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1.
Pediatr Blood Cancer ; 67(7): e28335, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32391946

RESUMO

Oncologists and cancer biologists are frequently confronted by the question of what causes cancer? This is particularly vexing for cancers affecting children and young adults who have had limited exposure to environmental mutagens and the effects of aging. Here, I focus on a general framework of the causes of early-onset cancer development in children and young adults by relating inherited and constitutional cancer predisposition, oncogenic pathogens, and developmental mutations. This framework has implications not only for mechanistic investigation of young cancers, but should also clarify improved strategies for their treatment, screening, and potential prevention.


Assuntos
Predisposição Genética para Doença/epidemiologia , Mutação , Neoplasias/epidemiologia , Vírus Oncogênicos , Adolescente , Carcinógenos Ambientais , Criança , Suscetibilidade a Doenças , Humanos , Oncologia , Mutagênicos , Neoplasias/genética , Neoplasias/virologia , Síndromes Neoplásicas Hereditárias/epidemiologia , Pediatria , Adulto Jovem
2.
Clín. investig. ginecol. obstet. (Ed. impr.) ; 47(1): 25-29, ene.-mar. 2020.
Artigo em Espanhol | IBECS | ID: ibc-187070

RESUMO

El cáncer de mama es el que con más frecuecia afecta a las mujeres. Aunque no se ha podido todavía establecer una causa asociada a esta neoplasia, sí se conocen ciertos factores que podrían favorecer este proceso. Se ha investigado la presencia de algunos virus oncogénicos en el cáncer de mama (virus del papiloma humano, virus del tumor mamario del ratón y el virus de Epstein-Barr). Las técnicas moleculares actuales no permiten aplicar los postulados de Koch. Mediante las técnicas moleculares convencionales se ha podido detectar la presencia de estos virus en el 0-86% de los tejidos tumorales mamarios; sin embargo, no se ha mostrado evidencia de la transcripción activa de los genes virales en estos tejidos. Partiendo del criterio de que concentraciones de transcriptos inferiores a 2 ppm son inconsistentes con la participación de un determinado virus, puede concluirse que no existe actualmente ninguna evidencia científica de que un virus conocido esté implicado


Breast cancer is the most common cancer that affects women. Although it is known that certain factors favour this process, it has not yet been possible to establish a cause associated with this neoplasm. The presence of some oncogenic viruses in breast cancer, such as such as human papillomavirus), mouse mammary tumour virus, and Epstein-Barr virus, has been investigated. The Koch postulates cannot be applied with current molecular techniques. Although using conventional molecular techniques it has been possible to detect the presence of these viruses in between 0-86% of breast tumour tissues. However, no evidence of active transcription of the viral genes in these tissues has been demonstrated. Based on the criterion that transcript concentrations lower than 2ppm are inconsistent with the participation of a certain virus, it can be concluded that there is currently no scientific evidence that a known virus is involved


Assuntos
Humanos , Feminino , Neoplasias da Mama/virologia , Infecções Tumorais por Vírus/diagnóstico , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/fisiopatologia , Vírus Oncogênicos
3.
Cell Mol Life Sci ; 77(16): 3103-3116, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32080753

RESUMO

Marek's disease virus (MDV) is a highly oncogenic alphaherpesvirus that causes deadly T-cell lymphomas and serves as a natural virus-induced tumor model in chickens. Although Marek's disease (MD) is well controlled by current vaccines, the evolution of MDV field viruses towards increasing virulence is concerning as a better vaccine to combat very virulent plus MDV is still lacking. Our understanding of molecular and cellular immunity to MDV and its immunopathogenesis has significantly improved, but those findings about cellular immunity to MDV are largely out-of-date, hampering the development of more effective vaccines against MD. T-cell-mediated cellular immunity was thought to be of paramount importance against MDV. However, MDV also infects macrophages, B cells and T cells, leading to immunosuppression and T-cell lymphoma. Additionally, there is limited information about how uninfected immune cells respond to MDV infection or vaccination, specifically, the mechanisms by which T cells are activated and recognize MDV antigens and how the function and properties of activated T cells correlate with immune protection against MDV or MD tumor. The current review revisits the roles of each immune cell subset and its effector mechanisms in the host immune response to MDV infection or vaccination from the point of view of comparative immunology. We particularly emphasize areas of research requiring further investigation and provide useful information for rational design and development of novel MDV vaccines.


Assuntos
Galinhas/imunologia , Galinhas/virologia , Imunidade Celular/imunologia , Doença de Marek/imunologia , Vírus Oncogênicos/imunologia , Linfócitos T/imunologia , Animais , Herpesvirus Galináceo 2/imunologia , Humanos , Doença de Marek/virologia , Linfócitos T/virologia , Virulência/imunologia
4.
Proc Natl Acad Sci U S A ; 117(3): 1722-1730, 2020 01 21.
Artigo em Inglês | MEDLINE | ID: mdl-31919284

RESUMO

Viruses activate inflammasomes but then subvert resulting inflammatory responses to avoid elimination. We asked whether viruses could instead use such activated or primed inflammasomes to directly aid their propagation and spread. Since herpesviruses are experts at coopting cellular functions, we investigated whether Epstein-Barr virus (EBV), an oncoherpesvirus, exploits inflammasomes to activate its replicative or lytic phase. Indeed, our experiments reveal that EBV exploits several inflammasome sensors to actually activate its replicative phase from quiescence/latency. In particular, TXNIP, a key inflammasome intermediary, causes assembly of the NLRP3 inflammasome, resulting in caspase-1-mediated depletion of the heterochromatin-inducing epigenetic repressor KAP1/TRIM28 in a subpopulation of cells. As a result, only TXNIPhiKAP1lo cells, that is, in a primed/prolytic state, turn expression of the replication/lytic/reactivation switch protein on to enter the replicative phase. Our findings 1) demonstrate that EBV dovetails its escape strategy to a key cellular danger-sensing mechanism, 2) indicate that transcription may be regulated by KAP1 abundance aside from canonical regulation through its posttranslational modification, 3) mechanistically link diabetes, which frequently activates the NLRP3 inflammasome, to deregulation of a tumor virus, and 4) demonstrate that B lymphocytes from NOMID (neonatal onset multisystem inflammatory disease) patients who have NLRP3 mutations and suffer from hyperactive innate responses are defective in controlling a herpesvirus.


Assuntos
Inflamassomos/metabolismo , Inflamassomos/farmacologia , Vírus Oncogênicos/efeitos dos fármacos , Vírus Oncogênicos/metabolismo , Replicação Viral/efeitos dos fármacos , Replicação Viral/fisiologia , Linfócitos B/metabolismo , Proteínas de Transporte , Caspase 1/metabolismo , Linhagem Celular , Glucose/metabolismo , Herpesvirus Humano 4/efeitos dos fármacos , Herpesvirus Humano 4/metabolismo , Humanos , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Proteína 28 com Motivo Tripartido
5.
Braz Oral Res ; 33: e091, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31778470

RESUMO

Human Papillomavirus (HPV) has considerable tropism for epithelial and mucosal tissues and can therefore be found in several anatomical sites, including the oral cavity. This study aimed to investigate the presence of HPV-DNA and the most frequent viral types in patients using full dentures, compare to patients not using full dentures and to associate its presence with socio-epidemiological and behavioral factors. The study consisted of 90 patients with or without full dentures at the time of collection, treated at a public dental clinic. The samples were obtained by exfoliating the oral cavity, and analyzed for HPV-DNA using the nested PCR with PGMY09/11 (450-bp), and general primers GP5+/GP6+ (150-bp). Genotyping was performed by specific-type PCR to HPV 6, 11, 16, 18, 31, 33, and 45; and Restriction Fragment Length Polymorphism (RFLP). Pearson's Chi-square test (x 2 ) or Fisher's exact test were applied and significant variables in these tests were analyzed by multinomial logistic regression analysis to estimate odds ratio (OR). HPV-DNA was detected in 27.7% of samples and, among those obtained from patients using full dentures, positivity for HPV-DNA was 41.9% (p = 0.025). The most frequent viral types were low-risk HPV 6 and 11, and high-risk HPV 31 and 45. Patients who used full dentures had an odds ratio of 2.1 to be positive for HPV DNA. Our results indicate the need for periodic dental follow-up of patients with full dentures in order to preserve the basic conditions of oral health, and also to monitor the appearance of lesions with malignant potential.


Assuntos
Prótese Total/virologia , Vírus Oncogênicos/isolamento & purificação , Papillomaviridae/genética , Papillomaviridae/isolamento & purificação , Infecções por Papillomavirus/virologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Brasil/epidemiologia , Carcinogênese , Estudos Transversais , DNA Viral/isolamento & purificação , Feminino , Humanos , Modelos Logísticos , Masculino , Pessoa de Meia-Idade , Mucosa Bucal/virologia , Infecções por Papillomavirus/epidemiologia , Reação em Cadeia da Polimerase , Prevalência , Fatores de Risco , Fatores Socioeconômicos
6.
Klin Onkol ; 32(Supplementum 3): 72-77, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31627709

RESUMO

BACKGROUND: Cellular transformation induced by oncogenic viruses is a complex process including viral molecules, host cells and environmental factors. Viruses alone are unable to reproduce and thus they need a host to use their signalling, proteosynthetic and metabolic pathways. One target host molecule is the p53 tumour suppressor. Viral proteins functionally inactivate p53 and deregulate the expression of proteins active during apoptosis, cell proliferation and DNA damage response. Hepatitis virus B HbX protein and hepatitis virus C proteins NS2 and NS5A interact with p53 and prevent its localisation to the nucleus and thus reduce its transcriptional activity. Another mechanism lies in elevated p53 degradation caused by the BZLF1 protein of the Epstein-Barr virus, the LANA protein of the Kaposi sarcoma virus and human papilloma virus E6. The Merkel cell polyomavirus large T antigen does not interact directly with p53, however it acts through downregulation of p53 mediated transcription. The tax protein of human T cell lymphotropic virus type 1 modifies p53 posttranslationally and thus blocks its interaction with other factors of transcription machinery. Due to its tumour suppressor function and role in the maintenance of the genome integrity, the p53 protein is one of the best studied proteins. Following this, evolutionary homologues with important developmental functions p63 and p73 are intensively studied as well. Their roles in oncogenesis have not been clarified yet. PURPOSE: This review describes some of their known interactions with oncogenic viral proteins.


Assuntos
Carcinogênese/patologia , Interações Hospedeiro-Patógeno , Neoplasias/patologia , Vírus Oncogênicos/patogenicidade , Proteína Supressora de Tumor p53/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Proteínas Virais/metabolismo , Carcinogênese/metabolismo , Humanos , Família Multigênica , Neoplasias/metabolismo , Neoplasias/virologia , Proteína Supressora de Tumor p53/genética , Proteínas Supressoras de Tumor/genética , Proteínas Virais/genética
7.
Annu Rev Virol ; 6(1): 31-47, 2019 09 29.
Artigo em Inglês | MEDLINE | ID: mdl-31567064

RESUMO

I always loved biology and to do experiments. This passion and a great deal of good fortune and serendipity landed me in the field of retrovirology at the time when it opened to experimental analysis. I became involved in viral replication, genetics, and viral oncogenes. In more recent years, I have applied what I learned in tumor virology to human cancer. The early years of my personal life were marked by displacements and migration: deportation into East Germany, escape to the West, and emigration to the United States. As a young man I faced heartbreaking personal tragedies but attained a peaceful and steady course in the second half of my life. I am fortunate to have found my home in Southern California and to continue in cancer research.


Assuntos
Oncogenes , Retroviridae , Vírus/genética , Alemanha , História do Século XX , História do Século XXI , Humanos , Vírus Oncogênicos/genética , Estados Unidos
8.
Mol Biol (Mosk) ; 53(5): 871-880, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31661485

RESUMO

Numerous studies on the nature of neoplastic growth have demonstrated that oncogenic viruses maybe one of the factors causing cancer. According to various estimates, 10-20% of all human cancers are caused by viruses. For example, the Epstein-Barr virus (EBV), hepatitis B and C viruses, human papillomavirus (HPV), human T-lymphotropic virus type 1 (HTLV-1), human herpesvirus type 8 (HHV-8), and Merkel cell polyomavirus were implicated in initiating tumors. At the same time, the long period between viral infection and the manifestation of cancer significantly complicates the search for a causal relationship between the presence of a virus in the human organism and the malignant transformation. For this reason, the role of certain viruses in the initiation of neoplastic processes in humans remains an unresolved issue.


Assuntos
Transformação Celular Neoplásica , Neoplasias/patologia , Neoplasias/virologia , Vírus Oncogênicos/patogenicidade , Viroses/patologia , Viroses/virologia , Humanos
9.
Rev Med Virol ; 29(6): e2076, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31407416

RESUMO

Seven oncogenic viruses are known for tumorigenesis and contribute to 12% of all human cancers. The oncogenic factors, the target tissue, and pathology of cancer vary among these viruses with several mechanisms proposed for the initiation and development of cancer. Aneuploidy in cells is associated with anomalies in chromosome number that can be a hallmark of cancer, a disease defined by expanded proliferative potential. In this review, we summarize the different mechanisms of aneuploidy and furthermore discuss recent findings of the role of viral oncoproteins in inducing cellular aneuploidy that might facilitate tumorigenesis. Improved understanding of viral oncogenesis may help to find new strategies for controlling virus-associated cancers.


Assuntos
Aneuploidia , Transformação Celular Viral , Vírus Oncogênicos/fisiologia , Animais , Humanos , Neoplasias/etiologia , Neoplasias/metabolismo , Neoplasias/patologia , Infecções Tumorais por Vírus/complicações , Infecções Tumorais por Vírus/virologia
10.
Genes (Basel) ; 10(8)2019 08 13.
Artigo em Inglês | MEDLINE | ID: mdl-31412687

RESUMO

Acute myeloid leukemia (AML) is one of the most frequent, complex, and heterogeneous hematological malignancies. AML prognosis largely depends on acquired cytogenetic, epigenetic, and molecular abnormalities. Despite the improvement in understanding the biology of AML, survival rates remain quite low. Animal models offer a valuable tool to recapitulate different AML subtypes, and to assess the potential role of novel and known mutations in disease progression. This review provides a comprehensive and critical overview of select available AML animal models. These include the non-mammalian Zebrafish and Drosophila models as well as the mammalian rodent systems, comprising rats and mice. The suitability of each animal model, its contribution to the advancement of knowledge in AML pathophysiology and treatment, as well as its advantages and limitations are discussed. Despite some limitations, animal models represent a powerful approach to assess toxicity, and permit the design of new therapeutic strategies.


Assuntos
Modelos Animais de Doenças , Leucemia Mieloide Aguda/etiologia , Animais , Carcinógenos/toxicidade , Drosophila melanogaster , Leucemia Mieloide Aguda/patologia , Camundongos , Mutagênese , Vírus Oncogênicos/patogenicidade , Ratos , Peixe-Zebra
11.
Discov Med ; 27(148): 163-166, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-31095925

RESUMO

Breast cancer is the most common form of cancer in women. The cause of sporadic cases is usually difficult to ascertain. Viruses that might be related to breast cancer are human papillomaviruses and herpes viruses. Mouse mammary tumor virus (MMTV) has also been a suspect. MMTV is a milk-transmitted beta retrovirus, a form of single-stranded positive-sense RNA virus that inserts a copy of its genome into the DNA of a host cell, thus altering the cell's genome. MMTV DNA sequences have been found in 36% of human breast tumor samples and 24% of non-cancerous breast tissue. The sequences were 98% similar to the MMTV envelope (env) gene. But a search for MMTV sequences within the human genome found no env sequences, although there were sequences from the MMTV GAGdUTPase and POL genes. Therefore, env sequences from breast tumors and normal breast tissue identified in other studies may have come from an MMTV infection. Humans apparently acquire MMTV infection from one species of mice, Mus domesticus. MMTV transmission from mice to humans may explain the relationship of breast cancer to high socioeconomic status. Many infectious diseases are associated with low income and poverty. The association is usually detrimental, but not always. During the 20th century, improved sanitation delayed exposure to the poliovirus and onset of infection in middle and upper class children. These children contracted paralytic polio, while children from low-income families living in poor neighborhoods and substandard housing, infected in infancy, were spared. Humoral immunity passively transferred from the mother protected them from paralytic polio, and they remained immune for life. A similar relationship may exist with MMTV. High income and affluence are linked to increasedbreastcancer incidence. Girls of high socioeconomic status living in affluent, clean homes would have delayed exposure to Mus domesticus and MMTV. When infection finally occurred they would be vulnerable to MMTV-induced breast cancer in later life. Impoverished girls living in substandard, mouse-infested housing would be exposed to mice and MMTV in early life. Humoral MMTV immunity passively transferred from the mother would protect them and render them immune to MMTV-induced breast cancer in later life.


Assuntos
Neoplasias da Mama , Neoplasias Mamárias Animais , Vírus Oncogênicos/metabolismo , Infecções Tumorais por Vírus , Animais , Neoplasias da Mama/metabolismo , Neoplasias da Mama/patologia , Neoplasias da Mama/virologia , Bovinos , Feminino , Genoma Humano , Humanos , Neoplasias Mamárias Animais/metabolismo , Neoplasias Mamárias Animais/patologia , Neoplasias Mamárias Animais/virologia , Camundongos , Infecções Tumorais por Vírus/metabolismo , Infecções Tumorais por Vírus/patologia , Infecções Tumorais por Vírus/virologia
12.
Crit Rev Oncol Hematol ; 137: 108-114, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-31014506

RESUMO

Human cancers attributed to viral infections represent a growing proportion of the global cancer burden, with these types of cancers being the leading cause of morbidity and mortality in some regions. The concept that viruses play a causal role in human cancers is not new, but the mechanism thereof, while well described for some viruses, still remains elusive and complex for others, especially in the case of HIV-associated B-cell derived cancers. In the last decade, compelling evidence has demonstrated that cellular microRNAs are deregulated in cancers, with an increasing number of studies identifying microRNAs as potential biomarkers for human cancer diagnosis, prognosis and therapeutic targets or tools. Recent research demonstrates that viruses and viral components manipulate host microRNA expressions to their advantage, and the emerging picture suggests that the virus/microRNA pathway interaction is defined by a plethora of complex mechanisms. In this review, we highlight the current knowledge on virus/microRNA pathway interactions in the context of cancer and provide new insights on HIV as an oncogenic virus.


Assuntos
HIV/fisiologia , MicroRNAs/genética , Neoplasias/genética , Neoplasias/virologia , Vírus Oncogênicos/fisiologia , Animais , Carcinogênese , Humanos , MicroRNAs/biossíntese , Prognóstico
13.
Philos Trans R Soc Lond B Biol Sci ; 374(1773): 20190041, 2019 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-30955496

RESUMO

One out of 10 cancers is estimated to arise from infections by a handful of oncogenic viruses. These infectious cancers constitute an opportunity for primary prevention through immunization against the viral infection, for early screening through molecular detection of the infectious agent, and potentially for specific treatments, by targeting the virus as a marker of cancer cells. Accomplishing these objectives will require a detailed understanding of the natural history of infections, the mechanisms by which the viruses contribute to disease, the mutual adaptation of viruses and hosts, and the possible viral evolution in the absence and in the presence of the public health interventions conceived to target them. This issue showcases the current developments in experimental tissue-like and animal systems, mathematical models and evolutionary approaches to understand DNA oncoviruses. Our global aim is to provide proximate explanations to the present-day interface and interactions between virus and host, as well as ultimate explanations about the adaptive value of these interactions and about the evolutionary pathways that have led to the current malignant phenotype of oncoviral infections. This article is part of the theme issue 'Silent cancer agents: multi-disciplinary modelling of human DNA oncoviruses'.


Assuntos
Infecções por Vírus de DNA/virologia , Vírus de DNA/patogenicidade , Vírus Oncogênicos/patogenicidade , Infecções Tumorais por Vírus/virologia , Animais , Vírus de DNA/fisiologia , Evolução Molecular , Humanos , Vírus Oncogênicos/fisiologia , Virulência
14.
Philos Trans R Soc Lond B Biol Sci ; 374(1773): 20180304, 2019 05 27.
Artigo em Inglês | MEDLINE | ID: mdl-30955500

RESUMO

Most known oncogenic viruses of humans use DNA as their genomic material. Research over the past quarter century has revealed that their oncogenicity results largely from direct interference with barriers to oncogenesis. In contrast to viruses that have been accepted causes of particular cancers, candidate viral causes tend to have fewer viral than cellular genomes in the tumours. These low viral loads have caused researchers to conclude that the associated viruses are not primary causes of the associated cancers. Consideration of differential survival, reproduction and infiltration of cells in a tumour suggest, however, that viral loads could be low even when viruses are primary causes of cancer. Resolution of this issue has important implications for human health because medical research tends to be effective at preventing and controlling infectious diseases. Mathematical models may clarify the problem and help guide future research by assessing whether low viral loads are likely outcomes of the differential survival, reproduction, and infiltration of cells in a tumour and, more generally, the extent to which viruses contribute to cancer. This article is part of the theme issue 'Silent cancer agents: multi-disciplinary modelling of human DNA oncoviruses'.


Assuntos
Evolução Biológica , Carcinogênese , Neoplasias/virologia , Vírus Oncogênicos/fisiologia , Humanos
15.
FEMS Microbiol Rev ; 43(2): 181-192, 2019 03 01.
Artigo em Inglês | MEDLINE | ID: mdl-30649299

RESUMO

Human γ-herpesviruses include the closely related tumor viruses Epstein Barr virus (EBV) and Kaposi sarcoma-associated herpesvirus (KSHV). EBV is the most growth-transforming pathogen known and is linked to at least seven human malignancies. KSHV is also associated with three human cancers. Most EBV- and KSHV-infected individuals fortunately remain disease-free despite persistent infection and this is likely due to the robustness of the immune control that they mount against these tumor viruses. However, upon immune suppression EBV- and KSHV-associated malignancies emerge at increased frequencies. Moreover, primary immunodeficiencies with individual mutations that predispose to EBV or KSHV disease allow us to gain insights into a catalog of molecules that are required for the immune control of these tumor viruses. Curiously, there is little overlap between the mutation targets that predispose individuals to EBV versus KSHV disease, even so both viruses can infect the same host cell, human B cells. These differences will be discussed in this review. A better understanding of the crucial components in the near-perfect life-long immune control of EBV and KSHV should allow us to target malignancies that are associated with these viruses, but also induce similar immune responses against other tumors.


Assuntos
Herpesviridae/imunologia , Interações Hospedeiro-Patógeno/imunologia , Síndromes de Imunodeficiência/virologia , Neoplasias/virologia , Vírus Oncogênicos/imunologia , Predisposição Genética para Doença , Herpesvirus Humano 4/imunologia , Herpesvirus Humano 8/imunologia , Humanos , Imunocompetência/genética
16.
Nat Commun ; 10(1): 332, 2019 01 18.
Artigo em Inglês | MEDLINE | ID: mdl-30659187

RESUMO

Drugs that modify the epigenome are powerful tools for treating cancer, but these drugs often have pleiotropic effects, and identifying patients who will benefit from them remains a major clinical challenge. Here we show that medulloblastomas driven by the transcription factor Gfi1 are exquisitely dependent on the enzyme lysine demethylase 1 (Kdm1a/Lsd1). We demonstrate that Lsd1 physically associates with Gfi1, and that these proteins cooperate to inhibit genes involved in neuronal commitment and differentiation. We also show that Lsd1 is essential for Gfi1-mediated transformation: Gfi1 proteins that cannot recruit Lsd1 are unable to drive tumorigenesis, and genetic ablation of Lsd1 markedly impairs tumor growth in vivo. Finally, pharmacological inhibitors of Lsd1 potently inhibit growth of Gfi1-driven tumors. These studies provide important insight into the mechanisms by which Gfi1 contributes to tumorigenesis, and identify Lsd1 inhibitors as promising therapeutic agents for Gfi1-driven medulloblastoma.


Assuntos
Carcinogênese/efeitos dos fármacos , Neoplasias Cerebelares/patologia , Proteínas de Ligação a DNA/metabolismo , Histona Desmetilases/metabolismo , Meduloblastoma/patologia , Fatores de Transcrição/metabolismo , Animais , Antibióticos Antineoplásicos/uso terapêutico , Proliferação de Células/efeitos dos fármacos , Neoplasias Cerebelares/genética , Neoplasias Cerebelares/terapia , Proteínas de Ligação a DNA/genética , Doxorrubicina/uso terapêutico , Regulação Neoplásica da Expressão Gênica , Células HEK293 , Histona Desmetilases/genética , Humanos , Meduloblastoma/genética , Meduloblastoma/terapia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Camundongos SCID , Células NIH 3T3 , Transplante de Neoplasias , Vírus Oncogênicos , Retroviridae , Fatores de Transcrição/genética
17.
J Med Virol ; 91(1): 1-13, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30133783

RESUMO

It is evidenced that 20% of all tumors in humans are caused by oncoviruses, including human papilloma viruses, Epstein-Barr virus, Kaposi sarcoma virus, human polyomaviruses, human T-lymphotrophic virus-1, and hepatitis B and C viruses. Human immunodeficiency virus is also involved in carcinogenesis, although not directly, but by facilitating the infection of many oncoviruses through compromising the immune system. Being intracellular parasites with the property of establishing latency and integrating into the host genome, these viruses are a therapeutic challenge for biomedical researchers. Therefore, strategies able to target nucleotide sequences within episomal or integrated viral genomes are of prime importance in antiviral or anticancerous armamentarium. Recently, clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) has emerged as a powerful genome editing tool. Standing out as a precise and efficient oncoviruses method, it has been extensively applied in recent experimental ventures in the field of molecular medicine, particularly in combating infections including tumor inducing viruses. This review is aimed at collating the experimental and clinical advances in CRISPR/Cas9 technology in terms of its applications against oncoviruses. Primarily, it will focus on the application of CRISPR/Cas9 in combating tumor viruses, types of mechanisms targeted, and the significant outcomes till date. The technical pitfalls of the CRISPR/Cas9 and the comparative approaches in evaluating this technique with respect to other available alternatives are also described briefly. Furthermore, the review also discussed the clinical aspects and the ethical, legal, and social issues associated with the use of CRISPR/Cas9.


Assuntos
Edição de Genes/métodos , Terapia Genética/métodos , Terapia de Alvo Molecular/métodos , Vírus Oncogênicos/genética , Infecções Tumorais por Vírus/terapia , Pesquisa Biomédica/tendências , Proteína 9 Associada à CRISPR/metabolismo , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas , Humanos
18.
Cancer Treat Res ; 177: 1-21, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30523619

RESUMO

Malignancies were one of the earliest recognized manifestations that led to the description of the acquired immune deficiency syndrome (AIDS). The majority of cancers in AIDS patients are associated with coinfection with oncogenic viruses, such as Epstein-Barr virus, human herpesvirus 8, and human papillomavirus, with resulting malignancies occurring secondary to diminished immune surveillance against viruses and virus-infected tumor cells. Over 50% of AIDS lymphomas are associated with Epstein-Barr virus (EBV) and/or HHV8 infection. HHV8-associated diseases include Kaposi sarcoma (KS), primary effusion lymphoma (PEL), and multicentric Castleman disease (MCD). EBV is associated with several malignancies, including Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL). Coinfection with HIV and HPV is associated with an increased risk of various squamous cell carcinomas of epithelial tissues. HAART has significantly impacted the incidence, management, and prognosis of AIDS-related malignancies. In addition to changing the natural history of HIV infection in regard to incidence and survival, HAART has dramatically decreased the incidence of certain virally mediated HIV-associated malignancies such as KS and primary CNS lymphoma. The beneficial effects of HAART on these tumors are attributed to drug-mediated HIV suppression and immune reconstitution. However, HAART has had a less favorable impact on EBV- and HPV-related malignancies. This chapter presents an overview of HIV-associated malignancies mediated by HHV-8, EBV, and HPV, and reviews the effect of HAART on the epidemiology, presentation, treatment, and outcomes of these cancers.


Assuntos
Síndrome de Imunodeficiência Adquirida/virologia , Terapia Antirretroviral de Alta Atividade , Infecções por Herpesviridae/tratamento farmacológico , Neoplasias , Infecções por Papillomavirus/tratamento farmacológico , Infecções Tumorais por Vírus/virologia , Síndrome de Imunodeficiência Adquirida/complicações , Coinfecção/virologia , Infecções por HIV/complicações , Infecções por HIV/virologia , Infecções por Herpesviridae/complicações , Herpesvirus Humano 4 , Herpesvirus Humano 8 , Humanos , Neoplasias/diagnóstico , Neoplasias/epidemiologia , Neoplasias/terapia , Neoplasias/virologia , Vírus Oncogênicos , Papillomaviridae , Infecções por Papillomavirus/complicações , Sarcoma de Kaposi
19.
Cell Immunol ; 343: 103770, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-29523417

RESUMO

Patients following solid organ transplantation show a higher risk of developing cancer compared to the general population. Elevated risk is likely due to the interplay of a combination of factors, such as chronic inflammation, coexisting medical conditions, immunosuppressive regimen and persistent infection with oncogenic viruses. In addition, the tumor microenvironment plays a pivotal role in cancer progression, by driving recruitment and in situ differentiation of anti-inflammatory cells of the adaptive and innate immune system such as regulatory T cells, Th17, Dendritic Cells, Myeloid Derived Suppressor Cells, Type 2 Macrophages. Here we discuss the molecular role and the contribution to oncogenesis of Epstein-Barr virus (EBV), Kaposi's sarcoma-associated herpesvirus (KSHV/HHV8) and Hepatitis C virus (HCV) in immunocompromised patients and describe how these viruses may contribute to oncogenesis both directly and indirectly.


Assuntos
Neoplasias/virologia , Vírus Oncogênicos , Animais , Hepacivirus , Herpesvirus Humano 4 , Herpesvirus Humano 8 , Humanos , Hospedeiro Imunocomprometido
20.
Cancer Immunol Immunother ; 68(5): 849-859, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30465060

RESUMO

Cancer immunotherapy has greatly advanced in recent years. Most immunotherapeutic strategies are based on the use of immune checkpoint blockade to unleash antitumor immune responses or on the induction or adoptive transfer of immune effector cells. We aim to develop therapeutic vaccines based on recombinant Semliki Forest virus vectors to induce tumor-specific effector immune cells. In this review, we describe our ongoing work on SFV-based vaccines targeted against human papillomavirus- and hepatitis C virus-related infections and malignancies, focusing on design, delivery, combination strategies, preclinical efficacy and product development for a first-in-man clinical trial with an HPV-specific vaccine.


Assuntos
Alphavirus/genética , Vacinas Anticâncer/imunologia , Neoplasias/terapia , Vírus Oncogênicos/fisiologia , Viroses/terapia , Animais , Ensaios Clínicos como Assunto , Vetores Genéticos , Humanos , Imunização , Neoplasias/imunologia , Viroses/imunologia
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