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Biomedical subjects

E P Cohen

Publications and source records attributed to E P Cohen.

At least 19 recordsLinked to original sources
PubMed2003

ACE inhibitors and AII receptor antagonists in the treatment and prevention of bone marrow transplant nephropathy.

Radiation nephropathy has emerged as a major complication of bone marrow transplantation (BMT) when total body irradiation (TBI) is used as part of the regimen. Classically, radiation nephropathy has been assumed to be inevitable, progressive, and untreatable. However, in the early 1990's, it was demonstrated that experimental radiation nephropathy could be treated with a thiol-containing ACE inhibitor, captopril. Further studies showed that enalapril (a non-thiol ACE inhibitor) was also effective in the treatment of experimental radiation nephropathy, as was an AII receptor antagonist. Studies also showed that ACE inhibitors and AII receptor antagonists were effective in the prophylaxis of radiation nephropathy. Interestingly, other types of antihypertensive drugs were ineffective in prophylaxis, but brief use of a high-salt diet in the immediate post-irradiation period decreased renal injury. A placebo-controlled trial of captopril to prevent BMT nephropathy in adults is now underway. Since excess activity of the renin-angiotensin system (RAS) causes hypertension, and hypertension is a major feature of radiation nephropathy; an explanation for the efficacy of RAS antagonism in the prophylaxis of radiation nephropathy would be that radiation leads to RAS activation. However, current studies favor an alternative explanation, namely that the normal activity of the RAS is deleterious in the presence of radiation injury. On-going studies suggest that efficacy of RAS antagonists may involve interactions with a radiation-induced decrease in renal nitric oxide activity or with radiation-induced tubular cell proliferation. We hypothesize that while prevention (prophylaxis) of radiation nephropathy with ACE inhibitors, AII receptor antagonists, or a high-salt diet work by suppression of the RAS, the efficacy of ACE inhibitors and AII receptor antagonists in treatment of established radiation nephropathy depends on blood pressure control.

Angiotensin Receptor Antagonists↗
PubMed2002

The glomerulo-tubular junction: a target in renal diseases.

Both global and segmental glomerulopathies may damage specific areas of the renal glomerulus. Diseases associated with glomerular hyperperfusion cause lesions at the vascular pole, while diseases associated with proteinuria often damage the tubular pole. Atubular glomeruli are now known to be plentiful in a variety of common renal diseases. These glomeruli are disconnected from their tubule at the tubular pole and therefore cannot participate in the production of urine. It is widely believed that the disconnection is a result of external compression by periglomerular fibrosis. However, the variable anatomy and cell populations within both the glomerulus and the beginning of the proximal tubule at the glomerulo-tubular junction may also have important roles to play in the response to damage at this sensitive site of the nephron.

Humans↗
PubMed2002

An optimum anti-melanoma response in mice immunized with fibroblasts transfected with DNA from mouse melanoma cells requires the expression of both syngeneic and allogeneic MHC-determinants.

Most neoplasms do not induce antitumor immune responses that can control tumor growth. Tumor associated antigens (TAAs) are insufficiently immunogenic. A vaccine that augments the immunogenic properties of TAAs could be of importance in the treatment of cancer patients. In an animal model, we prepared a vaccine by transfection of highly antigenic allogeneic mouse fibroblasts (LM; H-2(k)) with DNA from B16 mouse melanoma cells. We then tested the transfected cells' immunogenic properties in C57BL/6 mice, syngeneic with the melanoma (H-2(b)). We hypothesized that the immunogenic properties of 'weak' TAAs formed by the neoplasm would be enhanced if they were expressed by highly antigenic cells. The results indicated that mice with melanoma treated by immunization with the DNA-transfected fibroblasts survived significantly longer than mice in various control groups. To investigate the contribution of MHC determinants expressed by the transfected cells to their immunogenic properties, we compared the antimelanoma responses in mice immunized with transfected cells that expressed allogeneic or syngeneic class I determinants. The results indicated that the immunogenic properties of the DNA-transfected cells were enhanced if the cells expressed allogeneic MHC determinants. The antimelanoma responses of greatest magnitude, however, mediated predominantly by CD8(+) T cells, were in mice immunized with transfected fibroblasts that expressed both syngeneic and allogeneic class I determinants.

Animals↗
PubMed2002

Dietary sodium modification and experimental radiation nephropathy.

PURPOSE: To determine whether suppression of the renin-angiotensin system (RAS) with high dietary sodium (salt) has the same beneficial effect on radiation nephropathy as suppression of the RAS with angiotensin-converting-enzyme (ACE) inhibitors or angiotensin II (AII) receptor antagonists. MATERIALS AND METHODS: Normal and irradiated rats were placed on high- or low-salt diets and assessed for effects on blood pressure, on AII levels and on the development of radiation nephropathy. RESULTS: In unirradiated animals, a high-salt diet suppressed AII and caused hypertension, while a low-salt diet produced no detectable effects. Use of a high-salt diet 3-9 weeks after irradiation exacerbated radiation-induced hypertension but attenuated the development of radiation nephropathy. Continuous use of a high-salt diet slowed the progression of radiation nephropathy, but eventually exacerbated radiation-induced hypertension and accelerated renal failure. Use of a high-salt diet in animals with established radiation nephropathy was deleterious. A low-salt diet had no effect on the development of radiation nephropathy. CONCLUSIONS: These studies provide further support for the hypothesis that the beneficial effect of AII receptor antagonists, ACE inhibitors and high dietary sodium in the prophylaxis of radiation nephropathy is due to their suppression of the RAS, not to their anti-hypertensive effects.

Angiotensin Receptor Antagonists↗
PubMed2001

Up-regulation of MUC1 in mammary tumors generated in a double-transgenic mouse expressing human MUC1 cDNA, under the control of 1.4-kb 5' MUC1 promoter sequence and the middle T oncogene, expressed from the MMTV promoter.

In this study we examined the regulation of expression of the human MUC1 gene in vivo, by developing MUC1 transgenic mice. The data showed that epithelial-specific expression of MUC1 can be directed by just 1.4 kb of 5' flanking sequence using MUC1 cDNA as a reporter gene in vivo. Furthermore, high levels of MUC1 expression were seen in the lactating mammary gland and in spontaneous mammary tumors generated by crossing the MUC1 transgenics with mice transgenic for the polyoma middle T oncogene under the control of the mouse mammary tumor virus promoter. This pattern of expression in epithelial tissues is comparable to the expression of MUC1 in humans and also to the expression pattern in another transgenic mouse line developed with a 10.6-kb genomic MUC1 fragment. This study confirmed that MUC1 is a compact gene and demonstrated that the 1.4-kb 5' sequence not only directs epithelial-specific expression of MUC1 in vivo but also contains the elements governing the up-regulation observed during lactation and in malignancy.

Animals↗
PubMed2001

Polyoma virus infection after renal transplantation. Use of immunostaining as a guide to diagnosis.

BACKGROUND: Polyoma virus infection is characterized by lymphocytic interstitial infiltrate in the kidney, and it mimics acute rejection. The purpose of this study is to estimate renal allograft outcome with this infection and characterize the lymphocytic infiltrates in polyoma virus-infected renal allografts. METHODS: Patients who had polyoma virus inclusions in renal allograft biopsies were identified. Other viral inclusions were excluded by immunohistochemistry. The lymphocytic infiltrates of six cases of polyoma virus infection were compared with six cases of definite acute rejection by immunostaining for T and B cells. RESULTS: There were 10 cases of polyoma virus infections in renal transplant recipients. Immunosuppressants consisted of mycophenolate mofetil with tacrolimus in eight cases and mycophenolate mofetil with cyclosporine in two. The median time of diagnosis of polyoma virus infection after transplantation was 9.5 months, and the time to graft failure after the diagnosis was 4 months. Reduced allograft survival was seen in patients who had polyoma virus infection. Immunostaining for T and B cells revealed marked increase in the B cells (CD20) in renal allografts with polyoma virus infection of 21% (range, 5-40%) compared with 6% (range, 0-10%) in those with acute rejection (P=0.039). Reduced cytotoxic T cells (TIA-1: median, 7%; range, 2-15%) were seen in polyoma virus-infected allografts compared with 24% (range, 15-30%) in those patients who had acute rejection (P=0.0159). CONCLUSION: Irreversible graft failure is more prevalent with polyoma virus infection. Enhanced immunosuppressants with mycophenolate mofetil with tacrolimus may play a role in the development of this infection. An increase in CD20 and a decrease in cytotoxic T cells in allografts is characteristic of polyoma virus infection.

Acute Disease↗
PubMed2001

Subtotal parathyroidectomy in renal failure: still needed after all these years.

There are scant data on the frequency of parathyroidectomy (PTX) for end-stage renal disease (ESRD). Medical therapy for ESRD and secondary hyperparathyroidism has evolved to include better dialytic urea removal and the use of calcitriol. The aim of this study was to determine whether medical therapy has changed the frequency or indications for PTX in the management of renal failure. Hospital and clinic records were analyzed to gather information on all patients undergoing PTX for secondary hyperparathyroidism (2HPT) (n = 48) and tertiary hyperparathyroidism (3HPT) (n = 26) from 1986 through 1998 at our institution. Prospective computer databases were queried for information concerning both chronic dialysis and renal transplant patients at our center. The patients were divided based on date of operation before or after 1991, a divider that separated the patients into groups before or after the widespread adoption of intravenous calcitriol treatment during hemodialysis at our institution. Over the 12 year period, the proportion of our chronic dialysis patients undergoing PTX did not change significantly, ranging from 0% to 2.5% per year. Comparing all patients undergoing PTX for 2HPT during 1986-1991 versus 1992-1998, there was no significant difference in time on dialysis [7.0 +/- 4.2 (n = 11) vs. 7.5 +/- 4.6 (n = 36) years, mean +/- SD]. The later group had higher intact parathyroid hormone (iPTH) levels [765 +/- 415 (n = 6) vs. 1377 +/- 636 (n = 28) pg/ml; p = 0.03], lower serum calcium [11.2 +/- 1.0 (n = 12) vs. 9.9 +/- 1.5 (n = 34) mg/dl; p = 0.006], and higher serum phosphate [5.7 +/- 1.6 (n = 12) vs. 7.2 +/- 2.3 (n = 31) mg/dl; p = 0.042]. Among the population of patients with transplants undergoing PTX for 3HPT, the average percent per year undergoing PTX ranged from 0% to 4.2% and did not change during the study period. Comparing the 1986-1991 group to the 1992-1998 group, the time from transplantation to PTX did not change during the study period (3.3 +/- 2.3 vs. 2.9 +/- 3.0 years; p = 0.391), and there were no significant differences between preoperative calcium levels or iPTH levels. Despite advances in dialysis technique and pharmacologic therapy, there has been no change in the proportion of dialysis patients requiring PTX for 2HPT or 3HPT. There was also no change in the time on dialysis for patients with 2HPT or the time from transplant to PTX for patients with 3HPT. Analysis of preoperative biochemical markers as evidence of disease severity suggests there was no change in indications for PTX during our study. From this information we conclude that parathyroid pathophysiology is incompletely understood and medical therapy is not optimal, resulting in a continuing need for PTX in some patients.

Adult↗
PubMed2001

DNA-based vaccines for the treatment of cancer--an experimental model.

Antigenic differences between normal and malignant cells form the basis of clinical immunotherapy protocols. Because the antigenic phenotype varies widely among different cells within the same tumor mass, immunization with a vaccine that stimulates immunity to a broad array of tumor antigens expressed by the entire population of malignant cells is likely to be more efficacious than immunization with a vaccine for a single antigen. One strategy is to prepare a vaccine by transfer of DNA from the patient's tumor into a highly immunogenic cell line. Weak tumor antigens, characteristic of malignant cells, become strongly antigenic if they are expressed by immunogenic cells. In animal models of melanoma and breast cancer, immunization with a DNA-based vaccine is sufficient to deter tumor growth and to prolong the lives of tumor-bearing mice.

Animals↗
PubMed2001

Loss of renal function following bone marrow transplantation: an analysis of angiotensin converting enzyme D/I polymorphism and other clinical risk factors.

Chronic renal failure is an acknowledged late complication of BMT. It is related to the intensive chemotherapy, radiation and supporting medications. Polymorphism in the angiotensin converting enzyme (ACE) gene is associated with progression of nephropathy caused by diabetes and IgA nephropathy. We sought to determine whether ACE genotype and other clinical factors were associated with loss of renal function after BMT. We determined the genotype of 106 adult allogeneic BMT recipients, who received a similar preparative regimen, survived 1 year, and had assessment of renal function up to 3 years after BMT. We found that the distribution of genotypes was similar to the general population; 29%, 51%, and 20% for the DD, DI, and II genotypes, respectively. There was no statistical difference in patient survival between the three groups. Among all patients, the average creatinine clearance declined from 124 (95% CI 117, 131) to 89 (95% CI 78, 100) ml/min over the 36 months after BMT. Decline in renal function over time was less for patients with the DD compared to the II genotype (P = 0.040). Renal function in patients with the DD genotype was also better than those with the DI genotype, but this was of borderline statistical significance (P = 0.055). Renal shielding reduced decline in renal function compared to no shielding (P = 0.026). We conclude that the ACE genotype does not seem to influence survival, but the DD genotype may be protective against renal injury after BMT. Furthermore, we confirm that renal shielding during TBI reduces the renal injury after BMT.

Adolescent↗
PubMed2001

Parathyroidectomy in chronic renal failure: has medical care reduced the need for surgery?

Subtotal or total parathyroidectomy is sometimes required for the management of severe secondary or tertiary hyperparathyroidism. Advances in medical and dialysis care may have a beneficial effect on hyperphosphatemia and vitamin D status, which could, in turn, reduce the need for parathyroidectomy. We used the United States Renal Data System to test this hypothesis. We found that the percentage of prevalent end-stage renal disease patients undergoing subtotal or total parathyroidectomy has declined significantly from 1988 to 1998. It is likely that improved medical and dialysis care has enabled this result.

Databases as Topic↗
PubMed2001

Prevention of radiation-induced nephropathy and fibrosis in a model of bone marrow transplant by an angiotensin II receptor blocker.

Nephropathy, interstitial pneumopathy, and renal and lung fibrosis are major complications of bone marrow transplantation (BMT). This study evaluated the antifibrotic property of an angiotensin II (A2) type-1 receptor blocker (L-159,809) and compared it with those of Captopril and Enalapril, two angiotensin-converting enzyme (ACE) inhibitors, in a rat model of BMT. Male WAG/Rij/MCW rats received a preparative regimen of 60 mg/kg body wt of cytoxan (i.p., Days 9 and 8) and 18.5 Gy of total body irradiation (TBI) in six twice daily fractions (Days 2, 1, and 0) followed immediately (Day 0) by BMT. Modifiers were given in drinking water from Day 10 until autopsy, 8 weeks after BMT. Rats treated with TBI plus cytoxan alone developed severe nephropathy. Trichrome staining showed marked collagen deposition in glomeruli, renal interstitium, and renal arteries and arterioles (especially in their adventitia). Collagen deposition and renal damage were markedly reduced by the three modifiers. Of the three, L-158,809-treated rats had slightly thinner vessels and slightly less collagen than nonirradiated normal controls. The study shows the effectiveness of these drugs in the protection of the renal parenchyma from the development of radiation-induced fibrosis. It also indicates a role for angiotensin II in the modulation of collagen synthesis.

Aldosterone↗
PubMed2001

Early detection of radiation-induced glomerular injury by albumin permeability assay.

Renal irradiation leads predictably to glomerular vascular injury, cell lysis, matrix accumulation, sclerosis and loss of renal function. The immediate effects of renal irradiation that may be associated with glomerular pathology and proteinuria are not clear in the human disease or its rat model. We hypothesized that radiation-induced injury causes immediate and subtle alterations in glomerular physiology independent of the neurohumoral and hemodynamic regulatory mechanisms. We employed a sensitive in vitro functional assay of glomerular albumin permeability (P(alb)) to demonstrate radiation-induced damage to the glomerular filtration barrier immediately after total-body irradiation of rats. In blinded experiments, control rats were sham-treated, and experimental rats received 9.5 Gy X rays. Rats were killed humanely at 1 h to 9 weeks after irradiation and glomeruli were isolated. In parallel experiments, glomeruli were isolated from normal rats and irradiated in vitro. The change in glomerular capillary permeability due to an experimental oncotic gradient was determined using videomicroscopy and P(alb) was calculated. Results show that in vivo or in vitro irradiation of glomeruli caused an increased P(alb) at 1 h. Increased P(alb) was observed up to 3 weeks after irradiation. Glomeruli from mice irradiated with 9.5 or 19.0 Gy X rays did not show increased P(alb) at 1 h postirradiation. We conclude that glomerular protein permeability of irradiated rats increases in a dose-dependent manner immediately after irradiation and that it appears to be independent of hemodynamic or systemic influences.

Albumins↗
PubMed2001

Induction of heme oxygenase 1 in radiation nephropathy: role of angiotensin II.

Datta, P. K., Moulder, J. E., Fish, B. L., Cohen, E. P. and Lianos, E. A. Induction of Heme Oxygenase 1 in Radiation Nephropathy: Role of Angiotensin II. Radiat. Res. 155, 734-739 (2001). In a rat model of radiation-induced nephropathy, we investigated changes in expression of heme oxygenase 1 (Hmox1, also known as HO-1), an enzyme that catalyzes conversion of heme into biliverdin, carbon monoxide and iron. The study explored whether radiation induces Hmox1 expression in the irradiated kidney and whether angiotensin II (AII) mediates Hmox1 expression in glomeruli isolated from irradiated kidneys. To assess the effects of radiation on Hmox1 expression, rats received 20 Gy bilateral renal irradiation and were randomized to groups receiving an AII type 1 (AT(1)) receptor antagonist (L-158,809) or no treatment. Drug treatment began 9 days prior to bilateral renal irradiation and continued for the duration of the study. Estimation of Hmox1 levels in glomerular protein lysates assessed by Western blot analysis revealed a significant increase in Hmox1 protein at 50 and 65 days postirradiation. In animals treated with the AT(1) receptor antagonist, there was no induction of Hmox1, suggesting that AII may be a mediator of Hmox1 induction. To confirm that AII stimulates Hmox1 expression, animals were infused with 200, 400 or 800 ng/kg min(-1) of AII for 18-19 days, and Hmox1 protein levels in glomeruli were assessed. There was a significant induction of Hmox1 in glomeruli of animals infused with 800 ng/kg min(-1) of AII. These studies demonstrate that glomerular Hmox1 expression is elevated in the middle phase of radiation nephropathy and that AII can increase glomerular Hmox1 levels.

Angiotensin II↗
PubMed2001

Immunogene therapy with interleukin-2-secreting fibroblasts for intracerebrally metastasizing breast cancer in mice.

OBJECT: Breast cancer is the second leading cause of cancer-related death in American women. Brain metastases occur in 15 to 30% of patients with breast cancer, and this usually results in death. Despite the availability of surgery, radiotherapy, and chemotherapy, the prognosis for patients with breast cancer that has metastasized to the intracerebral region remains poor. This study was designed to determine if an intracerebrally metastasizing breast tumor could be treated successfully with a cellular vaccine consisting of allogeneic fibroblasts (H-2K) modified to secrete interleukin (IL)-2. METHODS: The authors used EO771 breast cancer cells, derived from a spontaneously arising breast-cancer tumor in C57BL/6 mice. The authors first determined the length of survival of C57BL/6 mice that had been injected with varying numbers of EO771 cells into the right frontal lobes and found that 100% of those animals that received a dose of 10(4) cells died within 41 days, whereas 100% of the group that received 10(3) cells died within 23 days. Based on these results, 5 x 10(4) EO771 cells were injected into the right frontal lobe of C57BL/6 mice and the animals were treated intracerebrally with a single intratumoral injection of 10(6) allogeneic fibroblasts genetically engineered to secrete IL-2. The allogeneic fibroblasts transfected with the IL-2 gene formed large quantities of IL-2 as measured by an enzyme-linked immunosorbent assay. Control groups of animals were treated with either allogeneic fibroblasts transfected with the retroviral vector, but not the IL-2 gene, or with media. The effects of this treatment on the animal's survival and the tumor's histopathological characteristics were investigated. The results indicate a significant prolongation (p < 0.005) of survival in animals with intracerebrally metastasizing breast cancer treated only with IL-2-secreting allogeneic fibroblasts. Tumor did not develop in four of 10 animals in the IL-2-treated group, and these animals were rechallenged at 90 days by intracerebral injection of tumor, but no treatment cells, and compared with four naive animals receiving intracerebral tumor. Again, animals that previously had been treated with IL-2-secreting fibroblasts had a markedly prolonged survival (p < 0.05) compared with control animals following a second challenge with tumor cells. Histopathological examination revealed smaller tumors associated with lymphocytic infiltrations in the treated animals. CONCLUSIONS: This work represents a new treatment for breast cancer that has metastasized to the brain in which a cellular vaccine consisting of allogeneic fibroblasts genetically engineered to secrete cytokines is used as a novel means for delivery of immunogene therapy and demonstrates the induction of long-term immunity against tumor.

Adenocarcinoma↗
PubMed2000

Cytokine immunogene therapy.

The prognosis for patients with either a primary or metastatic brain tumor is poor. Clearly new forms of therapy to improve the long-term survival of patients with malignant brain tumors are urgently needed. The authors are in the process of developing a new and novel form of treatment for primary and metastatic brain tumors in which they use genes involved in growth repression. In particular most tumors fail to induce an antitumor immune response strong enough to kill the tumor. Under appropriate circumstances, however, immunity can be produced in unique structures on the tumor cells known as antigens. To prepare the vaccine, genes are transferred into a fibroblast cell line that causes the cell to produce cytokines, the potent proteins known to stimulate the immune system. These cells are subsequently injected into the tumor bed, resulting in the development of an antitumor immune response. In experiments described in this manuscript, the authors have investigated a number of ways of augmenting the immune response by administering this type of cellular vaccine. They found that mice with a primary intracerebral glioma, melanoma, or breast cancer treated with this allogeneic cytokine-secreting vaccine survived significantly longer than untreated mice. Additionally the vaccine was found to stimulate a systemic antitumor immune response, as shown by immunocytotoxic studies, histopathological examination, and delayed immune memory responses. In summary, these results indicate that immunogene therapy is a promising new targeted therapy for the treatment of intracerebral malignant tumors.

Brain Neoplasms↗