RESUMEN
Purpose: The purpose of this paper is to develop a method to automatic classify capsule gastroscope image into three categories to prevent high-risk factors for carcinogenesis, such as atrophic gastritis (AG). The purpose of this research work is to develop a deep learning framework based on transfer learning to classify capsule gastroscope image into three categories: normal gastroscopic image, chronic erosive gastritis images, and ulcer gastric image. Method: In this research work, we proposed deep learning framework based on transfer learning to classify capsule gastroscope image into three categories: normal gastroscopic image, chronic erosive gastritis images, and ulcer gastric image. We used VGG- 16, ResNet-50, and Inception V3 pre-trained models, fine-tuned them and adjust hyperparameters according to our classification problem. Results: A dataset containing 380 images was collected for each capsule gastroscope image category, and divided into training set and test set in a ratio of 70%, and 30% respectively, and then based on the dataset, three methods, including as VGG- 16, ResNet-50, and Inception v3 are used. We achieved highest accuracy of 94.80% by using VGG- 16 to diagnose and classify capsule gastroscopic images into three categories: normal gastroscopic image, chronic erosive gastritis images, and ulcer gastric image. Our proposed approach classified capsule gastroscope image with respectable specificity and accuracy. Conclusion: The primary technique and industry standard for diagnosing and treating numerous stomach problems is gastroscopy. Capsule gastroscope is a new screening tool for gastric diseases. However, a number of elements, including image quality of capsule endoscopy, the doctors' experience and fatigue, limit its effectiveness. Early identification is necessary for high-risk factors for carcinogenesis, such as atrophic gastritis (AG). Our suggested framework will help prevent incorrect diagnoses brought on by low image quality, individual experience, and inadequate gastroscopy inspection coverage, among other factors. As a result, the suggested approach will raise the standard of gastroscopy. Deep learning has great potential in gastritis image classification for assisting with achieving accurate diagnoses after endoscopic procedures.
RESUMEN
Whole-genome sequencing (WGS) permits comprehensive cancer genome analyses, revealing mutational signatures, imprints of DNA damage and repair processes that have arisen in each patient's cancer. We performed mutational signature analyses on 12,222 WGS tumor-normal matched pairs, from patients recruited via the UK National Health Service. We contrasted our results to two independent cancer WGS datasets, the International Cancer Genome Consortium (ICGC) and Hartwig Foundation, involving 18,640 WGS cancers in total. Our analyses add 40 single and 18 double substitution signatures to the current mutational signature tally. Critically, we show for each organ, that cancers have a limited number of 'common' signatures and a long tail of 'rare' signatures. We provide a practical solution for utilizing this concept of common versus rare signatures in future analyses.
Asunto(s)
Neoplasias , Secuencia de Bases , Estudios de Cohortes , Análisis Mutacional de ADN/métodos , Humanos , Mutación , Neoplasias/genética , Población/genética , Reino UnidoRESUMEN
We explored human induced pluripotent stem cells (hiPSCs) derived from different tissues to gain insights into genomic integrity at single-nucleotide resolution. We used genome sequencing data from two large hiPSC repositories involving 696 hiPSCs and daughter subclones. We find ultraviolet light (UV)-related damage in ~72% of skin fibroblast-derived hiPSCs (F-hiPSCs), occasionally resulting in substantial mutagenesis (up to 15 mutations per megabase). We demonstrate remarkable genomic heterogeneity between independent F-hiPSC clones derived during the same round of reprogramming due to oligoclonal fibroblast populations. In contrast, blood-derived hiPSCs (B-hiPSCs) had fewer mutations and no UV damage but a high prevalence of acquired BCOR mutations (26.9% of lines). We reveal strong selection pressure for BCOR mutations in F-hiPSCs and B-hiPSCs and provide evidence that they arise in vitro. Directed differentiation of hiPSCs and RNA sequencing showed that BCOR mutations have functional consequences. Our work strongly suggests that detailed nucleotide-resolution characterization is essential before using hiPSCs.
Asunto(s)
Células Madre Pluripotentes Inducidas , Diferenciación Celular/genética , Genómica , Humanos , Mutación , Nucleótidos , Proteínas Proto-Oncogénicas/genética , Proteínas Represoras/genéticaRESUMEN
BACKGROUND: Despite extensive investigations on photothermal therapy, the clinical application is restricted due to poor stability, low therapeutic efficacy of photothermal therapy agents and its affinity loss in the multistep synthesis of delivery carriers. To address this, we designed an IR792-MCN@ZIF-8-PD-L1 siRNA (IM@ZP) nanoparticle drug delivery system. IM@ZP was prepared by in situ synthesis and physical adsorption, followed by characterization. Photothermal conversion ability of IM@ZP was assessed by irradiation of near-infrared (NIR) laser, followed by analysis of its effect on 4T1 cell viability, maturation of dendritic cells (DCs) and the secretion of related cytokines in vitro, and the changes of tumor infiltrating T cells and natural killer (NK) cells in vivo. Subcutaneous 4T1 tumor-bearing mouse and lung metastasis models were established to investigate the role of IM@ZP in killing tumor and inhibiting metastasis in vivo. RESULTS: IM@ZP was uniform nanoparticles of 81.67 nm with the characteristic UV absorption peak of IR792, and could effectively adsorb PD-L1 siRNA. Under the irradiation of 808 nm laser, IM@ZP exhibited excellent photothermal performance. IM@ZP could be efficiently uptaken by 4T1 cells, and had high transfection efficiency of PD-L1 siRNA. Upon NIR laser irradiation, IM@ZP effectively killed 4T1 cells, upregulated HSP70 expression, induced DC maturation and increased secretion of TNF-α and IL-6 in vitro. Moreover, in vivo experimental results revealed that IM@ZP enhanced photothermal immunotherapy as shown by promoted tumor infiltrating CD8 + and CD4 + T cells and NK cells, and inhibited tumor growth and lung metastasis. CONCLUSION: Together, biocompatible IM@ZP nanoparticles result in high photothermal immunotherapy efficiency and may have a great potential as a delivery system for sustained cancer therapy.
Asunto(s)
Nanopartículas , Neoplasias de la Mama Triple Negativas , Animales , Antígeno B7-H1 , Línea Celular Tumoral , Doxorrubicina/farmacología , Sistemas de Liberación de Medicamentos , Humanos , Inmunoterapia , Rayos Láser , Ratones , Fototerapia/métodos , ARN Interferente Pequeño/uso terapéutico , Neoplasias de la Mama Triple Negativas/tratamiento farmacológicoRESUMEN
Germline mutations in the mismatch repair (MMR) genes MSH2, MSH6, MLH1, and PMS2 are linked to cancer of the colon and other organs, characterized by microsatellite instability and a large increase in mutation frequency. Unexpectedly, mutations in EXO1, encoding the only exonuclease genetically implicated in MMR, are not linked to familial cancer and cause a substantially weaker mutator phenotype. This difference could be explained if eukaryotic cells possessed additional exonucleases redundant with EXO1. Analysis of the MLH1 interactome identified FANCD2-associated nuclease 1 (FAN1), a novel enzyme with biochemical properties resembling EXO1. We now show that FAN1 efficiently substitutes for EXO1 in MMR assays and that this functional complementation is modulated by its interaction with MLH1. FAN1 also contributes to MMR in vivo; cells lacking both EXO1 and FAN1 have an MMR defect and display resistance to N-methyl-N-nitrosourea (MNU) and 6-thioguanine (TG). Moreover, FAN1 loss amplifies the mutational profile of EXO1-deficient cells, suggesting that the two nucleases act redundantly in the same antimutagenic pathway. However, the increased drug resistance and mutator phenotype of FAN1/EXO1-deficient cells are less prominent than those seen in cells lacking MSH6 or MLH1. Eukaryotic cells thus apparently possess additional mechanisms that compensate for the loss of EXO1.
Asunto(s)
Proteínas Aviares/metabolismo , Reparación de la Incompatibilidad de ADN , Endodesoxirribonucleasas/metabolismo , Exodesoxirribonucleasas/metabolismo , Enzimas Multifuncionales/metabolismo , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Línea Celular , Pollos , Endodesoxirribonucleasas/química , Exodesoxirribonucleasas/química , Exodesoxirribonucleasas/deficiencia , Exodesoxirribonucleasas/genética , Guanosina/análogos & derivados , Células HEK293 , Humanos , Metilnitronitrosoguanidina , Enzimas Multifuncionales/química , Mutación/genética , TionucleósidosRESUMEN
Whole-genome sequencing has brought the cancer genomics community into new territory. Thanks to the sheer power provided by the thousands of mutations present in each patient's cancer, we have been able to discern generic patterns of mutations, termed 'mutational signatures', that arise during tumorigenesis. These mutational signatures provide new insights into the causes of individual cancers, revealing both endogenous and exogenous factors that have influenced cancer development. This Review brings readers up to date in a field that is expanding in computational, experimental and clinical directions. We focus on recent conceptual advances, underscoring some of the caveats associated with using the mutational signature frameworks and highlighting the latest experimental insights. We conclude by bringing attention to areas that are likely to see advancements in clinical applications.
Asunto(s)
Análisis Mutacional de ADN , Genómica , Mutación , Neoplasias/genética , Carcinogénesis/genética , Humanos , Neoplasias/terapiaRESUMEN
Mutational signatures are imprints of pathophysiological processes arising through tumorigenesis. We generated isogenic CRISPR-Cas9 knockouts (Δ) of 43 genes in human induced pluripotent stem cells, cultured them in the absence of added DNA damage, and performed whole-genome sequencing of 173 subclones. ΔOGG1, ΔUNG, ΔEXO1, ΔRNF168, ΔMLH1, ΔMSH2, ΔMSH6, ΔPMS1, and ΔPMS2 produced marked mutational signatures indicative of being critical mitigators of endogenous DNA modifications. Detailed analyses revealed mutational mechanistic insights, including how 8-oxo-dG elimination is sequence-context-specific while uracil clearance is sequence-context-independent. Mismatch repair (MMR) deficiency signatures are engendered by oxidative damage (C>A transversions), differential misincorporation by replicative polymerases (T>C and C>T transitions), and we propose a 'reverse template slippage' model for T>A transversions. ΔMLH1, ΔMSH6, and ΔMSH2 signatures were similar to each other but distinct from ΔPMS2. Finally, we developed a classifier, MMRDetect, where application to 7,695 WGS cancers showed enhanced detection of MMR-deficient tumors, with implications for responsiveness to immunotherapies.
Asunto(s)
Neoplasias Colorrectales , Células Madre Pluripotentes Inducidas , Neoplasias Encefálicas , Repeticiones Palindrómicas Cortas Agrupadas y Regularmente Espaciadas , Neoplasias Colorrectales/genética , Daño del ADN/genética , Humanos , Mutación , Síndromes Neoplásicos HereditariosRESUMEN
The development of retinoblastoma is thought to require pathological genetic changes in both alleles of the RB1 gene. However, cases exist where RB1 mutations are undetectable, suggesting alternative pathways to malignancy. We used whole-genome sequencing (WGS) and transcriptomics to investigate the landscape of sporadic retinoblastomas derived from twenty patients, sought RB1 and other driver mutations and investigated mutational signatures. At least one RB1 mutation was identified in all retinoblastomas, including new mutations in addition to those previously identified by clinical screening. Ten tumours carried structural rearrangements involving RB1 ranging from relatively simple to extremely complex rearrangement patterns, including a chromothripsis-like pattern in one tumour. Bilateral tumours obtained from one patient harboured conserved germline but divergent somatic RB1 mutations, indicating independent evolution. Mutational signature analysis showed predominance of signatures associated with cell division, an absence of ultraviolet-related DNA damage and a profound platinum-related mutational signature in a chemotherapy-exposed tumour. Most RB1 mutations are identifiable by clinical screening. However, the increased resolution and ability to detect otherwise elusive rearrangements by WGS have important repercussions on clinical management and advice on recurrence risks.
RESUMEN
BACKGROUND: The integrin ß6 gene, which is expressed in epithelial cancer, plays a pivotal role in various aspects of cancer progression. The present research for integrin ß6 regulation mainly focuses on the post-transcription and translation related regulation mechanism and its role in tumorigenesis. The mechanisms of how the integrin ß6 gene is regulated transcriptionally, and the promoter and transcription factors responsible for basic transcription of integrin ß6 gene remain unknown. AIM: To clone and characterize the integrin ß6 promoter. METHODS: Software analysis was used to predict the region of integrin ß6 promoter. Luciferase reporter plasmids, which contained the integrin ß6 promoter, were constructed. Element deletion analysis was performed to identify the location of core promoter and binding sites for transcription factors. RESULTS: The regulatory elements for the transcription of the integrin ß6 gene were located between -286 and -85 and contained binding sites for transcription factors such as STAT3 and Ets-1. CONCLUSION: For the first time, we found the region of ß6 core promoter and demonstrated the binding sites for transcription factors such as Ets-1 and STAT3, which are important for integrin ß6 promoter transcription activity. These findings are important for investigating the mechanism of integrin ß6 activation in cancer progression.
RESUMEN
Integrin αvß8 expressed on tumor cells executes crucial regulatory functions during cell adhesion in the tumor microenvironment and supports the activation of TGF-ß1. This study aimed to investigate the expression of integrin αvß8 and its clinical significance in colon cancer, in addition to its influence on the invasion and migration of cancer cells. Our results showed that integrin αvß8 was an indicator of progression and poor prognosis in patients with colon cancer. Moreover, integrin αvß8 significantly promoted the invasion and migration of colon cancer cells by the activation of TGF-ß1 and upregulation of metalloproteinase-9. Furthermore, suppression of integrin αvß8 was found to inhibit the growth of colon cancer in vivo. Our results indicate that integrin αvß8 promotes tumor invasiveness and the migration of colon cancer through TGF-ß1 activation and is a potential prognostic biomarker. This study may provide clues to further understand the manner in which the tumor microenvironment mediates the development of colon cancer and develop strategies for novel therapeutic targets in the prevention and treatment of colon cancer.
RESUMEN
Mutational signatures are patterns of mutations that arise during tumorigenesis. We present an enhanced, practical framework for mutational signature analyses. Applying these methods on 3,107 whole genome sequenced (WGS) primary cancers of 21 organs reveals known signatures and nine previously undescribed rearrangement signatures. We highlight inter-organ variability of signatures and present a way of visualizing that diversity, reinforcing our findings in an independent analysis of 3,096 WGS metastatic cancers. Signatures with a high level of genomic instability are dependent on TP53 dysregulation. We illustrate how uncertainty in mutational signature identification and assignment to samples affects tumor classification, reinforcing that using multiple orthogonal mutational signature data is not only beneficial, it is essential for accurate tumor stratification. Finally, we present a reference web-based tool for cancer and experimentally-generated mutational signatures, called Signal (https://signal.mutationalsignatures.com), that also supports performing mutational signature analyses.
Asunto(s)
Neoplasias , Carcinogénesis , Humanos , Mutación/genética , Neoplasias/genéticaRESUMEN
Mutational signatures provide a powerful alternative for understanding the pathophysiology of cancer. Currently, experimental efforts aimed at validating and understanding the etiologies of cancer-derived mutational signatures are underway. In this review, we highlight key aspects of mutational signature experimental design and describe the analytical framework. We suggest guidelines and quality control measures for handling whole-genome sequencing data for mutational signature analyses and discuss pitfalls in interpretation. We envision that improved next-generation sequencing technologies and molecular cell biology approaches will usher in the next generation of studies into the etiologies and mechanisms of mutational patterns uncovered in cancers.
Asunto(s)
Biomarcadores de Tumor/genética , Pruebas Genéticas/métodos , Tasa de Mutación , Neoplasias/genética , Secuenciación Completa del Genoma/métodos , Animales , Pruebas Genéticas/normas , Humanos , Guías de Práctica Clínica como Asunto , Secuenciación Completa del Genoma/normasRESUMEN
Patients with CYLD cutaneous syndrome (CCS; syn. Brooke-Spiegler syndrome) carry germline mutations in the tumor suppressor CYLD and develop multiple skin tumors with diverse histophenotypes. Here, we comprehensively profile the genomic landscape of 42 benign and malignant tumors across 13 individuals from four multigenerational families and discover recurrent mutations in epigenetic modifiers DNMT3A and BCOR in 29% of benign tumors. Multi-level and microdissected sampling strikingly reveal that many clones with different DNMT3A mutations exist in these benign tumors, suggesting that intra-tumor heterogeneity is common. Integrated genomic, methylation and transcriptomic profiling in selected tumors suggest that isoform-specific DNMT3A2 mutations are associated with dysregulated methylation. Phylogenetic and mutational signature analyses confirm cylindroma pulmonary metastases from primary skin tumors. These findings contribute to existing paradigms of cutaneous tumorigenesis and metastasis.
Asunto(s)
ADN (Citosina-5-)-Metiltransferasas/genética , Enzima Desubiquitinante CYLD/genética , Epigénesis Genética , Mutación , Síndromes Neoplásicos Hereditarios/genética , Proteínas Proto-Oncogénicas/genética , Proteínas Represoras/genética , Neoplasias Cutáneas/genética , ADN (Citosina-5-)-Metiltransferasas/metabolismo , Metilación de ADN , ADN Metiltransferasa 3A , Análisis Mutacional de ADN , Enzima Desubiquitinante CYLD/metabolismo , Femenino , Perfilación de la Expresión Génica/métodos , Humanos , Masculino , Síndromes Neoplásicos Hereditarios/metabolismo , Linaje , Proteínas Proto-Oncogénicas/metabolismo , Proteínas Represoras/metabolismo , Estudios Retrospectivos , Neoplasias Cutáneas/metabolismo , Secuenciación del ExomaRESUMEN
As important factors in the tumor microenvironment, interleukin-6 (IL-6) and integrin ανß6 play significant roles in accumulating mutations that drive the progression and metastatic capacities of cancer. The aim of this study was to investigate the expression of IL-6 and integrin ανß6, their clinical significance, as well as their correlation in the colon cancer tissues of 145 cases using immunohistochemistry. Our results showed that IL-6 and integrin ανß6 are indicators of cancer progression and poor prognosis in patients with colon cancer. Moreover, their relationship may provide clues for further studies on how the tumor microenvironment mediates the development of colon cancer, as well as strategies for the identification of novel therapeutic targets in the prevention and treatment of colon cancer.
Asunto(s)
Antígenos de Neoplasias/biosíntesis , Neoplasias del Colon/metabolismo , Integrinas/biosíntesis , Interleucina-6/biosíntesis , Microambiente Tumoral , Neoplasias del Colon/patología , Progresión de la Enfermedad , Femenino , Humanos , Inmunohistoquímica , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Análisis Multivariante , Invasividad Neoplásica , Estadificación de Neoplasias , PronósticoRESUMEN
Whole-genome-sequencing (WGS) of human tumors has revealed distinct mutation patterns that hint at the causative origins of cancer. We examined mutational signatures in 324 WGS human-induced pluripotent stem cells exposed to 79 known or suspected environmental carcinogens. Forty-one yielded characteristic substitution mutational signatures. Some were similar to signatures found in human tumors. Additionally, six agents produced double-substitution signatures and eight produced indel signatures. Investigating mutation asymmetries across genome topography revealed fully functional mismatch and transcription-coupled repair pathways. DNA damage induced by environmental mutagens can be resolved by disparate repair and/or replicative pathways, resulting in an assortment of signature outcomes even for a single agent. This compendium of experimentally induced mutational signatures permits further exploration of roles of environmental agents in cancer etiology and underscores how human stem cell DNA is directly vulnerable to environmental agents. VIDEO ABSTRACT.
Asunto(s)
Carcinógenos Ambientales/clasificación , Neoplasias/genética , Carcinógenos Ambientales/efectos adversos , Daño del ADN/genética , Análisis Mutacional de ADN/métodos , Reparación del ADN/genética , Replicación del ADN , Perfil Genético , Genoma Humano/genética , Humanos , Mutación INDEL/genética , Mutagénesis , Mutación/genética , Células Madre Pluripotentes/metabolismo , Secuenciación Completa del Genoma/métodosRESUMEN
Global loss of DNA methylation and CpG island (CGI) hypermethylation are key epigenomic aberrations in cancer. Global loss manifests itself in partially methylated domains (PMDs) which extend up to megabases. However, the distribution of PMDs within and between tumor types, and their effects on key functional genomic elements including CGIs are poorly defined. We comprehensively show that loss of methylation in PMDs occurs in a large fraction of the genome and represents the prime source of DNA methylation variation. PMDs are hypervariable in methylation level, size and distribution, and display elevated mutation rates. They impose intermediate DNA methylation levels incognizant of functional genomic elements including CGIs, underpinning a CGI methylator phenotype (CIMP). Repression effects on tumor suppressor genes are negligible as they are generally excluded from PMDs. The genomic distribution of PMDs reports tissue-of-origin and may represent tissue-specific silent regions which tolerate instability at the epigenetic, transcriptomic and genetic level.
Asunto(s)
Neoplasias de la Mama/genética , Islas de CpG , Metilación de ADN , Epigénesis Genética , Femenino , Humanos , Modelos LogísticosRESUMEN
Multiple primary cancer (MPC) is relatively rare. With the development of diagnostic and anti-cancer therapeutic techniques, the incidence of MPC is rising annually. However, the incidence of triple or quadruple cancers in a single patient remains low. In this report, the case of a 58-year-old male with triple malignant cancer is outlined. Synchronous sigmoid colon cancer and thyroid cancer were diagnosed in May 2015; on subsequent re-examination, metastasis to the liver and a malignant kidney tumor were also identified. The diagnosis was established via computed tomography (CT), Positron emission tomography-CT (PET-CT) and other laboratory examination results, including analysis of tumor markers and liver function, and was confirmed by pathological diagnosis. The patient underwent radical surgery and standardized chemotherapy. Through literature review, the definition, characteristics, classification, incidence, possible causes of and treatment strategies for MPC were more clearly understood. In addition, immunohistochemical staining of integrin αvß6 was performed on patient tissue specimens, where integrin αvß6 expression was confirmed in cancer of the colon, thyroid and liver, as a result of colonic metastasis. Therefore, the involvement of integrin αvß6 in the malignant progression of MPC was hypothesized, which may aid the investigation of MPC etiology in the future.
RESUMEN
Photo-switchable dual-color fluorescent nanogels were fabricated via nanoprecipitation in aqueous solution. The spiropyran-modified ß-cyclodextrin (ß-CD-SP) and 4-amino-7-nitro-1,2,3-benzoxadiazole (NBDNH2) were encapsulated into nanogels in the presence of 1,6-hexamethylene diisocyanate (HMDI). In the nanogels, spiropyran moiety acted as fluorescence molecule acceptors under the irradiation of UV or visible light to quench or recover the fluorescence of the NBDNH2 to achieve reversible dual-color fluorescence. The feed ratio of the two fluorophores played vital role on the energy transfer efficiency (E) of the nanogels, and the results showed that high E (90.7%) can be achieved when the feed ratio of NBDNH2/ß-CD-SP is 1:2 (mol/mol). In addition, the nanogels can maintain good photo-switchable fluorescent behavior as long as 5 weeks. With rapid photo-responsiveness (within 60 s), good reversibility, long-term stability, and excellent cytocompatibility, the as-prepared nanogels have been successfully applied to photo-switchable dual-color fluorescent imaging in cancer cell.
Asunto(s)
Ciclodextrinas/química , Colorantes Fluorescentes/química , Nanoestructuras/química , Imagen Óptica/métodos , Benzopiranos/química , Línea Celular Tumoral , Color , Geles , Humanos , Indoles/química , Isomerismo , Cinética , Ensayo de Materiales , Nitrocompuestos/química , Rayos Ultravioleta , Agua/químicaRESUMEN
In the Methods section of this Article, 'greater than' should have been 'less than' in the sentence 'Putative regions of clustered rearrangements were identified as having an average inter-rearrangement distance that was at least 10 times greater than the whole-genome average for the individual sample.â'. The Article has not been corrected.