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Biomedical subjects

M R Smith

Publications and source records attributed to M R Smith.

At least 109 records · Page 6Linked to original sources
PubMed1995

Lead poisoning of spectacled eiders (Somateria fischeri) and of a common eider (Somateria mollissima) in Alaska.

Lead poisoning was diagnosed in four spectacled eiders (Somateria fischeri) and one common eider (Somateria mollissima) found dead or moribund at the Yukon Delta National Wildlife Refuge, Alaska (USA) in 1992, 1993, and 1994. Ingested lead shot was found in the lower esophagus of one spectacled eider and in the gizzard of the common eider. Lead concentrations in the livers of the spectacled eiders were 26 to 38 ppm wet weight, and 52 ppm wet weight in the liver of the common eider. A blood sample collected from one of the spectacled eiders before it was euthanized had a lead concentration of 8.5 ppm wet weight. This is the first known report of lead poisoning in the spectacled eider, recently listed as a threatened species by the U.S. Fish and Wildlife Service.

Alaska↗
PubMed1995

Induced expression of a ubiquitin COOH-terminal hydrolase in acute lymphoblastic leukemia.

To identify potential effector molecules of human B-cell differentiation, the acute lymphoblastic leukemia cells (Reh) were induced to terminal differentiation in vitro using the phorbol ester, 12-O-tetradecanoylphorbol-13-acetate. Proteins of parent and differentiated Reh cells were mapped using powerful two-dimensional gel electrophoresis coupled with ultrasensitive silver stain. New protein (MW-pl; p34-5.3) spot was induced in the differentiated Reh cells. The NH2-terminal sequencing of this protein revealed 100% homology with the ubiquitin COOH-terminal hydrolase isozyme L1 (UCH-L1). The presence of UCH-L1 protein in the differentiated Reh cells but not in parent cells was confirmed by immunocytochemistry and Western blot. The cDNA for this enzyme was cloned from the differentiated Reh cells, and the UCH-L1 mRNA was detected in both parent and 12-O-tetradecanoylphorbol-13-acetate-induced cells. However, the message was more abundant in the differentiated cells than parent cells, indicating a posttranscriptional regulation. Until now, UCH-L1 was thought to be neuron-specific. The induced expression of UCH-L1 in differentiated Reh cells argues for a role of this enzyme, and the ubiquitin system, in B-cell differentiation.

Adolescent↗
PubMed1995

Antisense oligodeoxyribonucleotide down-regulation of bcl-2 gene expression inhibits growth of the low-grade non-Hodgkin's lymphoma cell line WSU-FSCCL.

The BCL-2 gene product is involved in preventing apoptosis. The t(14,18) chromosomal translocation, which results in a fusion messenger RNA containing the entire coding region of BCL-2 and a portion of the immunoglobulin heavy chain gene, is commonly found in follicular lymphoma and appears to play a role in lymphomagenesis by inhibiting cell death. We tested the hypothesis that downregulation of BCL-2 would decrease accumulation of follicular lymphoma cells by treating the t(14,18)-carrying follicular lymphoma cell line WSU-FSCCL in vitro with antisense oligodeoxyribonucleotides (ODNs) directed against BCL-2. We found dose-dependent, sequence-specific inhibition of cell accumulation by an antisense unmodified ODN directed at codons 2 to 7, which downregulated BCL-2 protein levels. This effect was near maximal at an ODN concentration of 40 micrograms/mL (6.9 mumol/L), with minimal toxicity by control sense, reverse, and mutated antisense ODN at the same concentration. The pre-B leukemia cell line REH showed no sequence-specific growth inhibition by the antisense ODN at these concentrations, and BCL-2 protein levels were not altered. These data suggest that WSU-FSCCL may be useful in a murine model to optimize antisense ODN for potential therapeutic utility.

Base Sequence↗
PubMed1995

Neoadjuvant and adjuvant chemotherapy for invasive bladder cancer.

Patients with muscle-invasive transitional cell carcinoma of the bladder are at high risk of systemic relapse following primary therapy. Several randomized trials of neoadjuvant and adjuvant chemotherapy suggest that chemotherapy administered before or after primary therapy may improve the disease-free survival of patients with invasive bladder cancer. The effects of neoadjuvant and adjuvant chemotherapy on long-term survival remain controversial. Potential differences in the long-term outcome of patients treated with neoadjuvant and adjuvant chemotherapy are not known. The only randomized trial comparing these 2 approaches showed no difference in survival with short median follow-up. Treatment recommendations for an individual patient require consideration of the relative advantages and disadvantages of chemotherapy administered before or after primary therapy. Recommendations regarding the optimal treatment of patients with invasive bladder cancer await the results of ongoing randomized trials. Because the use of adjuvant and neoadjuvant chemotherapy in patients with invasive bladder cancer represents a promising but unproven approach, physicians should encourage patients with invasive bladder cancer to enroll in clinical trials.

Antineoplastic Agents↗
PubMed1995

[Hemodynamic impact of thrombolytic therapy in acute pulmonary thromboembolism].

PURPOSE: To evaluate pre and post-hemodynamic changes after thrombolytic therapy in patients with acute pulmonary embolism with multiple pulmonary segments compromised. METHODS: Nine patients, 5 females, aged between 27 and 83 (mean 62 +/- 16) years, with the onset of symptoms preceding 7 days, were submitted to thrombolytic therapy, administered after baseline perfusion-ventilation lung scan, echodopplercardiography (ECO) and hemodynamic measurements with a Swan-Ganz thermodilution catheter. The same procedures were done after the thrombolytic infusion. Streptokinase (SK) was used in 7 (78%) cases and recombinant human tissue-type plasminogen activator (rt-PA, alteplase) in 2 with the following doses: SK-250,000 i.u. infusion over 30 min, then 100,000 i.v/h over 24 to 72 h and rt-PA-20 mg in bolus infusion, then 80 mg over 6 h. Thrombolytic was infused in pulmonary artery trunk in 8 (88%) cases and a peripheral vein in 1 (12%) case, until mean pulmonary artery pressure (PAP) reached 20 mmHg. All patients received i.v. heparin and oral anticoagulation after thrombolytic therapy. RESULTS: A significant (p < 0.05) decrease in right atrial pressure (12 +/- 3 vs 8 +/- 2 mmHg), PAP (32 +/- 5 vs 19 +/- 2 mmHg), pulmonary vascular resistance (397 +/- 125 vs 87 +/- 24 dyne.s/cm5) and increase in cardiac output (3.4 +/- 0.5 vs 5.5 +/- 1.0 l/min) and stroke volume (30 +/- 5 vs 57 +/- 10 ml/beat) were observed after thrombolytic infusion. Two patients died as a result of pulmonary infection unrelated to the embolic event or thrombolysis. Minor bleeding complications occurred in two cases and major in one patient with orthopedic prosthesis. CONCLUSION: Thrombolytic therapy exert desirable effects on hemodynamic abnormalities, achieving lungs scan and ECO improvement in patients with acute pulmonary embolism.

Acute Disease↗
PubMed1995

C-JUN/AP-1 as possible mediators of tumor necrosis factor-alpha-induced apoptotic response in mouse JB6 tumor cells.

Sensitivity to cell killing by tumor necrosis factor (TNF)-alpha was seen in the JB6-derived transformed mouse RT101 cell variants previously described as resistant to 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced killing, while the TPA-sensitive variants were resistant to killing by TNF-alpha. Morphological and biochemical changes characteristic of apoptosis were found to precede TNF-alpha-induced cell death in TNF-alpha-sensitive (TNFs) but not TNF-alpha-resistant (TNFr) cells. In TNFr cells, TNF-alpha increased the cell cycle rate. The onset of cellular damage in TNFs cells, as indicated by propidium iodide uptake, was seen as early as 6 h after TNF-alpha treatment. 4,6-diamidino-2-phenylindole staining revealed chromosomal condensation approximately 4-6 h after TNF-alpha treatment. The DNA oligonucleosomal ladder of 180 bp and its multiples, a characteristic feature of apoptosis, was seen at 48 h. Little or no significant differences were found in the basal or induced levels of mRNA expression of several potential apoptosis mediator genes or apoptosis inhibitor genes. A dephosphorylated species of anti-c-Jun immunoprecipitated protein appeared in TNFs cells at 3 h posttreatment, accompanied by a parallel increase in AP-1 activity. Higher constitutive levels of the antioxidant enzymes superoxide dismutase and catalase were found in TNFr cells, but TNF-alpha did not significantly affect the activities of these enzymes or differentially induce their expression. The findings suggest that the preferential and transient increase in c-Jun dephosphorylation and AP-1 transcriptional activity may contribute to the preferential apoptotic response in TNFs cells; and that the greater constitutive oxidant defense in TNFr cells may contribute to their resistance.

Animals↗
PubMed1994

Induction of T cell differentiation and lymphomagenesis in the thymus of mice with severe combined immune deficiency (SCID).

Severe combined immune deficiency (SCID) mice have a defect in their recombinase system and cannot productively rearrange their immune receptor genes. Thus, SCID thymocytes are arrested at the immature "triple negative" phase, not expressing CD3, CD4, or CD8 surface markers. Whole body irradiation of SCID mice induced maturation of their thymocytes to the CD4+/CD8+ double positive, CD3+low stage of differentiation, and resulted in the generation of a thymic cortical region on histologic examination. No mature single positive T cells were detected in the thymus or the periphery. VDJ rearrangements of TCR-beta with restricted clonality were observed in the double positive cells from a given individual. The CD3 complex was expressed on some of these cells, but the cells failed to mobilize intracellular calcium after cross-linking with CD3 Abs. The double positive cells appeared several weeks after irradiation, persisted for many months in the thymus, and by 6 mo generally developed into metastatic lymphoma. Retroviral activation was undetectable in both the preneoplastic and transformed thymocytes. Thus, it appears that the earliest steps in T cell development can be induced in SCID mice by inducing DNA breaks with radiation. This system represents a model of early thymic development, preneoplasia, and neoplasia.

Animals↗
PubMed1994

Phospholipase C-gamma 1 can induce DNA synthesis by a mechanism independent of its lipase activity.

Inositol phospholipid-specific phospholipase C (PLC) is involved in several signaling pathways leading to cellular growth and differentiation. Our previous studies reported the induction of DNA synthesis in quiescent NIH 3T3 cells after microinjection of PLC and the inhibition of serum- or Ras-stimulated DNA synthesis by a mixture of monoclonal antibodies to PLC-gamma 1. In the course of our investigation of anti-PLC-gamma 1 monoclonal antibodies, we found that each antibody exerts different inhibitory effects on the phosphatidylinositol-hydrolyzing activity of PLC-gamma 1 and that the inhibition of enzymatic activity does not correlate with the inhibition of DNA synthesis observed in the microinjection assay. PLC-gamma 1 with defective enzymatic activity was synthesized by substituting phenylalanine for histidine within the PLC-gamma 1 catalytic domain at amino acids 335 and 380, and mutant enzymes were expressed using a vaccinia expression system. The mutant enzymes were purified and microinjected into quiescent NIH 3T3 cells to evaluate their mitogenic activity. A moderate induction of DNA synthesis occurred after injection of mutant PLC-gamma 1. This mitogenic activity was inhibited by an antibody (alpha E 8-4) that does not significantly inhibit PLC-gamma 1 enzyme activity, which indicates that something else has to be inhibited. Furthermore, the partial induction of DNA synthesis observed with mutant PLC-gamma 1 was increased to levels seen with wild-type PLC-gamma 1 by coinjection of mutant PLC-gamma 1 with two second messengers, diacylglycerol and inositol trisphosphate. These results suggest that the mitogenic activity of PLC-gamma 1 does not exclusively result from the enzymatic activity of the lipase and that another activity inherent to the PLC-gamma 1 molecule can also induce DNA synthesis in quiescent cells.

3T3 Cells↗
PubMed1994

c-erbB-2 promoter-specific DNA-binding protein isolated from human breast cancer tissues displays mitogenic activity.

Amplification and overexpression of the c-erbB-2 gene appears to play a role in the pathogenesis of human breast and other cancers. Frequent amplification (20-30%) of the c-erbB-2 gene was observed in human adenocarcinomas of kidney, pancreas, lung, ovarian, and breast cancer. The gene product is a 185-kDa glycoprotein that has intrinsic tyrosine kinase activity and is believed to be a receptor. Several candidate ligands have been described. In the present study we have identified and purified a novel DNA-binding protein from malignant human breast tissues. The protein binds to a core element (-22 to +9, +1 being the transcription start site) of the c-erbB-2 promoter region in a sequence-specific manner. The affinity-purified protein has the ability to induce DNA synthesis in quiescent NIH/3T3 cells, suggesting that the factor has mitogenic activity. The purified protein induces c-erbB-2 expression on the surface of microinjected NIH/3T3 cells. This DNA-binding protein is a sequence-specific cellular factor that is associated with high level expression of the c-erbB-2 gene and appears to play a role in cell transformation. Understanding the control and expression of this DNA-binding protein may shed light on the mechanism(s) of c-erbB-2 gene regulation and its potential role in the pathogenesis of human adenocarcinomas.

3T3 Cells↗
PubMed1994

Continuous infusion ABDIC therapy for relapsed or refractory Hodgkin's disease.

BACKGROUND: Patients whose Hodgkin's disease is refractory to standard combination chemotherapy usually have a poor prognosis. These patients are generally considered for bone marrow transplantation if the disease is still sensitive to chemotherapy. METHODS: Between May 1988 and January 1992, 19 patients with refractory or relapsed Hodgkin's disease were treated with a regimen of doxorubicin, bleomycin, dacarbazine, lomustine, and prednisone (ABDIC). The ABDIC regimen as modified for continuous infusion by Hagemeister consisted of doxorubicin 25 mg/m2 by continuous infusion daily for 2 days, dacarbazine 200 mg/m2 by continuous infusion daily for 5 days, bleomycin 5 U/m2 intravenously on days 1 and 5, CCNU 40 mg/m2 on day 1, and prednisone 40 mg/m2 daily on days 1-5. Treatment was repeated every 28 days. RESULTS: At the time of treatment, mean age was 30.5 years (range 19-70), and time to ABDIC from initial diagnosis was 5.6 years (range 1-14). The mean number of prior chemotherapy regimens was 2.7 (range 1-5), and three of the patients had had autologous bone marrow transplantation before ABDIC: All patients had earlier received either mechlorethamine, vincristine, procarbazine, and prednisone or a regimen of doxorubicin, bleomycin, vinblastine, and dacarbazine, and 16 had received both. The mean number of ABDIC cycles was 3.9 (range 2-12). Total response rate was 63%, with 10 patients having partial response and 2 having complete response of 12 and 27 months' duration. Seven patients subsequently underwent bone marrow transplantation; two of these are free of disease at 35 and 41 months. The treatment was well tolerated; major toxicities were nausea and bone marrow suppression. CONCLUSION: ABDIC is an active and well tolerated therapy in patients with relapsed or refractory Hodgkin's disease, including those previously treated with ABVD. More importantly, perhaps, ABDIC as cytoreductive therapy followed by bone marrow transplantation offers the possibility of long term disease free survival in this heavily pretreated patient population.

Adult↗
PubMed1994

Isolation of a morphologically and functionally distinct smooth muscle cell type from the intimal aspect of the normal rat aorta. Evidence for smooth muscle cell heterogeneity.

Recent studies indicate that the neointima of injured rat arteries is composed of a subpopulation of smooth muscle cells (SMCs) distinct from medial smooth muscle cells. However, SMC diversity in normal adult aorta has remained elusive. This study characterizes two morphologically and functionally distinct SMC types isolated from different anatomic regions of the normal rat aorta. Rat aortic medial smooth muscle cells (MSMCs) were isolated from the media after removal of the intimal and adventitial cells. Rat aortic intimal smooth muscle cells (ISMCs) were isolated from the intimal aspect of everted rat aortas. The two cell types were characterized morphologically and immunohistochemically and were compared for their capacity to contract collagen gels in response to endothelin-1. MSMCs were spindle-shaped and grew in hills and valleys showing features previously described for vascular SMCs. Conversely, ISMCs displayed a polygonal and epitheloid shape, grew mainly as a monolayer, and had a higher proliferative rate. Both cell types expressed alpha-smooth muscle actin and were negative for Factor VIII-RAg. ISMCs produced large amounts of a laminin and type IV collagen-rich extracellular matrix which had a characteristic pericellular distribution. ISMCs, but not MSMCs, rapidly contracted collagen gels in response to endothelin-1. This study indicates that the normal rat aorta contains two types of SMCs located in anatomically distinct regions of the vessel wall. Because of their functional characteristics, the SMCs isolated from the intimal aspect of the aorta may play an important role in physiologic as well as pathologic conditions.

Animals↗
PubMed1994

The utilization of 3-mercapto-2-methylpropionate as sulphur source by a phototrophic bacterium.

A bacterium (strain photoB) photoassimilated 3-mercapto-2-methylpropionate as sole source of sulphur with methacrylate accumulating in the medium. This was thought to be the product of a sulphur-lyase type enzyme attacking the 3-mercapto-2-methylpropionate. Detailed examination of the biochemistry of the utilization of 3-mercapto-2-methylpropionate showed however that the thiol was first activated to 3-mercapto-2-methylpropionyl CoA. It appeared that this CoA-derivative then served as the substrate for a sulphur-lyase type enzyme, with methacrylyl-CoA as product. Further metabolism was via beta-hydroxyisobutyryl-CoA and beta-hydroxyisobutyrate.

Acyl Coenzyme A↗
PubMed1994

Cisplatin, doxorubicin hydrochloride, and cyclophosphamide followed by radiotherapy in high-risk endometrial carcinoma.

OBJECTIVE: Our purpose was to assess the effect of adjuvant platinum-based, multiagent chemotherapy followed by conventional radiotherapy on the recurrence-free interval, patterns of recurrence, and survival of women with completely resected, poor-prognosis endometrial carcinoma. STUDY DESIGN: Surgical stage IC and II endometrial carcinomas involving the outer one third of myometrium and completely resected stage III and IV carcinomas were eligible for six cycles of cisplatin (Platinol), doxorubicin hydrochloride (Adriamycin), and cyclophosphamide (Cytoxan) (50, 50, 500 mg/m2), followed by external beam radiotherapy to pelvis, pelvis and periaortic chain, or whole abdomen, on the basis of documented disease. RESULTS: Forty-seven women were registered between April 1, 1984, and Oct. 10, 1992; 39 were eligible for review. Six were stage I, 28 were stage III, and five were stage IV. Two tumors were grade I, eight were grade 2, and 29 were grade 3. Twenty-three were endometrioid adenocarcinomas, eight papillary serous, six adenosquamous, and two clear cell. Thirty-seven patients (94.9%) completed six courses of chemotherapy, with no deaths ascribed to treatment. Grade 3 or 4 neutropenia was experienced by 17 (44%) and sepsis by three (8%). Current median follow-up is 27.3 months. Fifteen patients (38.5%) have recurrence, and 14 have died after a median interval of 26.9 months. The 2-year progression-free interval is 72.5% for nonpapillary serous histologic types and 22.5% for papillary serous cancers (p = 0.0074). CONCLUSION: Adjuvant chemotherapy with Platinol, Adriamycin, and Cytoxan followed by radiation therapy is well tolerated and seems to confer a survival advantage to women with nonpapillary serous endometrial carcinoma with a poor prognosis compared with historic controls treated by surgery or radiotherapy.

Adult↗
PubMed1994

Altered levels of prothymosin immunoreactive peptide, a growth-related gene product, during liver regeneration after chronic ethanol feeding.

Liver regeneration is regulated by the orderly activation of growth-related genes. Although ethanol impairs induction of liver regeneration by partial hepatectomy, we have not identified ethanol-associated differences in the hepatic mRNA levels of several proto-oncogenes, including c-myc, which peaks 3-6 hr post-partial hepatectomy. Prothymosin alpha, a gene encoding a ubiquitous nuclear protein, is activated by c-myc in resting fibroblasts and has been implicated as a regulator of cell proliferation. Prothymosin alpha mRNA levels reportedly increase 12-32 hr post-partial hepatectomy, several hours after c-myc induction. We sought to determine if chronic ethanol intake alters the expected induction post-partial hepatectomy of prothymosin alpha steady-state mRNA expression and protein levels. Comparing rats chronically fed ethanol with pair-fed controls, we found no significant differences in steady-state levels of prothymosin alpha mRNA; however, we did see a delay in the increase of prothymosin immunoreactive peptide in rats chronically fed alcohol. This suggests that the inhibition in protein levels in ethanol fed rats is not due to lower steady-state mRNA levels, but may occur post-transcriptionally. Further data are needed to determine if this finding is important in the inhibition in cell growth following partial hepatectomy in rats chronically fed ethanol.

Alcoholism↗
PubMed1994

Glucosyltransferase Mutants of Leuconostoc mesenteroides NRRL B-1355.

Leuconostoc mesenteroides NRRL B-1355 produces dextrans and alternan from sucrose. Alternan is an unusual dextran-like polymer containing alternating alpha(1-->6)/alpha(1-->3) glucosidic bonds. Cultures were mutagenized with UV and ethyl methanesulfonate, and colony morphology mutants were selected on 10% sucrose plates. Colony morphology variants exhibited changes from parent cultures in the production of one or more glucosyltransferases (GTFs) and glucans. Mutants were characterized by measuring resistance of glucan products to dextranase digestion, by electrophoresis, and by high-pressure liquid chromatography of maltose acceptor products generated from sucrose-maltose mixtures. Some mutants produced almost pure fraction L dextran, and cultures exhibited a single principal GTF band on sodium dodecyl sulfate-acrylamide gels. Other mutants produced glucans enriched for alternan. Colony morphology characteristics (size, smoothness, and opacity) and liquid culture properties (clumpiness, color, and viscosity in 10% sucrose medium) were explained on the basis of GTF production. Three principal GTF bands were detected.

Journal Article↗
PubMed1994

Alpha interferon, leucovorin, and 5-fluorouracil (ALF) in advanced cancer: results of a dose-finding study and evidence of activity in non-small cell lung cancer.

In a phase I trial, 17 patients were treated with 5-fluorouracil (5-FU) 500 mg/m2 and leucovorin (LV) 500 mg/m2 intravenously weekly for 6 weeks followed by 2 weeks' rest and interferon alfa-2b 1, 3, 5, 8, or 10 million units (MU) subcutaneously tiw with no rest period. The most common toxicities were fatigue (12), diarrhea (10), nausea/vomiting (7), and fever (7). The maximum tolerated interferon dose was 8 MU tiw. Fatigue and increased incidence of other toxicities rather than a single dose-limiting toxicity occurred at the next highest interferon level. ECOG grade III/IV toxicity occurred in 5 patients and included transient supraventricular tachycardia and brief seizure episode (1), dyspnea (1), decreased performance status (1), anemia requiring transfusion (1), and deep vein thrombosis (1). No toxic deaths occurred. Two patients with non-small cell lung cancer (NSCLC) had partial responses lasting 5 and 4 months. Two other patients with NSCLC had either minor response or stable disease, and 1 patient with colon cancer had a significant decline in serum CEA. The recommended alpha interferon dose is 8 MU tiw when given with this schedule of 5-FU/LV.

Adult↗
PubMed1994

[Diagnosis of papillary muscle rupture in acute myocardial infarction by transesophageal Doppler echocardiography].

Three patients, two females, ages ranging from 62 to 78 years were studied, evolving with hypotension, acute pulmonary edema and cardiogenic shock. One had anterior myocardial infarction, and in two, infero-posterior. Due to severe hemodynamic instability and necessity of vasoactive drug therapy to maintain adequate arterial pressure, coronary angiography was performed in two, showing total occlusion of the circumflex artery and severe mitral regurgitation. In one case, angioplasty on the circumflex artery was successfully achieved. No hemodynamic improvement was observed, however. Doppler echocardiography depicted mild to moderate mitral regurgitation in the three cases. Transesophageal echo confirmed the clinical suspicion of papillary muscle rupture: total rupture of antero-lateral papillary muscle in one patient, as well as total and partial rupture of the postero-medial papillary muscle in the other two patients. Two patients were submitted to mitral valve replacement, and the surgical findings confirmed the transesophageal echo conclusions. One of them died in the immediate pos-operative period, whereas the other was discharged from the hospital and is doing well. The third patient died before operation. Differential diagnosis of acute mitral regurgitation due to papillary muscle dysfunction or rupture was not possible by left ventriculography or by transthoracic echo. Transesophageal echo was the only exam to clearly confirm papillary muscle rupture, as should be done promptly after clinical suspicion of this severe condition arises.

Aged↗