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1.
J Clin Pathol ; 73(1): 35-41, 2020 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-31296605

RESUMO

AIMS: Precision medicine therapy is remodelling the diagnostic landscape of cancer. The success of these new therapies is often based on the presence or absence of a specific mutation in a tumour. The Idylla platform is designed to determine the mutational status of a tumour as quickly and accurately as possible, as a rapid, accurate diagnosis is of the utmost importance for the treatment of patients. This is the first complete prospective study to investigate the robustness of the Idylla platform for EGFR, KRAS and BRAF mutations in non-small cell lung cancer, metastatic colorectal cancer and metastatic melanoma, respectively. METHODS: We compared prospectively the Idylla platform with the results we obtained from parallel high-throughput next-generation sequencing, which is the current gold standard for mutational testing. Furthermore, we evaluated the benefits and disadvantages of the Idylla platform in clinical practice. Additionally, we reviewed all the published Idylla performance articles. RESULTS: There was an overall agreement of 100%, 94% and 94% between the next-generation panel and the Idylla BRAF, KRAS and EGFR mutation test. Two interesting discordant findings among 48 cases were observed and will be discussed together with the advantages and shortcoming of both techniques. CONCLUSION: Our observations demonstrate that the Idylla cartridge for the EGFR, KRAS and BRAF mutations is highly accurate, rapid and has a limited hands-on time compared with next-generation sequencing.


Assuntos
Biomarcadores Tumorais/genética , Análise Mutacional de DNA/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Mutação , Neoplasias/genética , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Receptores ErbB/genética , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Melanoma/genética , Melanoma/secundário , Neoplasias/patologia , Valor Preditivo dos Testes , Estudos Prospectivos , Reprodutibilidade dos Testes , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Fluxo de Trabalho
2.
Recent Results Cancer Res ; 215: 77-88, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31605224

RESUMO

Circulating tumor cells (CTCs) provide valuable information about the molecular evolution of cancers, as they may initially respond and ultimately progress on therapy. As intact tumor cells isolated from the bloodstream, CTCs also enable assessment of heterogeneous subpopulations, and their analysis may include DNA, RNA, and protein biomarkers. New microfluidic cell isolation strategies greatly facilitate the challenge of enriching viable tumor cells from the billions of hematopoietic cells within a standard blood specimen. While counting and characterization of enriched CTCs have primarily relied on immunostaining for tumor cell-specific antigens, new RNA-based analytic platforms are providing new insight into the identity of CTCs and providing new tools for clinical applications. Single-cell RNA sequencing of CTCs reveals a high degree of heterogeneity among cancer cells from a single individual, while new digital RNA-based amplification platforms may now allow high-sensitivity and high-throughput quantitative scoring of CTCs for clinical applications. Here, we focus on transcriptomic analysis of CTCs and its relevance in understanding metastatic cancer progression and in developing diagnostic assays to monitor cancer.


Assuntos
Separação Celular/métodos , Neoplasias/genética , Neoplasias/patologia , Células Neoplásicas Circulantes , RNA Neoplásico/análise , Progressão da Doença , Humanos , Neoplasias/diagnóstico , Células Neoplásicas Circulantes/metabolismo , RNA Neoplásico/genética
4.
Nature ; 575(7781): 60-61, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31690848
5.
Adv Exp Med Biol ; 1168: 9-30, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31713162

RESUMO

Following the completion of the Human Genome Project in 2003, research in oncology has progressively focused on the sequencing of cancer genomes, with the aim of better understanding the genetic basis of oncogenesis and identifying actionable alterations. The development of next-generation-sequencing (NGS) techniques, commercially available since 2006, allowed for a cost- and time-effective sequencing of tumor DNA, leading to a "genomic era" of cancer research and treatment. NGS provided a significant step forward in Personalized Medicine (PM) by enabling the detection of somatic driver mutations, resistance mechanisms, quantification of mutational burden, germline mutations which settled the foundation of a new approach in cancer care. In this chapter we discuss the history, available techniques and applications of NGS in oncology, with a particular referral to the PM approach and the emerging role of the research field of pharmacogenomics.


Assuntos
Sequenciamento de Nucleotídeos em Larga Escala , Neoplasias , Farmacogenética , Medicina de Precisão , Humanos , Neoplasias/genética , Neoplasias/terapia , Farmacogenética/métodos , Farmacogenética/tendências , Medicina de Precisão/métodos , Medicina de Precisão/tendências
6.
Adv Exp Med Biol ; 1168: 91-101, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31713166

RESUMO

The rapid advancements of treatment modalities and vast amounts of information being generated through novel technologies, paint the picture of a very promising future, one that will allow for a more efficient and precise DNA sequencing and potentially more tailored cancer therapies for patients. However, with all these advances we must address the ethical and legal considerations each one of these technologies will raise. This is a necessity in order for advancement, not to stand in the way of science and development, but as a safeguard in protecting humanity and our personal genetic information.


Assuntos
Neoplasias , Farmacogenética , Registros de Saúde Pessoal/ética , Humanos , Neoplasias/tratamento farmacológico , Neoplasias/genética , Farmacogenética/ética
7.
Biochemistry (Mosc) ; 84(9): 1028-1039, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31693462

RESUMO

Here, we put forward the hypothesis on the mechanism of functioning of cancer stem cells, provided that they exist. The hypothesis is based on the following postulates. 1) Paracrine exchange between cancer and stromal cells is efficient only if they are in a close contact and form a synapse-like cleft between them for the cell-cell crosstalk. The concentration of paracrine signaling molecules in the cleft is high because of the cleft small volume. 2) Cancer stem cells per se do not exist. Instead, there are cancer stem complexes formed by cancer cells tightly bound to stromal cells (portable niches) that exchange paracrine signals. 3) Cancer stem complex is a complex system with newly emerged properties, such as a stemness and resistance to external impacts, including therapeutic interventions. 4) The stemness manifests itself as the ability of cancer cells within the complex to divide asymmetrically: one daughter cell remains in the complex forming a renewed stem complex, whereas the other daughter cell detaches from the complex and transforms in a non-stem cell capable of differentiation. 5) An increased resistance of a cancer stem complex is due to the integration of its intrinsic defense systems through the exchange of paracrine signals, i.e., represents a microresistance at the cell level. 6) Cancer stem complexes can stochastically dissociate with the formation of non-stem cancer cells. Partially differentiated non-stem cancer cells are able to stochastically bind to the stromal component, dedifferentiate under the action of paracrine signals, and form new cancer stem complexes. Therefore, a tumor is a flexible system existing in the pseudo-equilibrium state. Such systems comply with the Le Chatelier's principle stating that an equilibrium system under the action of external factors activates the processes antagonistic to the changes (homeostasis). This promotes tumor resistance at the level of cell populations, i.e., the macroresistance. 7) The portable niche travels with the cancer cell during metastasis. We propose a general therapeutic strategy targeting the contacts between cancer and stromal cells. The disruption of these contacts should lead to the destruction of cancer stem complexes and elimination of tumors.


Assuntos
Neoplasias/genética , Neoplasias/patologia , Nicho de Células-Tronco/fisiologia , Humanos , Células-Tronco Neoplásicas/metabolismo , Células-Tronco Neoplásicas/patologia
8.
Biochemistry (Mosc) ; 84(10): 1117-1128, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31694508

RESUMO

According to modern concepts, tumor formation is associated with impairments in the structure of protooncogenes and/or deactivation of suppressor genes, regardless of the nature of carcinogenic factor. As a consequence, unregulated oncoproteins activate extracellular proteases, resulting in the destruction of the extracellular matrix, which facilitates cell invasion, deterioration of the cell-cell contacts, and metastasis. Tumor development requires activation of certain transcription factors; however, many oncoproteins are not transcription factors. It can be assumed that these oncoproteins are not the ultimate effectors of tumor development, but rather transmitters of the carcinogenic signal to the transcription factors promoting tumorigenesis. Here, we describe the mechanisms of carcinogenesis caused by various oncogenes/oncoproteins. We conclude that the common feature of these mechanisms is stimulation of aerobic glycolysis (Warburg effect) regulated, as a rule, through the activation of the HIFα transcription factor. The role of aerobic glycolysis at the early stages of carcinogenesis is discussed.


Assuntos
Carcinogênese/metabolismo , Glicólise , Neoplasias/metabolismo , Proteínas Oncogênicas/metabolismo , Animais , Carcinogênese/genética , Humanos , Neoplasias/genética , Proteínas Oncogênicas/genética
10.
Cytogenet Genome Res ; 159(1): 12-18, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31593956

RESUMO

The human genome harbors many duplicated segments, which sometimes show very high sequence identity. This may complicate assignment during genome assembly. One such example is in Xq28, where the arrangement of 2 recently duplicated segments varies between genome assembly versions. The duplicated segments comprise highly similar genes, including MAGEA3 and MAGEA6, which display specific expression in testicular germline cells, and also become aberrantly activated in a variety of tumors. Recently, a new gene was identified, CT-GABRA3, the transcription of which initiates inside the segmental duplication but extends far outside. According to the latest genome annotation, CT- GABRA3 starts near MAGEA3, with which it shares a bidirectional promoter. In an earlier annotation, however, the duplicated segment was positioned in the opposite orientation, and CT-GABRA3 was instead coupled with MAGEA6. To resolve this discrepancy, and based on the contention that genes connected by a bidirectional promoter are almost always co-expressed, we decided to compare the expression profiles of CT-GABRA3, MAGEA3, and MAGEA6. We found that in tumor tissues and cell lines of different origins, the expression of CT-GABRA3 was better correlated with that of MAGEA6. Moreover, in a cellular model of experimental induction with a DNA demethylation agent, activation CT-GABRA3 was associated with that of MAGEA6, but not with that of MAGEA3. Together these results support a connection between CT-GABRA3 and MAGEA6 and illustrate how promoter-sharing genes can be exploited to resolve genome assembly uncertainties.


Assuntos
Antígenos de Neoplasias/genética , Cromossomos Humanos X/genética , Proteínas de Neoplasias/genética , Regiões Promotoras Genéticas/genética , Receptores de GABA-A/genética , Duplicações Segmentares Genômicas/genética , Antígenos de Neoplasias/metabolismo , Epigênese Genética/genética , Duplicação Gênica/genética , Regulação Neoplásica da Expressão Gênica/genética , Genoma Humano/genética , Humanos , Proteínas de Neoplasias/metabolismo , Neoplasias/genética , Neoplasias/patologia , Células Tumorais Cultivadas
12.
Nature ; 574(7776): 127-131, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31570881

RESUMO

The large-scale genetic profiling of tumours can identify potentially actionable molecular variants for which approved anticancer drugs are available1-3. However, when patients with such variants are treated with drugs outside of their approved label, successes and failures of targeted therapy are not systematically collected or shared. We therefore initiated the Drug Rediscovery protocol, an adaptive, precision-oncology trial that aims to identify signals of activity in cohorts of patients, with defined tumour types and molecular variants, who are being treated with anticancer drugs outside of their approved label. To be eligible for the trial, patients have to have exhausted or declined standard therapies, and have malignancies with potentially actionable variants for which no approved anticancer drugs are available. Here we show an overall rate of clinical benefit-defined as complete or partial response, or as stable disease beyond 16 weeks-of 34% in 215 treated patients, comprising 136 patients who received targeted therapies and 79 patients who received immunotherapy. The overall median duration of clinical benefit was 9 months (95% confidence interval of 8-11 months), including 26 patients who were experiencing ongoing clinical benefit at data cut-off. The potential of the Drug Rediscovery protocol is illustrated by the identification of a successful cohort of patients with microsatellite instable tumours who received nivolumab (clinical benefit rate of 63%), and a cohort of patients with colorectal cancer with relatively low mutational load who experienced only limited clinical benefit from immunotherapy. The Drug Rediscovery protocol facilitates the defined use of approved drugs beyond their labels in rare subgroups of cancer, identifies early signals of activity in these subgroups, accelerates the clinical translation of new insights into the use of anticancer drugs outside of their approved label, and creates a publicly available repository of knowledge for future decision-making.


Assuntos
Antineoplásicos/uso terapêutico , Descoberta de Drogas/métodos , Reposicionamento de Medicamentos/tendências , Neoplasias/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Neoplasias Colorretais/tratamento farmacológico , Neoplasias Colorretais/genética , Feminino , Humanos , Imunoterapia , Masculino , Pessoa de Meia-Idade , Terapia de Alvo Molecular , Neoplasias/genética , Nivolumabe/uso terapêutico , Medicina de Precisão , Intervalo Livre de Progressão , Projetos de Pesquisa , Adulto Jovem
13.
Niger J Clin Pract ; 22(10): 1319-1323, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31607718

RESUMO

Background: Morphine is a common analgesic often used to manage chronic pain, especially for patients with pain due to malignancies. Since UGT2B7 plays an important role in the metabolism of morphine, UGT2B7 gene mutation may influence the efficacy of morphine in patients with cancer being treated by this medication. Aims: The aim of this study is to investigate the relationship between the polymorphisms of UGT2B7 and the efficacy of morphine treatment on cancer pain among the Chinese Han population. Materials and Methods: A total of 120 patients with cancer pain were enrolled in this study. Morphine was administrated through patient-controlled analgesia infusion pump, and the visual analog score (VAS) was used for pain assessment at 0.5, 4, 6, 12, 24, 48, and 72-h post morphine treatment, respectively. The plasma concentration of morphine and genetic polymorphism of UGT2B7 C802T and G221T was analyzed, respectively. Results: The frequencies of UGT2B7 C802T were CC: 13.33%, CT: 45% and TT: 41.67%, and the frequencies of UGT2B7 G221T were GG: 76.67%, GT: 22.5% and TT: 0.83%. Moreover, the VAS score of patients with either C802T CT or TT was significantly higher than that in patients with C802T CC. However, no difference of VAS scores was observed between patients carrying G221T GG and patients carrying G221T GT. The plasma concentration of morphine for patients with the C802T CC was significantly lower than that in patients carrying C802T CT or TT, while there was no significant difference in the level of morphine between patients with G221T GG and G221T GT. Conclusion: The polymorphism of UGT2B7 C802T, but not UGT2B7 G221T, has been associated with the efficacy of morphine treatment on cancer pain among Chinese Han population.


Assuntos
Analgésicos Opioides/sangue , Grupo com Ancestrais do Continente Asiático/estatística & dados numéricos , Dor do Câncer/tratamento farmacológico , Glucuronosiltransferase/genética , Morfina/sangue , Neoplasias/sangue , Polimorfismo Genético/genética , Adulto , Analgesia Controlada pelo Paciente , Analgésicos Opioides/administração & dosagem , Analgésicos Opioides/uso terapêutico , Grupo com Ancestrais do Continente Asiático/genética , Dor do Câncer/genética , Feminino , Genótipo , Humanos , Bombas de Infusão , Masculino , Pessoa de Meia-Idade , Morfina/administração & dosagem , Morfina/uso terapêutico , Neoplasias/complicações , Neoplasias/tratamento farmacológico , Neoplasias/genética , Medição da Dor , Escala Visual Analógica
14.
Tumour Biol ; 41(10): 1010428319881344, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31608792

RESUMO

MicroRNAs are a family of small, single-stranded RNAs that have key roles in regulating multiple signaling pathways within a cell. Studies have implicated aberrant expression of microRNAs in the development and progression of several pathologies including cancer. MicroRNAs are relatively stable and readily available in body fluids and tissues, making them desirable biomarkers for prognostic and diagnostic purposes in an array of diseases. MicroRNA 628 (5p/3p variants) is located in the 15q21.3 cancer-related region, and evidence suggests its association with various pathologies. The -5p mature variant, microRNA 628-5p, has been reported to be differentially expressed in various cancers, and its expression has been mostly associated with tumor suppression but there are few reports identifying its role in cancer progression. Several studies have also suggested its utility in diagnosis and prognosis of various cancers. Dysregulation of microRNA 628-5p has also been implicated in embryonal implantation defects, autism, immune modulation, myogenesis, cardiovascular disease, viral infection, and skeletal muscle repair. Here, we have provided a comprehensive review on available literature explaining the role of microRNA 628-5p as a potential cancer biomarker as well as briefly describe its function in other diseases and normal physiological conditions.


Assuntos
Biomarcadores/análise , Regulação Neoplásica da Expressão Gênica , MicroRNAs/genética , Neoplasias/diagnóstico , Neoplasias/genética , Animais , Humanos , MicroRNAs/análise , Prognóstico , Transdução de Sinais
15.
Life Sci ; 236: 116918, 2019 Nov 01.
Artigo em Inglês | MEDLINE | ID: mdl-31610208

RESUMO

Long noncoding RNAs (lncRNAs) are characterized as a group of endogenous RNAs that are more than 200 nucleotides in length and have no protein-encoding function. More and more evidence indicates that lncRNAs play vital roles in various human diseases, especially in tumorigenesis. Focally amplified lncRNA on chromosome 1 (FAL1), a novel lncRNA with enhancer-like activity, has been identified as an oncogene in multiple cancers and high expression level of FAL1 is usually associated with poor prognosis. Dysregulation of FAL1 has been shown to promote the proliferation and metastasis of cancer cells. In the present review, we summarized and illustrated the functions and underlying molecular mechanisms of FAL1 in the occurrence and development of different cancers and other diseases. FAL1 has the potential to appear as a feasible diagnostic and prognostic tool and new therapeutic target for cancer patients though further investigation is needed so as to accelerate clinical application.


Assuntos
Carcinogênese/genética , Carcinogênese/patologia , Regulação Neoplásica da Expressão Gênica , Neoplasias/genética , Neoplasias/patologia , RNA Longo não Codificante/genética , Humanos , Transdução de Sinais
16.
Adv Exp Med Biol ; 1164: 47-61, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31576539

RESUMO

Stem cell antigen-1 (Sca-1) is the first identified member of mouse Ly6 gene family. We discovered that Sca-1 disrupts TGFß signaling and enhances mammary tumorigenesis in a DMBA-induced mammary tumor model. Sca-1 gene is lost during evolution in humans. Human Ly6 genes Ly6D, LyE, LyH, and LyK on human chromosome 8q24.3 genes are syntenic to the mouse chromosome 15 where Sca-1 is located. We found that Ly6D, E, H, and K are upregulated in human cancer compared to normal tissue and that the increased expression of these genes are associated with poor prognosis of multiple types of human cancer. Several other groups have indicated increased expression of Ly6 genes in human cancer. Here we described the relevance of expression of human Ly6D, LyE, LyH, and LyK in functioning of normal tissues and tumor progression.


Assuntos
Antígenos Ly , Biomarcadores , Regulação Neoplásica da Expressão Gênica , Neoplasias , Animais , Antígenos Ly/genética , Biomarcadores/metabolismo , Transformação Celular Neoplásica , Humanos , Neoplasias/diagnóstico , Neoplasias/genética , Prognóstico
17.
Adv Exp Med Biol ; 1164: 179-196, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31576549

RESUMO

DNA methylation is a chemically reversible epigenetic modification that regulates the chromatin structure and gene expression, and thereby takes part in various cellular processes like embryogenesis, genomic imprinting, X-chromosome inactivation, and genome stability. Alterations in the normal methylation levels of DNA may contribute to the development of pathological conditions like cancer. Even though both hypo- and hypermethylation-mediated abnormalities are prevalent in the cancer genome, the field of cancer epigenetics has been more focused on targeting hypermethylation. As a result, DNA hypomethylation-mediated abnormalities remained relatively less explored, and currently, there are no approved drugs that can be clinically used to target hypomethylation. Understanding the precise role of DNA hypomethylation is not only crucial from a mechanistic point of view but also for the development of pharmacological agents that can reverse the hypomethylated state of the DNA. This chapter focuses on the causes and impact of DNA hypomethylation in the development of cancer and describes the possible ways to pharmacologically target it, especially by using a naturally occurring physiologic agent S-adenosylmethionine (SAM).


Assuntos
Metilação de DNA , Epigênese Genética , Neoplasias , Epigenômica , Humanos , Neoplasias/genética , Neoplasias/terapia
19.
J Cancer Res Clin Oncol ; 145(12): 2891-2899, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31617076

RESUMO

PURPOSE: Microsatellites are widely distributed repetitive DNA motifs, accounting for approximately 3% of the genome. Due to mismatch repair system deficiency, insertion or deletion of repetitive units often occurs, leading to microsatellite instability. In this review, we aimed to explore the relationship between MSI and biological behaviour of colorectal carcinoma, gastric carcinoma, lymphoma/leukaemia and endometrial carcinoma, as well as the application of frameshift peptide vaccines in cancer therapy. METHODS: The relevant literature from PubMed and Baidu Xueshu were reviewed in this article. The ClinicalTrials.gov database was searched for clinical trials related to the specific topic. RESULTS: Microsatellite instability is divided into three subtypes: high-level, low-level microsatellite instability, and stable microsatellites. The majority of tumour patients with high-level microsatellite instability often show a better efficacy and prognosis than those with low-level microsatellite instability or stable microsatellites. In coding regions, especially for genes involved in tumourigenesis, microsatellite instability often results in inactivation of proteins and contributes to tumourigenesis. Moreover, the occurrence of microsatellite instability in coding regions can also cause the generation of frameshift peptides that are thought to be unknown and novel to the individual immune system. Thus, these frameshift peptides have the potential to be biomarkers to raise tumour-specific immune responses. CONCLUSION: MSI has the potential to become a key predictor for evaluating the degree of malignancy, efficacy and prognosis of tumours. Clinically, MSI patterns will provide more valuable information for clinicians to create optimal individualized treatment strategies based on frameshift peptides vaccines.


Assuntos
Mutação da Fase de Leitura/genética , Repetições de Microssatélites/genética , Neoplasias/genética , Animais , Carcinogênese/genética , Ensaios Clínicos como Assunto , Reparo de Erro de Pareamento de DNA/genética , Humanos , Instabilidade de Microssatélites , Prognóstico
20.
Bull Cancer ; 106(11): 975-982, 2019 Nov.
Artigo em Francês | MEDLINE | ID: mdl-31607391

RESUMO

While improvements in the environment and living conditions have contributed to a significant increase in human longevity for over a century, the role of environmental factors in the occurrence of cancer has become a public health concern. It is recognized that a number of environmental factors such as environmental quality (air, water, soil), or environmental changes contribute to the occurrence of certain cancers. Despite this awareness, their potential impacts on health raise many scientific questions. The development of new methodological tools for the characterization of exposure, the study of the association between environmental agents and cancer through an exposure-cancer approach and the health impacts associated, have led to changes in scientific paradigms including the concept of exposome. This concept, at the heart of health and environmental issues, takes into account the determinants of health related to the quality of populations' living environments and provides assistance in public policy decision-making. Ultimately, the aim is to develop measures likely to reduce exposure and prevent health risks and damage to the most vulnerable populations, both in their physical environment and in their living environment, including the economic and social determinants.


Assuntos
Carcinógenos Ambientais/toxicidade , Exposição Ambiental/efeitos adversos , Neoplasias/etiologia , Causalidade , Saúde Ambiental , Humanos , Neoplasias/genética , Neoplasias/prevenção & controle , Fatores de Risco
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