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1.
Clin Oncol (R Coll Radiol) ; 24(8): e106-12, 2012 Oct.
Article in English | MEDLINE | ID: mdl-22626521

ABSTRACT

AIMS: To assess visual outcome, tumour control and treatment-related morbidity in patients with optic nerve sheath meningiomas (ONSMs) treated with fractionated stereotactic radiotherapy (FSRT). PATIENTS AND METHODS: A retrospective analysis of 45 patients (13 men and 32 women, median age 46 years) with ONSMs (51 optic nerves involved) treated in a single institution between 1997 and 2010 was carried out. FSRT was delivered to a dose of 50 Gy in 30 or 33 fractions as primary treatment in 39 patients and after surgery in six patients. RESULTS: At a median follow-up of 30 months (range 1-13 years), the tumour control in 41 evaluable patients (four were lost to follow-up) was 100% at 5 years with no subsequent local or distant recurrence. Of the 46 evaluable optic nerves treated, 41 had residual vision (38 with impaired vision) before radiotherapy and five were blind in one eye. There was no recovery of vision in any of the blind eyes. Of 41 optic nerves with residual vision, 13 had improvement, 24 remained stable and four deteriorated; two patients (4%) developed radiation retinopathy. One patient developed a central retinal artery occlusion in the untreated eye 10 years after treatment. CONCLUSION: FSRT is highly effective at controlling the growth of ONSMs with improvement or stabilisation of visual deficit in 89% of the optic nerves retaining some vision, albeit with a small risk of radiation-induced retinopathy. The results support the use of FSRT as an effective approach in the management of ONSM. The lack of functional benefit in patients with severe visual impairment would argue for earlier institution of treatment before complete visual loss is established.


Subject(s)
Meningioma/radiotherapy , Optic Nerve Neoplasms/radiotherapy , Disease-Free Survival , Dose Fractionation, Radiation , Female , Humans , Male , Meningioma/surgery , Middle Aged , Optic Nerve Neoplasms/surgery , Radiotherapy, Conformal/methods , Retrospective Studies , Stereotaxic Techniques , Survival Analysis , Treatment Outcome
2.
Ann Oncol ; 16(6): 942-9, 2005 Jun.
Article in English | MEDLINE | ID: mdl-15870090

ABSTRACT

BACKGROUND: The aim of this study was to assess the efficacy of new agents in patients with malignant glioma in a neoadjuvant setting not confounded by surgery. The first study of neoadjuvant temozolomide aimed to provide a benchmark for future evaluation of new treatments. PATIENTS AND METHODS: This was a multicentre phase II study of chemotherapy in patients with histologically verified glioblastoma multiforme (GBM) and anaplastic astrocytoma (AA) who had undergone biopsy alone. Patients were planned to receive two cycles of temozolomide at 200 mg/m(2) orally daily for 5 days at a 28-day interval prior to radiotherapy. Response was assessed by two central observers on pre- and post-chemotherapy enhanced scans using bi-dimensional criteria and as progression-free survival (PFS) at the time of second assessment prior to radiotherapy. Withdrawal from the study due to worsening clinical condition was, in the absence of second imaging, assessed as progressive disease. Survival and quality of life (QOL) were secondary endpoints. RESULTS: Between August 1999 and June 2002, 188 patients from 15 UK and two Italian centres were entered into the study and 187 were analysed. Overall, 162 patients were assessable for response; seven had partial and 25 had minimal response. The objective response rate was 20% [95% confidence interval (CI) 14-26%] and PFS prior to commencing radiotherapy was 64% (95% CI 57-72%). The median survival was 10 months, and 1-year survival 41%. The median survival of responders was 16 months compared to 3 months in patients with progressive disease (P <0.001 on multivariate analysis). CONCLUSION: The phase II study design of primary chemotherapy in patients with malignant glioma following biopsy alone is feasible and provides as objective a method of assessment of efficacy as is currently available. The baseline data on temozolomide provide a benchmark for assessment of efficacy of other agents and combinations.


Subject(s)
Antineoplastic Agents, Alkylating/therapeutic use , Dacarbazine/analogs & derivatives , Glioma/drug therapy , Adult , Aged , Cohort Studies , Dacarbazine/therapeutic use , Female , Glioma/mortality , Glioma/pathology , Humans , Male , Middle Aged , Minimally Invasive Surgical Procedures , Neoadjuvant Therapy , Temozolomide
3.
Kidney Int ; 60(3): 957-68, 2001 Sep.
Article in English | MEDLINE | ID: mdl-11532090

ABSTRACT

BACKGROUND: Podocytes are highly differentiated glomerular epithelial cells with limited potential to divide. They are responsible for maintaining and supporting the glomerular basement membrane so as to facilitate efficient filtration. The hypothesis tested was whether the development of glomerulosclerosis in the puromycin aminonucleoside (PAN)-treated rat could be attributed to podocyte depletion. METHODS: PAN was injected in Sprague-Dawley rats once, twice, or three times at 30-day intervals. Podocytes were counted in glomeruli using immunoperoxidase histochemistry and antibodies to both GLEPP1 (PTPRO) and WT-1. Podocytes were assayed in urine using reverse transcription-quantitative polymerase chain reaction (RT-QPCR). Glomerular areas were measured by computerized morphometry. RESULTS: In a preliminary experiment, a single injection of PAN caused a reduction in the glomerular podocyte count by 25%. Additional independent confirmation that podocytes were lost from glomeruli after PAN injection was obtained identifying detached podocytes in Bowman's space, measurement of nephrin and GLEPP1 mRNAs in urine, ultrastructural analysis of glomeruli, and identification of TUNEL-positive apoptotic podocytes in glomeruli. In a second experiment, sequential podocyte depletion by 15, 31, and 53% was achieved by the administration of one, two, or three injections of PAN at 30-day intervals. The region of the glomerulus devoid of podocytes developed glomerulosclerosis, and this area progressively increased as podocytes were progressively depleted. The correlation coefficient (r(2)) value for the relationship between percent podocyte depletion and glomerulosclerotic area was 0.99. The Y intercept of this plot showed that glomerulosclerosis was initiated when only 10 to 20% of podocytes were lost. CONCLUSION: This report supports the growing body of data linking glomerulosclerosis directly to a reduction in relative podocyte number [increased glomerular area per podocyte (GAPP)]. It raises important questions related to the mechanisms of podocyte loss, strategies for prevention of podocyte depletion, and the prevention of progression of glomerular diseases.


Subject(s)
Glomerulosclerosis, Focal Segmental/physiopathology , Kidney Glomerulus/physiopathology , Puromycin Aminonucleoside , Animals , Cell Count , Epithelial Cells/drug effects , Glomerulosclerosis, Focal Segmental/chemically induced , Male , Rats , Rats, Sprague-Dawley
4.
J Clin Invest ; 106(10): 1281-90, 2000 Nov.
Article in English | MEDLINE | ID: mdl-11086029

ABSTRACT

Glomerular epithelial protein 1 (GLEPP1) is a receptor tyrosine phosphatase present on the apical cell surface of the glomerular podocyte. The GLEPP1 gene (PTPRO:) was disrupted at an exon coding for the NH(2)-terminal region by gene targeting in embryonic stem cells. Heterozygote mating produced the expected genotypic ratio of 1:2:1, indicating that the Ptpro(-/-) genotype does not lead to embryonic or neonatal lethality. Kidney and glomerular structure was normal at the gross and light microscopic levels. Scanning and transmission electron microscopy showed that Ptpro(-/-) mice had an amoeboid rather than the typical octopoid structure seen in the wild-type mouse podocyte and that there were blunting and widening of the minor (foot) processes in association with altered distribution of the podocyte intermediate cytoskeletal protein vimentin. Reduced filtration surface area in association with these structural changes was confirmed by finding reduced glomerular nephrin content and reduced glomerular filtration rate in Ptpro(-/-) mice. There was no detectable increase in the urine albumin excretion of Ptpro(-/-) mice. After removal of one or more kidneys, Ptpro(-/-) mice had higher blood pressure than did their wild-type littermates. These data support the conclusion that the GLEPP1 (Ptpro) receptor plays a role in regulating the glomerular pressure/filtration rate relationship through an effect on podocyte structure and function.


Subject(s)
Hypertension/physiopathology , Kidney Glomerulus/physiopathology , Membrane Proteins/physiology , Protein Tyrosine Phosphatases/physiology , Albumins/metabolism , Animals , Epithelial Cells/ultrastructure , Female , Fluorescent Antibody Technique, Indirect , Genetic Predisposition to Disease , Genotype , Glomerular Filtration Rate , Humans , Hypertension/genetics , Hypertension/metabolism , Kidney Glomerulus/cytology , Kidney Glomerulus/metabolism , Kidney Glomerulus/pathology , Male , Membrane Proteins/genetics , Mice , Mice, Inbred C57BL , Mice, Knockout , Phenotype , Protein Tyrosine Phosphatases/genetics , Proteins/metabolism , Rats , Receptor-Like Protein Tyrosine Phosphatases, Class 3 , Recombination, Genetic , Sialoglycoproteins/metabolism , Vimentin/metabolism
5.
Kidney Int ; 52(4): 1000-15, 1997 Oct.
Article in English | MEDLINE | ID: mdl-9328939

ABSTRACT

Progressive loss of normal structure associated with scarring is the hallmark of chronic diseases of most organs. To test the hypothesis that measurement of interstitial collagen mRNA levels would be a useful index to predict future scarring, we developed an assay to quantitate alpha 1(I) procollagen mRNA factored for GAPDH mRNA using RT-PCR (the "CI:G ratio"). We first defined conditions under which the assay could be used for analysis of renal biopsy samples. The CI:G ratio was then used to determine whether mRNA measurements performed at an early stage of inflammation (day 7) in a model of anti-GBM disease in the rabbit would predict outcome at day 30 as measured by interstitial and glomerular scarring and renal cortical hydroxyproline accumulation. The predictive value of this assay was compared to functional (serum creatinine and urine protein:creatinine ratio) and histologic (glomerular and interstitial scoring) parameters also measured at day 7. We found that the CI:G ratio alone provided a sensitive and discriminating assay over a wide range of renal injury that predicted various parameters of scarring with an average coefficient of determination (r2) of 0.69. This predictive power was higher than that found for conventional measures, which tended to have good discriminatory capacity over limited ranges of renal injury. The CI:G ratio provided significant additional predictive power over and above that available from combinations of conventional functional or histologic parameters. We conclude that measurement of the CI:G ratio in biopsy samples deserves further assessment as a potentially useful quantitative predictor of outcome that could lead to improved clinical decision-making.


Subject(s)
Anti-Glomerular Basement Membrane Disease/complications , Anti-Glomerular Basement Membrane Disease/metabolism , Cicatrix/etiology , Collagen/genetics , Kidney/metabolism , RNA, Messenger/metabolism , Amino Acid Sequence , Animals , Anti-Glomerular Basement Membrane Disease/pathology , Base Sequence , Biopsy , DNA, Complementary/genetics , Forecasting , Genes , Glyceraldehyde-3-Phosphate Dehydrogenases/genetics , Kidney/pathology , Molecular Sequence Data , Nephritis/pathology , Procollagen/genetics , Rabbits , Tissue Distribution
7.
J Biol Chem ; 272(25): 15708-14, 1997 Jun 20.
Article in English | MEDLINE | ID: mdl-9188463

ABSTRACT

Human renal cortex and heart cDNA libraries were screened for a human homolog of rabbit PCLP1 using the rabbit PCLP1 cDNA as a probe. Clones spanning 5869 base pairs with an open reading frame coding for a 528-amino acid peptide were obtained. The putative peptide contains a potential signal peptide and a single membrane-spanning region. The extracellular domain contains multiple potential sites for N- and O-linked glycosylation and 4 cysteines for potential disulfide bonding similar to rabbit PCLP1. On Northern blot a major transcript is seen at 5.9 kilobases. Antibodies to this protein show a doublet at 160/165 kDa on Western blots of human glomerular extract and a pattern of intense glomerular staining and vascular endothelial staining on immunofluorescence of human kidney sections. Comparison of the rabbit and human peptide sequences shows a high degree of identity in the transmembrane and intracellular domains (96%) with a lower degree of identity in the extracellular domain (36%). An antibody to the intracellular domain reacted across species (human, rabbit, and rat) and recognized both rabbit PCLP1 and rat podocalyxin. An interspecies Southern blot probed with a cDNA coding for the intracellular domain showed strong hybridization to all vertebrates tested in a pattern suggesting a single copy gene. We conclude that this cDNA and putative peptide represent the human homolog of rabbit PCLP1 and rat podocalyxin.


Subject(s)
Membrane Glycoproteins/genetics , Sialoglycoproteins/genetics , Amino Acid Sequence , Animals , Base Sequence , Blotting, Northern , Blotting, Western , Chromosome Mapping , Cloning, Molecular , Conserved Sequence , Fluorescent Antibody Technique, Indirect , Humans , Membrane Glycoproteins/chemistry , Molecular Sequence Data , Rabbits , Rats , Sialoglycoproteins/chemistry
8.
J Biol Chem ; 270(49): 29439-46, 1995 Dec 08.
Article in English | MEDLINE | ID: mdl-7493982

ABSTRACT

Podocytes are responsible in part for maintaining the size and charge filtration characteristics of the glomerular filter. The major sialoprotein of the podocyte foot process glycocalyx is a 140-kDa sialoprotein named podocalyxin. Monoclonal antibodies raised against isolated rabbit glomeruli that recognized a podocalyxin-like protein base upon size, Alcian blue staining, wheat germ agglutinin binding, and distribution in renal cortex were used to expression clone cDNAs from a rabbit glomerular library. On Northern blot the cDNAs hybridized to a 5.5-kilobase pair transcript predominantly present in glomerulus. The overlapping cDNAs spanned 5,313 base pairs that contained an open reading frame of 1,653 base pairs and were not homologous with a previously described sequence. The deduced 551-amino acid protein contained a putative 21-residue N-terminal signal peptide and a 26-amino acid transmembrane region. The mature protein has a calculated molecular mass of 55 kDa, an extracellular domain that contains putative sites for N- and O-linked glycosylation, and a potential glycosaminoglycan attachment sites. The intracellular domain contains potential sites for phosphorylation. Processing of the full-length coding region in COS-7 cells resulted in a 140-kDa band, suggesting that the 55-kDa core protein undergoes extensive post-translational modification. The relationship between the cloned molecule and the monoclonal antibodies used for cloning was confirmed by making a fusion protein that inhibited binding of the monoclonal antibodies to renal cortical tissue sections and then raising polyclonal antibodies against the PCLP1 fusion protein that also recognized glomerular podocytes and endothelial cells in tissue sections in a similar distribution to the monoclonal antibodies. We conclude that we have cloned and sequenced a novel transmembrane core glycoprotein from rabbit glomerulus, which has many of the characteristics of podocalyxin. We have named this protein podocalyxin-like protein 1.


Subject(s)
Endothelium, Vascular/chemistry , Kidney Glomerulus/chemistry , Membrane Glycoproteins/genetics , Membrane Proteins/genetics , Sialoglycoproteins/genetics , Amino Acid Sequence , Animals , Antibodies, Monoclonal/immunology , Base Sequence , Cloning, Molecular , DNA, Complementary/chemistry , Glycosylation , Membrane Proteins/analysis , Membrane Proteins/chemistry , Mice , Mice, Inbred BALB C , Molecular Sequence Data , Molecular Weight , Rabbits , Sialoglycoproteins/analysis , Sialoglycoproteins/chemistry
9.
J Am Soc Nephrol ; 5(12): 2087-90, 1995 Jun.
Article in English | MEDLINE | ID: mdl-7579058

ABSTRACT

Fibronectin is a multifunctional matrix protein important in wound healing that is markedly increased in glomerular crescents. A previous report established two phases of fibronectin metabolism in crescent formation in an anti-glomerular basement membrane model of crescentic nephritis in the rabbit. Phase I was associated with increased glomerular fibronectin content from plasma. Phase II was associated with increased fibronectin mRNA in glomeruli. To examine the hypothesis that fibronectin is synthesized in the developing crescent, rabbit fibronectin cDNA was cloned, sense and antisense riboprobes were prepared and their specificity under the conditions to be used was validated and in situ hybridization studies were performed in the model. The results showed that the cells in the developing glomerular crescent express an intense fibronectin mRNA signal at Day 7 and that this signal persisted in cells of the crescent at Day 14. This result shows that fibronectin synthesis does indeed take place in cells of the developing crescent in this model and supports the hypothesis that fibronectin may be an important agent regulating crescent formation and fibrosis.


Subject(s)
Fibronectins/genetics , Glomerulonephritis/metabolism , Kidney Glomerulus/metabolism , RNA, Messenger/metabolism , Amino Acid Sequence , Animals , Antibodies, Monoclonal/immunology , Antibody Specificity , Base Sequence , Basement Membrane , Cloning, Molecular , DNA, Complementary/genetics , Fibronectins/biosynthesis , Fibronectins/immunology , Glomerulonephritis/genetics , In Situ Hybridization , Inflammation , Molecular Sequence Data , Oligonucleotides, Antisense , Rabbits
10.
Genomics ; 27(1): 174-81, 1995 May 01.
Article in English | MEDLINE | ID: mdl-7665166

ABSTRACT

Human glomerular epithelial protein 1 (GLEPP1), a receptor-like membrane protein tyrosine phosphatase (PTPase), was cloned and sequenced from a human renal cortical cDNA library. The human nucleotide and derived amino acid sequences were, respectively, 90 and 97% identical to those of rabbit. Human GLEPP1 is predicted to contain 1188 amino acids. The predicted mature protein is 1159 amino acids long and contains a large extracellular domain, a single transmembrane domain, and a single intracellular PTPase domain. Monoclonal and polyclonal antibodies raised against a human GLEPP1 fusion protein recognized a protein with distribution restricted to the glomerulus in human kidney and with an apparent molecular weight of approximately 200 kDa. The GLEPP1 gene was assigned to human chromosome 12p12-p13 by fluorescence in situ hybridization.


Subject(s)
Chromosomes, Human, Pair 12 , Genes , Kidney Glomerulus/enzymology , Membrane Proteins/genetics , Protein Tyrosine Phosphatases/genetics , Receptors, Cell Surface/genetics , Amino Acid Sequence , Animals , Antibodies, Monoclonal/immunology , Base Sequence , Cell Size , Chromosome Mapping , DNA, Complementary/genetics , Humans , Kidney Glomerulus/cytology , Membrane Proteins/analysis , Membrane Proteins/immunology , Membrane Proteins/physiology , Molecular Sequence Data , Molecular Weight , Protein Tyrosine Phosphatases/analysis , Protein Tyrosine Phosphatases/immunology , Protein Tyrosine Phosphatases/physiology , Rabbits , Receptor-Like Protein Tyrosine Phosphatases, Class 3 , Receptors, Cell Surface/analysis , Receptors, Cell Surface/immunology , Receptors, Cell Surface/physiology , Recombinant Fusion Proteins/immunology , Sequence Homology, Amino Acid
11.
J Biol Chem ; 269(31): 19953-62, 1994 Aug 05.
Article in English | MEDLINE | ID: mdl-7519601

ABSTRACT

Podocytes are specialized epithelial cells with delicate interdigitating foot processes which cover the exterior basement membrane surface of the glomerular capillary. They are in part responsible for the extraordinary charge and size filtration characteristics of the glomerulus. To better understand disease processes affecting the glomerular filter, we searched for proteins with relative specificity to the podocyte using a monoclonal antibody strategy. The first such protein characterized (designated glomerular epithelial protein 1 (GLEPP1)) is a membrane protein-tyrosine phosphatase (PTPase) with a large extracellular domain containing eight fibronectin type III-like repeats, a hydrophobic transmembrane segment, and a single PTPase domain. The GLEPP1 PTPase domain shows homology with two other single domain transmembrane PTPases (PTP beta and Drosophila central nervous system PTP10D). This homology includes 2 cysteines in the PTPase domain not present in intracellular or tandem domain membrane PTPases. GLEPP1 PTPase protein is distributed to the podocyte foot processes themselves. RNase protection assay shows that GLEPP1 mRNA is also present in brain. By analogy with the CD45 PTPase of T cells, we expect that this receptor might play a role in maintaining foot process structure and/or function by regulating tyrosine phosphorylation of podocyte proteins.


Subject(s)
Kidney Glomerulus/enzymology , Membrane Proteins/genetics , Protein Tyrosine Phosphatases/genetics , Protein Tyrosine Phosphatases/metabolism , Amino Acid Sequence , Animals , Antibodies, Monoclonal , Antibody Specificity , Base Sequence , Cell Membrane/enzymology , Cloning, Molecular , DNA, Complementary , Epithelial Cells , Epithelium/enzymology , Epithelium/immunology , Epitopes , Humans , Kidney Glomerulus/cytology , Kidney Glomerulus/immunology , Membrane Proteins/metabolism , Mice , Mice, Inbred BALB C , Molecular Sequence Data , RNA, Messenger/genetics , RNA, Messenger/metabolism , Rabbits , Receptor-Like Protein Tyrosine Phosphatases, Class 3 , Sequence Homology, Amino Acid
12.
J Immunol ; 146(5): 1437-45, 1991 Mar 01.
Article in English | MEDLINE | ID: mdl-1993838

ABSTRACT

A human umbilical vein endothelial cell (EC)/monocyte (MC) coculture system was used to dissect cell:cell interactions associated with production of procoagulant activity (PCA) in response to two common stimuli of intravascular coagulation in vivo (LPS and immune complexes). We found that the presence of MC at a ratio of 1 MC:10 EC increased the sensitivity of EC to LPS by 4 logs and the maximal response approximately 20-fold. Aggregated IgG alone did not stimulate the system, but in the presence of small amounts of LPS (1 to 10 ng/ml) aggregated IgG was a powerful stimulus. More than 90% of the PCA was tissue factor as shown by clotting studies and mRNA analysis. PCA was not produced by either cell alone under the conditions of study, but was produced in large amounts when the EC and MC were cocultured. The supernatant from the coculture stimulated virgin EC, but not MC, to synthesize tissue factor. The major factor in the supernatant was IL-1 beta as shown by measuring IL-1 beta, IL-1 alpha, and TNF-alpha in supernatants and by blocking the production of PCA by preincubation of supernatants with anti-cytokine antibodies. Small amounts of TNF-alpha were present in the supernatant but anti-TNF-alpha did not inhibit PCA production. Studies using recombinant cytokines established that IL-1 beta was the most potent of the cytokines tested, that cytokines potentiated each other, and that the results could be explained in quantitative terms by the amounts of IL-1 beta measured. These data emphasize that cell:cell interactions are likely to modulate procoagulant events in vivo in the presence of both LPS and immune complexes, and that IL-1 beta may be an important cytokine in these events.


Subject(s)
Antigen-Antibody Complex/physiology , Cell Communication/immunology , Endothelium, Vascular/metabolism , Lipopolysaccharides/pharmacology , Monocytes/metabolism , Thromboplastin/biosynthesis , Blood Coagulation Factors/biosynthesis , Endothelium, Vascular/cytology , Endothelium, Vascular/drug effects , Gene Expression Regulation/immunology , Humans , Immunoglobulin G/physiology , In Vitro Techniques , Interleukin-1/physiology , Monocytes/cytology , Monocytes/drug effects , RNA, Messenger/biosynthesis , Thromboplastin/genetics , Tumor Necrosis Factor-alpha/physiology
13.
Biochem Biophys Res Commun ; 162(2): 694-700, 1989 Jul 31.
Article in English | MEDLINE | ID: mdl-2787988

ABSTRACT

A number of cytokines are active during the evolution of an inflammatory response, including tumor necrosis factor-alpha, interleukin-1, and novel chemotactic cytokines. This latter group of mediators belong to supergene families of inflammatory signals that play a key role in the selective recruitment of immune cells. In this presentation, we present data demonstrating, for the first time, endothelial cell expression of monocyte chemotactic protein (MCP) mRNA induced by LPS, interleukin-1 or tumor necrosis factor. Human fibroblasts were also found to express monocyte chemotactic factor mRNA in response to interleukin-1 or tumor necrosis factor, but LPS was not effective. In addition, neither primary cultures expressed MCP in response to interleukin-6. These studies demonstrate that non-immune "bystander" cells can play an active role in the recruitment of inflammatory cells via the production of novel chemotactic cytokines.


Subject(s)
Chemotactic Factors/genetics , Endothelium, Vascular/metabolism , Fibroblasts/metabolism , Gene Expression Regulation , Interleukin-1/pharmacology , Tumor Necrosis Factor-alpha/pharmacology , Cells, Cultured , Chemokine CCL2 , Humans , Kinetics , Lipopolysaccharides/pharmacology , RNA, Messenger/biosynthesis
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