[show abstract][hide abstract] ABSTRACT: Coping with the immune rejection of allotransplants or autologous cells in patients with an active sensitization towards their autoantigens and autoimmunity presently necessitates life-long immune suppressive therapy acting on the immune system as a whole, which makes the patients vulnerable to infections and increases their risk of developing cancer. New technologies to induce antigen selective long-lasting immunosuppression or immune tolerance are therefore much needed.
The DNA demethylating agent Zebularine, previously demonstrated to induce expression of the genes for the immunosuppressive enzymes indolamine-2,3-deoxygenase-1 (IDO1) and kynureninase of the kynurenine pathway, is tested for capacity to suppress rejection of allotransplants. Allogeneic pancreatic islets from Lewis rats were transplanted under the kidney capsule of Fischer rats previously made diabetic by a streptozotocin injection (40 mg/kg). One group was treated with Zebularine (225 mg/kg) daily for 14 days from day 6 or 8 after transplantation, and a control group received no further treatment. Survival of the transplants was monitored by blood sugar measurements. Rats, normoglycemic for 90 days after allografting, were subjected to transplant removal by nephrectomy to confirm whether normoglycemia was indeed due to a surviving insulin producing transplant, or alternatively was a result of recovery of pancreatic insulin production in some toxin-treated rats. Of 9 Zebularine treated rats, 4 were still normoglycemic after 90 days and became hyperglycemic after nephrectomy. The mean length of normoglycemia in the Zebularine group was 67±8 days as compared to 14±3 days in 9 controls. Seven rats (2 controls and 5 Zebularine treated) were normoglycemic at 90 days due to pancreatic recovery as demonstrated by failure of nephrectomy to induce hyperglycemia.
Zebularine treatment in vivo induces a long-lasting suppression of the immune destruction of allogeneic pancreatic islets resulting in protection of allograft function for more than 10 weeks after end of treatment.
PLoS ONE 01/2013; 8(8):e71981. · 3.73 Impact Factor
[show abstract][hide abstract] ABSTRACT: 75 RG2 glioma-carrying Fischer rats were treated by photon activation therapy (PAT) with monochromatic synchrotron radiation and stable thallium. Three groups were treated with thallium in combination with radiation at different energy; immediately below and above the thallium K-edge, and at 50 keV. Three control groups were given irradiation only, thallium only, or no treatment at all. For animals receiving thallium in combination with radiation to 15 Gy at 50 keV, the median survival time was 30 days, which was 67% longer than for the untreated controls (p = 0.0020) and 36% longer than for the group treated with radiation alone (not significant). Treatment with thallium and radiation at the higher energy levels were not effective at the given absorbed dose and thallium concentration. In the groups treated at 50 keV and above the K-edge, several animals exhibited extensive and sometimes contra-lateral edema, neuronal death and frank tissue necrosis. No such marked changes were seen in the other groups. The results were discussed with reference to Monte Carlo calculated electron energy spectra and dose enhancement factors.
Physics in Medicine and Biology 11/2012; 57(24):8377-8391. · 2.70 Impact Factor
[show abstract][hide abstract] ABSTRACT: We describe the cytogenetic findings in short-term cultures from 40 malignant gliomas, all of which had at least one clone with a simple numerical chromosome aberration. More than one aberrant clone was found in 17 tumors. The most frequent changes were loss of a gonosome (sole aberration in 38 clones), trisomy 7 (sole aberration in four clones), and combinations thereof (the aberrations + 7 and — X or — Y were found together as the only changes in four clones). Clones with solitary trisomies for other autosomes—3, 5, 6, and 18—were seen in five tumors. Clones with structural rearrangements were found in nine tumors. The bands most commonly involved were I p36, 7p22, 9p22, 17p 13, and 19q 13. An extra copy of chromosome 7 was seen as part of a structurally abnormal clone in five tumors. In one case, trisomy 7 and even tetrasomy 7 were found in clones with simple numerical changes, but not in the clone with structural rearrangements. Likewise, the clonal loss of a gonosome was in six tumors, with structural abnormalities not present in the structurally aberrant clones; on the other hand, in two clones with structural aberrations a sex chromosome had been lost. The combined findings indicate that loss of a sex chromosome and trisomy 7 should not be seen as tumor-specific aberrations in gliomas. Instead, both glioma parenchyma cells and nonneoplastic cells in brain tumors may have a propensity to acquire extra copies of chromosome 7 and to lose gonosomes.
Genes Chromosomes and Cancer 07/2006; 3(6):474 - 479. · 3.55 Impact Factor
[show abstract][hide abstract] ABSTRACT: Since the late 1980s, our group has examined the effects of radiofrequency electromagnetic fields (RF-EMF), including pulse-modulated
waves of the type emitted by mobile phones, upon the blood–brain barrier. In more than 2,000 rats, we have repeatedly demonstrated
a passage of the rats’ own albumin from the blood through the brain capillaries into the surrounding brain parenchyma at SAR
values down to 0.1mW/kg. In most of these experiments, the animals were exposed in TEM-cells, ventilated by an external electrical
fan at 50Hz. In the present study, we examined whether the extremely low frequency (ELF) magnetic fields from the fan (50Hz,
0.3–1.5μT) might add to the RF effect. Sixty-four rats were divided into 4 groups: RF only, ELF only and RF+ELF exposure
plus a sham group. The GSM-900MHz RF exposure was at the very low, nonthermal, average whole-body SAR level 0.4mW/kg. Demonstration
of the normally occurring albumin extravasation in the basal hypothalamus is our inbuilt control proving that the staining
is reliable. Two full series of staining of the whole material gave negative results for hypothalamus. Not until we changed
to avidin, biotin, and antibodies from a third supplier, we received an acceptable staining. Twenty-five percent of the RF
animals had a pathological albumin leakage, while the ELF and RF+ELF groups with three and two pathological findings, respectively,
were not significantly different from the control group. We conclude that the use of external fans has had no major influence
upon the result.
KeywordsAlbumin–Blood–brain barrier–Electromagnetic field–Histopathology–Mobile phone–Rat