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Biomedical subjects

M R Clarke

Publications and source records attributed to M R Clarke.

At least 19 recordsLinked to original sources
PubMed1997

Extracellular matrix expression in metastasizing and nonmetastasizing adenocarcinomas of the lung.

Alterations in extracellular matrix, cell-cell and cell-matrix adhesion, and oncogenes are thought to be important in tumor progression and metastasis. Adenocarcinomas of the lung from 31 patients were studied for immunohistochemical expression of basement membrane molecule type IV collagen, type IV collagenase, and integrins alpha2,3,v adhesion molecules to assess their diagnostic and prognostic importance in pathological stage T2 tumors. The results indicate that with decreasing tumor differentiation, there is a progressive loss of type IV basement membrane collagen (P = .06) and decreased integrin alpha2 expression (P = .03). Type IV collagenase expression was significantly associated with the presence of lymph node metastases, with moderate to strong expression present in 53% T2N1 tumors compared with none (0%) of the T2N0 tumors (P = .008). Integrin alpha(v) was increased in tumors with nodal metastases compared with those without (P = .08). Loss of alpha2 and alpha3 integrins was associated with increased alpha v expression (P = .03). Median survival was 48 months for T2N0 and 20 months for T2N1 (P = .07). In correlating expression of the immunohistochemical markers and survival, type IV collagenase expression was found to be a predictor of survival at a level of P = .07. Measurable alterations in integrins and extracellular matrix, and in particular, expression of matrix-degrading enzyme type IV collagenase may be of prognostic importance in resectable adenocarcinoma of the lung.

Adenocarcinoma↗
PubMed1996

Therapy of murine tumors with tumor peptide-pulsed dendritic cells: dependence on T cells, B7 costimulation, and T helper cell 1-associated cytokines.

Antigen presentation by host dendritic cells (DC) is critical for the initiation of adaptive immune responses. We have previously demonstrated in immunogenic murine tumor models that bone marrow (BM)-derived DC pulsed ex vivo with synthetic tumor-associated peptides, naturally expressed by tumor cells, serve as effective antitumor vaccines, protecting animals against an otherwise lethal tumor challenge (Mayordomo, J.I., T. Zorina, W.J. Storkus, C. Celluzzi, L.D. Falo, C.J. Melief, T. Ildstad, W.M. Kast, A.B. DeLeo, and M.T. Lotze. 1995. Nature Med. 1:1297-1302). However, T cell-defined epitopes have not been identified for most human cancers. To explore the utility of this approach in the treatment of tumors expressing as yet uncharacterized epitopes, syngeneic granulocyte/macrophage colony-stimulating factor-stimulated and BM-derived DC, pulsed with unfractionated acid-eluted tumor peptides (Storkus, W.J., H.J. Zeh III, R.D. Salter, and M.T. Lotze. 1993. J. Immunother. 14:94-103) were used to treat mice bearing spontaneous, established tumors. The adoptive transfer of 5 x 10(5) tumor peptide-pulsed DC dramatically suppressed the growth of weakly immunogenic tumors in day 4 to day 8 established MCA205 (H-2b) and TS/A (H-2d) tumor models, when applied in three biweekly intravenous injections. Using the immunogenic C3 (H-2b) tumor model in B6 mice, tumor peptide-pulsed DC therapy resulted in the erradication of established d14 tumors and long-term survival in 100% of treated animals. The DC-driven antitumor immune response was primarily cell mediated since the transfer of spleen cells, but not sera, from immunized mice efficiently protected sublethally irradiated naive mice against a subsequent tumor challenge. Furthermore, depletion of either CD4+ or CD8+ T cells from tumor-bearing mice before therapy totally suppressed the therapeutic efficacy of DC pulsed with tumor-derived peptides. Costimulation of the host cell-mediated antitumor immunity was critical since inoculation of the chimeric fusion protein CTLA4-Ig virtually abrogated the therapeutic effects of peptide-pulsed DC in vivo. The analysis of the cytokine pattern in the draining lymph nodes and spleens of tumor-bearing mice immunized with DC pulsed with tumor-eluted peptides revealed a marked upregulation of interleukin (IL) 4 and interferon (IFN) gamma production, as compared with mice immunized with DC alone or DC pulsed with irrelevant peptides. DC-induced antitumor effects were completely blocked by coadministration of neutralizing monoclonal antibody directed against T helper cell 1-associated cytokines (such as IL-12, tumor necrosis factor alpha, IFN-gamma), and eventually, but not initially, blocked by anti-mIL-4 mAb. Based on these results, we believe that DC pulsed with acid-eluted peptides derived from autologous tumors represents a novel approach to the treatment of established, weakly immunogenic tumors, and serves as a basis for designing clinical trials in cancer patients.

Animals↗
PubMed1996

Interleukin-12 and B7.1 co-stimulation cooperate in the induction of effective antitumor immunity and therapy of established tumors.

Interleukin-12 (IL-12) promotes specific and long-lasting anti-tumor immunity mediated by T cells in a variety of murine tumor models. IL-12 also synergizes with B7.1 (CD80) co-stimulation to induce proliferation and cytokine production by both human and murine T cells in vitro. We evaluated the combined anti-tumor efficacy of IL-12 and B7.1 gene delivery in two apparently poorly immunogenic tumor models (TS/A and MCA207). In both of these models, expression of B7.1 and production of IL-12 in the inoculum led to improved anti-tumor immunity, with up to 80% long-term tumor-free animals (vs 0-20% of mice remaining tumor free when inoculated with either B7.1- or IL-12-transfected tumors alone). Tumor-free mice were capable of rejecting a subsequent rechallenge with the wild-type tumor in 66% of the cases. Cooperativity was dependent upon the level of IL-12 secreted by engineered cells. IL-12 delivery required B7 expression of therapeutic effects to be observed in these models. Vaccines provided at a site distal to a control, non-transfected tumor slowed (TS/A) or abrogated (MCA207) the progression of wild-type tumors. The synergistic anti-tumor effects associated with combined application of B7.1- and IL-12-transfected tumors were partially negated by systemic administration of the CD28-B7.1/B7.2 antagonist CTLA4-Ig or by inoculation with neutralizing antibodies directed against murine interferon-gamma or tumor necrosis factor-alpha, two cytokines elicited in response to IL-12 stimulation. These data support the potential clinical utility of combined gene therapy using IL-12- and B7.1-engineered autologous cells (tumor or fibroblasts) as a vaccine to elicit specific anti-tumor immunity.

Abatacept↗
PubMed1996

Near-tetraploidy in adult acute myelogenous leukemia.

Tetraploidy and near-tetraploidy are observed infrequently in hematologic malignancies, most commonly seen in cases of childhood acute lymphoblastic leukemia, and are associated with large blast size. Four cases of adult acute myelogenous leukemia (AML) with tetraploid or near-tetra-ploid karyotypes are reported, along with review of the related literature. AML subtypes included M1, M1, M4, and M5b. Tetraploidy was determined cytogenetically and confirmed by image cytometry (DNA index 2.0). The subjective impression of large blast size was confirmed by image cytometry, demonstrating mean blast nuclear areas of 237, 177, 203, and 216 microns2, (mean 208 microns2) in the cases with tetraploidy, compared to a mean of 134 microns2 in 10 control cases of AML with diploid or near diploid chromosome patterns. The clinical course was variable in the four cases reported. When compared with previously published cases, the occurrence of tetraploidy or near-tetraploidy in adult AML, unlike childhood ALL, does not appear to define a distinct subgroup in terms of FAB classification or to carry prognostic implications.

Adult↗
PubMed1996

Parathyroid adenomas: accurate detection and localization with Tc-99m sestamibi SPECT.

PURPOSE: To evaluate the ability to detect and localize parathyroid adenomas with technetium-99m sestamibi single photon emission computed tomography (SPECT). MATERIALS AND METHODS: Forty-seven adult patients underwent Tc-99m sestamibi SPECT. Early (15-30 minutes after injection) and delayed (2-4 hours after injection) images were acquired. Thirty-three patients were examined for initial parathyroid surgery; the remaining 14, for repeat surgery because of persistent or recurrent hyperparathyroidism. SPECT reprojection images viewed in a rotating cine-display mode were read independently by two nuclear medicine physicians who were blinded to the results of other localization studies. Thirty-seven patients underwent subsequent neck exploration. SPECT findings were compared with surgical and histopathologic findings. RESULTS: In the 37 patients who underwent surgery, parathyroid adenomas were confirmed in 34 (92%) and hyperplasia in three (8%). In 31 patients, adenomas were correctly detected and localized with early SPECT images (sensitivity, 91%). In contrast, the sensitivity of delayed SPECT images was 74% (25 of 34 patients) for detection and 32% (11 of 34 patients) for localization. Early SPECT images were significantly better for localization (P < .001) and detection (P = .03). CONCLUSION: For Tc-99m sestamibi parathyroid imaging, early SPECT images were the most accurate in the detection and localization of parathyroid adenomas.

Adenoma↗
PubMed1996

Primary malignant melanoma of the esophagus.

A case of primary malignant melanoma of the esophagus is presented, followed by a review of the literature. This uncommon tumor generally manifests itself as a pedunculated, polypoid lesion in the middle-lower third of the esophagus. The histological diagnosis is usually made post-resection. The treatment of choice is surgical resection. The advanced stage of the disease at the time of presentation and the aggressive biological behavior of the tumor result in a dismal prognosis.

Aged↗
PubMed1995

Cancer immunotherapy of established tumors with IL-12. Effective delivery by genetically engineered fibroblasts.

IL-12 is a heterodimeric cytokine produced by macrophages, mitogen stimulated- or EBV infected-B lymphocytes, keratinocytes, and probably dendritic cells, with important immunoregulatory functions in vitro and in vivo. It directly stimulates activated NK and T cells to produce high levels of IFN-gamma, enhances their cytolytic activity, and promotes maturation of Th1 cells as well as IL-2-activated B cells. We have tested paracrine delivery of IL-12 using autologous or allogeneic fibroblasts engineered to secrete high levels of IL-12 to treat established tumors. Injection of IL-12-engineered fibroblasts at the site of an established (day 8) MCA207 sarcoma could efficiently eliminate or suppress tumor growth in a dose-dependent manner, requiring delivery of > 150 ng/kg/dose of bioactive IL-12. Weekly inoculations for 3 wk could also be used to effectively treat a day 4 sarcoma located intradermally in the opposite flank (80% protection using autologous fibroblasts), resulting in long-term protective antitumor immunity. In less immunogenic tumors (MCA102, MC38), 7-day established lung metastases could be significantly reduced (p = 0.001) following IL-12 delivery by fibroblasts and systemic administration of low doses of IL-2. Histologic findings included a mixed infiltrate of CD4+ and CD8+ T effectors and macrophages in the regressing sarcoma on day 21. In a day 41 MCA207 sarcoma locally injected in situ, similar findings were observed. No lymphoid hyperplasia or tissue necrosis were noted in liver, spleen, or lungs in mice receiving repeated inocula of IL-12-engineered fibroblasts. Tests of liver and renal function monitored during the repetitive weekly treatments were within the normal range. IL-12-engineered fibroblasts thus seem to serve as a safe and efficient means to deliver IL-12 in these three tumor models.

Animals↗
PubMed1995

Irritable bladder syndrome in an animal model: a continuous monitoring study.

Irritable bladder syndrome (IBS) was induced in four female African green monkeys (Cercopithecus aethiops) by the use of intravesical instillation of acetone. The animals were housed in a modified metabolic cage for continuous micturition monitoring, and two uroflowmeters connected to a remote PC monitored the frequency, voided volumes, and peak flows. Before and after, urea absorption studies and urodynamics were obtained for each animal. Urea absorption increased significantly after acetone instillation and returned to baseline after 4 weeks (26 to 66 to 32%). Intravesical acetone instillation produced marked effects on bladder physiology in the first week. Bladder compliance dropped from a baseline of 10.47 to 0.58 ml/cm H2O. The voiding pattern changed from a normal pattern with a mean voided volume of 17.58 ml into marked increase in frequency and dribbling pattern with few voids (mean = 5.03 ml). Systematic behavioral observations were carried out for 4 hours per day utilizing an observation program on a laptop computer. Activity patterns, attention, sterotypic behaviors, and self-directed activities were recorded for each monkey. The animals demonstrated decreased frequency of activity and increased frequency in self-directed activities (groom, scratch), behaviors consistent with an animal experiencing pain or discomfort. The findings suggested that IBS induction in monkeys is feasible and produces a clinical picture similar to interstitial cystitis in humans. It offers a suitable animal model to enhance the understanding of voiding dysfunction with its neural pathways and to test the different therapeutic modalities to control IBS.

Acetone↗
PubMed1995

Pyruvate inhibits clofibrate-induced hepatic peroxisomal proliferation and free radical production in rats.

In an effort to identify the effects of the 3-carbon compound pyruvate on free radical production, we measured hepatic total peroxisomal beta-oxidation and catalase activity and the production of lipofuscin-like products in male Sprague-Dawley rats consuming an adequate diet supplemented with pyruvate, vitamin E, or the peroxisome proliferator and free radical enhancer clofibrate for 22 days (n = 5 in each group). Clofibrate feeding induced hepatomegaly, a fivefold increase in total peroxisomal beta-oxidation activity, and a threefold increase in hepatic lipofuscin-like products (P < .05). Pyruvate but not vitamin E inhibited the increase in liver size by 70% (P < .05). Both pyruvate and vitamin E completely inhibited clofibrate-induced increases in lipofuscin-like products (P < .05). Pyruvate but not clofibrate or vitamin E increased plasma concentrations of the nitric oxide metabolites nitrite and nitrate (P < .05). We conclude that with clofibrate-induced peroxisomal proliferation and free radical production, pyruvate will inhibit peroxisomal proliferation and free radical production, inhibit free radical-induced lipid peroxidation, and enhance metabolism of nitric oxide.

Animals↗
PubMed1995

Developmental expression and anatomical localization of endothelin-1 messenger ribonucleic acid and immunoreactivity in the rat placenta: a northern analysis and immunohistochemistry study.

Endothelin-1 (ET-1) immunoreactivity and messenger ribonucleic acid (mRNA) have previously been identified in the mammalian placenta. In the present study we examined the developmental expression of ET-1 mRNA and the localization of ET-1 mRNA and immunoreactivity within the rat placenta. Placental tissues were removed from primiparous Sprague-Dawley rats on gestational days 14, 18, and 21 and processed for blot hybridization of ET-1 mRNA and immunohistochemistry of ET-1 immunoreactive peptide. Placental tissue contained a 2.3 kb size ET-1 mRNA transcript. Placental ET-1 mRNA abundance increased approximately five-fold from day 14 to 21 of gestation (p = 0.02). To localize ET-1 mRNA within the rat placenta, day 18 placentas were dissected into the basal and labyrinth layers and processed separately for blot hybridization of ET-1 mRNA. ET-1 mRNA localized to the labyrinth zone. This was confirmed by immunohistochemical staining of day 18, 20, and 21 placental tissues with an antiserum specific to ET-1. The presence of ET-1 immunoreactivity and the stage-specific increase in ET-1 mRNA in the rat placenta suggest that ET-1 may exert paracrine effects on the placenta or uterus of the pregnant rat.

Animals↗
PubMed1994

Pyruvate inhibits growth of mammary adenocarcinoma 13762 in rats.

The growth of implanted mammary adenocarcinoma 13762 was measured in rats consuming a liquid diet (35% fat, 18% protein, 47% carbohydrate) supplemented with pyruvate (37.3 g/liter; n = 13) or maltose-dextrin (placebo; n = 13) for 21 days. Mean tumor diameter, measured on day 11, 14, 18, and 21 subsequent to tumor implantation, was 41, 32, 21, and 19% smaller in the pyruvate group (P < 0.05). When euthanized, tumor weight was also smaller in the pyruvate group: pyruvate = 15.0 +/- 2.3 (SEM) g; placebo = 24.9 +/- 3.2 g, P < 0.05. Visual inspection of organs suggested decreased lung metastases with pyruvate feeding (P < 0.05). Upon microscopic evaluation of organs, hepatic tumor was found only in the placebo group. We conclude that pyruvate inhibits implanted tumor growth in rats.

Adenocarcinoma↗
PubMed1994

Intraoperative imprint cytology for evaluation of mediastinal lymphadenopathy.

Frozen-section (FS) analysis of mediastinal lymph nodes is commonly used in the staging of lung cancer and the evaluation of diagnostic tissue at mediastinoscopy. This approach facilitates definitive surgical intervention in a single operation and reduces costs. However, FS analysis can be labor intensive for the pathology department and time-consuming while the patient is anesthetized. Imprint cytology is more rapid than the FS procedure (average, 2 minutes versus 11 minutes per node) and allows more extensive sampling of the specimen. In this prospective study, we compared the diagnostic accuracy of imprint cytology and permanent sections on 121 mediastinal lymph nodes from 38 patients. There were no false-positive results and one false-negative result, although that patient was correctly classified based on positive cytology from another node. The sensitivity was 96.6%, the specificity was 100%, and the predictive value of a positive result was 100%, as no false-positives results were observed. The predictive value of a negative result was 98.9%, and the overall efficiency was 99.2%. These results compare favorably with those in other studies comparing the diagnostic accuracy of imprint cytology with that of FS analysis and with reported accuracy rates of FS technique. Our findings confirm the usefulness of this technique as an adjunct or substitute for FS analysis in the intraoperative pathologic evaluation of mediastinal lymphadenopathy.

Adult↗
PubMed1993

The diet of sperm whales (Physeter macrocephalus Linnaeus 1758) off the Azores.

Stomach contents from 17 sperm whales, 15 males and two females, caught during commercial activities in 1981-1984 in the Azores region were identified and measured. A total of 28,738 cephalopods and 16 fish were represented in the collections. In addition, there were tunicates in two whales and man-made products in three whales. None of the stomachs were empty. Flesh was present in 94.1% and indigestible fragments alone, including mandibles (beaks) of cephalopods, were present in 5.9% of the stomachs. Twelve species of cephalopod were represented by flesh and 40 species were represented by lower beaks. The cephalopod families contributing food to the whales in this region are, in order of their contribution by estimated mass, the Octopoteuthidae (39.8%), the Histioteuthidae (32.7%), the Architeuthidae (12.1%), the Lepidoteuthidae (4.5%), the Ommastrephidae (3.4%), the Pholidoteuthidae (2.1%), the Cycloteuthidae (1.9%), the Cranchiidae (1.7%) and eight other families each contributing less than 1% by mass. Presence of Gonatus beaks in the stomachs show which whales have migrated southwards to the Azores just prior to capture and the presence of a large Megalocranchia species possibly shows which whales have migrated from higher latitudes off Iceland. However, the presence of Teuthowenia maculata shows which whales came north from the West coast of Africa, just prior to capture. The modal mass of cephalopods consumed is 400-450 g which represents 0.00001 of the whales' body mass. 77.5% of the species eaten have luminous organs and 82% of the species are neutrally buoyant. It seems likely that the sperm whale is obtaining 77% of its food by swimming through luminous shoals of slow-swimming, neutrally bouyant squids and only about 23% by chasing faster swimming, larger cephalopods. Cephalopods not previously recorded from the North Atlantic are Onychoteuthis boreali-japonicus, and Histioteuthis bonnellii corpuscula. Histioteuthis ?miranda may have been collected by the whales much further south than the Azores. Species not recorded previously in the diet of sperm whales in the North Atlantic are Ommastrephes bartrami, Gonatus steenstrupi, Histioteuthis ?miranda, H. bonnellii corpuscula, H. meleagroteuthis, Discoteuthis laciniosa, Mastigoteuthis species, Chiroteuthis species, ?Helicocranchia, Liocranchia reinhardti, and ?Liguriella.

Animal Nutritional Physiological Phenomena↗
PubMed1993

Uterine malignant mixed müllerian tumor in a patient on long-term tamoxifen therapy for breast cancer.

A case of malignant mixed müllerian tumor of the uterus, heterologous type, in an 83-year-old woman on tamoxifen (TAM) therapy for 9 years for breast cancer is presented. Benign endometrial polyps were diagnosed on endometrial curettings for postmenopausal bleeding after the patient had been on TAM for 5 years. Recurrent postmenopausal bleeding developed 4 years later. Endometrial curettings and hysterectomy revealed a 10-cm polypoid malignant mixed müllerian tumor (MMMT) and endometrial polyps. There was no invasion of the myometrium or endocervix and no evidence of metastatic tumor in 13 pelvic lymph nodes, peritoneal washings, or omentum. TAM has been associated with the development of endometrial polyps, hyperplasia, and adenocarcinoma possibly mediated through its agonistic estrogenic properties. Only one other case of MMMT arising in patients on TAM therapy has been previously reported, but may also be a consequence of the estrogenic effects of TAM therapy.

Aged↗
PubMed1993

Endothelin-1 gene expression in human pheochromocytoma.

We examined expression of human endothelin-1 (ET-1) in adrenal tissues removed from five patients with pheochromocytomas and two patients with aldosterone-producing adenomas. The pheochromocytomas contained a 2.3 kilobase ET-1 transcript, which was not found int he aldosteronomas. Constitutive expression of ET-1 varied in magnitude among the pheochromocytomas but was generally at a low level. Immunohistochemical staining of the pheochromocytomas with an antiserum to human ET-1 showed the presence of immunoreactive ET-1 as well. The presence of ET-1 messenger ribonucleic acid and ET-1 immunoreactivity in human pheochromocytomas suggests a possible paracrine role for this peptide in human chromaffin cells.

Adenoma↗
PubMed1990

Behavioral development and socialization of infants in a free-ranging group of howling monkeys (Alouatta palliata).

A 22-month field study was carried out on free-ranging mantled howlers in Costa Rica. Six female and 5 male infants were observed systematically from birth until they died, left the group, or the study ended. Interaction patterns, activity patterns, and proximity data were analyzed from 703 h of focal observations and 753 h of ad lib observations. Developmental trends in weaning and nonmother care were associated with mothers' feeding patterns, suggesting an increase in maternal feeding efficiency. As howler immigration patterns resulted in groups of adults of low relatedness, analyses based on social bonding or kin selection were inappropriate, and socialization patterns instead appeared to prepare howler infants to respond predictably in an adult world. Females, which were more sociable as adults, were also more sociable as infants, initiating interactions and reacting positively. They also exhibited less weaning stress than males. Males, which were forced out of the group sooner, remained solitary longer, and primarily interacted with adult females as adults, were forced to be independent sooner, reacted negatively to interactions, and ceased interacting with adult males by 3 months of age. Ecological constraints on development could not be determined from this study, although there was no evidence for developmental trends being influenced by predator stress.

Age Factors↗