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1.
Eur Rev Med Pharmacol Sci ; 25(1): 154-160, 2021 01.
Article in English | MEDLINE | ID: mdl-33506903

ABSTRACT

OBJECTIVE: Triple negative breast cancer (TNBC) is an aggressive subtype of breast cancer (BC) with poor prognosis. Identification of reliable biomarkers for predicting prognosis of TNBC contributes significantly to improve the clinical outcome and disease management. Long non-coding RNAs (LncRNAs) have been demonstrated to play a critical role in tumorigenesis of TNBC. In this study, we aimed to investigate the prognostic significance of serum exosomal lncRNA small ubiquitin-like modifier 1 pseudogene 3 (SUMO1P3) in TNBC. PATIENTS AND METHODS: The expression level and clinical significance of tissue lncRNA SUMO1P3 in BC were analyzed using the public The Cancer Genome Atlas (TCGA) dataset. Then,A. Na-er, Y.-Y. Xu, Y.-H. Liu, Y.-J. Gan the serum exosomal lncRNA SUMO1P3 levels were examined in patients with TNBC, patients with non-TNBC, patients with benign breast disease and healthy controls using the quantitative real-time PCR. The potential clinical significance of serum exosomal lncRNA SUMO1P3 was further evaluated. RESULTS: Based on the TCGA data, tissue lncRNA SUMO1P3 was upregulated in BC tissues, and its upregulation was significantly correlated with poor survival. Our findings showed that the expression level of serum exosomal lncRNA SUMO1P3 was significantly higher in patients with TNBC compared to patients with non-TNBC, patients with benign breast disease and healthy controls. In addition, serum exosomal lncRNA SUMO1P3 was closely correlated with lymphovascular invasion, lymph node metastasis and histological grade. The serum exosomal lncRNA SUMO1P3 levels were markedly decreased in chemosensitive cases, while not in the chemoresistance cases. Moreover, patients in the high serum exosomal lncRNA SUMO1P3 group had worse overall survival than the patients in the low serum exosomal lncRNA SUMO1P3 group. The multivariate analysis showed that serum exosomal lncRNA SUMO1P3 was an independent prognostic factor for TNBC. CONCLUSIONS: Collectively, serum exosomal lncRNA SUMO1P3 might be a reliable and robust prognostic biomarker for TNBC.


Subject(s)
Exosomes/metabolism , RNA, Long Noncoding/metabolism , Triple Negative Breast Neoplasms/metabolism , Up-Regulation , Female , Humans , Middle Aged , Prognosis , RNA, Long Noncoding/blood , SUMO-1 Protein , Triple Negative Breast Neoplasms/blood , Triple Negative Breast Neoplasms/diagnosis
2.
Cancer ; 89(2): 463-6, 2000 Jul 15.
Article in English | MEDLINE | ID: mdl-10918180

ABSTRACT

BACKGROUND: Epstein-Barr virus (EBV) infection has been implicated in the pathogenesis of certain subtypes of salivary gland tumors in the adult population. However, to the authors' knowledge its role in pediatric salivary gland tumors, a rare disease, has not been explored previously. METHODS: Thirteen cases of primary tumors of the salivary gland occurring in children were retrieved from the tumor registry at the St. Jude Children's Research Hospital in Memphis, Tennessee. Clinical data were analyzed from the medical records and formalin fixed, paraffin embedded tumor tissues were examined by the in situ hybridization (ISH) technique for the presence of latent EBV infection. RESULTS: Twelve of 13 tumors originated from the parotid gland and 1 originated from the submandibular gland. Mucoepidermoid carcinoma was the predominant tumor type; it was observed in seven patients, rhabdomyosarcoma was the diagnosis in three patients, acinic cell carcinoma was noted in two patients, and malignant fibrous histiocytoma was diagnosed in one patient. The ages of the patients ranged from 4.1-29.2 years, with a median age of 11 years. The outcome was excellent with all patients alive and free of disease at the time of last follow-up. The ISH tested negative in all tumor samples. CONCLUSIONS: Based on the results of the current study, EBV infection does not appear to play a major role in the pathogenesis of pediatric salivary gland tumors.


Subject(s)
Epstein-Barr Virus Infections/complications , Parotid Neoplasms/virology , Submandibular Gland Neoplasms/virology , Adolescent , Adult , Carcinoma, Mucoepidermoid/pathology , Carcinoma, Mucoepidermoid/virology , Child , Child, Preschool , Epstein-Barr Virus Infections/genetics , Female , Herpesvirus 4, Human/genetics , Herpesvirus 4, Human/physiology , Humans , In Situ Hybridization , Male , Parotid Neoplasms/pathology , RNA, Viral/analysis , Submandibular Gland Neoplasms/pathology , Virus Latency
3.
Virology ; 266(2): 387-96, 2000 Jan 20.
Article in English | MEDLINE | ID: mdl-10639323

ABSTRACT

In polarized epithelium direction of viral entry and release correlates with proclivity of a virus to establish local versus systemic infection. The Epstein-Barr virus (EBV), whose principal tissue reservoir is B lymphocytes, also has disease manifestations in epithelium, suggesting intertissue spread potentially influenced by epithelial cell polarity. We stably transfected the B lymphocyte EBV receptor (CR2/CD21) into Madin-Darby canine kidney (MDCK) epithelial cells used extensively to study effects of cell polarity on infection by both DNA and RNA viruses. CR2/CD21 was detected on both apical and basolateral surfaces of polarized MDCK cells, with predominant expression basolaterally. However, infectivity was up to four-fold greater apically, suggesting that endogenous cell surface molecules, sorted asymmetrically onto polarized plasma membranes, may be involved in EBV entry into MDCK cells. EBV gp350/220, a replicative cycle glycoprotein added to the virus envelope on egress through the cell membrane, was immunolocalized by confocal microscopy to basolateral cell surfaces only. Apical entry of EBV with subsequent basolateral release of newly replicated virus favors systemic infection by viral dissemination to underlying lymphocytic aggregations. Under conditions of long-term culture, latent EBV was not stably maintained in these cells, suggesting that the epithelial phase of acute EBV infection may be transient.


Subject(s)
Herpesvirus 4, Human/pathogenicity , Receptors, Complement 3d/metabolism , Animals , B-Lymphocytes/immunology , B-Lymphocytes/virology , Base Sequence , Cell Line , Cell Polarity , DNA Primers/genetics , Dogs , Epithelial Cells/immunology , Epithelial Cells/virology , Epstein-Barr Virus Infections/etiology , Epstein-Barr Virus Infections/immunology , Epstein-Barr Virus Infections/virology , Herpesvirus 4, Human/genetics , Herpesvirus 4, Human/physiology , Receptors, Complement 3d/genetics , Transfection , Viral Matrix Proteins/metabolism
4.
Br J Haematol ; 101(2): 345-8, 1998 May.
Article in English | MEDLINE | ID: mdl-9609533

ABSTRACT

Primary central nervous system lymphoma (PCNSL), observed among immunocompromised AIDS patients, has not been reported during chemotherapy for acute lymphoblastic leukaemia (ALL). We report a case of PCNSL occurring in a child receiving intensive multiagent chemotherapy for B-cell ALL. In situ hybridization studies demonstrated Epstein-Barr virus genome in both tumours, suggesting a possible link between the two diseases. The clinical response of the PCNSL to conservative therapy highlights the importance of accurately diagnosing such EBV-related disorders, especially in patients where immune compromise can be reversed.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Burkitt Lymphoma/virology , Central Nervous System Neoplasms/virology , Herpesvirus 4, Human/isolation & purification , Burkitt Lymphoma/complications , Burkitt Lymphoma/drug therapy , Central Nervous System Neoplasms/complications , Central Nervous System Neoplasms/drug therapy , Female , Herpesvirus 4, Human/genetics , Humans , Immunocompromised Host , Infant , Opportunistic Infections/complications , RNA, Viral/analysis
5.
Blood ; 91(8): 2925-34, 1998 Apr 15.
Article in English | MEDLINE | ID: mdl-9531603

ABSTRACT

Adoptive transfer of Epstein-Barr virus (EBV)-specific cytotoxic T lymphocytes (CTLs) is effective prophylaxis and treatment of EBV-positive immunoblastic lymphoma in immunocompromised patients. In 50% of patients with Hodgkin's disease, the tumor cells are EBV antigen-positive and may therefore also be suitable targets for treatment with virus-specific CTLs. However, Hodgkin's disease may produce several inhibitory effects on immune induction and effector function in vivo, which may preclude the generation or effector function of CTLs reactive against EBV viral proteins, including those expressed by the tumor cells. We have investigated whether EBV-specific CTLs could be generated ex vivo from 13 patients with Hodgkin's disease: nine with active relapsed disease and four who were in clinical remission after a first or subsequent relapse. CTL lines were successfully generated from nine of 13 patients (five active disease, four remission). Although these lines had an abnormal pattern of expansion comparable to EBV-specific CTLs generated from normal donors, their phenotype was normal except for reduced expression of the zeta chain of the T-cell receptor (TCR). Their cytotoxicity was also compared to EBV-specific lines generated from normal donors and included activity against LMP2a, one of the three weakly immunogenic viral antigens expressed by Hodgkin's tumor cells. To assess the activity of the CTLs in vivo, they were gene-marked and infused into three patients with multiply relapsed disease. The CTLs persisted for more than 13 weeks postinfusion and retained their potent antiviral effects in vivo, thereby enhancing the patient immune response to EBV. This approach may therefore have value in the treatment of EBV-positive Hodgkin's disease.


Subject(s)
Antigens, Viral/immunology , Herpesvirus 4, Human/immunology , Hodgkin Disease/therapy , Immunotherapy, Adoptive , T-Lymphocytes, Cytotoxic/immunology , Adolescent , Antigen Presentation , Child , Herpesvirus 4, Human/isolation & purification , Hodgkin Disease/immunology , Hodgkin Disease/pathology , Hodgkin Disease/virology , Humans , Recurrence , Treatment Outcome
6.
J Infect Dis ; 177(5): 1194-201, 1998 May.
Article in English | MEDLINE | ID: mdl-9593003

ABSTRACT

The hallmark of infection by human herpesviruses, life-long persistence in the host, is unaffected by current antiviral therapies effective against replication of virus. In vitro studies indicated that low concentrations of the ribonucleotide reductase inhibitor, hydroxyurea, completely eliminated Epstein-Barr virus (EBV) episomes from latently infected Burkitt's lymphoma (BL) cell subsets, providing the first example of chemotherapeutic eradication of a latent herpesvirus from any cell population. Unlike parental EBV-positive BL cells, virus-free cell progeny from one treated cell line no longer exhibited the malignant phenotype in tumorigenicity assays. Hydroxyurea-treated primary B lymphocytes immortalized by EBV ceased to proliferate as episomes were lost. The altered growth phenotype of both BL cells and immortalized primary B cells suggests that latent EBV is an appropriate and accessible therapeutic target for treatment of some EBV-induced lymphoproliferations.


Subject(s)
Burkitt Lymphoma/pathology , Cell Transformation, Neoplastic/drug effects , Cell Transformation, Viral/drug effects , Herpesvirus 4, Human/drug effects , Hydroxyurea/pharmacology , Virus Replication/drug effects , Animals , Burkitt Lymphoma/virology , Cell Division/drug effects , Cell Line , Clone Cells , DNA, Viral/analysis , Herpesvirus 4, Human/physiology , Humans , Mice , Mice, SCID , Phenotype , Ribonucleotide Reductases/antagonists & inhibitors , Transplantation, Heterologous , Tumor Cells, Cultured , Virus Latency
7.
Med Pediatr Oncol ; 28(4): 248-54, 1997 Apr.
Article in English | MEDLINE | ID: mdl-9078320

ABSTRACT

Epidemiologic studies have implicated Epstein-Barr virus (EBV) in the great majority (80%-100%) of Hodgkin disease (HD) cases in South American countries, versus only 30%-40% in the United States and other industrialized countries. Other EBV-related malignancies are known to be geographically localized, including nasopharyngeal carcinoma in south China and Burkitt lymphoma in equatorial Africa. Some studies, however, have suggested that age and histiotype, rather than geographic region, are the major determinants of the association between EBV and HD. To further characterize this relationship in children, we matched 26 cases of pediatric Hodgkin disease from south Brazil and 26 cases from the U.S.-forhistiotype and age. The Brazilian children (22 males, 4 females) had a median age of 9 years, while the median age of the U.S. group (11 males, 15 females) was 7.5 years. Formalin-fixed, paraffin-embedded biopsy material was examined for EBV early RNA1 (EBER1) expression by in situ hybridization. This antigen was detected solely in Reed-Sternberg cells or their variants in positive samples. The same proportion of cases was positive (15/26 or 58%) in both groups of children. After adjustment for histiotype and age, the association between EBV and HD remained independent of geographic location, but was more frequent in children aged < or = 10 years at diagnosis. These findings support the multiple-etiology hypothesis for Hodgkin disease.


Subject(s)
Herpesviridae Infections/virology , Herpesvirus 4, Human/isolation & purification , Hodgkin Disease/virology , Tumor Virus Infections/virology , Adolescent , Adult , Age Factors , Brazil/epidemiology , Child , Child, Preschool , Cohort Studies , Female , Herpesviridae Infections/epidemiology , Hodgkin Disease/epidemiology , Hodgkin Disease/pathology , Humans , In Situ Hybridization , Incidence , Male , Sex Factors , Tumor Virus Infections/epidemiology , United States/epidemiology
8.
J Virol ; 71(1): 519-26, 1997 Jan.
Article in English | MEDLINE | ID: mdl-8985380

ABSTRACT

Diseases of the nasopharyngeal epithelium due to Epstein-Barr virus (EBV) infection typically occur in chronic virus carriers with preexisting virus-specific antibodies. In vitro studies have shown that EBV-specific immunoglobulin A (IgA) promotes infection of human epithelial cells, otherwise refractory to EBV, via the polymeric immunoglobulin receptor (pIgR). To determine if EBV similarly exploits IgA transport mechanisms in vivo, we examined the fate of IgA-EBV complexes in the blood of mice, where pIgR-mediated transcytosis of IgA immune complexes through hepatocytes eliminates exogenous antigens from the circulation. By PCR analysis we showed hepatobiliary transport of IgA-EBV in viremic mice, but without detectable hepatocellular infection by immunostaining. Because efficient transport of EBV immune complexes might avert an infectious outcome, we modulated the transcytotic pathway in polarized Madin-Darby canine kidney (MDCK) cells transfected with pIgR to determine the effect on viral antigen expression. Like hepatocytes in vivo, MDCK cells in polarized monolayers translocated IgA-EBV from the basal cell face into apical medium without evidence for infection. However, when exposed to IgA-EBV as unpolarized single-cell suspensions, MDCK cells expressed EBV immediate-early and early antigens. These results suggest that pIgR-mediated transcytosis of pIgA-EBV through epithelium facilitates endogenous spread of EBV in long-term virus carriers, with infection being confined to cells with altered polarity from prior cytopathology.


Subject(s)
Herpesvirus 4, Human/immunology , Immunoglobulin A/immunology , Receptors, Polymeric Immunoglobulin/immunology , Viral Matrix Proteins/immunology , Animals , Cell Line , Cell Polarity , Dogs , Epithelial Cells , Epithelium/immunology , Female , Humans , Mice , Mice, Inbred BALB C , Tumor Cells, Cultured
9.
Ophthalmology ; 103(4): 687-90, 1996 Apr.
Article in English | MEDLINE | ID: mdl-8618773

ABSTRACT

BACKGROUND: Epstein-Barr virus (EBV) is a ubiquitous mucosal pathogen with a propensity for lifelong, asymptomatic persistence. Because of reported association between EBV and ocular inflammatory disorders, we tested ocular tissues from normal eyes for presence of the EBV genome. METHODS: Ten freshly harvested cadaveric human eyes were dissected into limbal cornea, central cornea, aqueous humor, iris, vitreous humor, and optic nerve. Total cellular DNA preparations were screened for DNA sequences specific to EBV's large internal repeat region. After Southern transfer, polymerase chain reaction products were detected by a 32P-labeled oligonucleotide probe specific to amplified sequences internal to the polymerase chain reaction primers. RESULTS: Seven of ten eyes from deceased donors yielded a polymerase chain reaction product, indicating presence of EBV genome. In all, 12 (20%) of 60 cadaveric ocular samples contained EBV DNA. Only the optic nerve was consistently negative for EBV DNA. CONCLUSIONS: Detection of EBV DNA in cadaveric ocular tissues indicates a broad anatomic distribution of this persistent mucosal pathogen. The frequency with which EBV was found at apparently normal ocular sites raises the possibility for viral involvement in disease states, but emphasizes the need for specific criteria to implicate EBV in ocular pathology.


Subject(s)
DNA, Viral/analysis , Eye Infections, Viral/diagnosis , Eye/virology , Genome, Viral , Herpesviridae Infections/diagnosis , Herpesvirus 4, Human/genetics , Tumor Virus Infections/diagnosis , Cadaver , Carrier State/diagnosis , Herpesvirus 4, Human/isolation & purification , Humans , Polymerase Chain Reaction/methods
10.
J Infect Dis ; 170(2): 436-9, 1994 Aug.
Article in English | MEDLINE | ID: mdl-8035032

ABSTRACT

Infectious Epstein-Barr virus (EBV) is shed from the oropharynx of infected hosts intermittently throughout life, but in the peripheral circulation the viral genome characteristically maintains itself in a noninfectious, cell-associated form. Sera from 125 persons with heterophil-positive acute infectious mononucleosis or EBV-associated nasopharyngeal carcinoma or who were healthy virus carriers were examined for evidence of cell-free viral DNA. EBV DNA suggesting viremia was detected in 11 (27%) of 41 infectious mononucleosis patients by polymerase chain reaction analysis but infrequently in healthy seropositive carriers and patients with nasopharyngeal carcinoma. In serial samples examined from 2 patients, serum EBV DNA was detected over a 3-day interval. Viral DNA was found in concert with one serologic marker of acute infection, EBV-specific polymeric IgA, that could affect patterns of viral spread and clinical symptomatology.


Subject(s)
Carrier State/microbiology , DNA, Viral/blood , Herpesvirus 4, Human/genetics , Infectious Mononucleosis/microbiology , Viremia/microbiology , Acute Disease , Antibodies, Viral/blood , Carrier State/blood , Hepatitis, Viral, Human/complications , Herpesvirus 4, Human/immunology , Humans , Immunoglobulin A/blood , Infectious Mononucleosis/blood , Infectious Mononucleosis/complications , Polymerase Chain Reaction , Viremia/blood
11.
J Infect Dis ; 168(6): 1349-55, 1993 Dec.
Article in English | MEDLINE | ID: mdl-8245519

ABSTRACT

The Epstein-Barr virus (EBV), a human herpesvirus that is predominantly latent after infection, can be induced to replicate by deleted, rearranged EBV DNA from cultures of laboratory strain P3HR-1. Because mucosal surfaces are permissive of EBV replication, 101 oral biopsies from 70 Chinese and 5 American patients were examined for natural counterparts to tissue culture defective virus (WZhet), using as marker the abnormal juxtaposition of BamHI W and Z EBV DNA restriction fragments. Of the 49 oral biopsies that contained EBV DNA, 12 (24%) had the rearranged WZ fragment by polymerase chain reaction analysis: 3 (42%) of 7 EBV-positive epithelial dysplasias or carcinomas, 6 (38%) of 16 hairy leukoplakias, and 3 (12%) of 25 nonmalignant salivary gland biopsies. Accompanying viral replication was confirmed by in situ cytohybridization and demonstration of the linear configuration of the genome in select WZhet-positive lesions. These findings indicate that defective EBV with the unusual property of disrupting EBV latency is prevalent in natural infections and may contribute to EBV's pathogenic diversity.


Subject(s)
Defective Viruses/physiology , Herpesviridae Infections/microbiology , Herpesvirus 4, Human/physiology , Tumor Virus Infections/microbiology , Virus Latency , Blotting, Southern , Cell Line , DNA, Viral , Defective Viruses/genetics , Defective Viruses/pathogenicity , Herpesvirus 4, Human/genetics , Herpesvirus 4, Human/pathogenicity , Humans , In Situ Hybridization , Leukoplakia/microbiology , Mouth Neoplasms/microbiology , Mutagenesis , Pharyngeal Diseases/microbiology , Polymerase Chain Reaction , Sjogren's Syndrome/microbiology , Stomatognathic Diseases/microbiology , Virus Replication/genetics
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