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At least 523 records · Page 29Linked to original sources
PubMed1999

Proliferation not apoptosis as a prognostic indicator in retinoblastoma.

The balance between proliferation and cell death is the major determinant of tumour growth. We analysed the proliferative and apoptotic indices (PI and AI, respectively) of 33 children with retinoblastoma. PI and AI were assessed by immunohistochemistry for Ki-67 antigen and TUNEL staining, respectively. The mean PI was 21.0+/-21.1%, and higher PI was associated with more advanced tumour stage (P<0.0001) and poor clinical outcome (P<0.05). Patients in whom amplified N-myc oncogene was found (n=6) determined by the multiplex polymerase chain reaction tended to have a higher PI (37.6+/-27.2%) than those without amplified N-myc (n=27; PI=17.3+/-18.1). A PI value of over 40% was clearly associated with an unfavourable prognosis. The AI, however, did not correlate with any of the other variables analysed. The findings suggest that proliferation, but not apoptosis, is of critical significance in retinoblastoma biology. PI, as determined by the Ki-67 antigen labelling index, seems to be a relevant histopathological parameter that can predict the clinical outcome of retinoblastoma.

Apoptosis↗
PubMed2006

cAMP-response element-binding protein mediates acid-induced NADPH oxidase NOX5-S expression in Barrett esophageal adenocarcinoma cells.

Gastroesophageal reflux disease complicated by Barrett esophagus (BE) is a major risk factor for esophageal adenocarcinoma (EA). The mechanisms whereby acid reflux may accelerate the progression from BE to EA are not known. We found that NOX1 and NOX5-S were the major isoforms of NADPH oxidase in SEG1-EA cells. The expression of NOX5-S mRNA was significantly higher in these cells than in esophageal squamous epithelial cells. NOX5 mRNA was also significantly higher in Barrett tissues with high grade dysplasia than without dysplasia. Pulsed acid treatment significantly increased H(2)O(2) production in both SEG1-EA cells and BE mucosa, which was blocked by the NADPH oxidase inhibitor apocynin. In SEG1 cells, acid treatment increased mRNA expression of NOX5-S, but not NOX1, and knockdown of NOX5 by NOX5 small interfering RNA abolished acid-induced H(2)O(2) production. In addition, acid treatment increased intracellular Ca(2+) and phosphorylation of cAMP-response element-binding protein (CREB). Acid-induced NOX5-S expression and H(2)O(2) production were significantly inhibited by removal of extracellular Ca(2+) and by knockdown of CREB using CREB small interfering RNA. Two novel CREB-binding elements TGACGAGA and TGACGCTG were identified in the NOX5-S gene promoter. Overexpression of CREB significantly increased NOX5-S promoter activity. Knockdown of NOX5 significantly decreased [(3)H]thymidine incorporation, which was restored by 10(-13) M H(2)O(2). Knockdown of NOX5 also significantly decreased retinoblastoma protein phosphorylation and increased cell apoptosis and caspase-9 expression. In conclusion, in SEG1 EA cells NOX5-S is overexpressed and mediates acid-induced H(2)O(2) production. Acid-induced NOX5-S expression depends on an increase in intracellular Ca(2+) and activation of CREB. NOX5-S contributes to increased cell proliferation and decreased apoptosis.

Adenocarcinoma↗
PubMed2001

[Amplifying variable region gene of light chain of monoclonal antibody against human retinoblastoma by PCR].

OBJECTIVE: To acquire the variable region gene of light chain of monoclonal antibody against human retinoblastoma. METHODS: Total RNA were extracted from hybridoma cells secreting specific monoclonal antibody(McAb) against human retinoblastoma(RB), then transcripted reversely into cDNA with random primers. The variable region of the light chain(VL) gene fragments were ampliflied using polymerase chain reaction(PCR) method. Agrose gel electrophoresis was confirmed. RESULTS: 1.5% agrose gel electrophoresis indicated that VL gene was about 340 base pairs. CONCLUSION: The light chain variable region gene of the McAb against human RB was amplified successfully, which lays a good basis for construction of a recombinant antibody.

Antibodies, Monoclonal↗
PubMed1998

Trilateral retinoblastoma--a case report.

A sporadic case of trilateral retinoblastoma in a male child of 20 months is described using clinical and imaging approaches. Attempts were made to find out a tumour marker by analysing human chorionic gonadotrophin (hCG), alpha-feto protein (AFP), carcinoembryonic antigen (CEA), and lactic dehydrogenase (LDH) in blood and cerebrospinal fluid (CSF). Only LDH was elevated in CSF and the rest were normal. Retinoblastoma gene could not be isolated in this patient. It is proposed that LDH in CSF should be analysed in patients with bilateral retinoblastoma who had normal brain scan initially. If LDH level in CSF is elevated, the patient should be periodically monitored by non-invasive imaging of the brain to detect intracranial tumour at an early stage.

Biomarkers, Tumor↗
PubMed2005

SEREX identification of new tumor antigens linked to melanoma-associated retinopathy.

Metastatic melanoma still has a very poor prognosis since it withstands conventional therapies like surgery or chemotherapy. A paraneoplastic autoimmune manifestation of this disease is melanoma-associated retinopathy (MAR). MAR has been associated with prolonged survival and may be an early marker of tumor progression. By screening a retina and a melanoma cDNA phage library by SEREX using sera of patients suffering from melanoma and, in some cases, clinical symptoms of MAR, we identified 20 new antigens (HD-MM-28-47), of which 14 clones had high homology to well-known genes. Six of these genes had previously been associated with retina: rhodopsin, visual arrestin, MEK1, SRPX, BBS1 and galectin-3. Individual clones were recognized by up to 43% of patients' sera, while sera of healthy volunteers were negative except in 2 cases. The expression profile of the antigens identified on the basis of homologous EST database entries in healthy tissues was ubiquitous to differential. Using RT-PCR, we found frequent expression of preselected antigens in melanoma cell lines. For rhodopsin, this could be quantified by quantitative PCR. Retinal proteins were recognized by serum antibodies of melanoma patients but not healthy controls. The role of these antigens in MAR awaits further investigation. (Supplementary material for this article can be found on the International Journal of Cancer website at http://www.interscience.wiley.com/jpages/0020-7136/suppmat/index.html.)

Antigens, Neoplasm↗
PubMed2000

DNA-based diagnosis of the von Hippel-Lindau syndrome.

PURPOSE: To evaluate the etiology of a unilateral hemangioblastoma noted in a male with a family history remarkable only for spine surgery in the proband's father. METHODS: Genomic DNA was isolated from peripheral blood of family members, and the three exons of the von Hippel-Lindau gene were examined for mutations by direct sequencing. RESULTS: A three base pair (bp) deletion in exon 1 of the VHL gene was found in the father and both sons. This in-frame deletion results in the loss of a phenylalanine residue from the von Hippel-Lindau protein product, at amino acid position 76. CONCLUSION: Genetic screening has confirmed that von Hippel-Lindau syndrome is responsible for the hemangioblastoma in the proband. Magnetic resonance imaging scans performed as a consequence of these results indicated spinal tumors present in the father and tumors present in the cerebellum of the proband's sibling. As close, lifelong follow-up is warranted with this disease, this case demonstrates the value of DNA testing in patients with ocular findings consistent with von Hippel-Lindau disease in the absence of a recognized family history.

Adolescent↗
PubMed1998

Overview of RB gene mutations in patients with retinoblastoma. Implications for clinical genetic screening.

OBJECTIVE: This study aimed to determine the distribution of germline mutations in the retinoblastoma (RB) gene in patients with retinoblastoma to design more effective genetic testing. DESIGN: A meta-analysis. PARTICIPANTS: 192 cases identified from literature. METHODS: All identifiable reported cases of bilateral retinoblastoma, which included DNA sequence analysis of the RB gene, were reviewed. MAIN OUTCOME MEASURE: Type of genetic mutation. RESULTS: Among 192 patients with retinoblastoma with identifiable germline mutations in the RB gene, the DNA alteration was a nonsense mutation in 83 (43%), frameshift in 67 (35%), intron mutation in 23 (12%), missense mutation in 11 (6%), in-frame deletion in 5 (3%), and promoter mutation in 3 (2%). Mutations were distributed throughout 24 of the 27 exons of the RB gene with no single mutational "hotspot." Exons 8, 17, 18, and 23 were involved most often, and 189 (98%) of the mutations were predicted to affect the RB large pocket domain. CONCLUSIONS: A single genetic test is unlikely to detect all germline RB gene mutations in patients with retinoblastoma because of the variety of types and locations of mutations that occur. However, a series of complementary tests may be able to rapidly detect mutations based on the observation that most mutations alter the protein size and disrupt the large pocket domain.

Americas↗
PubMedDate not supplied

[Spectrum and frequencies of RB1 gene structural defects in retinoblastoma].

The spectrum and frequencies of RB1 structural defects were studied in tumors and peripheral blood lymphocytes of patients with various forms of retinoblastoma. Single strand conformation polymorphism (SSCP) and heteroduplex (HA) analyses, along with direct sequencing, revealed 47 mutations, including 24 new ones. Of these, 42.5% were nonsense mutations, 15% were missense mutations, 15% affected splicing sites, and 27.5% were frameshifts resulting from microdeletions or microinsertions. Six polymorphisms were found, including three new ones located in the coding region. Microsatellite analysis with markers Rbint2, Rbint20, D13S262, and D13S284 revealed a loss of heterozygosity for at least one marker in 71% tumors.

Alternative Splicing↗
PubMed1999

[Ocular blood flow defect in gaze-evoked amaurosis].

PURPOSE: To investigate the mechanism of gaze-evoked amaurosis. CASE: A patient with an optic nerve tumor presented gaze-evoked amaurosis. A large central scotoma and constricted visual field were detected after shifting the gaze laterally. However, the patient did not notice this change until his fellow eye was occluded. Computed tomography/magnetic resonance imaging (CT/MRI) demonstrated a tubularly enlarged optic nerve extending for 1 cm from the eye ball, and the condition was judged to be optic nerve sheath meningioma. He underwent fluorescein fundus angiography twice, once during straight gaze and again during lateral gaze. RESULTS: Manifestly decreased blood flow in the central retinal artery and filling defect in the optic nerve head were seen during lateral gaze. CONCLUSION: Forced lateral gaze may have increased the intra-optic nerve pressure at the optic nerve head and decreased the blood flow of the central retinal artery and peripapillary choroidal flow irrigating the optic nerve head.

Blindness↗
PubMed2004

Retinoblastoma, pinealoma, and mild overgrowth in a boy with a deletion of RB1 and neighbor genes on chromosome 13q14.

We report on a 10-year-old boy with a normal karyotype and a chromosome 13q14 deletion of the retinoblastoma gene (RB1) by fluorescence in situ hybridization (FISH). He showed subtle signs of overgrowth, including macrocephaly, hepatomegaly, and inguinal hernia. The boy also had cryptorchism and mild developmental delay. In his first months of life, variant Wiedemann-Beckwith syndrome was tentatively suspected and he was included in a careful tumor prevention program. At the age of 11 months, bifocal retinoblastoma of the left eye was diagnosed. Pinealoma was suspected at the age of 19 months and was removed by neurosurgery at the age of 29 months. At 4 years and 4 months, the deletion of the RB1 gene was suspected on clinical grounds and was diagnosed by FISH and molecular studies. At that time, he was a near-normal healthy playful kindergarten child, height 107 cm (-0.3 SD), OFC 52.5 cm (+0.8 SD), developmental age 3-3.5 years. The combination of retinoblastoma, pinealoma, and deletion of the RB1 gene diagnosed by FISH has not been reported previously. The deletion spans at least 370-420 kb in size and is predicted to include proximal and distal neighbor genes. This report may assist in establishing the clinical signs of the contiguous gene syndrome at the RB1 locus on 13q14.

Brain Neoplasms↗
PubMed2000

Beta-catenin expression in human neural cell lines following exposure to cytokines and growth factors.

Beta-catenin acts as a key mediator of the Wnt/Wingless signaling pathway involved in cell proliferation, differentiation and survival. Recent studies have shown that an unstable interaction between beta-catenin and the mutant presenilin-1 induces neuronal apoptosis, and that beta-catenin levels are decreased in the brains of patients with Alzheimer's disease (AD). Since activated microglia and astrocytes play a role in the process of neuronal degeneration in AD, the cytokine/growth factor-regulated expression of beta-catenin in human neural cell lines, including NTera2 teratocarcinoma-derived differentiated neurons (NTera2-N), IMR-32 neuroblastoma, SKN-SH neuroblastoma and U-373MG astrocytoma, was studied quantitatively following exposure to epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), brain-derived neurotrophic factor (BDNF), tumor necrosis factor-alpha (TNF-alpha), interleukin (IL)-1beta, IL-6, interferon (IFN)-gamma, transforming growth factor (TGF)-beta1, dibutyryl cyclic adenosine 3',5'-cyclic monophosphate (cAMP) (dbcAMP) or phorbol 12-myristate 13-acetate (PMA). Beta-catenin mRNA expressed constitutively in all of these cell lines was unaffected by treatment with any factors examined. In contrast, beta-catenin protein levels were reduced markedly in NTera2-N cells by exposure to dbcAMP, EGF or bFGF, and in U-373MG cells by treatment with dbcAMP or PMA, but were unaffected in any cell lines by BDNF, TNF-alpha, IL-1beta, IL-6, IFN-gamma or TGF-beta1. These results indicate that beta-catenin is expressed constitutively in human neural cells and downregulated at a protein level by a set of growth factors in a cell type-specific manner.

Astrocytoma↗
PubMed2002

Quantitative analysis of apoptosis in retinoblastoma.

PURPOSE: The rate of apoptosis in retinoblastoma (Rb) and the factors that may influence this rate, such as therapy prior to surgery, amount of necrosis in tumour tissue, differentiation and laterality of the tumour, were investigated. METHODS: Thirty-one specimens (25 enucleation, six exenteration) with Rb were studied. Prior to final surgery, three patients received systemic chemotherapy, one intravitreal chemotherapy, one transpupillary thermotherapy, one external beam radiotherapy and one high-dose oral methylprednisolone therapy. The apoptotic index (AI,%) was calculated by counting at least 1000 cells under light microscopy (x 100) using TUNEL (terminal deoxynu-cleotidyl transferase-mediated dUTP nick-end labelling) method. RESULTS: The mean AI was 2.75 plus minus 1.2. No statistically significant association was observed between rate of apoptosis and the presurgical treatment, extent of necrosis, tumour differentiation and laterality. CONCLUSION: Apoptosis is an important mechanism of cell death, and may be a limiting factor for tumour progression. In this study, the rate of apoptosis was not affected by any of the studied parameters.

Apoptosis↗
PubMed1991

[Retinal degeneration and embryonal rhabdomyosarcoma of the thorax].

We discuss a paraneoplastic retinopathy in a 6-year-old boy who had an embryonal rhabdomyosarcoma of the thorax. Opacities of the vitreous body, optical atrophy, contracted arteries and changes in the structure of the retina--especially the retinal pigment epithelium--characterized the ophthalmological findings. The asymmetrical localization of the changes makes the differential diagnosis of hereditary retinal dystrophies easier. It is probably an immunological disease caused by an antigenic antibody reaction.

Child↗
PubMed2007

Mitofilin and titin as target antigens in melanoma-associated retinopathy.

Melanoma-associated retinopathy (MAR) is a rare paraneoplastic syndrome in patients with melanoma. Since the onset of MAR symptoms is often associated with tumor progression or recrudescence of metastases, MAR-related symptoms are prognostic relevant. The pathomechanism underlying MAR is supposed to result from antibody production against yet unknown melanoma-associated antigens that are also expressed in retinal tissue, leading to the destruction of retinal cells and resulting in defective signal transduction. Only a 35 kDa protein in Müller glial cells, a 22 kDa neuronal antigen and retinal transducin have been identified as MAR-associated antigens to date. To identify additional antigens potentially involved in the pathogenesis of MAR, we screened a retina cDNA phage library for reactivity with antibodies in the sera from 9 patients with MAR or subclinical MAR using the serological analysis of recombinantly expressed clones (SEREX) approach. Six sera from melanoma patients without evidence of MAR and 10 sera from healthy donors served as controls. Mitofilin and titin were identified as antigens against which antibodies were found exclusively in sera of MAR patients, but not in the sera of MM patients without MAR or healthy donors. This is the first study to demonstrate that titin is highly expressed from retinal tissue and melanoma. The fact that none of the MAR-associated antigens detected to date by their capacity to elicit a humoral immune response is located on the cell surface questions a major pathogenetic role of the respective antibodies and suggests that cellular, rather than humoral mechanisms are operative in the primary immune attack against the retina in MAR.

Antibodies, Neoplasm↗