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Biomedical subjects

K S Smith

Publications and source records attributed to K S Smith.

At least 37 records · Page 2Linked to original sources
PubMed1999

Disrupted differentiation and oncogenic transformation of lymphoid progenitors in E2A-HLF transgenic mice.

The hepatic leukemia factor (HLF) gene codes for a basic region-leucine zipper (bZIP) protein that is disrupted by chromosomal translocations in a subset of pediatric acute lymphoblastic leukemias. HLF undergoes fusions with the E2A gene, resulting in chimeric E2a-Hlf proteins containing the E2a transactivation domains and the Hlf bZIP DNA binding and dimerization motifs. To investigate the in vivo role of this chimeric bZIP protein in oncogenic transformation, its expression was directed to the lymphoid compartments of transgenic mice. Within the thymus, E2a-Hlf induced profound hypoplasia, premature involution, and progressive accumulation of a T-lineage precursor population arrested at an early stage of maturation. In the spleen, mature T cells were present but in reduced numbers, and they lacked expression of the transgene, suggesting further that E2a-Hlf expression was incompatible with T-cell differentiation. In contrast, mature splenic B cells expressed E2a-Hlf but at lower levels and without apparent adverse or beneficial effects on their survival. Approximately 60% of E2A-HLF mice developed lymphoid malignancies with a mean latency of 10 months. Tumors were monoclonal, consistent with a requirement for secondary genetic events, and displayed phenotypes of either mid-thymocytes or, rarely, B-cell progenitors. We conclude that E2a-Hlf disrupts the differentiation of T-lymphoid progenitors in vivo, leading to profound postnatal thymic depletion and rendering B- and T-cell progenitors susceptible to malignant transformation.

Age Factors↗
PubMed1998

The use and selection of sources in information seeking: the Cancer Information Service experience. Part 8.

The Cancer Information Service (CIS), the voice of the National Cancer Institute (NCI) for more than 20 years, disseminates information through two channels: a toll-free telephone service (1-800-4-CANCER) and an outreach program which develops partnerships with organizations that reach underserved populations. In 1996, the telephone service handled approximately 500,000 calls on a range of topics, including cancer treatment, clinical trials, coping issues, referrals to services, prevention, causes, and symptoms of cancer. As part of a national telephone service user survey, conducted in 1996, that examined the impact of the CIS program, callers were asked what additional sources they went to for the same information that they requested from the CIS. The survey revealed that the CIS plays a critical role for information seekers. Almost 59% of surveyed callers contacted no other sources to address the topic they discussed with the CIS. Almost half of the callers who contacted other sources made all of those contacts before calling the CIS. Younger callers (under 40), those with a higher level of education, and those seeking information about treatment and causes of cancer were more likely to contact other sources for the same information. Health professionals, libraries, and bookstores were the most commonly used non-CIS sources. This variety in information seeking highlights the need for services, like the CIS, that can meet the diverse information needs of callers.

Adolescent↗
PubMed1997

Chimeric oncoprotein E2a-Pbx1 induces apoptosis of hematopoietic cells by a p53-independent mechanism that is suppressed by Bcl-2.

The chimeric oncoprotein E2a-Pbx1 results from fusion of the E2A and PBX1 genes following t(1;19) chromosomal translocations in B cell precursor acute leukemias. Experimentally B cell progenitors do not tolerate constitutive expression of E2a-Pbx1 which contrasts with transformation of several other cell types following its stable expression both in vitro and in vivo. To further investigate the effects of E2a-Pbx1 on the B cell progenitors, we conditionally expressed E2a-Pbx1 under control of a metal response element in hematopoietic precursor cell lines in vitro. Inducible expression of E2a-Pbx1 resulted in cell death with the morphologic and molecular features of apoptosis. A structure-function analysis demonstrated that induction of apoptosis was not a dominant-negative effect of the E2a moiety but, rather, required the DNA-binding homeodomain of Pbx1. E2a-Pbx1-induced apoptosis proceeded through a BCL2-responsive checkpoint eventuating in PARP inactivation but did require p53. Constitutive expression of E2a-Pbx1 did not induce apoptosis or continued cycling of Rat-1 fibroblasts in low serum conditions. These studies demonstrate that E2a-Pbx1 initiates programmed cell death of hematopoietic precursers by a mechanism that requires its chimeric transcriptional properties, but, unlike other nuclear oncoproteins, is independent of p53.

Animals↗
PubMed1997

Methane and trichloroethylene oxidation by an estuarine methanotroph, Methylobacter sp. strain BB5.1.

An estuarine methanotroph was isolated from sediment enrichments and designated Methylobacter sp. strain BB5.1. In cells grown on medium with added copper, oxidation of methane and trichloroethylene occurred with similar Ks values, but the Vmax for trichloroethylene oxidation was only 0.1% of the methane oxidation Vmax. Cells grown on low-copper medium did not oxidize trichloroethylene and showed a variable rate of methane oxidation.

Copper↗
PubMed1997

Identification of cysteine and arginine residues essential for the phosphotransacetylase from Methanosarcina thermophila.

Phosphotransacetylase catalyzes the following reaction: CoASH + CH3CO2PO3(2-) <==> CH3COSCoA + HPO4(2-) (where CoA is coenzyme A). Based on biochemical characterization of the enzyme from the obligate anaerobe Clostridium kluyveri, a ternary mechanism was proposed in which an unspecified cysteine abstracts a proton from CoASH forming a nucleophilic thiolate anion which attacks acetyl phosphate (J. Henkin and R. H. Abeles, Biochemistry 15:3472-3479, 1976). Heterologous production in Escherichia coli of the phosphotransacetylase from Methanosarcina thermophila, an obligately anaerobic methanoarchaeon, allowed site-specific replacements to identify essential residues. All four cysteines present in the sequence were individually replaced with alanine, and the kinetic constants of the altered enzymes were determined. The results indicated that only C159 is essential for activity; however, replacement with serine resulted in a fully active enzyme. Activity of the unaltered phosphotransacetylase was sensitive to N-ethylmaleimide. Inhibition kinetics of altered enzymes indicated that this sensitivity resulted from modification of C312, which is at the active site but itself is nonessential for catalysis. Five arginines were individually replaced with glutamine. Kinetic analysis of the altered enzymes identified R310 as essential for activity. Of the four nonessential for activity, R87 and R133 appear to be involved in binding CoA.

Amino Acid Sequence↗
PubMed1997

Associations between soil lead and childhood blood lead in urban New Orleans and rural Lafourche Parish of Louisiana.

This study evaluates associations between soil lead concentrations (SPb), age of housing, and blood lead levels (BPb) of children in metropolitan New Orleans and Lafourche Parish, Louisiana. The database includes over 2,600 SPb and 6,000 BPb samples paired by their median values and pre-1940 housing percentages for 172 census tracts. Associations were evaluated with Fisher's exact test and Spearman's rho test and modeled with the least sum of absolute deviations regression. Census tracts with low SPb are associated with new housing, but census tracts with high SPb are evenly split between old and new housing [Fisher's exact test, p = 8.60 X 10(-13) for the percentage of housing built before 1940 (percent pre-1940 housing) versus SPb]. The p-value for SPb versus BPb is 12 orders of magnitude stronger than the p-value for percent pre-1940 housing versus BPb. Census tracts with low BPb are associated with new housing, but census tracts with high BPb are split evenly between old and new housing (Fisher's exact test, p = 1. 67 X 10(-12) for percent pre-1940 housing versus BPb). Census tracts with high SPb are associated with high BPb and census tracts with low SPb are associated with low BPb (Fisher's exact test, p = 3.18 X 10(-24) for BPb versus SPb). The Spearman's rho test of the association of SPb and BPb in Orleans and Lafourche Parishes yielded a p-value of 6.12 X 10(-24). The least sum of absolute deviations regression model of the data is BPb = 1. 845 + 0.7215 (SPb)0.4. A comparison of the modeled BPb versus observed BPb has an r(2) of 0.552 and a p-value of 2.83 X 10(-23) that this relation was due to chance. If blood lead in children is more closely associated to soil lead than to the age of housing, then primary lead prevention should also include soil lead.

Age Factors↗
PubMed1997

Differential attachment of oral treponemes to monolayers of epithelial cells.

This in vitro study describes the attachment properties of several oral treponemes to monolayers of epithelial cells and the effect of epithelial cell confluence on treponeme attachment. Four serotypes of Treponema denticola, Treponema scoliodontum, three subspecies of Treponema socranskii, and Treponema vincentii were tested with monolayers of epithelial cells of human and canine origin. Attachment of oral treponemes were compared to attachment by T. pallidum subsp. pallidum, and by the non-pathogen Treponema phagedenis. Results indicated that different serotypes of T. denticola had similar abilities to attach to epithelial cells. However, subspecies of T. socranskii differed in their ability to attach to epithelial cells. The proportion of epithelial cells susceptible to attachment by oral spirochetes was strongly related to the confluence level of the monolayer. In contrast, T. pallidum attached equally well to both epithelial cell lines at all confluence levels. T. phagedenis attached to < 1% of all epithelial cells. In general, attachment of oral treponemes to canine cells was lower than to human cells, suggesting species-specificity for adherence. Attachment of oral treponemes to epithelial cells may promote colonization of the periodontal pocket, as well as retention of treponeme colonies within plaque. The preference of oral treponemes to attach to cells of low confluence fields may translate in vivo to an increased ability to attach to cells which are actively dividing. Such cells are found in areas of repair, a common status within inflamed periodontal pockets. Furthermore, attachment of oral treponemes to epithelial cell barriers may promote or potentiate cytopathic processes.

Animals↗
PubMed1996

Associations between Porphyromonas gingivalis and oral treponemes in subgingival plaque.

Colonization and/or proliferation of Treponema denticola may depend on the presence of Porphyromonas gingivalis. The aims of this study were to confirm this synergistic relationship, to determine whether other oral bacteria were similarly associated with P. gingivalis and to relate coinfection to the periodontal status of plaque donors. Subgingival plaque was collected from every tooth except third molars in 106 subjects who were grouped by their worst periodontal condition. In addition to P. gingivalis, monoclonal antibodies were used to identify Campylobacter rectus, Eikenella corrodens, T. denticola, Treponema socranskii and pathogen-related oral spirochetes. Associations of these bacteria with coinfection by P. gingivalis were assessed by estimated odds ratios. The results indicate that coinfection with P. gingivalis is linked to all tested bacteria, but each pair was associated with distinct periodontal conditions. The distribution of coinfected sites suggests biased colonization of facial surfaces over lingual surfaces.

Adult↗
PubMed1996

Periodontal status and detection frequency of bacteria at sites of periodontal health and gingivitis.

It is generally recognized that bacteria in dental plaque at sites of periodontal diseases are not commonly found at sites of periodontal health. One hypothesis to explain the etiology of periodontitis is that pathogenic bacteria from diseased sites infect healthy sites. It has been suggested that gingival inflammation may predispose sites to colonization by bacteria associated with periodontal diseases. The purpose of this cross-sectional study was to determine whether the detection frequency of selected bacteria at sites of periodontal health or gingivitis differed between subjects who were in good periodontal health, subjects who had gingivitis, or subjects with periodontitis. The clinical status of every tooth (except third molars) from 106 subjects was characterized by means of clinical attachment level, probing depth and by signs of inflammation. Subgingival plaque was collected from mesio-facial and disto-lingual surfaces. Specific monoclonal antibodies were used in an immunocytochemical assay to identify Campylobacter rectus, Eikenella corrodens, Porphyromonas gingivalis, pathogen-related oral spirochetes (PROS, using Treponema pallidum subspecies pallidum monoclonal antibodies), T. denticola (serotypes A-D), T. socranskii subspecies buccale and T. socranskii subspecies socranskii. Differences in detection of bacteria between groups of subjects were measured using odds ratios (OR). Results of this study indicate that PROS was the only identified bacterium at sites of both health and gingivitis that demonstrated a significant positive relationship with the presence of periodontitis. These findings do not prove that bacteria spread from periodontitis sites, nor do they imply that disease necessarily results from infection. However, these data do suggest that some bacteria associated with periodontitis are more likely than others to tolerate conditions at healthy sites and that the presence of periodontitis increases risk of infection at healthy sites.

Adult↗
PubMed1995

Synergistic and additive combinations of several antitumor drugs and other agents with the potent alkylating agent adozelesin.

Adozelesin is a highly potent alkylating agent that undergoes binding in the minor groove of double-stranded DNA (ds-DNA) at A-T-rich sequences followed by covalent bonding with N-3 of adenine in preferred sequences. On the basis of its high-potency, broad-spectrum in vivo antitumor activity and its unique mechanism of action, adozelesin has entered clinical trial. We report herein the cytotoxicity for Chinese hamster ovary (CHO) cells of several agents, including antitumor drugs, combined with adozelesin. The additive, synergistic, or antagonistic nature of the combined drug effect was determined for most combinations using the median-effect principle. The results show that in experiments using DNA- and RNA-synthesis inhibitors, prior treatment with the DNA inhibitor aphidicolin did not affect the lethality of adozelesin. Therefore, ongoing DNA synthesis is not needed for adozelesin cytotoxicity. Combination with the RNA inhibitor cordycepin also did not affect adozelesin cytotoxicity. In experiments with alkylating agents, combinations of adozelesin with melphalan or cisplatin were usually additive or slightly synergistic. Adozelesin-tetraplatin combinations were synergistic at several different ratios of the two drugs, and depending on the schedule of exposure to drug. In experiments using methylxanthines, adozelesin combined synergistically with noncytotoxic doses of caffeine or pentoxifylline and resulted in several logs of increase in adozelesin cytotoxicity. In experiments with hypomethylating agents, adozelesin combined synergistically with 5-azacytidine (5-aza-CR) and 5-aza-2'-deoxycytidine (5-aza-2'-CdR). Combinations of adozelesin with tetraplatin or 5-aza-2'-CdR were also tested against B16 melanoma cells in vitro and were found to be additive and synergistic, respectively. The synergistic cytotoxicity to CHO cells of adozelesin combinations with tetraplatin, 5-aza-CR, or pentoxifylline was not due to increased adozelesin uptake or increased alkylation of DNA by adozelesin.

Animals↗
PubMed1995

Mucopolysaccharidosis: MPS VI and associated delayed tooth eruption.

Eight cases of mucopolysaccharidosis Type VI (Maroteaux-Lamy syndrome) are reviewed and two cases are presented in detail. Developmental dental anomalies including unerupted and impacted permanent teeth and associated hyperplastic tooth follicles are seen frequently in MPS patients. The surgical implications and management are discussed. All patients reviewed had significant cardiovalvular disease. It is essential for the primary medical provider to establish early basic dental care and evaluation for delayed eruption of primary and permanent dentition. This will probably minimize the possibility of infective endocarditis and allow for early treatment of impacted teeth.

Child↗
PubMed1995

Subgingival distribution of Treponema denticola, Treponema socranskii, and pathogen-related oral spirochetes: prevalence and relationship to periodontal status of sampled sites.

Aims of this study were to comprehensively describe the intraoral distribution of the spirochete morphogroup and of 7 antigenically distinct oral treponema, and to relate their presence to periodontal status. Periodontal tissues were evaluated at 4 sites on every tooth except third molars and 76 subjects were classified according to the worst periodontal condition at any one site: Group 1, gingivitis (n = 13); Group 2, early periodontitis (n = 38); and Group 3, advanced periodontitis (n = 25). Subgingival plaque was collected from each half of every tooth evaluated clinically. Spirochetes were identified with phase contrast microscopy and specific treponema were detected immunochemically using monoclonal antibodies to Treponema denticola serovars A-D, T. socranskii subspecies bucalle, T. socranskii subspecies socranskii, and T. pallidum (pathogen-related oral spirochetes, PROS). The counting protocol was conservative and probably underestimated the actual presence of organisms. Spirochetes were found at one or more sites in approximately 60% of subjects in all groups. PROS were found in approximately 40% of subjects in all groups while T. denticola (predominantly serotype B) and T. socranskii (exclusively T. socranskii subsp. buccale) were more frequently observed in Group 2 (roughly 25% for both treponema) than in Groups 1 or 3. Overall, spirochetes were detected in less than 15% of the 4,040 sites examined. Spirochetes were found at more sites of periodontitis (group mean range 20 to 40%) than of gingivitis (6 to 20%), and were only infrequently found at sites of periodontal health (4 to 10%). Spirochetes were identified most often in plaque from around molars and they were usually found in only one of two samples from individual teeth. Results of this study suggest that although spirochetes are most often found associated with periodontitis, their distribution is restricted and most periodontitis sites do not harbor spirochetes.

Adult↗
PubMed1995

Temporal changes of MR findings in central pontine myelinolysis.

We report central pontine myelinolysis in orthotopic liver transplant patients. Sequential MR imaging of these patients with central pontine myelinolysis shows progressive decrease of T2-weighted MR signal in the pons, which may not resolve despite complete neurologic recovery.

Adult↗
PubMed1994

V79 Chinese hamster lung cells resistant to the bis-alkylator bizelesin are multidrug-resistant.

Bizelesin (U-77779) is a highly potent bis-alkylating antitumor agent that is effective against several tumor systems in vitro and in vivo. V79 cells that were 125- to 250-fold resistant to bizelesin developed after constant exposure to gradually increasing concentrations of the drug. Resistant cells exhibited a multidrug-resistant phenotype and genotype as indicated by cross-resistant to several structurally and functionally unrelated drugs, e.g., colchicine, actinomycin D, and Adriamycin, and overexpression of mdr mRNA. Very low levels of cross-resistance to the alkylating agents cisplatin and melphalan were seen. Multidrug-resistant mouse leukemia (P388/Adriamycin-resistant) and human (KB/vinblastine-resistant) cells were also resistant to bizelesin. Bizelesin resistance was unstable and decreased when cells were grown in the absence of the drug. Resistant and sensitive cell lines had similar levels of glutathione, and bizelesin cytotoxicity for resistant cells was not markedly affected by treatment with buthionine sulfoximine. Cross-resistance between bizelesin and several of its analogs is reported.

Alkylating Agents↗
PubMed1994

Elevated tyrosine hydroxylase in the locus coeruleus of suicide victims.

The amounts of tyrosine hydroxylase protein in locus coeruleus from nine pairs of antidepressant-free suicide victims and age-matched, sudden-death control cases were determined by quantitative blot immunolabeling of cryostat-cut sections from the caudal portion of the nucleus. In each of the nine age-matched pairs, the concentration of tyrosine hydroxylase was greater in the sample from the suicide victim, with values ranging from 108 to 172% of the matched control value (mean = 136%). By contrast, there were no differences in the concentrations of neuron-specific enolase protein in the same set of samples. Similarly, the number of neuromelanin-containing cells, counted in sections of locus coeruleus adjacent to those taken for blot immunolabeling analyses, did not differ between the two groups. These data indicate that locus coeruleus neurons from suicide victims contain higher than normal concentrations of tyrosine hydroxylase, thus raising the possibility that the expression of tyrosine hydroxylase in locus coeruleus may be relevant in the pathophysiology of suicide.

Adult↗