentiation, and CD4+ T cell costimulation and cytokine production were involved in the differential induction of RF in mice exposed to different bacteria. In summary, periodontal microbiome might shape RF status by affecting the humoral immune response during RA pathogenesis.
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Artrite Experimental , Artrite Reumatoide , Microbiota , Camundongos , Animais , Fator Reumatoide , RNA Ribossômico 16S/genética , Microbiota/genética , Treponema denticolaRESUMO
In biomedical natural language processing, named entity recognition (NER) and named entity normalization (NEN) are key tasks that enable the automatic extraction of biomedical entities (e.g. diseases and drugs) from the ever-growing biomedical literature. In this article, we present BERN2 (Advanced Biomedical Entity Recognition and Normalization), a tool that improves the previous neural network-based NER tool by employing a multi-task NER model and neural network-based NEN models to achieve much faster and more accurate inference. We hope that our tool can help annotate large-scale biomedical texts for various tasks such as biomedical knowledge graph construction. AVAILABILITY AND IMPLEMENTATION: Web service of BERN2 is publicly available at http://bern2.korea.ac.kr. We also provide local installation of BERN2 at https://github.com/dmis-lab/BERN2. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
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Redes Neurais de Computação , Software , Processamento de Linguagem NaturalRESUMO
Chemical identification involves finding chemical entities in text (i.e. named entity recognition) and assigning unique identifiers to the entities (i.e. named entity normalization). While current models are developed and evaluated based on article titles and abstracts, their effectiveness has not been thoroughly verified in full text. In this paper, we identify two limitations of models in tagging full-text articles: (1) low generalizability to unseen mentions and (2) tagging inconsistency. We use simple training and post-processing methods to address the limitations such as transfer learning and mention-wise majority voting. We also present a hybrid model for the normalization task that utilizes the high recall of a neural model while maintaining the high precision of a dictionary model. In the BioCreative VII NLM-Chem track challenge, our best model achieves 86.72 and 78.31 F1 scores in named entity recognition and normalization, significantly outperforming the median (83.73 and 77.49 F1 scores) and taking first place in named entity recognition. In a post-challenge evaluation, we re-implement our model and obtain 84.70 F1 score in the normalization task, outperforming the best score in the challenge by 3.34 F1 score. Database URL: https://github.com/dmis-lab/bc7-chem-id.
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Mineração de Dados , Mineração de Dados/métodos , Bases de Dados FactuaisRESUMO
Graph Neural Networks (GNNs) have been widely applied to various fields due to their powerful representations of graph-structured data. Despite the success of GNNs, most existing GNNs are designed to learn node representations on the fixed and homogeneous graphs. The limitations especially become problematic when learning representations on a misspecified graph or a heterogeneous graph that consists of various types of nodes and edges. To address these limitations, we propose Graph Transformer Networks (GTNs) that are capable of generating new graph structures, which preclude noisy connections and include useful connections (e.g., meta-paths) for tasks, while learning effective node representations on the new graphs in an end-to-end fashion. We further propose enhanced version of GTNs, Fast Graph Transformer Networks (FastGTNs), that improve scalability of graph transformations. Compared to GTNs, FastGTNs are up to 230× and 150× faster in inference and training, and use up to 100× and 148× less memory while allowing the identical graph transformations as GTNs. In addition, we extend graph transformations to the semantic proximity of nodes allowing non-local operations beyond meta-paths. Extensive experiments on both homogeneous graphs and heterogeneous graphs show that GTNs and FastGTNs with non-local operations achieve the state-of-the-art performance for node classification tasks. The code is available: https://github.com/seongjunyun/Graph_Transformer_Networks.
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Aprendizagem , Redes Neurais de Computação , SemânticaRESUMO
MOTIVATION: Current studies in extractive question answering (EQA) have modeled the single-span extraction setting, where a single answer span is a label to predict for a given question-passage pair. This setting is natural for general domain EQA as the majority of the questions in the general domain can be answered with a single span. Following general domain EQA models, current biomedical EQA (BioEQA) models utilize the single-span extraction setting with post-processing steps. RESULTS: In this article, we investigate the question distribution across the general and biomedical domains and discover biomedical questions are more likely to require list-type answers (multiple answers) than factoid-type answers (single answer). This necessitates the models capable of producing multiple answers for a question. Based on this preliminary study, we propose a sequence tagging approach for BioEQA, which is a multi-span extraction setting. Our approach directly tackles questions with a variable number of phrases as their answer and can learn to decide the number of answers for a question from training data. Our experimental results on the BioASQ 7b and 8b list-type questions outperformed the best-performing existing models without requiring post-processing steps. AVAILABILITY AND IMPLEMENTATION: Source codes and resources are freely available for download at https://github.com/dmis-lab/SeqTagQA. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
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Biologia Computacional , SoftwareRESUMO
The number of biomedical literature on new biomedical concepts is rapidly increasing, which necessitates a reliable biomedical named entity recognition (BioNER) model for identifying new and unseen entity mentions. However, it is questionable whether existing models can effectively handle them. In this work, we systematically analyze the three types of recognition abilities of BioNER models: memorization, synonym generalization, and concept generalization. We find that although current best models achieve state-of-the-art performance on benchmarks based on overall performance, they have limitations in identifying synonyms and new biomedical concepts, indicating they are overestimated in terms of their generalization abilities. We also investigate failure cases of models and identify several difficulties in recognizing unseen mentions in biomedical literature as follows: (1) models tend to exploit dataset biases, which hinders the models' abilities to generalize, and (2) several biomedical names have novel morphological patterns with weak name regularity, and models fail to recognize them. We apply a statistics-based debiasing method to our problem as a simple remedy and show the improvement in generalization to unseen mentions. We hope that our analyses and findings would be able to facilitate further research into the generalization capabilities of NER models in a domain where their reliability is of utmost importance.
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Scientific novelty drives the efforts to invent new vaccines and solutions during the pandemic. First-time collaboration and international collaboration are two pivotal channels to expand teams' search activities for a broader scope of resources required to address the global challenge, which might facilitate the generation of novel ideas. Our analysis of 98,981 coronavirus papers suggests that scientific novelty measured by the BioBERT model that is pretrained on 29 million PubMed articles, and first-time collaboration increased after the outbreak of COVID-19, and international collaboration witnessed a sudden decrease. During COVID-19, papers with more first-time collaboration were found to be more novel and international collaboration did not hamper novelty as it had done in the normal periods. The findings suggest the necessity of reaching out for distant resources and the importance of maintaining a collaborative scientific community beyond nationalism during a pandemic.
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Most electronic medical records, such as free-text radiological reports, are unstructured; however, the methodological approaches to analyzing these accumulating unstructured records are limited. This article proposes a deep-transfer-learning-based natural language processing model that analyzes serial magnetic resonance imaging reports of rectal cancer patients and predicts their overall survival. To evaluate the model, a retrospective cohort study of 4,338 rectal cancer patients was conducted. The experimental results revealed that the proposed model utilizing pre-trained clinical linguistic knowledge could predict the overall survival of patients without any structured information and was superior to the carcinoembryonic antigen in predicting survival. The deep-transfer-learning model using free-text radiological reports can predict the survival of patients with rectal cancer, thereby increasing the utility of unstructured medical big data.
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A continuing challenge in modern medicine is the identification of safer and more efficacious drugs. Precision therapeutics, which have one molecular target, have been long promised to be safer and more effective than traditional therapies. This approach has proven to be challenging for multiple reasons including lack of efficacy, rapidly acquired drug resistance, and narrow patient eligibility criteria. An alternative approach is the development of drugs that address the overall disease network by targeting multiple biological targets ('polypharmacology'). Rational development of these molecules will require improved methods for predicting single chemical structures that target multiple drug targets. To address this need, we developed the Multi-Targeting Drug DREAM Challenge, in which we challenged participants to predict single chemical entities that target pro-targets but avoid anti-targets for two unrelated diseases: RET-based tumors and a common form of inherited Tauopathy. Here, we report the results of this DREAM Challenge and the development of two neural network-based machine learning approaches that were applied to the challenge of rational polypharmacology. Together, these platforms provide a potentially useful first step towards developing lead therapeutic compounds that address disease complexity through rational polypharmacology.
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Desenvolvimento de Medicamentos , Neoplasias/tratamento farmacológico , Inibidores de Proteínas Quinases/farmacologia , Proteínas Proto-Oncogênicas c-ret/antagonistas & inibidores , Tauopatias/tratamento farmacológico , Humanos , Neoplasias/metabolismo , Redes Neurais de Computação , Polifarmacologia , Inibidores de Proteínas Quinases/química , Inibidores de Proteínas Quinases/uso terapêutico , Proteínas Proto-Oncogênicas c-ret/genética , Proteínas Proto-Oncogênicas c-ret/metabolismo , Proteínas tau/genética , Proteínas tau/metabolismoRESUMO
Osteoporosis is commonly treated via the long-term usage of anti-osteoporotic agents; however, poor drug compliance and undesirable side effects limit their treatment efficacy. The parathyroid hormone-related protein (PTHrP) is essential for normal bone formation and remodeling; thus, may be used as an anti-osteoporotic agent. Here, we developed a platform for the delivery of a single peptide composed of two regions of the PTHrP protein (1-34 and 107-139); mcPTHrP 1-34+107-139 using a minicircle vector. We also transfected mcPTHrP 1-34+107-139 into human mesenchymal stem cells (MSCs) and generated Thru 1-34+107-139-producing engineered MSCs (eMSCs) as an alternative delivery system. Osteoporosis was induced in 12-week-old C57BL/6 female mice via ovariectomy. The ovariectomized (OVX) mice were then treated with the two systems; (1) mcPTHrP 1-34+107-139 was intravenously administered three times (once per week); (2) eMSCs were intraperitoneally administered twice (on weeks four and six). Compared with the control OVX mice, the mcPTHrP 1-34+107-139-treated group showed better trabecular bone structure quality, increased bone formation, and decreased bone resorption. Similar results were observed in the eMSCs-treated OVX mice. Altogether, these results provide experimental evidence to support the potential of delivering PTHrP 1-34+107-139 using the minicircle technology for the treatment of osteoporosis.