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Biomedical subjects

P J Bergman

Publications and source records attributed to P J Bergman.

At least 19 recordsLinked to original sources
PubMed2006

Prognostic significance of intratumoral microvessel density in canine soft-tissue sarcomas.

The prognosis of canine soft-tissue sarcomas (STS) has traditionally been based on histologic grading. We have recently demonstrated the prognostic value of cellular proliferation markers in canine STS. Another method of predicting the behavior of neoplasms is intratumoral microvessel density (IMD), which is a measure of tumor angiogenesis. The prognostic significance of IMD has been documented in many human neoplasms and in a limited number of canine and feline neoplasms. To evaluate the prognostic value of IMD in canine STS, we studied 57 STS and compared IMD with histologic features, histologic grade, cellular proliferation, metastatic propensity, and survival. Using immunohistochemistry, the STS were labeled with anti-factor VIII-related antigen (FVIII-RA) and anti-CD31 antibodies to determine 3 IMD parameters: mean microvessel density, high microvessel density, and microvessel area. Using FVIII-RA and CD31, increasing IMD was statistically associated with increasing histologic grade, necrosis scores, and mitotic scores. Higher FVIII-RA IMD values were significantly associated with higher median argyrophilic nucleolar organizing region (AgNOR) values (as previously investigated) and increased metastatic propensity. Fibrosarcomas appear to be the least vascularized of STS. There is no correlation between IMD and survival. Our results indicate that IMD is of prognostic value for histologic grade, histologic features, cellular proliferation (based on AgNOR), and metastatic propensity of canine STS, specifically when using FVIII-RA as the endothelial marker. Assessing histologic grading, cellular proliferation, and IMD of canine STS at the time of diagnosis could therefore provide better prognostic information for the veterinary clinician.

Animals↗
PubMed2005

P-glycoprotein expression in lamina propria lymphocytes of duodenal biopsy samples in dogs with chronic idiopathic enteropathies.

P-glycoprotein (p-gp) is a transmembrane protein functioning as a drug-efflux pump in the intestinal epithelium. Human patients with inflammatory bowel disease (IBD) who fail to respond to treatment with steroids express high levels of p-gp in lamina propria lymphocytes. The purpose of this study was to investigate p-gp expression in duodenal biopsy samples of dogs with chronic enteropathies and to evaluate the expression of p-gp after treatment with a known inducer of p-gp (prednisolone). Duodenal biopsy samples from 48 dogs were evaluated immunohistochemically with the mouse monoclonal antibody C219 for expression of p-gp in lamina propria lymphocytes. Biopsy samples were available from 15 dogs after treatment with prednisolone and 16 dogs after dietary therapy alone ("elimination diet"). Treatment with prednisolone resulted in an increase in p-gp expression (P=0.005). In contrast, dietary treatment alone produced no significant change in p-gp expression (P=0.59). A low p-gp score before initiation of steroid treatment was significantly associated with a positive response to treatment (P=0.01). These results indicate that lamina propria lymphocyte expression of p-gp is upregulated after prednisolone treatment in dogs with IBD, and that mucosal expression of p-gp may be of value in predicting the response to therapy.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed2005

Development of a xenogeneic DNA vaccine program for canine malignant melanoma at the Animal Medical Center.

INTRODUCTION: Canine malignant melanoma (CMM) is an aggressive neoplasm treated with surgery and/or fractionated RT; however, metastatic disease is common and chemoresistant. Preclinical and clinical studies by our laboratory and others have shown that xenogeneic DNA vaccination with tyrosinase family members can produce immune responses resulting in tumor rejection or protection and prolongation of survival. These studies provided the impetus for development of a xenogeneic DNA vaccine program in CMM. MATERIALS AND METHODS: Cohorts of three dogs each received increasing doses of xenogeneic plasmid DNA encoding either human tyrosinase (huTyr; 100/500/1500 mcg), murine GP75 (muGP75; 100/500/1500 mcg), murine tyrosinase (muTyr; 5 dogs each at 100/500 mcg), muTyr+/-HuGM-CSF (9 dogs at 50 mcg muTyr, 3 dogs each at 100/400/800 mcg HuGM-CSF, or 3 dogs each at 50 mcg muTyr with 100/400/800 mcg HuGM-CSF), or 50 mcg MuTyr intramuscularly biweekly for a total of four vaccinations. RESULTS: The Kaplan-Meier median survival time (KM MST) for all stage II-IV dogs treated with huTyr, muGP75 and muTyr are 389, 153 and 224 days, respectively. Preliminarily, the KM MST for stage II-IV dogs treated with 50 mcg MuTyr, 100/400/800 mcg HuGM-CSF or combination MuTyr/HuGM-CSF are 242, 148 and >402 (median not reached) days, respectively. Thirty-three stage II-III dogs with loco-regionally controlled CMM across the xenogeneic vaccine studies have a KM MST of 569 days. Minimal to mild pain was noted on vaccination and one dog experienced vitiligo. We have recently investigated antibody responses in dogs vaccinated with HuTyr and found 2- to 5-fold increases in circulating antibodies to human tyrosinase. CONCLUSIONS: The results of these trials demonstrate that xenogeneic DNA vaccination in CMM: (1) is safe, (2) leads to the development of anti-tyrosinase antibodies, (3) is potentially therapeutic, and (4) is an attractive candidate for further evaluation in an adjuvant, minimal residual disease Phase II setting for CMM.

Animals↗
PubMed2005

Canine hepatic neuroendocrine carcinoma: an immunohistochemical and electron microscopic study.

Ten dogs with neuroendocrine carcinoma of the liver were selected for inclusion in the study. Clinical signs were anorexia (7), vomiting (5), polydipsia/polyuria (3), icterus (2), lethargy (2), weight loss (2), paresis (1), ataxia (1), weakness (1), collapse (1), and urinary tract infection (1). Hematologic and biochemical abnormalities included anemia (2/8), leukocytosis (4/8), high liver enzyme activity (serum alkaline phosphatase, 7/9; alanine transaminase, 7/9; aspartate transaminase, 8/9), and high total bilirubin (6/9). Grossly, the tumors were diffuse, involving all liver lobes in six dogs, and two dogs had various-sized nodules in addition to diffuse involvement. Histologically, there were eight tumors with solid or trabecular pattern (group A), one tumor with cords or rows of neoplastic cells (group B), and one tumor with multiple rosette-like structures (group C). Immunohistochemical studies revealed that all 10 neoplasms were positive for at least one of the endocrine markers used: neuron-specific enolase (NSE; 8/10), synaptophysin (5/10), and chromogranin-A (3/10). A panel of NSE, chromagranin-A, and synaptophysin detected 100% of the tumors in our series. Electron microscopy confirmed the diagnosis by the presence of intracytoplasmic neurosecretory granules in the two examined cases. Our results show that neuroendocrine markers commonly used in humans can be used for the diagnosis of hepatic neuroendocrine carcinoma in dogs, preferably a panel of synaptophysin, chromagranin-A, and NSE because chromogranin-A alone is not as useful in dogs as in humans.

Animals↗
PubMed1997

An N-myristoylated protein kinase C-alpha pseudosubstrate peptide that functions as a multidrug resistance reversal agent in human breast cancer cells is not a P-glycoprotein substrate.

Protein kinase C-alpha (PKC-alpha) activation is an important contributing factor in human breast cancer MCF-7 MDR cell drug resistance. We recently reported the use of N-myristoylated PKC-alpha pseudosubstrate peptides with potent PKC-alpha inhibitory activity as reversal agents of drug resistance in MCF-7 MDR cells. The peptides potently inhibit phosphorylation of the PKC-alpha substrates P-glycoprotein (P-gp), raf kinase and PKC-alpha itself in MCF-7 MDR cells in association with a severalfold induction of intracellular uptake of P-gp substrate chemotherapeutics and a statistically significant twofold increase in cellular chemosensitivity. We now report that the N-myristoylated PKC-alpha pseudosubstrate peptide N-myristoyl-RFARKGALRQKNV (P3) is not a P-gp substrate in MCF-7 MDR cells based on a comparison of the cellular uptake of [125I]-radiolabeled P3 in MCF-7 MDR vs MCF-7 WT cells. The extent of cellular uptake of the radiolabeled peptide in the drug-resistant cell line MCF-7 MDR was either greater than or equivalent to the uptake in the parental drug-sensitive MCF-7 WT cell line over a time course of 30 min to 6 h, and across a peptide concentration range of 25-100 microM. Additionally, treatment of the MCF-7 MDR cells with verapamil (VPL), a known P-gp efflux inhibitor, had no effect on the cellular accumulation of radiolabeled P3. Our results provide direct evidence that the N-myristoylated pseudosubstrate peptide is taken up equivalently by drug-sensitive and MDR cancer cells and therefore has potential value as an MDR reversal agent that operates by a novel mechanism.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1997

Radiation therapy toxicities.

Since the infancy of radiology and radiation therapy, reactions to radiation have been noted and followed, and attempts have been made to minimize these reactions. We have turned to radiobiologists to explain these reactions and to radiation oncologists to prevent or decrease the normal tissue effects of radiation therapy. Radiation toxicities are divided into early (acute) and late (chronic) reactions; however, it is important to note that severe toxicities are rare and occur typically in less than 5% of veterinary radiation therapy patients.

Animals↗
PubMed1997

Radioresistance, chemoresistance, and apoptosis resistance. The past, present, and future.

A wide variety of cancer therapy resistance mechanisms are available, with perhaps surprising overlap between causes of chemotherapy and radiation resistance. As previously discussed, most of the widely used chemotherapeutic agents and gamma-radiation utilize apoptosis as the common death pathway, thereby making apoptosis and the ability to manipulate apoptosis of integral importance to the future of cancer therapy. This is evidenced by the information explosion on this topic in the last 5 years. Obviously much remains to be learned. However, with the aforementioned cooperation of the oncology team and a greater understanding of the molecular mechanisms behind cancer and cancer therapy resistance, response rates, survival times, the quality of life of patients enduring antineoplastic therapies, and the importance of comparative oncology can only increase. We look forward to the findings in the coming years on this incredibly clinically relevant topic with great fondness and uncertainty.

Animals↗
PubMed1997

Radiation oncology of head and neck tumors.

Malignant tumors of the head and neck region occur commonly in veterinary medicine. Unfortunately, tumors in the head and neck can cause treatment dilemmas because many neoplastic entities at this site are locally aggressive. Additional local therapies such as radiation therapy are becoming commonplace as standardized therapies for many head and neck tumors in veterinary medicine.

Animals↗
PubMed1997

Potent induction of human colon cancer cell uptake of chemotherapeutic drugs by N-myristoylated protein kinase C-alpha (PKC-alpha) pseudosubstrate peptides through a P-glycoprotein-independent mechanism.

Phorbol ester protein kinase C (PKC) activators and PKC isozyme over-expression have been shown to significantly reduce intracellular accumulation of chemotherapeutic drugs, in association with the induction of multidrug resistance (MDR) in drug-sensitive cancer cells and enhancement of drug resistance in MDR cancer cells. These observations constitute solid evidence that PKC plays a significant role in the MDR phenotype of cancer cells. PKC-catalyzed phosphorylation of the drug-efflux pump P-glycoprotein was recently ruled out as a contributing factor in MDR. At present, the sole drug transport-related event that has been identified as a component of the role of PKC in MDR is PKC-induced expression of the P-glycoprotein-encoding gene mdr1. The objective of this study was to test the hypothesis that PKC can modulate the uptake of chemotherapeutic drugs in cancer cells independently of P-glycoprotein. We analyzed the effects of selective PKC activators/inhibitors on the uptake of radiolabelled cytotoxic drugs by cultured human colon cancer cells that lacked P-glycoprotein activity and did not express the drug efflux pump at the level of message (mdr1) or protein. We found that the selective PKC activator 12-O-tetradecanoylphorbol-13-acetate (TPA) significantly reduced uptake of [14C] Adriamycin and [3H] vincristine in human colon cancer cells devoid of P-glycoprotein activity, and that PKC-inhibitory N-myristoylated PKC-alpha pseudosubstrate synthetic peptides potently and selectively induced uptake of the cytotoxic drugs in the phorbol ester-treated and non-treated colon cancer cells. TPA treatment of the cells did not induce expression of either P-glycoprotein or its message mdr1. In contrast with [14C]Adriamycin and [3H] vincristine uptake, [3H] 5-fluorouracil uptake by the cells was unaffected by TPA and reduced by the PKC-inhibitory peptides. These results indicate that PKC activation can significantly reduce the uptake of multiple cytotoxic drugs by cancer cells independently of P-glycoprotein, and that N-myristoylated PKC-alpha pseudosubstrate peptides potently and selectively induce uptake of multiple cytotoxic drugs in cultured human colon cancer cells by a novel mechanism that does not involve P-glycoprotein and may involve PKC isozyme inhibition. Thus, N-myristoylated PKC-alpha pseudosubstrate peptides may offer a basis for the development of agents that reverse intrinsic drug resistance in human colon cancer.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1996

Partial reversal of multidrug resistance in human breast cancer cells by an N-myristoylated protein kinase C-alpha pseudosubstrate peptide.

The predominant characteristics of multidrug resistant (MDR) cancer cells are broad spectrum resistance to chemotherapeutic agents and a pronounced defect in intracellular accumulation of the drugs, in association with overexpression of the drug efflux pump P-glycoprotein. Protein kinase C (PKC) phosphorylates the linker region of P-glycoprotein. Evidence has been presented that the isozyme PKC-alpha may contribute to the drug resistance phenotype of human breast cancer MCF7-MDR cells, PKC-alpha is markedly overexpressed in MCF7-MDR cells, and artificial overexpression of PKC-alpha in MCF7 constructs that overexpress P-glycoprotein significantly enhances the MDR phenotype of the cells in association with increased P-glycoprotein phosphorylation. Verapamil, cyclosporin A, and a number of other agents that compete with cytotoxic drugs for binding sites on P-glycoprotein can potently reverse MDR, but this is accompanied by severe toxicity in vivo. In this report, we demonstrate that an N-myristoylated peptide that contains a sequence corresponding to the pseudosubstrate region of PKC-alpha (P1) partially reverses multidrug resistance in MCF7-MDR cells by a novel mechanism that involves inhibition of PKC-alpha. P1 and two related PKC inhibitory N-myristoylated peptides restored intracellular accumulation of chemotherapeutic drugs in association with inhibition of the phosphorylation of three PKC-alpha substrates in MCF7-MDR cells: PKC-alpha, Raf-1 kinase, and P-glycoprotein. A fourth N-myristoylated peptide substrate analog of PKC, P7, did not affect drug accumulation in the MCF7-MDR cells and failed to inhibit the phosphorylation of the PKC-alpha substrates. The effects of P1 and verapamil on drug accumulation in MCF7-MDR cells were additive. P1 did not affect P-glycoprotein expression. MCF7-MDR cells were not cross-resistant to P1, which suggest that the peptide was not transported by P-glycoprotein. Furthermore, P1 was distinguished from MDR reversal agents such as verapamil and cyclosporin A by its inability to inhibit [3H]azidopine photoaffinity labeling of P-glycoprotein. P1 actually increased [3H] azidopine photoaffinity labeling of P-glycoprotein in MCF7-MDR cells, providing evidence that the effects of P1 on P-glycoprotein in MCF7-MDR cells are not restricted to inhibition of the phosphorylation of the pump. P1 may provide a basis for developing a new generation of MDR reversal agents that function by a novel mechanism that involves inhibition of PKC-alpha-catalyzed P-glycoprotein phosphorylation.

ATP Binding Cassette Transporter, Subfamily B, Mem↗
PubMed1994

Toxicoses associated with the administration of mitoxantrone to dogs with malignant tumors: a dose escalation study.

Forty-four dogs with histologically confirmed malignant tumors were used in a prospective study to determine the toxicity of the chemotherapeutic agent mitoxantrone, when administered at dosages higher than what has been previously reported for use in dogs. After each dose was administered, dogs were evaluated for signs of toxicosis for 3 weeks or until the dog developed progressive disease, died, or was euthanatized. Forty dogs had been refractory to 1 or more treatment modalities (surgery, n = 26; chemotherapy other than mitoxantrone, n = 17; radiation, n = 2) prior to entering this study. Ten dogs were given mitoxantrone at a dosage of 5.5 mg/m2 of body surface, IV, every 3 weeks (39 total doses); 11 were given mitoxantrone at a dosage of 6.0 mg/m2, IV, every 3 weeks (26 total doses); and 23 were given mitoxantrone at a dosage of 6.5 mg/m2, IV, every 3 weeks (70 total doses). The most common signs of toxicosis were vomiting, anorexia, diarrhea, lethargy, and sepsis secondary to myelosuppression. Two dogs, both of which received the highest dosage, died of complications attributable to mitoxantrone administration. The prevalence of toxicoses was not associated with age, breed, sex, tumor type, number of doses, or dosage. Dogs did develop myelosuppression 7 days after they were given mitoxantrone.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1994

Infiltrative lipoma in dogs: 16 cases (1981-1992).

Medical records of 15 dogs with infiltrative lipoma, 1 of which had 2 lesions, were reviewed. Median age of affected dogs was 6.0 years, and median weight was 30.5 kg. The ratio of females to males was 4:1. Eight of the dogs were Labrador Retrievers. In 8 dogs, the lesions had previously been excised. There was not any apparent site predilection. Excision was the only treatment in all 15 dogs, and follow-up information was available for all dogs. Two dogs, each of which had 1 tumor, were euthanatized immediately after surgery, because the tumor could not be completely excised. Of the remaining 14 tumors, 5 (36%) recurred. Median time to recurrence for these 5 tumors was 239 days (range, 96 to 487 days). By means of Kaplan-Meier analysis, the percentage of dogs disease free 1 year after surgery was calculated to be 67%.

Animals↗
PubMed1990

Glucocorticoid inhibition of growth in rats: partial reversal with somatostatin antibodies.

Clinically, glucocorticoids are important immunosuppressive hormones. Yet, these steroids are also potent inhibitors of growth. We hypothesized that glucocorticoids may partially inhibit growth by increased somatostatin (SRIF) secretion. We tested this hypothesis using passive immunization techniques. Male rats (approximately 50 g) were treated daily (ip) for 33 days with saline (SAL) or dexamethasone (DEX, 40 micrograms/kg) and every fourth day with normal sheep serum (NSS) or SRIF antiserum (SRIF-ab, 0.25 ml). Body wts were recorded daily. Groups (n = 6) were: 1) SAL + NSS, 2) SAL + SRIF-ab, 3) DEX + NSS, and 4) DEX + SRIF-ab. Regression analysis of the growth curves clearly demonstrated differences in body wt gain for the four treatment groups (P less than 0.01). Final body wt of SAL + NSS treated rats was 285 +/- 5 g and 285 +/- 12 g in SAL + SRIF-ab treated rats. DEX + NSS treated rats weighed significantly less (227 +/- 4 g, P less than 0.01) than SAL-treated rats. This glucocorticoid-induced decrease in body wt was partially reversed by the concomitant treatment of rats with SRIF-ab (241 +/- 6 g, P less than 0.05). This observation leads to the conclusion that the inhibitory effect of glucocorticoids on growth may be mediated, in part, by increased SRIF secretion.

Animals↗
PubMed1979

A survey of students' awareness of and attitudes toward drug abuse prevention programs in New York State, winter 1974/75.

The present paper reports some results from a winter 1974-1975, New York State survey of junior and senior public high school youths' awareness of and attitudes toward the drug prevention efforts their schools had undertaken. The findings indicate that most youths are not aware of community resources available for assistance with a drug problem. Substantial discrepancies were found between student ratings of the effectiveness of prevention programs and the programs which they were most frequently exposed. Finally, the data highlight the peer context and drug culture aspect of the youths' substance taking, emphasizing that the sociocultural backgrounds of students need to be taken into account in prevention program development.

Adolescent↗
PubMed1977

A survey of substances use among junior and senior high school students in New York state, Winter 1974-75.

A survey designed to assess drug and alcohol use among the 1,600,000 students in Grades 7 through 12 who attend New York State public schools was administered in 10i schools during the winter of 1974-75. Findings indicate that over 80% of the students have used alcohol and that almost one-third of the students have used marijuana at least once. In addition, 60% of the marijuana users have used no other substance, with the possible exception of alcohol. Also, if a student has used a substance, he is likely to have used it within the last 6 months. Finally, multiple substance use is not predominant among marijuana users, but is predominant among users of other substances.

Adolescent↗
PubMedDate not supplied

Amputation and carboplatin for treatment of dogs with osteosarcoma: 48 cases (1991 to 1993).

Forty-eight dogs with histologically confirmed appendicular osteosarcoma (OSA) entered a prospective clinical trial evaluating treatment with amputation and up to 4 doses of carboplatin given every 21 days. The median disease-free interval (DFI) was 257 days, with 31.2% of the dogs disease-free at 1 year. The median survival time was 321 days, with 35.4% of the dogs alive at 1 year. Dogs with proximal humeral OSA had shorter DFI (P = .016) and survival (P = .037) times than dogs with OSA at other locations. Dogs with lower body weights ( < 40 kg) had longer DFI (P = .0056) and survival (P = .007) times than larger dogs. Survival times for dogs that received carboplatin were statistically longer than those previously reported for amputation alone (P < .001). DFI and survival times are similar to those previously reported for 2 to 4 doses of cisplatin. Carboplatin appears to be a well-tolerated chemotherapeutic drug that can be given safely every 21 days at a dose of 300 mg/m2. Neutropenia was the dose-limiting toxicity in this study.

Amputation, Surgical↗
PubMedDate not supplied

Monoclonal antibody C219 immunohistochemistry against P-glycoprotein: sequential analysis and predictive ability in dogs with lymphoma.

In the present study, the prevalence of positive staining for P-glycoprotein using C219 monoclonal antibody was assessed in 58 tissue samples of high-grade lymphoma from dogs before initiation of chemotherapy. Samples were also evaluated at relapse in 22 dogs, at necropsy in 34 dogs, and at all 3 times in 15 dogs. The frequency of positive staining was significantly higher than that found prior to the initiation of chemotherapy at the following times: relapse (P = .0001), necropsy (P < .0001), and both relapse and necropsy (P < .001, sequential data). The frequency of positive staining prior to the initiation of chemotherapy was significantly inversely related to remission (P < .001) and survival times (P = .0012). Similarly, when populations below and above the median initial C219 score were compared with respect to remission and survival times, the population with scores greater than the median had significantly lower remission (P < .001) and survival (P = .008) times, respectively. The frequency of positive staining determined at relapse was significantly inversely related to the time from relapse to death (P = .0102). Similarly, when populations below and above the median relapse C219 score were compared with respect to the time from relapse to death, the population with C219 scores greater than the median had a significantly lower time from relapse to death (P = .006). It appears that this immunohistochemical methodology may be used as a predictor of remission time, survival time, and the time from relapse to death. Additional studies are required to confirm the usefulness of C219 as a true marker of P-glycoprotein and to evaluate P-glycoprotein as a useful prognostic factor in dogs with lymphoma.

Animals↗