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Biomedical subjects

L C Stephens

Publications and source records attributed to L C Stephens.

At least 37 records · Page 2Linked to original sources
PubMed1999

Apoptotic and mitotic indices predict survival rates in lymph node-negative colon carcinomas.

An imbalance between apoptosis and mitosis is believed to underlie colon cancer development and progression. These processes regulate the growth of normal and neoplastic epithelia, and in tumors, may confer prognostic information. To test this hypothesis, we determined apoptotic and mitotic indices (AI, MI) by morphology in H&E sections of 154 lymph node-negative, sporadic colon carcinomas. The relationship of these indices to genetic (p53 and Bcl-2) and biological features (DNA ploidy and cell kinetics) and patient survival rates was determined. Tumor features were compared in proximal and distal tumors, given postulated differences in their pathogenesis. Bcl-2 and p53 proteins were examined using immunohistochemistry and DNA ploidy and proliferative indices (PIs) by flow cytometry. Tumor features were dichotomized for analysis of relapse-free survival and overall survival (OS) rates using a Cox proportional hazards model. Median patient follow-up was 8.8 years. The median AI and MI were 1.2% (0-7.6) and 0.40% (0-1.8), respectively, and did not differ by tumor site. AI correlated with histological grade (P = 0.03); MI correlated with PI (P = 0.02) and inversely with Bcl-2 in distal tumors (P = 0.02). p53 and Bcl-2 expression were detected in 52 and 53% of tumors, respectively. Distal tumor site was associated with aneuploidy (P = 0.001), p53 (P = 0.001), and PI > 15% (P = 0.002). In a univariate analysis, colon cancers with high MIs (>0.5%) had a poor prognosis (P = 0.04). Bcl-2 overexpression (>20% + tumor cells) was associated with more favorable OS (P = 0.04). The association of ploidy and PI with outcome was of borderline significance for all tumors; however, diploidy predicted better survival in proximal cancers. In distal cancers, low AIs (< or = 0.25%) and high MIs (>0.5%) were adverse prognostic markers. After adjustment for other variables, an increased MI predicted shorter OS with a hazard ratio (HR) for death of 2.70; 95% confidence interval (CI) was 1.23-5.91 (P = 0.01). Expression of Bcl-2 was associated with more favorable OS (HR, 0.46; 95% CI, 0.21-1.0; P = 0.06). In proximal cancers, Bcl-2 expression was the most important predictor of OS (HR, 0.17; 95% CI, 0.03-0.85; P = 0.03). In distal tumors, low AIs (HR, 3.33; 95% CI, 1.27-9.09; P = 0.01) and high MIs predicted poor survival. In conclusion, increased mitosis and low or absent Bcl-2 expression are significant risk factors for death in node-negative colon cancers, as are low rates of apoptosis in distal tumors. If validated prospectively, our results may identify patient subsets than can benefit from adjuvant chemotherapy.

Adenocarcinoma↗
PubMed1998

A morphometric analysis of glomerular and tubular alterations following fast-neutron irradiation of the pig and monkey kidney.

PURPOSE: The morphologic responses of the pig and monkey kidney to fractionated fast-neutron irradiation were assessed. METHODS AND MATERIALS: The right kidney of approximately 14-week-old female Large White pigs was irradiated with 6.6-12.2 Gy of fast neutrons (42 MeVd-->Be) given as 12 fractions over 18 days; the left kidney served as the contralateral unirradiated kidney. Both kidneys were removed at necropsy 2 years postirradiation. In addition, the remaining hypertrophied kidney of four unilaterally nephrectomized adult rhesus monkeys was irradiated with a total dose of 11.0 Gy fast neutrons (45 MeVp-->Be) given in an identical fractionation regimen to that used in the pig studies. These kidneys were removed when the animals exhibited renal failure, between 32-94 weeks postirradiation. Glomeruli were assessed for the presence of pathologic features, including intercapillary eosinophilic material (ICE), ectatic capillaries, thrombi, hemorrhage, and sclerosis. The relative proportion of renal cortex occupied by glomeruli, interstitium, normal, or abnormal tubules was determined using a Chalkley point grid. RESULTS: The incidence of normal glomeruli, ectatic capillaries, thrombosis, and periglomerular fibrosis were significantly different in the irradiated pig kidneys compared with the unirradiated contralateral kidneys (p < or = 0.02). Linear regression analysis demonstrated a significant dose relationship in terms of normal glomeruli, ectatic capillaries, and ICE (r > or = 0.64; p < or = 0.04). Irradiation was also associated with a significant (p < 0.0001) decrease and increase in the volume of renal cortex occupied by normal and abnormal tubules, respectively. Similar morphometric changes were noted in the irradiated monkey kidneys. CONCLUSIONS: The morphologic changes seen in the pig and monkey kidney after fractionated irradiation with fast neutrons are similar to those previously noted after single-dose or fractionated-photon irradiation. These findings support the hypothesis that the development of radiation nephropathy in these various models involves common pathophysiological mechanisms.

Animals↗
PubMed1998

Complete regression of well-established tumors using a novel water-soluble poly(L-glutamic acid)-paclitaxel conjugate.

Despite an intensive search, few water-soluble paclitaxel derivatives have been shown to have a therapeutic index superior to paclitaxel itself. We now report a water-soluble poly(L-glutamic acid)-paclitaxel conjugate (PG-TXL) that produces striking antitumor effects with diminished toxicity. A single i.v. injection of PG-TXL at its maximum tolerated dose (defined as that dose that produces a maximum 12-15% body weight loss within 2 weeks after a single i.v. injection) equivalent to 60 mg of paclitaxel/kg and at even a lower dose equivalent to 40 mg of paclitaxel/kg resulted in the disappearance of an established implanted 13762F mammary adenocarcinoma (mean size, 2000 mm3) in rats. (An equivalent dose of PG-TXL is the amount of conjugate that contains the stated amount of paclitaxel.) Similarly, mice bearing syngeneic OCA-1 ovarian carcinoma (mean size, 500 mm3) were tumor-free within 2 weeks after a single i.v. injection of the conjugate at a dose equivalent to 160 mg of paclitaxel/kg. The conjugate has little if any intrinsic tubulin polymerization activity in vitro and is >20 times less potent in supporting the growth of a paclitaxel-dependent CHO mutant cell line. PG-TXL has a prolonged half-life in plasma and greater uptake in tumor as compared with paclitaxel. Furthermore, only a small amount of total radioactivity from PG-[3H]TXL was recovered as free [3H]paclitaxel in either the plasma or the tumor tissue within 144 h after drug injection. Histological studies of tumor tissues obtained from mice treated with PG-TXL show fewer apoptotic cells but more extensive tumor necrosis as compared with paclitaxel treatment. These data suggest that in addition to its role as a carrier for selective delivery of paclitaxel to the tumor, PG-TXL exerts distinct pharmacological actions of its own that may contribute to its remarkable antitumor efficacy.

Animals↗
PubMed1998

Therapeutic efficacy and apoptosis and necrosis kinetics of doxorubicin compared with cisplatin, combined with whole-body hyperthermia in a rat mammary adenocarcinoma.

We have compared the therapeutic efficacy as well as the kinetics of treatment-induced apoptosis and necrosis of the maximum tolerated dose (MTD) of doxorubicin (DOX) or cisplatin (CDDP) combined with long-duration, low-temperature whole-body hyperthermia (LL-WBH, at 40.0 degrees C for 6 hr), with the combination of the MTDs of either DOX or CDDP with short-duration, high-temperature WBH (SH-WBH, at 41.5 degrees C for 2 hr), in a rat mammary adenocarcinoma (MTLn3). The MTD of LL-WBH + DOX resulted in increased therapeutic efficacy, compared with the MTD of DOX alone and SH-WBH + DOX. The MTD of LL-WBH + CDDP, however, did not increase therapeutic efficacy, when compared with the MTD of CDDP alone or SH-WBH + CDDP. The MTD of LL-WBH + DOX caused a significant delay in the development of spontaneous axillary lymph node (ALN) metastasis and tended to cause longer mean survival, compared with SH-WBH + DOX. The peak of treatment-induced apoptosis was higher for the MTD of DOX + LL-WBH, compared with SH-WBH + DOX, whereas the apoptosis peak of the MTD of SH-WBH + CDDP was higher than that of LL-WBH + CDDP. The most extensive levels of tumor necrosis appeared to occur earlier with SH-WBH alone and the MTD of SH-WBH + DOX or CDDP than with other groups. Our results suggest that LL-WBH + DOX may be a promising therapy for breast cancer, and the extent of treatment-induced tumor apoptosis appears to correlate with antitumor response for MTDs of LL-WBH + DOX and SH-WBH + DOX, but not for the MTDs of CDDP with SH-WBH or LL-WBH.

Adenocarcinoma↗
PubMed1998

Radiation-induced tumorigenesis in preneoplastic mouse mammary glands in vivo: significance of p53 status and apoptosis.

In mouse mammary tumorigenesis, p53 mutations facilitate tumorigenesis in concert with other oncogenic alterations. Ionizing radiation enhances tumorigenesis in preneoplastic mammary outgrowth lines and induces p53-dependent apoptosis. We asked if normal p53 function modulates radiation-induced tumorigenesis in preneoplastic mammary lesions by affecting the apoptotic pathway of cell deletion. Three different hyperplastic outgrowth lines were compared. Outgrowth line D1 overexpressed wild-type p53 and responded to irradiation with enhanced tumorigenicity but no induction of apoptosis. Outgrowth line TM12 exhibited normal wild-type p53 expression and responded to irradiation with no alteration in tumorigenicity but with a marked increase in apoptosis. Outgrowth line TM2L also exhibited normal wild-type p53 expression and responded to irradiation with a marked enhancement in both tumorigenicity and apoptosis. These results indicate that the two radiation-induced responses, apoptosis and tumorigenesis, are dissociable events in the mammary gland. Furthermore, radiation-induced tumorigenicity was not abrogated by either enhanced wild-type p53 expression or a robust apoptotic response. The radiation dose of 5 Gy most likely induces multiple genetic alterations in surviving cells, including genomic instability, and this may account for the tumorigenicity. Future experiments will examine lower doses of irradiation that still induce a significant apoptotic response but significantly less genomic instability.

Animals↗
PubMed1998

Specific Th1 cell lines that confer protective immunity against experimental Borrelia burgdorferi infection in mice.

Although humoral responses to Borrelia burgdorferi (Bb) have been shown to be protective in some animal models of Lyme disease, the role of T cells in this disease is less well understood. This work describes three Bb-specific T cell lines that prevent disease progression in syngeneic mice. The T cell lines were generated in C3H mice immunized with Bb in complete Freund's adjuvant. All lines were Bb-specific, CD4+, TCRalphabeta+, and they proliferated and produced interferon-gamma and interleukin-2 on stimulation with Bb. Injection of the cell lines into naive C3H recipients significantly reduced the number of organisms recoverable from the blood and tissues of infected mice and protected them from developing Bb-induced periarthritis. These studies demonstrated that Th1 cells can confer resistance to Bb infection in susceptible mice and suggested that the timing of this T cell response may be critical for determining disease outcome.

Adoptive Transfer↗
PubMed1998

The pre-conditioning incidence of antiphospholipid antibodies is not significantly increased in patients with bone marrow transplant-related organ dysfunction.

Hepatic dysfunction resulting from hepatic veno-occlusive disease (VOD) is a common complication of bone marrow transplantation (BMT). Some investigators believe that hepatic dysfunction, along with pulmonary and central nervous system (CNS) dysfunction, is part of a systemic disorder called multiple organ dysfunction syndrome (MODS). Endothelial damage by pretransplant chemo-radiation and activation of hemostasis are considered early events in the development of hepatic VOD. The pathological mechanism leading to fibrous obliteration of hepatic vessels may also take place in pulmonary and CNS vessels. Since antiphospholipid antibodies (aPA) are associated with venous and arterial thrombosis, which can lead to vessel occlusion, we asked if the incidence of aPA before conditioning was greater in patients who developed MODS following BMT. Samples drawn before pretransplant chemo-radiation from 57 patients who subsequently developed MODS and 55 control patients who did not develop MODS were studied blindly for aPA by ELISA. The number of aPA-positive patients who developed MODS (10/57), compared to the number of aPA-positive patient controls who did not develop MODS (7/55) was not statistically significant (P = 0.48). Our data indicate that the incidence of aPA before conditioning was not greater in patients who developed MODS, including hepatic VOD, following BMT.

Antibodies, Antiphospholipid↗
PubMed1998

A prospective randomized double-blind trial of antithrombin III concentrate in the treatment of multiple-organ dysfunction syndrome during hematopoietic stem cell transplantation.

Many of the complications of high-dose therapy with hematopoietic stem cells are caused by or lead to the multiple-organ dysfunction syndrome (MODS). In hematopoietic stem cell transplantation (HSCT), acquired antithrombin III (ATIII) deficiency is independently associated with MODS to the exclusion of transplant type, preparative regimen, and bacteremia. In experimental settings, replacement of ATIII can ameliorate the severity of MODS that develops in response to a variety of pathologic stimuli, suggesting that ATIII supplementation might improve the clinical course of MODS in patients undergoing HSCT. We performed a study to determine if ATIII can improve the morbidity of MODS in HSCT. Forty-nine patients undergoing HSCT, who developed pulmonary dysfunction (oxygen saturation of <90%), central nervous system dysfunction (drop of >4 points in the mini-mental status exam), or hepatic dysfunction (bilirubin >34 micromol/L [2.0 mg%], weight gain of >5% over baseline, and abdominal pain, possibly of hepatic origin) with a concomitant ATIII activity of <84% were double-blind randomized to receive ATIII concentrate, 70 units/kg within 24 hours of recognition of initial organ dysfunction followed by 50 units/kg 8, 16, 48, and 72 hours later, or albumin placebo. The group randomized to ATIII had a lower severity-of-illness score (15.7 +/- 19.2 vs. 28.6 +/- 25.2, p = 0.03), shorter duration of hospitalization (14.9 +/- 16.7 vs. 25.7 /- 17.9 days, p = 0.03), and lower hospital charges ($138,700 +/- $23,500 vs. $206,400 +/- $34,000). ATIII concentrate was associated with improved morbidity of MODS in patients undergoing HSCT when given early in the evolution of the syndrome.

Adult↗
PubMed1998

Hormone-induced refractoriness to mammary carcinogenesis in Wistar-Furth rats.

One of the most consistent results in the epidemiology of human breast cancer is the inverse relationship of risk and early full-term parity. The goal of this study was to investigate the molecular mechanisms through which early full-term pregnancy protects the breast from cancer development. We used Wistar-Furth (WF) rats as our experimental system and mimicked pregnancy using estrogen and progesterone (E/P). Sexually mature female rats were treated with steroid hormones for 21 days and after 28 days of gland involution, the rats were administered MNU. Rats that received a high dose of 20 microg E and 20 mg P exhibited an 82% reduction in the incidence of mammary adenocarcinomas as compared to the rats receiving only blank pellets. Decreasing doses of E/P were partially protective suggesting that complete differentiation of the gland was not required for refractoriness. We measured the RNA expression levels of several target genes involved in the regulation of mammary cell proliferation and/or differentiation including estrogen receptor (ER) and progesterone receptor (PR), cyclins D1 and D2, the cell cycle inhibitors p16, p21 and p27, and the tumor suppressor p53. At the time of MNU treatment we found no significant differences in the expression of these genes, with the possible exception of p21, indicating that hormone treatment did not result in constitutive changes in expression levels. The numbers of apoptotic cells were low and comparable in the hormone exposed and age-matched virgin gland (AMV) at the time of carcinogen challenge and remained low for 8 days after MNU treatment. The number of BrdU-labeled cells at the time of carcinogen challenge were also low in both the AMV (1.8%) and hormone exposed (0.8%) animals. In contrast, cell proliferation in the AMV (5.7%) was significantly different from both the parous involuted (1.2%) and the E/P-treated involuted (1.5%) animals 8 days after MNU treatment. We interpret these data to indicate that hormone treatment results in mammary epithelial cells that have persistent alterations in intracellular pathways governing proliferation responses to carcinogens.

Animals↗
PubMed1998

Loss of p21WAF1/Cip1 protein expression accompanies progression of sporadic colorectal neoplasms but not hereditary nonpolyposis colorectal cancers.

p21 (p21WAF1/Cip1), a cyclin-dependent kinase inhibitor, induces G1 arrest and can inhibit the activity of the proliferating cell nuclear antigen (PCNA). We analyzed p21 expression during colorectal tumorigenesis, its association with its transcriptional regulator p53, and its relationship to rates of cell proliferation and apoptosis. p21 and p53 protein expression were examined in sporadic tumors and hereditary nonpolyposis colorectal cancers (HNPCCs) by immunohistochemistry (IHC) and immunoblotting. Apoptosis was examined using a DNA nick end-labeling assay, and cell proliferation was examined by PCNA staining. In normal colorectal epithelia, nuclear p21 staining was uniformly detected in crypt cells of the superficial compartment (upper one-third) that stained negatively for PCNA. p21 and PCNA expression were, therefore, mutually exclusive. In sporadic cases, a decrease in the frequency of p21 expression accompanied adenoma development and progression to carcinoma. Specifically, p21 was detected in 12 of 16 (75%) adenomas and 10 of 32 (31%) carcinomas. In contrast to sporadic cases, HNPCCs with known mutations in DNA mismatch repair genes expressed p21 in 12 of 15 (80%) carcinomas. An inverse relationship between p21 and p53 was observed wherein mutant p53 proteins were detected in 4 of 15 (27%) HNPCCs versus 22 of 32 (69%) sporadic carcinomas. Although p21+ carcinoma cells were generally negative for p53, IHC revealed that some carcinoma cells expressed both p21 and p53 proteins. Furthermore, p53-mutated SW480 colon carcinoma cells were found to coexpress p21 and p53, suggesting that p21 can also be activated by a p53-independent mechanism. No association was found between p21 or PCNA and apoptotic labeling indices in adenomas or carcinomas. In conclusion, a decrease in p21 expression accompanies neoplastic progression in sporadic cases but not in HNPCCs. This finding appears related to p53 status in that the frequency of p53 expression was significantly reduced in HNPCCs compared to sporadic cases, suggesting a difference in their molecular pathways of tumorigenesis.

Colorectal Neoplasms↗
PubMed1997

Preclinical analysis of radiolabeled anti-GD2 immunoglobulin G.

BACKGROUND: Unlabeled murine monoclonal anti-GD2 immunoglobulin (Ig)G (14G2a) reactive with nervous system diganglioside and neuroblastoma, melanoma, and small cell lung carcinoma produces tumor regression. However, serious acute abdominal pain, paresthesia, hypotension and hypertension, syndrome of inappropriate secretion of antidiuretic hormone (SIADH), and occasional motor weakness occur. Studies in preclinical animal models can elucidate the mechanism of the observed neurotoxicity and lead to anti-GD2 antibody treatment with a higher therapeutic ratio. METHODS: One mg of 14G2a or control IgG was labeled with 1-2 mCi of indium-111 and administered intravenously to beagles (n = 8). In 2 dogs, additional high dose (200 mg) unlabeled 14G2a was given over 5 days. Whole body gamma camera images and SPECT scans were obtained repeatedly over 7 days. On Day 7, sciatic nerve conduction studies were performed, and after euthanasia radioactivity was determined in major organs. RESULTS: Unlabeled high dose 14G2a administered to mice, rats, or rabbits did not cause neurotoxicity within 3 weeks. GD2 antigens were shown by immunochemistry to be present in brain and peripheral nerve tissues of rodents and beagles. After in vivo administration of radiolabeled 14G2a, canine lymph nodes showed specific uptake, but only minimal radioactivity was found in the nervous system. Dogs that received additional high dose unlabeled 14G2a showed much higher lymph node uptake and follicular lymph node hyperplasia. Low motor response amplitudes on nerve conduction studies were noted. CONCLUSIONS: A radioisotope label on IgG and its visualization in a large series of animal models indicate that a low protein dose of anti-GD2 IgG will not cause neurologic side effects in patients. High protein dose anti-GD2 IgG may enhance antineoplastic effects and contribute to neurotoxicity through stimulation of normal lymphocytes with subsequent release of cytokines.

Animals↗
PubMed1997

Identification of quantitative trait loci controlling levels of radiation-induced thymocyte apoptosis in mice.

Thymocyte apoptosis levels are higher in C57BL/6J mice than in C3Hf/Kam mice. Low-dose irradiation increases the numbers of thymocytes undergoing apoptosis, but the strain difference persists. We mapped three loci controlling radiation-induced thymocyte apoptosis levels in F2 intercross progeny of these strains. The strongest association of a genomic region with an apoptosis level occurred in a region of chromosome 11 known to harbor a locus (or loci) important in the pathogenesis of several rodent models of autoimmune disease. Additional loci influencing radiation-induced thymocyte apoptosis were identified on chromosomes 9 and 16. The genetic polymorphisms underlying these loci may have an evolutionary role in fine-tuning the apoptotic response in T cells and may be important in the etiology of lymphoproliferative disorders and autoimmunity.

Animals↗
PubMed1997

Laparoscopically guided bipolar radiofrequency ablation of areas of porcine liver.

BACKGROUND: Bipolar radiofrequency ablation (BRFA) is a promising technique with which to treat unresectable primary and metastatic liver tumors. Its effects on normal liver tissue and postoperative liver function, however, are unknown. We performed this study to determine (1) the feasibility of using laparoscopic ultrasound to guide placement of BRFA needle electrodes in the liver and (2) the histopathologic, hepatic biochemical, and systemic hemodynamic responses to BRFA. METHODS: Two BRFA lesions were created in the liver of adult domestic pigs to ablate 8-10% of the normal liver volume. Laparoscopic ultrasound was used to guide creation of one peripheral liver lesion and one central liver lesion (with a major hepatic or portal venous vein branch in the center of the BRFA lesions) in each animal. BRFA of liver tissue was performed by passing 12 W of RF power for 16 min across two 16-gauge active-needle electrodes placed 3 cm apart. RESULTS: All animals survived the procedure without significant hemodynamic alterations during or after BRFA. All animals had a transient elevation in serum transaminase levels that returned to normal within 1 week of the BRFA of liver tissue. Gross and microscopic histopathology of the BRFA lesions revealed 2.0-2.5-cm zones of complete coagulative necrosis around and between the BRFA needle tracks without destruction of major blood vessel walls. CONCLUSIONS: This study demonstrates (1) that laparoscopic ultrasound can be used to guide placement of BRFA needles in the liver and (2) that BRFA produces focal destruction of liver without significant systemic hemodynamic responses or alterations in liver function. Further studies of this technique to ablate malignant liver tumors are ongoing.

Animals↗
PubMed1997

Normal saline versus heparin flush for maintaining central venous catheter patency during apheresis collection of peripheral blood stem cells (PBSC).

Thrombotic occlusion is frequently a complication of central venous catheters (CVCs). The original designers and producers of CVCs recommended heparin flush regimens to prevent thrombosis and maintain patency. This has become standard practice although no studies have demonstrated a relationship between heparin flushing and reduction of catheter thrombosis. Many consider the routine use of heparin flushing innocuous. However, serious complications including drug interactions and heparin induced thrombocytopenia and thrombosis syndrome (HITS) have been reported in association with heparin flushing. Numerous studies comparing heparin to saline flushing in peripheral devices suggest equal rates of thrombotic occlusions. The purpose of this study was to examine the incidence of thrombotic occlusions in CVCs using heparin compared to saline flushing. The study involved 78 cancer patients undergoing apheresis collection for peripheral blood stem cells; 29 received saline flushes and 49 received heparin (100 U/ml of saline) flushes. Study endpoints included slow apheresis flow rate (< 50 ml/min), urokinase use for thrombolysis, and radiographic evidence of catheter thrombosis. No significant differences were found for any endpoint between the two groups. These findings suggest saline may be as effective as heparin for maintaining patency of CVCs.

Adult↗
PubMed1997

Safety studies of the intraperitoneal injection of E1A--liposome complex in mice.

The HER-2/neu (also called c-erbB-2) proto-oncogene is overexpressed in many human cancer cells, including those of breast cancer and ovarian cancer. We have previously shown that adenovirus 5 E1A inhibits HER-2/neu transcription and functions as a tumor suppressor gene in HER-2/neu-overexpressing cancer cells. Liposome-mediated E1A gene transfer suppresses tumor development and prolongs survival of tumor-bearing mice. In support of a phase I clinical trial of an E1A-liposome complex administered to patients with HER-2/neu-overexpressing breast of ovarian cancer, we conducted a series of studies to evaluate the safety of intraperitoneal injection of E1A in normal mice. The cumulative doses used were from five to 40 times the DNA-lipid starting dose proposed for the phase I clinical trial. In this dosing range, the administration of the E1A-liposome complex had no adverse effects on renal, hepatic and hematological parameters studied. No major organ pathologic changes were observed. We concluded that intraperitoneal administration of E1A-liposome complex at the proposed dose would not be expected to produce significant toxicity. The E1A-liposome clinical trial was recently approved by the Recombinant DNA Advisory Committee and Food and Drug Administration for a phase I trial in patients with HER-2/neu-overexpressing breast and ovarian cancer.

Adenoviridae↗
PubMed1997

Non-neoplastic and neoplastic thyroid disease in beagles irradiated during prenatal and postnatal development.

To evaluate the lifetime hazards of exposure to ionizing radiation, 1,680 beagles received whole-body exposures to 60Co gamma rays or sham exposures during development. Eight groups of 120 dogs each received mean doses of 16-18 or 81-88 cGy at 8, 28 or 55 days of gestation, or at 2 days after birth. One group of 120 dogs received a mean of 83 cGy at 70 days of age and one group of 240 dogs received a mean of 81 cGy at 365 days of age. Sham irradiations were given to 360 controls. Sexes were equally represented. In 1,343 dogs allowed to live out their life span, heritable lymphocytic thyroiditis with hypothyroidism was a major contributor to mortality. Irradiated dogs had a decreased risk for hypothyroidism, a finding that was surprising and not easily explained. Of the 1,343 life-span dogs, those exposed as neonates at 2 days of age or as juveniles at 70 days of age had evidence for an increased risk for thyroid follicular cell neoplasia. Hypothyroid dogs had a significantly increased risk for thyroid neoplasia, including greater risk for carcinomas, but no evidence of a greater sensitivity to radiation-induced tumors. In dogs with normal thyroid function irradiated at 2 or 70 days of age there was increased risk for benign and malignant follicular cell neoplasms, including multiple neoplasms. No difference between sexes was noted. These findings related to age sensitivity in the dog were consistent with the high risk for radiogenic thyroid neoplasia in humans after exposure during early childhood.

Aging↗
PubMed1997

Magnetic resonance imaging of the central nervous system of the rhesus monkey.

The purpose of the study reported here was to document the ability of magnetic resonance imaging to depict the imaging characteristics of normal structures within the central nervous system of adult rhesus monkeys. The head and the cervical and thoracic parts of the spinal cord of two rhesus monkeys were imaged in a clinical 1.5-T whole-body imager. Specific images were selected, and some notable structures were identified. Results of this study document the usefulness of MRI as an expeditious, noninvasive research and diagnostic imaging technique and illustrates the normal magnetic resonance signal patterns of the brain and spinal cord in rhesus monkeys.

Animals↗