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G R Rutteman

Publications and source records attributed to G R Rutteman.

At least 37 records · Page 2Linked to original sources
PubMed1997

P53 gene mutations in osteosarcomas in the dog.

Osteosarcomas in 18 dogs were examined for the presence of p53 mutations in exons 4-8 by single strand conformation polymorphism (SSCP) analysis, followed by sequence analysis in tumors demonstrating abnormal bands in the SSCP analysis. P53 mutations were found in four of the primary tumors in 17 dogs. Metastases studied in two of these dogs in which the primary tumor contained only wild type p53 did not contain mutations, nor those of one dog in which the primary tumor was not studied. The alterations that were found included three missense mutations and one 3 bp insertion.

Animals↗
PubMed1997

Expression of growth hormone in canine mammary tissue and mammary tumors. Evidence for a potential autocrine/paracrine stimulatory loop.

The role of progestins in the pathogenesis of breast cancer in women remains controversial. To advance this discussion, we report the demonstration and localization of progestin-induced biosynthesis of growth hormone (GH) in canine mammary gland tissue. Nontumorous mammary tissues and tumors, both benign and malignant, were obtained from private household dogs. Immunoreactive GH was localized in mammary epithelial cells and correlated with the presence of GH mRNA. Local synthesis of GH was also proven immunoelectron microscopically by demonstrating GH-containing secretory granules. Cellular GH production in nontumorous tissues was more extensive during the progesterone-dominated luteal phase of the ovarian cycle or during exposure to synthetic progestins than during anestrus. GH was also associated with areas of hyperplastic mammary epithelium, which may indicate that locally produced GH enhances proliferation, acting in an autocrine and/or paracrine manner. In 41 of 44 tumors, GH was present. Of 3 GH-negative tumor samples, 2 were from progestin-depleted, castrated bitches. In nonmalignant mammary tissues, GH production is stimulated by progesterone and synthetic progestins interacting with progesterone receptors. In some progesterone-receptor-negative malignant tumors, GH expression was found, indicating loss of this control. Progestin-induced GH probably participates in the cyclic development of the mammary gland but may promote mammary tumorigenesis by stimulating proliferation of susceptible, and sometimes transformed, mammary epithelial cells.

Animals↗
PubMed1997

In vitro and in vivo detection of functional somatostatin receptors in canine insulinomas.

UNLABELLED: Ten dogs with hypoglycemia due to insulinomas were studied to assess the expression of somatostatin receptors (SSTRs) in canine insulinomas and its potential diagnostic value. METHODS: The response of circulating glucose and insulin concentrations to the subcutaneous administration of a somatostatin analog, octreotide, was measured. SSTRs were visualized in vitro by autoradiography. [Iodine-125-Tyr3]-octreotide and [125I-Tyr11]-somatostatin-14 (SRIF-14) were used as radioligands. SPECT was performed 6 hr after the injection of [111In-DTPA-D-Phe1]-octreotide. RESULTS: After subcutaneous injection of 50 micrograms octreotide, plasma glucose concentration rose from 2.3 +/- 0.2 mmol/liter to 3.2 +/- 0.3 mmol/liter at 3.5 hr (p < 0.05) and plasma insulin concentration decreased from 451 +/- 135 pmol/liter to a nadir of 249 +/- 115 pmol/liter at 30 min (p < 0.05). In vitro autoradiography revealed that all primary insulinomas and their metastases had specific SSTRs for both [125I-Tyr3]-octreotide and [126I-Tyr11]-SRIF-14. Scatchard analysis of SSTR binding in the tumor tissue of one dog revealed high-affinity binding sites for [125I-Tyr3]-octreotide (dissociation constant (Kd) 1.7 nM, maximum binding capacity (Bmax) 499 fmol/mg membrane protein). The primary tumor and/or metastases in five of six dogs could be visualized and localized by SPECT with [111In-DTPA-D-Phe1]-octreotide. In the remaining dog, multiple metastases (< 3 mm) were found in the liver at necropsy, apparently too small to be visualized by SPECT. CONCLUSION: The in vitro autoradiography and ligand binding studies indicate that canine insulinomas express one type of SSTR. This is in contrast with findings in humans where, on the basis of ligand binding studies, different subtypes of SSTRs have been identified. The uniformity of SSTRs, their high frequency of expression and the high incidence of metastatic disease make canine insulinomas very suitable for investigation of the value of SRIF analogs in the diagnosis and treatment of metastasized endocrine pancreatic tumors.

Animals↗
PubMed1997

Effects of progestin administration on the hypothalamic-pituitary-adrenal axis and glucose homeostasis in dogs.

The effects of medroxyprogesterone acetate (MPA) and proligestone (PROL) on the hypothalamic-pituitary-adrenocortical axis and glucose homeostasis were studied in two groups of eight ovariohysterectomized beagle bitches. In addition, the binding characteristics of MPA and PROL for the progesterone and glucocorticoid receptor were investigated. The administration of both progestins resulted in suppression of the hypothalamic-pituitary-adrenal axis. Whereas basal plasma concentrations of adrenocorticotrophic hormone (ACTH) were only moderately affected, the basal plasma concentrations of cortisol and the cortisol:creatinine ratio in urine were significantly decreased after the first administration of both progestins. In the group given MPA the increase of ACTH after stimulation with corticotrophin-releasing hormone (CRH) remained normal but it was suppressed in the group treated with PROL. In both treatment groups the increase of cortisol after stimulation with CRH was lower. After cessation of progestin administration both basal and stimulated plasma ACTH concentrations returned to pretreatment concentrations within a few weeks. In contrast, it took 6 month to restore the basal plasma cortisol concentrations and cortisol:creatinine ratios in urine. Paradoxically, the stimulated cortisol concentrations returned to normal shortly after the cessation. Histological examinations revealed a severe atrophy of the zona fasciculata and reticularis of the adrenal gland in all treated dogs and a steroid-induced hepatopathy in 50% of them. During the first half of the progestin treatment, glucose homeostasis was maintained by increased plasma concentrations of insulin in both groups. After prolonged treatment the response to a glucose load became impaired. None of these parameters improved during the 6 month recovery period. Histological changes in the pancreas, characteristics of diabetes mellitus, were found in two dogs of each group. Most probably, the glucocorticoid action of the progestins is not the sole explanation for the insulin resistance since progestin treatment resulted in a concomitant increase in plasma concentrations of growth hormone which has diabetogenic properties. Experiments in vitro confirmed the strong glucocorticoid component of MPA and PROL. The inhibition constants (Ki) of PROL for both the progesterone receptor (PR) and the glucocorticoid receptor (GR) were approximately then times higher than those of MPA. Nonetheless, the ratios of the Ki for the GR and PR indicated that the specificity of MPA and PROL was only slightly different but considerably smaller than that of progesterone. It is long-term treatment with high doses of these progestins may result in a iatrogenic Cushing's syndrome and diabetes mellitus.

Adrenocorticotropic Hormone↗
PubMed1996

New insights in the molecular mechanism of progestin-induced proliferation of mammary epithelium: induction of the local biosynthesis of growth hormone (GH) in the mammary glands of dogs, cats and humans.

In contrast to the protective, anti-proliferative, action of progestins on the development of endometrium cancer, progestins may have local stimulatory and inhibitory effects on the proliferation of mammary epithelium. Until now there was no final molecular explanation of this discrepancy. Prolonged treatment of dogs with depot medroxyprogesterone acetate (DPMA) or with proligestone (PROL) results in enhanced plasma concentrations of growth hormone (GH), insulin-like growth factor (IGF)-I, IGF-II and IGF-binding proteins, together with the development of benign mammary tumours. The stimulated plasma GH levels do not have the typical pulsatile secretion pattern, and are not sensitive to stimulation with GHRH or to inhibition with somatostatin. The autonomous secretion can be inhibited by the anti-progestin RUU-486. The source of progestin-induced plasma GH levels has been demonstrated to be the canine mammary gland where progestins induce the expression of the gene encoding GH. The expression of the GH gene is restricted to focal areas of hyperplastic epithelium as shown by immunohistochemistry, and is predominantly located in single positive epithelial cells with an intermediate position between luminal- and myo-epithelium. Progestin-induced fibroadenomatous changes in the mammary gland of cats are also associated with locally enhanced GH expression. In both normal, benign and malignant mammary tumours of humans GH mRNA expression has been demonstrated by RT-PCR. The presence of GH mRNA is associated with the presence of immunoreactive GH as shown by immunohistochemistry. Sequence analysis revealed 100% homology to the pituitary expressed GH gene. In malignant mammary tumours of humans and dogs GH expression is also found in specimens negative for progesterone receptors as measured by ligand binding. It is concluded that the gene encoding GH is expressed in the mammary gland of a variety of species, including man. This appears to represent a contribution to the molecular explanation of the action of progestins on proliferation of mammary epithelium. It needs, however, to be proven whether this local biosynthesis of GH in the mammary gland is the cause of the local stimulatory effect of progestins on the proliferation of mammary epithelium.

Animals↗
PubMed1995

DNA flow cytometry of canine mammary tumours: the relationship of DNA ploidy and S-phase fraction to clinical and histological features.

The DNA ploidy status and S-phase fraction (SPF) of benign proliferative lesions (BPL) and malignant tumours (MT) in the mammary glands of dogs were determined by flow cytometric analysis and the results were related to their clinical and histological features. Seven (14.3 per cent) of 49 BPL and 16 (48.5 per cent) of 33 primary MT had aneuploid G0,1 peaks (P < 0.001). Hypodiploid G0,1 peaks were found in one BPL and in five primary MT. The DNA ploidy status of primary MT was not found to be associated with their size, nodal status, grade of histological malignancy or nuclear grade. In several cases there was intra-tumour heterogeneity in ploidy status independent of histological heterogeneity. The SPF was significantly higher in 27 primary MT than in 45 BPL when diploid and aneploid cases were combined for comparison (P < 0.05), but not when only diploid cases were compared. Among the primary MT the SPF was higher in aneuploid than in diploid tumours (P < 0.05) and it was higher in five MT from five dogs with regional disease than in 22 MT from 19 dogs with local disease (P < 0.05). The SPF was positively correlated with the grade of histological malignancy (P < 0.05) but not with nuclear grade.

Animals↗
PubMed1995

Growth hormone mRNA in mammary gland tumors of dogs and cats.

We have shown recently that in the dog progestin administration results in mammary production of immunoreactive growth hormone (GH). At present we demonstrate the expression of the gene encoding GH in the mammary gland of dogs and cats using reverse-transcriptase PCR. GH mRNA was found in the great majority of normal mammary tissues as well as benign and malignant mammary tumors of the dog and was associated with the presence of immunoreactive GH in cryostat sections. The mammary PCR product proved to be identical to that of the pituitary. The highest expression levels were found after prolonged treatment with progestins. In carcinomas GH mRNA was also found in progesterone receptor-negative tissue samples, indicating that after malignant transformation GH gene expression may become progestin independent. GH mRNA was also present in mammary tissues of cats with progestin-induced fibroadenomatous changes. It is concluded that GH gene expression occurs in normal, hyperplastic, and neoplastic mammary tissue of the dog. The expression in normal tissue is stimulated by progestins and might mediate the progestin-stimulated development of canine mammary tumors. The demonstration of progestin-stimulated GH expression in mammary tissue of cats indicates that the phenomenon is more generalized among mammals.

Amino Acid Sequence↗
PubMed1994

Prognostic factors for treatment of malignant lymphoma in dogs.

Pretreatment characteristics of 138 dogs with malignant lymphoma were analyzed to determine prognostic factors associated with outcome (ie, complete response rate, time to relapse after complete response, survival time). Dogs were all treated for 10 weeks, using a standard induction chemotherapy protocol, and were then given asparaginase weekly. Once the disease became progressive, second-line chemotherapy was instituted. Age, sex, weight, clinical stage, performance grade, immunophenotype, and malignancy grade assigned according to the National Cancer Institute's Working Formulation were not associated with complete response rate. However, malignancy grade assigned according to the Kiel classification was found to be associated with complete response rate; dogs with high-grade malignancies had a significantly higher complete response rate than did dogs with low-grade malignancies. By means of multivariate analysis, clinical stage and immunophenotype were found to be prognostic factors for time to relapse (among dogs that had had a complete response) and survival time. In addition, malignancy grade assigned according to the Kiel classification was found to be a prognostic factor for time to relapse; whereas, malignancy grade assigned according to the Working Formulation was determined to be a prognostic factor for survival time.

Animals↗
PubMed1994

[A female dog who grew progressively more lethargic and hoarse].

A female dog (Collie dog, eight years of age, non-spayed) was referred to the University Clinic for Companion Animals with signs and symptoms suggesting endogenous progesterone-induced acromegaly and cystic endometrial hyperplasia. The dog had glucose intolerance, but the growth hormone concentration in plasma was within the reference range. The latter was probably due to the decline of progesterone at the end of the luteal phase, resulting in an abrogation of the process of progesterone-induced growth hormone hypersecretion. After ovariohysterectomy the glucose-tolerance normalized.

Acromegaly↗
PubMed1994

Expression of epidermal growth factor receptor (EGFR) in non-affected and tumorous mammary tissue of female dogs.

Epidermal growth factor (EGFR), oestrogen (ER), and progestin (PR) receptor concentrations were determined by radioligand binding assay in non-affected mammary tissues (n = 13) and benign (n = 11) and primary/locally recurrent malignant proliferative mammary lesions (n = 45) and metastases (n = 19) in 65 female dogs. The number of specimens expressing EGFR was not significantly different among these tissues, but EGFR concentration was lower in metastases (P = 0.02) than in benign or primary/locally recurrent malignant lesions not mixed with non-affected mammary tissue. The presence of non-affected mammary tissue in primary cancer specimens was noticed as a factor that may influence results of receptor measurements. No relation was found between the expression of EGFR and that of ER or PR in non-affected or in tumorous mammary tissues. It was concluded that in the dog mammary gland EGFR expression is not associated with conditions of steroid receptor absence of biological agressiveness of neoplastic growth.

Animals↗
PubMed1994

Progestin-induced growth hormone excess in the dog originates in the mammary gland.

In the dog endogenous progesterone and synthetic progestins may incite overproduction of GH, resulting in acromegaly and insulin resistance. This progrestin-induced excessive GH secretion is characterized by disappearance of the pulsatile secretion pattern and insensitivity to both stimulation with GHRH and inhibition with a somatostatin analog. This progestin-induced GH hypersecretion is not associated with neoplastic transformation at the pituitary level. These observations were the impetus for a search of a possible extrapituitary site of GH production. In four ovariohysterectomized dogs elevated plasma GH levels (46.5 +/- 7.7 micrograms/liter; mean +/- SEM) were induced by administration of synthetic progestins. In these dogs hypophysectomy did not led to a significant decrease in plasma GH levels. Analysis of the GH content of various tissue homogenates revealed that the highest GH immunoreactivity was found in extracts of the mammary gland. Ectopic production of GH in the mammary gland was confirmed by lowering of plasma GH concentration to values within the reference range within 2 h after complete mammectomy in two dogs with progestin-induced elevations of plasma GH levels. In one of these dogs the arterial and elevations of plasma GH levels. In one of these dogs the arterial and venous GH concentrations across the mammary gland were measured and an arterio-venous GH gradient was demonstrated. Displacement studies in the RIA and analysis by reversed-phase HPLC revealed that mammary-derived GH is highly similar to pituitary-derived GH. Immuno-histochemical staining revealed that GH immunoreactivity was localized in focal areas of hyperplastic ductular epithelium. In mammary tissue of healthy untreated female dogs no GH immunoreactivity was found. It is concluded that treatment of dogs with synthetic progestins can induce the overproduction of GH in the mammary gland. This GH is biologically active, highly similar to pituitary derived GH, and originates from foci of hyperplastic ductular epithelium of the mammary gland.

Animals↗
PubMed1994

Progestin treatment in the dog. I. Effects on growth hormone, insulin-like growth factor I and glucose homeostasis.

The effects of two synthetic progestins, medroxyprogesterone acetate (MPA) and proligestone (PROL), on the release of growth hormone (GH) and glucose metabolism were studied in two groups of eight ovariohysterectomized dogs. Eight injections of long-acting progestins were administered at 3-week intervals. Recovery was studied in four dogs of each treatment group in the 6 months following cessation of progestin administration. Treatment with both MPA and PROL resulted in similar increases in plasma levels of GH and insulin-like growth factor I (IGF-I). The GH responses to both clonidine and growth hormone-releasing hormone became impaired. In neither treatment group did the elevated plasma GH levels decrease after administration of the synthetic somatostatin analogue SMS 201-995. The size and shape of the pituitary gland were not changed by progestin treatment. After cessation of progestin administration, basal plasma levels of GH and IGF-I did not return to pretreatment values. The GH response to growth hormone-releasing hormone remained impaired for at least 6 months after the last progestin administration. In both treatment groups, glucose homeostasis was sustained initially by increased insulin production. Prolonged treatment with MPA and PROL resulted in glucose intolerance. No amelioration was observed during the recovery period in either group. A small number of dogs developed diabetes mellitus. In more than 50% of the dogs in both treatment groups small mammary tumours developed. The recently discovered local production of GH probably played a role in mammary tumorigenesis.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Cortex↗
PubMed1994

Progestin treatment in the dog. II. Effects on the hypothalamic-pituitary-adrenocortical axis.

The effects of two synthetic progestins, medroxyprogesterone acetate (MPA) and proligestone (PROL), on the hypothalamic-pituitary-adrenocortical (HPA) axis were studied in two groups of eight ovariohysterectomized dogs each. Eight injections of long-acting progestins were administered at 3-week intervals. Recovery of the HPA axis was studied in four dogs of each group in the following 6 months. Basal levels of adrenocorticotrophin (ACTH) and cortisol in plasma and the urinary corticoid/creatinine ratio were measured. The responsiveness of the HPA axis was investigated by stimulation with ovine corticotrophin-releasing hormone. Both MPA and PROL caused sawtooth patterns of suppression of basal ACTH and cortisol levels in plasma, synchronous with the time of administration. The suppression of the adrenocortical component of the HPA axis was most pronounced. Adrenocorticotrophin production also was affected but to a lesser extent and occurred especially in PROL-treated dogs. Soon after the cessation of progestin administration ACTH levels increased, sometimes with a rebound. In both groups basal cortisol levels and urinary corticoid/creatinine ratios did not return to pretreatment levels until 6 months after the last progestin injection. It is concluded that MPA and PROL act as glucocorticoid agonists and suppress the HPA axis. The suppression at the adrenocortical level may last for 6 months.

Adrenal Cortex Hormones↗
PubMed1993

Disturbed release of growth hormone in mature dogs: a comparison with congenital growth hormone deficiency.

An acquired defect in growth hormone secretion in mature dogs has been associated with some forms of generalised alopecia. In an attempt to elucidate the pathogenesis of the disturbance in growth hormone release, the plasma concentrations of growth hormone and insulin-like growth factor I (IGF-I) were measured in two seven-year-old poodles with alopecia and, for comparison, in two young German sheperd dogs with congenital hyposomatotropism (pituitary dwarfism). In the poodles the basal concentrations of growth hormone were low, although often above the detection limit of the assay. The concentrations of IGF-I were in the reference range for healthy poodles. No growth hormone could be detected in the plasma of the German sheperd dogs and the concentrations of IGF-I were very low. Stimulation with clonidine and growth hormone releasing hormone (GHRH) before and after repeated injections of GHRH did not result in significant increases in growth hormone concentrations in plasma. The concentrations of growth hormone in the poodles fluctuated at low levels during the test period. In the German sheperd dogs the levels of growth hormone remained unmeasurable during the stimulation tests. It was concluded that in the two poodles the basal concentrations of growth hormone were sufficient to maintain normal IGF-I concentrations, and thus the release of growth hormone was considered appropriate. Based upon measurements of urinary corticoids and a review of the literature it is suggested that the lack of a growth hormone response to stimulation was due to the enhanced release of somatostatin as a result of mild and fluctuating hyperadrenocorticism.(ABSTRACT TRUNCATED AT 250 WORDS)

Adrenal Cortex Hormones↗
PubMed1993

Immunohistochemistry with keratin, vimentin, desmin, and alpha-smooth muscle actin monoclonal antibodies in canine mammary gland: benign mammary tumours and duct ectasias.

Duct ectasias (n = 2) and different types of benign canine mammary tumours (n = 19) were studied immunohistochemically with monoclonal antibodies (MoAbs) directed against various human keratin types (K), alpha-smooth muscle actin, vimentin, and desmin. In the duct ectasias and in most tumours the epithelial structures revealed an inner and outer cell layer. The inner cell layer was characterized by labelling with K 7, 8, 18, 19 and mostly also with K 4 and/or K 10 MoAbs. The outer cell layer was almost invariably labelled by K 14, K 14 and 17, and a-smooth muscle actin MoAbs. The labelling patterns of both duct ectasias and tumours corresponded largely to the patterns observed in normal mammary gland tissue, although a more distinct heterogeneity was seen. Tumours histomorphologically assumed to be of a myoepithelial origin did not show immunohistochemical features of myoepithelial cells. The myoepithelial nature of the vast majority of spindle-shaped cells present in the adenomas of the complex type and in the fibroadenomas of the benign mixed type could not be confirmed immunohistochemically. These cells, however, unequivocally expressed vimentin, suggesting proliferation of stromal cells in these tumours, which in the fibroadenomas of the benign mixed type may show metaplasia to bone or cartilage. In the duct ectasias and in some tumours, a fraction of elongated stromal cells, probably representing myofibroblasts, was labelled with the alpha-smooth muscle actin MoAb.

Actins↗
PubMed1993

Immunohistochemistry with keratin, vimentin, desmin, and alpha-smooth muscle actin monoclonal antibodies in canine mammary gland: malignant mammary tumours.

Ten malignant canine mammary gland tumours and five metastases from three of these tumours were studied immunohistochemically with monoclonal antibodies (MoAbs) directed against different human keratin types (K), alpha-smooth muscle actin, vimentin, and desmin. In all tumours the neoplastic epithelium was rather homogeneously labelled with the keratin MoAbs RCK 102 (K 5 and 8) and CAM 5.2 (K 8). The adenocarcinomas (n = 5), the solid carcinomas (n = 2), and the carcinosarcoma (n = 1) showed heterogeneous labelling with the MoAbs specific for luminal cell antigens in the normal canine mammary gland, i.e., K 18, K 7 and K 19 MoAbs. These cells were also immunoreactive with K 4 and K 10 MoAbs. The spindle cell carcinomas (n = 2), however, did not react with these MoAbs. All tumours except one adenocarcinoma were characterized by the absence of immunoreactive labelling with the alpha-smooth muscle actin MoAb. In the solid carcinomas this was associated with the absence of labelling with one or both basal cell specific keratin MoAbs, i.e., 8.7 (K 14 and 17) and RCK 107 (K 14), respectively. In contrast, the other malignant tumours showed marked labelling of neoplastic epithelium with these MoAbs. Another remarkable finding was the labelling of a limited to moderate number of neoplastic epithelial cells with the vimentin MoAb. The presence of such labelling patterns in canine mammary gland tumours may be indicative of malignancy. Metastatic tumour tissues had a labelling pattern largely similar to that of the primary tumour, although also loss of reactivity for some keratin MoAbs was seen.

Actins↗
PubMed1993

Immunohistochemistry with keratin, vimentin, desmin, and alpha-smooth muscle actin monoclonal antibodies in canine mammary gland: normal mammary tissue.

Normal canine mammary gland tissue was studied immunohistochemically with monoclonal antibodies (MoAbs) directed against various human keratin types, vimentin, desmin, and alpha-smooth muscle actin. Both ductal and alveolar luminal cells were immunoreactive with MoAbs recognizing respectively human keratins no. 7, 8, 18 and 19. In addition, some ductal luminal cells were labelled with a keratin 4 and a keratin 10 MoAb. Basal/myoepithelial cells were immunoreactive only with MoAbs directed against keratin 14, keratins 14 and 17, and alpha-smooth muscle actin. The vimentin MoAb merely labelled solitary loose intraluminal cells representing macro-phages or sloughed epithelial cells. These findings correspond largely to observations made in human breast tissue.

Actins↗