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1.
Horm Metab Res ; 47(1): 24-30, 2015 Jan.
Article in English | MEDLINE | ID: mdl-25365509

ABSTRACT

Transplantation of islet cells is an effective treatment for type 1 diabetes with critically labile metabolic control. However, during islet isolation, blood supply is disrupted, and the transport of nutrients/metabolites to and from the islet cells occurs entirely by diffusion. Adequate oxygen supply is essential for function/survival of islet cells and is the limiting factor for graft integrity. Recently, we developed an immunoisolated chamber system for transplantation of human islets without immunosuppression. This system depended on daily oxygen supply. To provide independence from this external source, we incorporated a novel approach based on photosynthetically-generated oxygen. The chamber system was packed sandwich-like with a slab of immobilized photosynthetically active microorganisms (Synechococcus lividus) on top of a flat light source (LEDs, red light at 660 nm, intensity of 8 µE/m(2)/s). Islet cells immobilized in an alginate slab (500-1,000 islet equivalents/cm(2)) were mounted on the photosynthetic slab separated by a gas permeable silicone rubber-Teflon membrane, and the complete module was sealed with a microporous polytetrafluorethylene (Teflon) membrane (pore size: 0.4 µm) to protect the contents from the host immune cells. Upon illumination, oxygen produced by photosynthesis diffused via the silicone Teflon membrane into the islet compartment. Oxygen production from implanted encapsulated microorganisms was stable for 1 month. After implantation of the device into diabetic rats, normoglycemia was achieved for 1 week. Upon retrieval of the device, blood glucose levels returned to the diabetic state. Our results demonstrate that an implanted photosynthetic bioreactor can supply oxygen to transplanted islets and thus maintain islet viability/functionality.


Subject(s)
Islets of Langerhans Transplantation/instrumentation , Islets of Langerhans/metabolism , Oxygen/metabolism , Photosynthesis , Animals , Diabetes Mellitus, Experimental/metabolism , Humans , Male , Oxygen Consumption , Rats, Inbred Lew , Reproducibility of Results , Synechococcus/metabolism
2.
Oncogene ; 20(22): 2826-35, 2001 May 17.
Article in English | MEDLINE | ID: mdl-11420694

ABSTRACT

Survival of patients with Glioblastoma Multiforme (GM), a highly malignant brain tumor, remains poor despite concerted efforts to improve therapy. The median survival of patients with GM has remained approximately 1 year regardless of the therapeutic approach. Since radiation therapy is the most effective adjuvant therapy for GM and nearly half of GM tumors harbor p53 mutations, we sought to identify genes that mediate p53-independent apoptosis of GM cells in response to ionizing radiation. Using broad-scale gene expression analysis we found that following radiation treatment, TRADD expression was induced in a uniquely radiosensitive GM cell line but not in radioresistant GM cell lines. TRADD over-expression killed GM cells and activated NF-kappa B. We found that blocking the TRADD-mediated pathway using a dominant-negative mutant of FADD (FADD-DN) enhanced radiation resistance of GM cells, as reflected in both susceptibility to apoptosis and clonogenic survival following irradiation. Conversely, stable expression of exogenous TRADD enhanced radiation-induced apoptosis of GM cell lines, reflecting the biological significance of TRADD regulation in p53-independent apoptosis. These findings generate interest in utilizing TRADD in gene therapy for GM tumors, particularly in light of its dual function of directly inducing rapid apoptosis and sensitizing GM cells to standard anti-neoplastic therapy.


Subject(s)
Adaptor Proteins, Signal Transducing , Apoptosis/radiation effects , Carrier Proteins/metabolism , Glioblastoma/genetics , Neoplasm Proteins/metabolism , Proteins/metabolism , Transcription, Genetic , Apoptosis/physiology , Carrier Proteins/genetics , Fas-Associated Death Domain Protein , Glioblastoma/pathology , Glioblastoma/radiotherapy , Humans , NF-kappa B/metabolism , Neoplasm Proteins/radiation effects , Proteins/radiation effects , Radiation Tolerance , TNF Receptor-Associated Factor 1 , Transcription, Genetic/radiation effects , Tumor Cells, Cultured/radiation effects , Tumor Suppressor Protein p53/physiology
3.
Curr Biol ; 8(21): 1195-8, 1998 Oct 22.
Article in English | MEDLINE | ID: mdl-9799739

ABSTRACT

Glioblastomas are highly malignant tumors of the central nervous system that are resistant to radiation and chemotherapy [1]. We explored the role of the phosphatidylinositol (PI) 3-kinase signal transduction pathway in glioblastomas, as this pathway has been shown to inhibit apoptosis induced by cytokine withdrawal and the detachment of cells from the extracellular matrix [2]. Components of this pathway have been implicated in tumor development [3-6]. We show that glioblastoma cells, in contrast to primary human astrocytes, contain high endogenous protein kinase B (PKB/Akt) activity and high levels of PI 3,4,5-triphosphate (PI(3,4,5)P3) and PI(3,4)P2, the lipid products of PI 3-kinase. These glioblastoma cells express mutant forms of the putative 3' phospholipid phosphatase PTEN, also known as MMAC. Expression of wild-type PTEN derived from primary astrocytes, but not of mutant forms of PTEN, reduced the levels of 3' phosphoinositides and inhibited PKB/Akt activity. PTEN antagonized the activation of PKB/Akt by growth factors, by activated PI 3-kinase and by PI-dependent protein kinase-1 (PDK1), but did not antagonize the phospholipid-independent activation of PKB/Akt lacking the pleckstrin homology (PH) domain. These results suggest a role for PTEN in regulating the activity of the PI 3-kinase pathway in malignant human cells.


Subject(s)
Genes, Tumor Suppressor , Glioblastoma/enzymology , Glioblastoma/genetics , Mutation , Phosphoric Monoester Hydrolases/genetics , Proto-Oncogene Proteins/genetics , Proto-Oncogene Proteins/metabolism , Tumor Suppressor Proteins , 3-Phosphoinositide-Dependent Protein Kinases , 3T3 Cells , Animals , Astrocytes/metabolism , COS Cells , Enzyme Activation , Humans , Mice , PTEN Phosphohydrolase , Phosphatidylinositol 3-Kinases/metabolism , Phosphatidylinositol Phosphates/metabolism , Phospholipids/metabolism , Protein Serine-Threonine Kinases/metabolism , Protein-Tyrosine Kinases/genetics , Protein-Tyrosine Kinases/metabolism , Proto-Oncogene Proteins c-akt , Recombinant Proteins/metabolism , Transfection
4.
Harefuah ; 127(9): 305-9, 359, 1994 Nov 01.
Article in Hebrew | MEDLINE | ID: mdl-7843656

ABSTRACT

A 19-year-old woman with insulin-dependent diabetes mellitus (IDDM) of 3.5 years duration had been suffering from recurrent episodes of diabetic ketoacidosis (DKA), dizziness, and weight loss (16 kg, 29%) for 6 months. History and physical examination gave evidence of severe peripheral and autonomic neuropathy. Radionuclide retention on gastric emptying test at 60 min was greater than 90% (normal < 60%). On autonomic cardiovascular testing there was evidence of both parasympathetic and sympathetic damage. There was no evidence of nephropathy or retinopathy. Optimal diabetic control using 4 insulin injections (2 u/kg/day) and high-dose cisapride terminated the vomiting, and she regained the weight lost within 5 months. This case is unique in that severe diabetic neuropathy followed relatively soon after onset of disease, without other microvascular complications. The correct diagnosis of gastroparesis as the cause of the recurrent DKA and weight loss, and the specific prokinetic therapy and nearly normoglycemic control of the diabetes led to dramatic clinical and functional improvement. Specific prokinetic therapy and the nearly normoglycemic control of the diabetes led to dramatic clinical and functional improvement. Gastroparesis can cause recurrent DKA even in young patients with IDDM of short duration.


Subject(s)
Autonomic Nervous System Diseases/diagnosis , Diabetic Neuropathies/diagnosis , Adult , Autonomic Nervous System Diseases/complications , Diabetes Mellitus, Type 1/complications , Diabetes Mellitus, Type 1/drug therapy , Diabetic Ketoacidosis/etiology , Diabetic Neuropathies/complications , Female , Gastroparesis/complications , Humans , Insulin/therapeutic use , Recurrence , Time Factors
5.
Harefuah ; 122(2): 124-6, 1992 Jan 15.
Article in Hebrew | MEDLINE | ID: mdl-1572557
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