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Biomedical subjects

D Dixon

Publications and source records attributed to D Dixon.

At least 55 records · Page 3Linked to original sources
PubMed1993

The novel metallothionein genes of Caenorhabditis elegans. Structural organization and inducible, cell-specific expression.

Two genes (mtl-1 and mtl-2) that encode the novel metallothioneins (MTs) of Caenorhabditis elegans (CeMTs) were cloned and characterized. Both genes contain a single intron that interrupts codon 6 and short 3'-untranslated regions. However, their promotor regions are distinctively non-homologous. The mtl-2 promoter contains a TATAA box and a single putative metal regulatory element. These elements are absent in the mtl-1 promoter. Nevertheless, both CeMT1 and CeMT2 mRNAs are induced by cadmium and contain precisely initiated, 5'-untranslated sequences. The inducibility and cell type specificity of metallothionein gene expression were investigated in transgenic C. elegans that carry the lacZ (beta-galactosidase) reporter gene under the control of an mtl-1 or mtl-2 promoter sequence. Upon treatment of transgenic C. elegans with cadmium or heat stress, the mtl-2:lacZ fusion gene is abundantly and exclusively expressed in the intestinal cells of larvae and adult animals. Expression is not detected in the absence of metal or heat shock. In contrast, an mtl-1:lacZ construct is constitutively expressed in the pharynx and induced by cadmium and heat shock in the intestinal cells of C. elegans larvae. The metal-inducible expression of the mtl-1:lacZ gene is attenuated in adult transgenic nematodes. Thus, the activity of each mtl promoter is modulated by metals as well as developmental and environmental factors.

Amino Acid Sequence↗
PubMed1993

Microvascular hemodynamics in the sickle red blood cell perfused isolated rat lung.

In this study the effects of alveolar hypoxia on pulmonary microvascular hemodynamics in sickle red blood cell (HbSS-RBC) perfused rat lungs were studied under conditions of high and low oxygen tensions and compared with lung perfused with rat (HbRat) and normal human (HbAA) RBC controls. Independent of the RBC suspension (hematocrit 5%) used, ventilation with the room air gas mixture did not result in any significant differences in the pulmonary arterial pressure (Ppa), capillary pressure (Ppc), total pulmonary vascular resistance (RT), or angiotensin II pressor response. Ventilation of HbSS-RBC perfused lungs with a hypoxic gas mixture significantly increased the Ppa, Ppc, and RT above that which was seen in HbRat and HbAA controls. The increase in RT occurred mainly in the pulmonary artery independent of RBC suspension. In addition, no significant accumulation of lung water occurred in HbSS-RBC perfused lungs compared with HbRat and HbAA controls, as indicated by the change in capillary filtration coefficient and wet-to-dry lung weight ratio. In conclusion, deoxygenation of the HbSS-RBC and hypoxic pulmonary vasoconstriction is additive in altering pulmonary microvascular hemodynamics.

Anemia, Sickle Cell↗
PubMed1993

Evaluation of ketamine-xylazine in Syrian hamsters.

Few parenteral anesthetics are safe and effective in the Syrian hamster. This study evaluated the anesthetic efficacy and potential for tissue damage of ketamine-xylazine (KX). Two dosage levels were administered intraperitoneally. Ketamine at 50 mg/kg combined with 10 mg/kg xylazine did not produce a consistent, reliable level of immobilization or anesthesia. Ketamine at 150 mg/kg combined with 10 mg/kg xylazine administered IP produced an adequate level of anesthesia without tissue damage for most procedures, but supplementation with lidocaine was necessary for peritoneal incision. Careful positioning of male hamsters for IP injection is imperative to prevent inadvertent injection into the testes with subsequent tissue damage.

Anesthesia↗
PubMed1992

Evaluation of Telazol-xylazine as an anesthetic combination for use in Syrian hamsters.

The availability of safe parenteral anesthetics for use in Syrian hamsters is limited. We evaluated the effects of Telazol-xylazine (TZX) combinations with respect to anesthetic efficacy and potential for tissue damage. Two dose levels of the combination were administered by both the intraperitoneal (IP) and intramuscular (IM) routes. TZX by the IM route failed to consistently produce anesthesia and caused gross and histopathologic muscle lesions. IP administration of 20 mg/kg Telazol combined with 10 mg/kg xylazine was adequate for restraint purposes. IP administration of 30 mg/kg Telazol combined with 10 mg/kg xylazine produced a safe, reliable level of surgical anesthesia without evidence of gross or histopathologic lesions. There was no nephrotoxicity at either concentration of the anesthetic. A dose level of TZX that provides safe parenteral anesthesia in Syrian hamsters was determined.

Anesthesia, General↗
PubMed1991

Molecular basis of the activation of the tumorigenic potential of Gag-insulin receptor chimeras.

A previous study showed that the human insulin receptor (IR) could be activated by insertion of a 3' portion of the cDNA encoding the beta subunit into a retrovirus genome to form a Gag-IR fusion protein. While capable of transforming cells in culture, this IR cDNA-containing virus, called UIR, was not able to induce tumors in animals. Subsequently, we isolated a spontaneous sarcomagenic variant called UIR19t from the parental UIR. UIR19t was molecularly cloned, sequenced, and found to harbor two mutations. A 44-amino acid deletion immediately upstream from the transmembrane domain of the Gag-IR fusion protein removes all the extracellular sequence of the IR remaining in the original UIR construct. In addition, a single nucleotide deletion at the 3' end results in truncation and replacement of the carboxyl-terminal 12 amino acids by 4 new amino acids. The specific kinase activity of UIR19t is 4- to 5-fold higher than that of the parental UIR. However, no new cellular substrates were detected in UIR19t-transformed cells as compared to UIR cells. Viruses containing either the 5' or the 3' deletion mutation were constructed and assessed for their biological function. Our data indicate that the 5' deletion alone is sufficient to confer tumorigenic ability. We conclude that sequence immediately upstream from the transmembrane domain imposes a negative effect on the transforming and tumorigenic potential of the Gag-IR fusion protein.

Amino Acid Sequence↗
PubMed1991

Two cycles of MOPP and radiotherapy: effective treatment for stage IIIA and IIIB Hodgkin's disease.

Two cycles of MOPP (mechlorethamine, vincristine (Oncovin), procarbazine, prednisone) and radiotherapy were used to treat 197 patients with stage III Hodgkin's disease. Prior to 1980, radiotherapy was delivered to the mantle, abdomen and pelvis; thereafter, pelvic irradiation was deleted for patients with stage III1 disease. Complete remission rates for IIIA and IIIB presentations were 91% and 89%. The 10-year freedom from tumor mortality (FTM) rate for all patients was 81%; for IIIA, it was 87% and for IIIB, it was 72%. Results were not significantly affected by gender, age, pathology, or deletion of pelvic radiotherapy. However, a subgroup of 28 patients with a tumor burden that included pelvic disease who also had B symptoms was identified as having a poor prognosis. Their FTM was 43%, compared with 87% for all other patients combined (P = 0.002). Based on this analysis, we conclude that limited chemotherapy in combination with radiation therapy can yield results similar to programs that use more chemotherapy for all patients with IIIA disease and for most patients with stage IIIB. However, patients with tumor burdens which include pelvic disease and B symptoms require a different approach.

Adult↗
PubMed1991

Histomorphologic features of spontaneous and chemically-induced pulmonary neoplasms in B6C3F1 mice and Fischer 344 rats.

The histomorphologic features of spontaneous and chemically-induced lung neoplasms in male and female B6C3F1 mice and Fischer 344 rats are described. Primary pulmonary neoplasms in mice and rats were classified as alveolar/bronchiolar (A/B) adenoma or carcinoma (including variants with squamous and mucinous cell differentiation), bronchial adenoma or carcinoma, squamous cell carcinoma or mesenchymal tumors. A/B adenomas and carcinomas were the most common spontaneous pulmonary neoplasms observed in both mice and rats, but were observed less frequently in rats. In the National Toxicology Program (NTP) historical control database the incidence of spontaneous A/B adenomas in male (n = 2,084) and female (n = 2,079) mice is 13.8% and 4.9%, respectively; for A/B carcinomas, it is 5.3% and 2.4%, respectively. In male (n = 3,877) and female (n = 3,919) rats, spontaneous pulmonary neoplasms are rare with historical control rates less than 3% for A/B adenomas or carcinomas in either sex. The spontaneous A/B adenomas and carcinomas observed in mice and rats typically had papillary, solid or mixed (papillary and solid) histologic growth patterns. Pulmonary neoplasms from mice and rats treated with chemical carcinogens reviewed from 2-year studies consisted primarily of A/B adenomas and carcinomas. These tumors had papillary, glandular/tubular, solid or mixed (combination of 2 or more) histologic growth patterns. A few of the A/B neoplasms had areas of squamous or mucinous cell differentiation. Other less frequently occurring spontaneous and chemically-induced neoplasms included squamous cell carcinomas, bronchial adenomas and carcinomas, and sarcomas.

Adenoma↗
PubMed1991

Multivariate analysis of prognostic factors in stage IV follicular low-grade lymphoma: a risk model.

We analyzed the records of 96 previously untreated patients with stage IV follicular low-grade lymphoma (FLGL) uniformly treated with cyclophosphamide, doxorubicin, vincristine, prednisone, and bleomycin (CHOP-Bleo) chemotherapy from 1972 to 1982. The overall complete remission (CR) rate was 77%. At a median follow-up of 138 months, the 10-year cause-specific survival rate was 42% with a median survival of 100 months. Failure-free survival (FFS) was 15% at 10 years with a median FFS of 30 months. Multivariate analysis showed peripheral lymph node size (LN), degree of marrow involvement, and sex, in that order, to be important for FFS, while the number of extranodal sites (#ENS), LN, sex, and degree of marrow involvement were important for cause-specific survival. We devised a tumor burden (TB) model, incorporating #ENS, LN, and degree of marrow involvement. Three groups were identified with statistically significant differences in cause-specific survival and FFS. Those with low TB (one ENS exclusive of extensive marrow and nodal disease less than 5 cm) had a 10-year cause-specific survival of 73% compared with 24% for patients with high TB (greater than or equal to two ENS and nodal disease greater than or equal to 5 cm) (P less than .001) and 40% for those with intermediate TB (either greater than or equal to 2 ENS, or extensive marrow only, or nodal disease greater than 5 cm) (P = .050). Patients with low TB had a 10-year FFS rate of 32%, while the intermediate and high TB groups had 10% and 9% FFS, respectively (P = .003). Because sex was a very strong prognostic variable, we created a risk model for survival and FFS based on TB and sex. Females with low TB had the best prognosis (92% survival and 50% FFS at 10 years) and males with high TB had the worst outlook (median survival and FFS, 43 and 12 months, respectively). Other TB-sex combinations defined two groups with statistically significant differences in survival but comparable FFS. This model should aid in the design and analysis of future trials.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1991

Confocal laser scanning immunofluorescence microscopy of lamellar bodies and pulmonary surfactant protein A in isolated alveolar type II cells.

We have determined the distribution of surfactant protein A (SP-A) in isolated type II cells from the lungs of rats by using immunofluorescence in conjunction with a laser scanning microscope fitted with a confocal aperture. Because of the very narrow depth of field of this microscope (less than 0.4 microns) in the confocal format, we were able to optically section type II cells and determine both the distribution of SP-A in the type II cell and the distribution of the lamellar bodies. The location of SP-A was determined by using fluorescein isothiocyanate-labeled secondary antibodies and the lamellar body distribution by using the lipid soluble fluorescent stain Phosphine 3R. SP-A was detected in the cytoplasm of type II cells as asymmetrically distributed punctate fluorescent bodies that resembled lamellar bodies in terms of size, number, and distribution within the cytoplasm of the cell. Most of the SP-A was located within bodies of the type II cell. Diffuse patches of fluorescence were seen in other cytoplasmic regions as well as the number of the cell. We conclude that SP-A is localized primarily, but not exclusively, in lamellar bodies of type II cells and that laser scanning microscopy is a much superior technique for the localization of SP-A than conventional microscopy in terms of both sensitivity and resolution.

Animals↗
PubMed1990

A modular set of lacZ fusion vectors for studying gene expression in Caenorhabditis elegans.

We describe a series of plasmid vectors which contain modular features particularly useful for studying gene expression in eukaryotic systems. The vectors contain the Escherichia coli beta-galactosidase (beta Gal)-encoding region (the lacZ gene) flanked by unique polylinker segments on the 5' and 3' ends, and several combinations of a variety of modules: a selectable marker (an amber suppressor tRNA), a translational initiation region, a synthetic intron segment, the early polyadenylation signal from SV40, and 3' regions from two nematode genes. A segment encoding the nuclear localization peptide from the SV40 T antigen is incorporated into many of the constructs, leading to beta Gal accumulation in nuclei, which can facilitate identification of producing cells in complex tissues. To make functional beta Gal fusions to secreted proteins, we constructed plasmids with an alternate module encoding a synthetic transmembrane domain upstream from lacZ. This domain is designed to stop transfer of secreted proteins across the membrane during secretion, allowing the beta Gal domain of the fusion polypeptide to remain in the cytoplasm and thus function in enzymatic assays. We have used the vectors to analyze expression of several genes in the nematode Caenorhabditis elegans, and have demonstrated in these studies that lacZ can be expressed in a wide variety of different tissues and cell types. These vectors should be useful in studying gene expression both in C. elegans and in other experimental systems.

Amino Acid Sequence↗
PubMed1990

Treatment of poor-prognosis, newly diagnosed acute myeloid leukemia with ara-C and recombinant human granulocyte-macrophage colony-stimulating factor.

We administered recombinant granulocyte-macrophage colony-stimulating factor (GM-CSF) (120 micrograms/m2/d by continuous intravenous [IV] infusion) to 12 patients with newly diagnosed acute myeloid leukemia (AML) at relatively high risk of early death during remission induction. GM-CSF began 3 days after completion of induction chemotherapy (ara-C 1.5 g/m2 d x 4 days by continuous IV infusion after a 3 g/m2 bolus). Rates of fatal infection (42%), pneumonia and/or sepsis (83%), and CR (50%) did not differ significantly (P less than .05) from those observed after administration of the identical chemotherapy without GM-CSF to 53 historical controls with newly diagnosed AML at similarly high risk of early death. There were no significant differences between the GM-CSF-treated and the historical groups in the time required to reach neutrophil counts of 500 or 1,000/microL after administration of chemotherapy. Four patients died of infection before they could have benefited from the earliest recovery of neutrophil count observed in patients who entered CR. Growth of leukemia after GM-CSF administration was observed in only 1 of the 8 patients who survived long enough for response to induction therapy to be fully evaluated. This observation suggests that it might be safe to undertake larger, randomized studies, perhaps using earlier administration of GM-CSF, to definitively determine the role of GM-CSF added to chemotherapy in patients with newly diagnosed AML.

Adult↗
PubMed1990

c-myc amplification in ovarian cancer.

The c-myc oncogene codes for a DNA binding protein that appears to play an important role in the regulation of cell growth. c-myc gene amplification has been documented to occur in both hematopoietic and solid neoplasms and often indicates more biologically aggressive tumors. Southern hybridization analysis was performed on high-molecular-weight DNA isolated from primary ovarian carcinomas. Major structural rearrangements of c-myc were not detected. Five of seventeen (29.4%) tumor samples demonstrated amplification of the myc oncogene. The 5 patients with ovarian carcinomas associated with c-myc amplification exhibited a median survival of 17 months. Of the 12 patients without evidence of tumor-associated c-myc amplification, 5 have exhibited disease-free survival for an average of 36.8 months and are currently alive. The remaining 7 patients, the majority of whom had advanced-stage, poorly differentiated lesions with a normal c-myc copy number, exhibited a median survival of 9 months. There was no apparent relationship between c-myc amplification, grade of tumor differentiation, and response to platinol-based chemotherapy. These data do not suggest a prognostic role for c-myc amplification in primary ovarian cancer. However, c-myc amplification is a common finding in advanced-stage ovarian cancer.

Adult↗
PubMed1990

Oncogene alterations in endometrial carcinoma.

The neu oncogene codes for a cell surface protein that has a high degree of homology with the epidermal growth factor receptor. Amplification of this oncogene in breast carcinoma and ovarian carcinoma is correlated with a poorer prognosis. The c-myc oncogene codes for a DNA binding protein and is believed to regulate cellular proliferation. Sixteen primary endometrial adenocarcinomas were analyzed for c-myc and c-neu amplification. Eleven of sixteen tumor samples exhibited amplification of the neu gene. Four of these eleven patients died of disease an average of 16 months after diagnosis. The five patients without tumor amplification of the c-neu gene have been followed an average of 31.2 months without evidence of recurrent disease. Ten of fifteen tumor samples exhibited amplification of the c-myc gene. Five of the ten patients died of disease an average of 13.4 months after diagnosis. The remaining five patients have been followed for an average of 31.2 months and are free of disease. Six of the sixteen tumor specimens exhibited amplification of the both c-neu and c-myc genes, and four of these patients died of recurrent disease. Amplification of the c-neu or c-myc oncogene correlated with advanced-stage disease and poorly differentiated lesions, suggesting that oncogene amplification may predict biologically aggressive adenocarcinomas of the endometrium.

Adenocarcinoma↗
PubMed1990

Subchronic toxicity studies indicate that tris(2-chloroethyl)phosphate administration results in lesions in the rat hippocampus.

Tris(2-chloroethyl)phosphate (TRCP), a flame-retardant plasticizer used in plastics, polymeric foams and synthetic fibers, was studied as part of the National Toxicology Program's class study of phosphate flame-retardants. TRCP was administered at 0, 22, 44, 88, 175 and 350 mg/kg to both sexes of rats and 0, 44, 88, 175, 350 and 700 mg/kg to both sexes of mice in both fourteen day repeat dose and sixteen week subchronic studies. Results of these studies showed that TRCP toxicity in the 14-day studies was limited to modest increases in male rat kidney and female rat liver weights. Little evidence of toxicity was observed in mice in the 14 day studies. Toxicity observed in mice in the sixteen week studies was limited to increased liver weights in both sexes and decreased kidney weights in males. Administration of TRCP to rats for sixteen weeks resulted in increased mortality of both males and females, increased liver and kidney weights and a lesion in the hippocampal region of the brain. The lesion observed in rat brain appeared as loss of the pyramidal neurons of the CA1 region of the hippocampus and was both more common and more severe in female rats. This lesion, which was not observed in mice, is unusual for any chemical and is unique for a trialkyl phosphate such as TRCP. It is speculated that this highly directed toxicity of TRCP might be used as a chemical probe to investigate the role of the hippocampus in behavior and other functions.

Animals↗
PubMed1990

Renal failure in multiple myeloma. Pathogenesis and prognostic implications.

The pathogenesis, prognosis, and reversibility of renal failure were assessed in 494 consecutive, previously untreated patients with multiple myeloma. For patients with a similar extent of disease, the presence or degree of azotemia did not adversely affect prognosis. Hypercalcemia and/or Bence Jones proteinuria explained the renal failure in 97% of patients. After treatment with a combination of hydration and chemotherapy, normal renal function was achieved in 51% of patients, reversibility usually being rapid and occurring more often in those with slight elevation of serum creatinine. Myeloma control was much more important for survival prolongation than reversal of renal failure, supporting the prompt institution of effective therapy for the underlying malignancy.

Acute Kidney Injury↗