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BACKGROUND: Substantial controversy exists regarding the clinical benefit of patients with severe paradoxical low-flow, low-gradient aortic stenosis (PLF-LG AS) from TAVI. Therefore, we compared post-TAVI benefit by long-term mortality (all-cause, CV and SCD), clinical improvement of heart failure symptoms, and cardiac reverse remodelling in guideline-defined AS subtypes. METHODS: We prospectively included 250 consecutive TAVI patients. TTE, 6mwt, MLHFQ, NYHA status and NT-proBNP were recorded at baseline and 6 months. Long-term mortality and causes of death were assessed. RESULTS: 107 individuals suffered from normal EF, high gradient AS (NEF-HG AS), 36 from low EF, high gradient AS (LEF-HG), 52 from "classic" low-flow, low-gradient AS (LEF-LG AS), and 38 from paradoxical low-flow, low-gradient AS (PLF-LG AS). TAVI lead to a significant decrease in MLHFQ score and NT-proBNP levels in all subtypes except for PLF-LG. Regarding reverse remodelling, a significant increase in EF and decrease in LVEDV was present only in subtypes with reduced baseline EF, whereas a significant decrease in LVMI and LAVI could be observed in all subtypes except for PLF-LG. During a follow-up of 3-5 years, PLF-LG patients exhibited the poorest survival among all subtypes (HR 4.2, P = 0.0002 for CV mortality; HR 7.3, P = 0.004 for SCD, in comparison with NEF-HG). Importantly, PLF-LG was independently predictive for CV mortality (HR 2.9 [1.3-6.9], P = 0.009). CONCLUSIONS: PLF-LG patients exhibit the highest mortality (particularly CV and SCD), the poorest symptomatic benefit and the least reverse cardiac remodelling after TAVI among all subtypes. Thus, this cohort seems to gain the least benefit.
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Treatment of patients with locally advanced rectal cancer (RC) is based on neoadjuvant chemoradiotherapy followed by surgery. In order to reduce the development of therapy resistance, it is necessary to further improve previous treatment approaches. Recent in vivo experimental studies suggested that the reduction of tumor hypoxia by tumor vessel normalization (TVN), through the inhibition of the glycolytic activator PFKFB3, could significantly improve tumor response to therapy. We have evaluated in vitro and in vivo the effects of the PFKFB3 inhibitor 2E-3-(3-pyridinyl)-1-(4-pyridinyl)-2-propen-1-one (3PO) on cell survival, clonogenicity, migration, invasion, and metabolism using colorectal cancer cells, patient-derived tumor organoid (PDO), and xenograft (PDX). 3PO treatment of colorectal cancer cells increased radiation-induced cell death and reduced cancer cell invasion. Moreover, gene set enrichment analysis shows that 3PO is able to alter the metabolic status of PDOs toward oxidative phosphorylation. Additionally, in vivo neoadjuvant treatment with 3PO induced TVN, alleviated tumor hypoxia, and increased tumor necrosis. Our results support PFKFB3 inhibition as a possible future neoadjuvant addition for patients with RC. SIGNIFICANCE: Novel therapies to better treat colorectal cancer are necessary to improve patient outcomes. Therefore, in this study, we evaluated the combination of a metabolic inhibitor (3PO) and standard radiotherapy in different experimental settings. We have observed that the addition of 3PO increased radiation effects, ultimately improving tumor cell response to therapy.
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Fosfofrutoquinase-2 , Neoplasias Retais , Animais , Humanos , Camundongos , Linhagem Celular Tumoral , Necrose , Terapia Neoadjuvante/métodos , Neovascularização Patológica/tratamento farmacológico , Fosfofrutoquinase-2/antagonistas & inibidores , Piridinas/farmacologia , Piridinas/uso terapêutico , Neoplasias Retais/tratamento farmacológico , Neoplasias Retais/radioterapia , Hipóxia Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
MOTIVATION: The inference of cellular compositions from bulk and spatial transcriptomics data increasingly complements data analyses. Multiple computational approaches were suggested and recently, machine learning techniques were developed to systematically improve estimates. Such approaches allow to infer additional, less abundant cell types. However, they rely on training data which do not capture the full biological diversity encountered in transcriptomics analyses; data can contain cellular contributions not seen in the training data and as such, analyses can be biased or blurred. Thus, computational approaches have to deal with unknown, hidden contributions. Moreover, most methods are based on cellular archetypes which serve as a reference; e.g. a generic T-cell profile is used to infer the proportion of T-cells. It is well known that cells adapt their molecular phenotype to the environment and that pre-specified cell archetypes can distort the inference of cellular compositions. RESULTS: We propose Adaptive Digital Tissue Deconvolution (ADTD) to estimate cellular proportions of pre-selected cell types together with possibly unknown and hidden background contributions. Moreover, ADTD adapts prototypic reference profiles to the molecular environment of the cells, which further resolves cell-type specific gene regulation from bulk transcriptomics data. We verify this in simulation studies and demonstrate that ADTD improves existing approaches in estimating cellular compositions. In an application to bulk transcriptomics data from breast cancer patients, we demonstrate that ADTD provides insights into cell-type specific molecular differences between breast cancer subtypes. AVAILABILITY AND IMPLEMENTATION: A python implementation of ADTD and a tutorial are available at Gitlab and zenodo (doi:10.5281/zenodo.7548362).
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Aprendizado de Máquina , Humanos , Perfilação da Expressão Gênica/métodos , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Transcriptoma , Algoritmos , Biologia Computacional/métodos , FemininoRESUMO
MOTIVATION: High-throughput screens (HTS) provide a powerful tool to decipher the causal effects of chemical and genetic perturbations on cancer cell lines. Their ability to evaluate a wide spectrum of interventions, from single drugs to intricate drug combinations and CRISPR-interference, has established them as an invaluable resource for the development of novel therapeutic approaches. Nevertheless, the combinatorial complexity of potential interventions makes a comprehensive exploration intractable. Hence, prioritizing interventions for further experimental investigation becomes of utmost importance. RESULTS: We propose CODEX (COunterfactual Deep learning for the in silico EXploration of cancer cell line perturbations) as a general framework for the causal modeling of HTS data, linking perturbations to their downstream consequences. CODEX relies on a stringent causal modeling strategy based on counterfactual reasoning. As such, CODEX predicts drug-specific cellular responses, comprising cell survival and molecular alterations, and facilitates the in silico exploration of drug combinations. This is achieved for both bulk and single-cell HTS. We further show that CODEX provides a rationale to explore complex genetic modifications from CRISPR-interference in silico in single cells. AVAILABILITY AND IMPLEMENTATION: Our implementation of CODEX is publicly available at https://github.com/sschrod/CODEX. All data used in this article are publicly available.
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Simulação por Computador , Aprendizado Profundo , Humanos , Linhagem Celular Tumoral , Ensaios de Triagem em Larga Escala/métodos , Neoplasias/metabolismo , Biologia Computacional/métodos , Software , Antineoplásicos/farmacologiaRESUMO
Nucleosome positioning is a key factor for transcriptional regulation. Nucleosomes regulate the dynamic accessibility of chromatin and interact with the transcription machinery at every stage. Influences to steer nucleosome positioning are diverse, and the according importance of the DNA sequence in contrast to active chromatin remodeling has been the subject of long discussion. In this study, we evaluate the functional role of DNA sequence for all major elements along the process of transcription. We developed a random forest classifier based on local DNA structure that assesses the sequence-intrinsic support for nucleosome positioning. On this basis, we created a simple data resource that we applied genome-wide to the human genome. In our comprehensive analysis, we found a special role of DNA in mediating the competition of nucleosomes with cis-regulatory elements, in enabling steady transcription, for positioning of stable nucleosomes in exons, and for repelling nucleosomes during transcription termination. In contrast, we relate these findings to concurrent processes that generate strongly positioned nucleosomes in vivo that are not mediated by sequence, such as energy-dependent remodeling of chromatin.
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Montagem e Desmontagem da Cromatina , DNA , Regulação da Expressão Gênica , Nucleossomos , Transcrição Gênica , Nucleossomos/metabolismo , Nucleossomos/genética , Humanos , Montagem e Desmontagem da Cromatina/genética , DNA/genética , DNA/metabolismo , Cromatina/metabolismo , Cromatina/genética , Genoma Humano , Sequência de BasesRESUMO
Dealing with sequence coordinates in different formats and reference genomes is challenging in genetic research. This complexity arises from the need to convert and harmonize datasets of different sources using alternating nomenclatures. Since manual processing is time-consuming and requires specialized knowledge, the Sequence Conversion and Analysis Toolbox (SeqCAT) was developed for daily work with genetic datasets. Our tool provides a range of functions designed to standardize and convert gene variant coordinates based on various sequence types. Its user-friendly web interface provides easy access to all functionalities, while the Application Programming Interface (API) enables automation within pipelines. SeqCAT provides access to human genomic, protein and transcript data, utilizing various data resources and packages and extending them with its own unique features. The platform covers a wide range of genetic research needs with its 14 different applications and 3 info points, including search for transcript and gene information, transition between reference genomes, variant mapping, and genetic event review. Notable examples are 'Convert Protein to DNA Position' for translation of amino acid changes into genomic single nucleotide variants, or 'Fusion Check' for frameshift determination in gene fusions. SeqCAT is an excellent resource for converting sequence coordinate data into the required formats and is available at: https://mtb.bioinf.med.uni-goettingen.de/SeqCAT/.
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Genômica , Software , Humanos , Genômica/métodos , Genoma Humano , Análise de Sequência de DNA/métodos , Internet , Interface Usuário-ComputadorRESUMO
High-throughput technologies are becoming increasingly important in discovering prognostic biomarkers and in identifying novel drug targets. With Mammaprint, Oncotype DX, and many other prognostic molecular signatures breast cancer is one of the paradigmatic examples of the utility of high-throughput data to deliver prognostic biomarkers, that can be represented in a form of a rather short gene list. Such gene lists can be obtained as a set of features (genes) that are important for the decisions of a Machine Learning (ML) method applied to high-dimensional gene expression data. Several studies have identified predictive gene lists for patient prognosis in breast cancer, but these lists are unstable and have only a few genes in common. Instability of feature selection impedes biological interpretability: genes that are relevant for cancer pathology should be members of any predictive gene list obtained for the same clinical type of patients. Stability and interpretability of selected features can be improved by including information on molecular networks in ML methods. Graph Convolutional Neural Network (GCNN) is a contemporary deep learning approach applicable to gene expression data structured by a prior knowledge molecular network. Layer-wise Relevance Propagation (LRP) and SHapley Additive exPlanations (SHAP) are methods to explain individual decisions of deep learning models. We used both GCNN+LRP and GCNN+SHAP techniques to construct feature sets by aggregating individual explanations. We suggest a methodology to systematically and quantitatively analyze the stability, the impact on the classification performance, and the interpretability of the selected feature sets. We used this methodology to compare GCNN+LRP to GCNN+SHAP and to more classical ML-based feature selection approaches. Utilizing a large breast cancer gene expression dataset we show that, while feature selection with SHAP is useful in applications where selected features have to be impactful for classification performance, among all studied methods GCNN+LRP delivers the most stable (reproducible) and interpretable gene lists.
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Biomarcadores Tumorais , Neoplasias da Mama , Redes Neurais de Computação , Humanos , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Biomarcadores Tumorais/genética , Feminino , Perfilação da Expressão Gênica/métodos , Aprendizado Profundo , Prognóstico , Aprendizado de MáquinaRESUMO
BACKGROUND: Osteoclasts are the tissue-specific macrophage population of the bone and unique in their bone-resorbing activity. Hence, they are fundamental for bone physiology in health and disease. However, efficient protocols for the isolation and study of primary human osteoclasts are scarce. In this study, we aimed to establish a protocol, which enables the efficient differentiation of functional human osteoclasts from monocytes. RESULTS: Human monocytes were isolated through a double-density gradient from donor blood. Compared to standard differentiation schemes in polystyrene cell culture dishes, the yield of multinuclear osteoclasts was significantly increased upon initial differentiation of monocytes to macrophages in fluorinated ethylene propylene (FEP) Teflon bags. This initial differentiation phase was then followed by the development of terminal osteoclasts by addition of Receptor Activator of NF-κB Ligand (RANKL). High concentrations of RANKL and Macrophage colony-stimulating factor (M-CSF) as well as an intermediate cell density further supported efficient cell differentiation. The generated cells were highly positive for CD45, CD14 as well as the osteoclast markers CD51/ITGAV and Cathepsin K/CTSK, thus identifying them as osteoclasts. The bone resorption of the osteoclasts was significantly increased when the cells were differentiated from macrophages derived from Teflon bags compared to macrophages derived from conventional cell culture plates. CONCLUSION: Our study has established a novel protocol for the isolation of primary human osteoclasts that improves osteoclastogenesis in comparison to the conventionally used cultivation approach.
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AIMS: Studies have reported a strongly varying co-prevalence of aortic stenosis (AS) and cardiac amyloidosis (CA). We sought to histologically determine the co-prevalence of AS and CA in patients undergoing transcatheter aortic valve replacement (TAVR). Consequently, we aimed to derive an algorithm to identify cases in which to suspect the co-prevalence of AS and CA. METHODS AND RESULTS: In this prospective, monocentric study, endomyocardial biopsies of 162 patients undergoing TAVR between January 2017 and March 2021 at the University Medical Centre Göttingen were analysed by one pathologist blinded to clinical data using haematoxylin-eosin staining, Elastica van Gieson staining, and Congo red staining of endomyocardial biopsies. CA was identified in only eight patients (4.9%). CA patients had significantly higher N-terminal pro-brain natriuretic peptide (NT-proBNP) levels (4356.20 vs. 1938.00 ng/L, P = 0.034), a lower voltage-to-mass ratio (0.73 vs. 1.46 × 10-2 mVm2/g, P = 0.022), and lower transaortic gradients (Pmean 17.5 vs. 38.0 mmHg, P = 0.004) than AS patients. Concomitant CA was associated with a higher prevalence of post-procedural acute kidney injury (50.0% vs. 13.1%, P = 0.018) and sudden cardiac death [SCD; P (log-rank test) = 0.017]. Following propensity score matching, 184 proteins were analysed to identify serum biomarkers of concomitant CA. CA patients expressed lower levels of chymotrypsin (P = 0.018) and carboxypeptidase 1 (P = 0.027). We propose an algorithm using commonly documented parameters-stroke volume index, ejection fraction, NT-proBNP levels, posterior wall thickness, and QRS voltage-to-mass ratio-to screen for CA in AS patients, reaching a sensitivity of 66.6% with a specificity of 98.1%. CONCLUSIONS: The co-prevalence of AS and CA was lower than expected, at 4.9%. Despite excellent 1 year mortality, AS + CA patients died significantly more often from SCD. We propose a multimodal algorithm to facilitate more effective screening for CA containing parameters commonly documented during clinical routine. Proteomic biomarkers may yield additional information in the future.
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Amiloidose , Estenose da Valva Aórtica , Substituição da Valva Aórtica Transcateter , Humanos , Masculino , Feminino , Estudos Prospectivos , Amiloidose/complicações , Amiloidose/diagnóstico , Idoso de 80 Anos ou mais , Estenose da Valva Aórtica/cirurgia , Estenose da Valva Aórtica/diagnóstico , Idoso , Biópsia , Cardiomiopatias/diagnóstico , Cardiomiopatias/etiologia , Miocárdio/patologia , Miocárdio/metabolismo , Seguimentos , PrevalênciaRESUMO
The oncological impact of portal vein resection (PVR) in pancreatic cancer surgery remains contradictory. Different variables might have an impact on the outcome. The aim of the present study is the retrospective assessment of the frequency of PVR, histological confirmation of tumor infiltration, and comparison of oncological outcomes in PVR patients. We retrieved n = 90 patients from a prospectively collected data bank who underwent pancreas surgery between 2012 and 2019 at the University Medical Centre Göttingen (Germany) and showed a histologically confirmed pancreatic ductal adenocarcinoma (PDAC). While 50 patients (55.6%) underwent pancreatic resection combined with PVR, 40 patients (44.4%) received standard pancreatic surgery. Patients with distal pancreatectomy or a tumor other than PDAC were excluded. PVR was performed either as local excision or circular resection of the portal vein. Clinical/patient data and follow-ups were retrieved. The median follow-up period was 20.5 months. Regarding the oncological outcome, a statistically poorer CSS (p = 0.04) was observed in PVR patients. There was no difference (p = 0.18) in patients' outcomes between tangential and complete PVR, while n = 21 (42% of PVR patients) showed portal vein infiltration. The correlation between performed PVR and resection status was statistically significant: 48.6% of PVR patients achieved R0 resections compared to 75% in non-PVR patients (p = 0.03). Patients who underwent PDAC surgery with PVR show a significantly poorer outcome regardless of PVR type. Tumor size and R-status remain two important variables significantly associated with outcome. Since there is a lack of standardization for the indication of PVR, it remains unknown if the need for resection of vein structures during pancreatic resection represents the biological aggressiveness of the tumor or is biased by the experience of the surgeon.
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SUMMARY: Federated learning enables collaboration in medicine, where data is scattered across multiple centers without the need to aggregate the data in a central cloud. While, in general, machine learning models can be applied to a wide range of data types, graph neural networks (GNNs) are particularly developed for graphs, which are very common in the biomedical domain. For instance, a patient can be represented by a protein-protein interaction (PPI) network where the nodes contain the patient-specific omics features. Here, we present our Ensemble-GNN software package, which can be used to deploy federated, ensemble-based GNNs in Python. Ensemble-GNN allows to quickly build predictive models utilizing PPI networks consisting of various node features such as gene expression and/or DNA methylation. We exemplary show the results from a public dataset of 981 patients and 8469 genes from the Cancer Genome Atlas (TCGA). AVAILABILITY AND IMPLEMENTATION: The source code is available at https://github.com/pievos101/Ensemble-GNN, and the data at Zenodo (DOI: 10.5281/zenodo.8305122).
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Metilação de DNA , Aprendizado de Máquina , Humanos , Redes Neurais de Computação , Mapas de Interação de Proteínas , SoftwareRESUMO
NGS is increasingly used in precision medicine, but an automated sequencing pipeline that can detect different types of variants (single nucleotide - SNV, copy number - CNV, structural - SV) and does not rely on normal samples as germline comparison is needed. To address this, we developed Onkopipe, a Snakemake-based pipeline that integrates quality control, read alignments, BAM pre-processing, and variant calling tools to detect SNV, CNV, and SV in a unified VCF format without matched normal samples. Onkopipe is containerized and provides features such as reproducibility, parallelization, and easy customization, enabling the analysis of genomic data in precision medicine. Our validation and evaluation demonstrate high accuracy and concordance, making Onkopipe a valuable open-source resource for molecular tumor boards. Onkopipe is being shared as an open source project and is available at https://gitlab.gwdg.de/MedBioinf/mtb/onkopipe.
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DNA , Medicina de Precisão , Reprodutibilidade dos Testes , Análise de Sequência de DNA , Sequência de BasesRESUMO
Psychopathological symptoms are common sequelae after traumatic brain injury (TBI), leading to increased personal and societal burden. Previous studies on factors influencing Post-traumatic Stress Disorder (PTSD), Generalized Anxiety Disorder (GAD), and Major Depressive Disorder (MDD) after TBI have produced inconclusive results, partly due to methodological limitations. The current study investigated the influence of commonly proposed factors on the clinical impairment, occurrence, frequency, and intensity of symptoms of PTSD, GAD, and MDD after TBI. The study sample comprised 2069 individuals (65% males). Associations between psychopathological outcomes and sociodemographic, premorbid, and injury-related factors were analyzed using logistic regression, standard, and zero-inflated negative binomial models. Overall, individuals experienced moderate levels of PTSD, GAD, and MDD. Outcomes correlated with early psychiatric assessments across domains. The clinical impairment, occurrence, frequency, and intensity of all outcomes were associated with the educational level, premorbid psychiatric history, injury cause, and functional recovery. Distinct associations were found for injury severity, LOC, and clinical care pathways with PTSD; age and LOC:sex with GAD; and living situation with MDD, respectively. The use of suitable statistical models supported the identification of factors associated with the multifactorial etiology of psychopathology after TBI. Future research may apply these models to reduce personal and societal burden.
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BACKGROUND: Artificial intelligence (AI) is influencing our society on many levels and has broad implications for the future practice of hematology and oncology. However, for many medical professionals and researchers, it often remains unclear what AI can and cannot do, and what are promising areas for a sensible application of AI in hematology and oncology. Finally, the limits and perils of using AI in oncology are not obvious to many healthcare professionals. METHODS: In this article, we provide an expert-based consensus statement by the joint Working Group on "Artificial Intelligence in Hematology and Oncology" by the German Society of Hematology and Oncology (DGHO), the German Association for Medical Informatics, Biometry and Epidemiology (GMDS), and the Special Interest Group Digital Health of the German Informatics Society (GI). We provide a conceptual framework for AI in hematology and oncology. RESULTS: First, we propose a technological definition, which we deliberately set in a narrow frame to mainly include the technical developments of the last ten years. Second, we present a taxonomy of clinically relevant AI systems, structured according to the type of clinical data they are used to analyze. Third, we show an overview of potential applications, including clinical, research, and educational environments with a focus on hematology and oncology. CONCLUSION: Thus, this article provides a point of reference for hematologists and oncologists, and at the same time sets forth a framework for the further development and clinical deployment of AI in hematology and oncology in the future.
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Inteligência Artificial , Hematologia , Humanos , Oncologia , PrevisõesRESUMO
BACKGROUND: Colorectal cancer liver metastases (CRCLM) are associated with a poor prognosis, reflected by a five-year survival rate of 14%. Anti-angiogenic therapy through anti-VEGF antibody administration is one of the limited therapies available. However, only a subgroup of metastases uses sprouting angiogenesis to secure their nutrients and oxygen supply, while others rely on vessel co-option (VCO). The distinct mode of vascularization is reflected by specific histopathological growth patterns (HGPs), which have proven prognostic and predictive significance. Nevertheless, their molecular mechanisms are poorly understood. METHODS: We evaluated CRCLM from 225 patients regarding their HGP and clinical data. Moreover, we performed spatial (21,804 spots) and single-cell (22,419 cells) RNA sequencing analyses to explore molecular differences in detail, further validated in vitro through immunohistochemical analysis and patient-derived organoid cultures. RESULTS: We detected specific metabolic alterations and a signature of WNT signalling activation in metastatic cancer cells related to the VCO phenotype. Importantly, in the corresponding healthy liver of CRCLM displaying sprouting angiogenesis, we identified a predominantly expressed capillary subtype of endothelial cells, which could be further explored as a possible predictor for HGP relying on sprouting angiogenesis. CONCLUSION: These findings may prove to be novel therapeutic targets to the treatment of CRCLM, in special the ones relying on VCO.
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Neoplasias Colorretais , Neoplasias Hepáticas , Humanos , Células Endoteliais/patologia , Neoplasias Hepáticas/genética , Neovascularização Patológica/patologia , Neoplasias Colorretais/patologiaRESUMO
Brain metastasis in breast cancer remains difficult to treat and its incidence is increasing. Therefore, the development of new therapies is of utmost clinical relevance. Recently, toll-like receptor (TLR) 4 was correlated with IL6 expression and poor prognosis in 1 215 breast cancer primaries. In contrast, we demonstrated that TLR4 stimulation reduces microglia-assisted breast cancer cell invasion. However, the expression, prognostic value, or therapeutic potential of TLR signaling in breast cancer brain metastasis have not been investigated. We thus tested the prognostic value of various TLRs in two brain-metastasis gene sets. Furthermore, we investigated different TLR agonists, as well as MyD88 and TRIF-deficient microenvironments in organotypic brain-slice ex vivo co-cultures and in vivo colonization experiments. These experiments underline the ambiguous roles of TLR4, its adapter MyD88, and the target nitric oxide (NO) during brain colonization. Moreover, analysis of the gene expression datasets of breast cancer brain metastasis patients revealed associations of TLR1 and IL6 with poor overall survival. Finally, our finding that a single LPS application at the onset of colonization shapes the later microglia/macrophage reaction at the macro-metastasis brain-parenchyma interface (MMPI) and reduces metastatic infiltration into the brain parenchyma may prove useful in immunotherapeutic considerations.
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Neoplasias Encefálicas , Neoplasias da Mama , Humanos , Feminino , Receptor 4 Toll-Like/metabolismo , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/metabolismo , Interleucina-6/metabolismo , Proteínas Adaptadoras de Transdução de Sinal/metabolismo , Neoplasias da Mama/genética , Encéfalo/patologia , Neoplasias Encefálicas/tratamento farmacológico , Proteínas Adaptadoras de Transporte Vesicular/metabolismo , Microambiente TumoralRESUMO
Traumatic brain injury (TBI) is frequently associated with neuropsychiatric impairments such as symptoms of post-traumatic stress disorder (PTSD), which can be screened using self-report instruments such as the Post-Traumatic Stress Disorder Checklist for DSM-5 (PCL-5). The current study aims to inspect the factorial validity and cross-linguistic equivalence of the PCL-5 in individuals after TBI with differential severity. Data for six language groups (n ≥ 200; Dutch, English, Finnish, Italian, Norwegian, Spanish) were extracted from the CENTER-TBI study database. Factorial validity of PTSD was evaluated using confirmatory factor analyses (CFA), and compared between four concurrent structural models. A multi-group CFA approach was utilized to investigate the measurement invariance (MI) of the PCL-5 across languages. All structural models showed satisfactory goodness-of-fit with small between-model variation. The original DSM-5 model for PTSD provided solid evidence of MI across the language groups. The current study underlines the validity of the clinical DSM-5 conceptualization of PTSD and demonstrates the comparability of PCL-5 symptom scores between language versions in individuals after TBI. Future studies should apply MI methods to other sociodemographic (e.g., age, gender) and injury-related (e.g., TBI severity) characteristics to improve the monitoring and clinical care of individuals suffering from PTSD symptoms after TBI.
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Lesões Encefálicas Traumáticas , Transtornos de Estresse Pós-Traumáticos , Lesões Encefálicas Traumáticas/complicações , Lesões Encefálicas Traumáticas/diagnóstico , Lista de Checagem , Manual Diagnóstico e Estatístico de Transtornos Mentais , Humanos , Idioma , Transtornos de Estresse Pós-Traumáticos/psicologiaRESUMO
Next-generation sequencing methods continuously provide clinicians and researchers in precision oncology with growing numbers of genomic variants found in cancer. However, manually interpreting the list of variants to identify reliable targets is an inefficient and cumbersome process that does not scale with the increasing number of cases. Support by computer systems is needed for the analysis of large scale experiments and clinical studies to identify new targets and therapies, and user-friendly applications are needed in molecular tumor boards to support clinicians in their decision-making processes. The MTB-Report tool annotates, filters and sorts genetic variants with information from public databases, providing evidence on actionable variants in both scenarios. A web interface supports medical doctors in the tumor board, and a command line mode allows batch processing of large datasets. The MTB-Report tool is available as an R implementation as well as a Docker image to provide a tool that runs out-of-the-box. Moreover, containerization ensures a stable application that delivers reproducible results over time. A public version of the web interface is available at: http://mtb.bioinf.med.uni-goettingen.de/mtb-report.
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Neoplasias , Variação Genética , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Oncologia , Neoplasias/genética , Medicina de PrecisãoRESUMO
PURPOSE: Preoperative (neoadjuvant) chemoradiotherapy (CRT) and total mesorectal excision is the standard treatment for rectal cancer patients (UICC stage II/III). Up to one-third of patients treated with CRT achieve a pathological complete response (pCR). These patients could be spared from surgery and its associated morbidity and mortality, and assigned to a "watch and wait" strategy. However, reliably identifying pCR based on clinical or imaging parameters remains challenging. EXPERIMENTAL DESIGN: We generated gene-expression profiles of 175 patients with locally advanced rectal cancer enrolled in the CAO/ARO/AIO-94 and -04 trials. One hundred and sixty-one samples were used for building, training and validating a predictor of pCR using a machine learning algorithm. The performance of the classifier was validated in three independent cohorts, comprising 76 patients from (i) the CAO/ARO/AIO-94 and -04 trials (n = 14), (ii) a publicly available dataset (n = 38) and (iii) in 24 prospectively collected samples from the TransValid A trial. RESULTS: A 21-transcript signature yielded the best classification of pCR in 161 patients (Sensitivity: 0.31; AUC: 0.81), when not allowing misclassification of non-complete-responders (False-positive rate = 0). The classifier remained robust when applied to three independent datasets (n = 76). CONCLUSION: The classifier can identify >1/3 of rectal cancer patients with a pCR while never classifying patients with an incomplete response as having pCR. Importantly, we could validate this finding in three independent datasets, including a prospectively collected cohort. Therefore, this classifier could help select rectal cancer patients for a "watch and wait" strategy. TRANSLATIONAL RELEVANCE: Forgoing surgery with its associated side effects could be an option for rectal cancer patients if the prediction of a pathological complete response (pCR) after preoperative chemoradiotherapy would be possible. Based on gene-expression profiles of 161 patients a classifier was developed and validated in three independent datasets (n = 76), identifying over 1/3 of patients with pCR, while never misclassifying a non-complete-responder. Therefore, the classifier can identify patients suited for "watch and wait".