Biomedical subjects

A T Davis

Publications and source records attributed to A T Davis.

At least 19 recordsLinked to original sources

PubMed2004

Serum carnitine concentrations correlated to clinical outcome parameters in chronic hemodialysis patients.

Carnitine metabolism and the therapeutic use of carnitine has been a major area of interest in dialysis patients. The purpose of this study was to determine whether any correlations exist between carnitine status and selected clinical parameters in hemodialysis (HD) patients. This study was an observational study of data from patients receiving HD at a Midwest dialysis center. The subjects (n=49) were 60+/-16 (mean+/-SD) years of age and 48% male. Fifteen percent of the subjects had type 1 diabetes mellitus (DM), 29% had type 2 DM, and 25% had left ventricular hypertrophy (LVH). The serum-free and total carnitine, and acylcarnitine concentrations were: 40.3+11.8 microm/l, 22.8+/-7.3, and 17.5+/-5.9 microm/l, respectively. The serum acylcarnitine to free carnitine ratio (A/F) was 0.80+/-0.27. Blood urea nitrogen (BUN), parathyroid hormone and ejection fraction were positively correlated and age and left atrial dilation (cm) were negatively correlated with serum total carnitine (P<0.05). BUN and hematocrit were positively correlated (P<0.05) and age was negatively correlated with free carnitine. Subjects who used mannitol or were male had significantly higher concentrations of both free and total carnitine, respectively (P<0.05). Subjects using aspirin had lower concentrations of serum total carnitine (P<0.10). These results suggest certain subgroups of patients may need to be targeted for further studies with carnitine replacement therapy, i.e. long-term patients, older patients, patients with left verticular hypertrophy and left atrial enlargement, females and patients on aspirin therapy.

Age Factors↗

PubMed2004

Protein kinase CK2 as regulator of cell survival: implications for cancer therapy.

Recent studies have generated sufficient information to warrant a consideration of protein kinase CK2 as a potential target for cancer therapy. CK2 is a ubiquitous and highly conserved protein serine/threonine kinase that has long been considered to play a role in cell growth and proliferation. It is essential for cell survival, and considerable evidence suggests that it can also exert potent suppression of apoptosis in cells. This is important since the cancer phenotype is characterized by deregulation of not only proliferation but also of apoptosis. In normal cells, the level of CK2 appears to be tightly regulated, and cells resist a change in their intrinsic level of CK2. However, in all the cancers that have been examined an elevation of CK2 has been observed. Further, it appears that modest deregulation in the CK2 expression imparts a potent oncogenic potential to the cells. Disruption of CK2 by treatment of cells with antisense CK2 results in induction of apoptosis in a time and dose-dependent manner. Thus, we propose that down-regulation of CK2 by employing specific strategies to deliver antisense CK2 in vivo could have a potential role in cancer therapy.

Animals↗

PubMed2001

Cervical dysplasia in women infected with the human immunodeficiency virus (HIV): a correlation with HIV viral load and CD4+ count.

OBJECTIVES: The incidence of cervical dysplasia and carcinoma is known to be increased in HIV-infected women. In addition, there is a positive correlation between HIV viral load (VL), CD4+ count, and opportunistic infections, as well as the incidence of various malignancies. This study compares HIV VL and CD4+ count with the presence of cervical dysplasia, as well as with the degree of severity of dysplasia. METHODS: A retrospective chart review of 350 HIV-infected women with polymerase chain reaction (PCR) quantitation of viral load was performed to identify 82 women with biopsy-proven cervical dysplasia and 25 women without any significant cervical pathology. The highest plasma VL within a year of the patients' cervical pathology and corresponding CD4+ count was selected and compared with cervical pathology. Univariate and multivariate statistical analysis using Student's t test and logistic regression analysis was used to analyze the significance of other risk factors such as age, race, smoking history, history of illicit drug use, and prior sexually transmitted disease as well as of viral load and CD4+ count. RESULTS: Of 82 cases of cervical dysplasia, 33 (40.24%) were mild (CIN I), 47 (57.32%) were either moderate or severe (CIN II-III) dysplasia, and 2 demonstrated invasive squamous cell carcinoma (2.44%). A significant statistical difference was found when comparing either HIV plasma VL or CD4+ T-cell counts with the presence of cervical dysplasia on biopsy (P < 0.005). However, only CD4+ count was identified as an independent risk factor for the presence of cervical dysplasia after multivariate analysis. CONCLUSION: In our population, there is a significant correlation between VL and CD4+ count and the presence of cervical dysplasia. However, VL does not appear to be an independent risk factor for cervical dysplasia in this population of HIV-infected women.

Adolescent↗

PubMed2000

A potential role of nuclear matrix-associated protein kinase CK2 in protection against drug-induced apoptosis in cancer cells.

Protein kinase CK2 (CK2) has long been implicated in the regulation of cell growth and proliferation. Its activity is generally elevated in rapidly proliferating tissues, and nuclear matrix (NM) is an important subnuclear locale of its functional signaling. In the prostate, nuclear CK2 is rapidly lost commensurate with induction of receptor-mediated apoptosis after growth stimulus withdrawal. By contrast, chemical-induced apoptosis in prostate cancer and other cells (by etoposide and diethylstilbestrol) evokes an enhancement in CK2 associated with the NM that appears to be because of translocation of CK2 from the cytoplasmic to the nuclear compartment. This shuttling of CK2 to the NM may reflect a protective response to chemical-mediated apoptosis. Supporting evidence for this was obtained by employing cells that were transiently transfected with various expression plasmids of CK2 (thereby expressing additional CK2) prior to treatment with etoposide or diethylstilbestrol. Cells transfected with the CK2alpha or CK2alphabeta showed significant resistance to chemical-mediated apoptosis commensurate with the corresponding elevation in CK2 in the NM. Transfection with CK2beta did not demonstrate this effect. These results suggest, for the first time, that besides the commonly appreciated function of CK2 in cell growth, it may also have a role in protecting cells against apoptosis.

Adenocarcinoma↗

PubMed2000

Antisense oligonucleotides against protein kinase CK2-alpha inhibit growth of squamous cell carcinoma of the head and neck in vitro.

BACKGROUND: Human squamous cell carcinomas of the head and neck (SCCHN) overexpress the protein kinase CK2, and elevated CK2 activity correlates with aggressive tumor behavior and poor clinical outcome. We therefore investigated whether interference with CK2 expression would inhibit SCCHN cell growth in vitro. METHODS: We targeted the catalytic (alpha) subunit of CK2 using an antisense oligodeoxynucleotide (ODN) strategy. Human Ca9-22 cells derived from SCCHN were transfected with CK2-alpha sense, nonsense, or antisense ODN; CK2 activity was measured; and the effect on CK2 activity and on cell growth was determined. RESULTS: Transfection of Ca9-22 cells with antisense CK2-alpha ODN resulted in significantly decreased CK2 kinase activity associated with nuclear chromatin and in dose-dependent growth inhibition of Ca9-22 cells in vitro. CONCLUSIONS: Interference with the protein kinase CK2 signal in SCCHN cells may offer a novel anticancer strategy for this malignancy.

Base Sequence↗

PubMed2000

Significance of protein kinase CK2 nuclear signaling in neoplasia.

Many stimuli play a role in influencing the structure and function of chromatin and nuclear matrix through post-translational modifications of the component proteins in these dynamic structures. We propose that the protein serine/threonine kinase CK2 (formerly casein kinase II) is one such agent that is involved in signal transduction in the nuclear matrix and chromatin in response to a variety of stimuli. Protein kinase CK2 appears to undergo rapid modulations in its association with nuclear matrix and nucleosomes in response to mitogenic signals and is involved in the phosphorylation of a variety of intrinsic proteins in these structures depending on the state of genomic activity. In addition, its association or loss from the nuclear matrix may also influence the apoptotic activity in the cell. CK2 has been found to be dysregulated in virtually all the neoplasias examined and nuclear association appears to be an important facet of its expression in tumor cells. We hypothesize that CK2 provides a functional paradigm linking the nuclear matrix and chromatin structures. Identification of precise loci of action of CK2 in these structures and how they influence the morphological appearance of the nucleus under normal and abnormal growth conditions would be an important future direction of investigation. J. Cell. Biochem. Suppl. 35:130-135, 2000. Published 2001 Wiley-Liss, Inc.

Animals↗

PubMed2000

Pituitary involvement in T cell renewal during development and metamorphosis of Xenopus laevis.

Studies of pituitary-deficient dwarf mice show that in the absence of a normally functioning pituitary, thymus development is impaired. Treatment with growth hormone, prolactin, and thyroid hormones restores thymus development. Smaller thymus size in pituitary-deficient animals could be due to defective development of precursors, impaired precursor immigration, impaired thymocyte expansion, or development of a smaller epithelial/stromal compartment in the thymus of pituitary-deficient animals. Using a well-characterized amphibian model to study stem cell immigration into the thymus, we show here that hypophysectomy (hypx) of young tadpoles interferes with overall growth of the frogs and with the broad lymphocyte expansion that occurs after metamorphosis, but it does not interfere with the immigration of T cell precursors into an implanted thymus. Diploid host cells moving into a triploid thymus implant do so at the same rate and to the same extent in hypx hosts as they do in intact control hosts. Analysis of cell division in the implanted thymus populations shows a significantly greater proportion of cells arrested in the G(0)/G(1) phase and a significantly lower proportion of cells in the S phase and G(2) + M phase of the cell cycle in hypx hosts than in intact hosts. Thus, smaller thymus size in hypx hosts could be due to a slower rate of expansion of precursors that migrate there.

Aging↗

PubMed2000

Monoclonal antibody-based therapy of lymphoid neoplasms: what's on the horizon?

Although exciting advances in monoclonal antibody therapy have already occurred, a review of agents in earlier stages of development reveals that many new agents may be approaching the clinic in the years to come. A look at the horizon of monoclonal antibody therapy reveals the following: novel strategies for augmenting the efficacy of monoclonal antibodies with which many clinicians are already familiar; novel antibodies with activity against lymphoma cells; novel technologies for generating and humanizing monoclonal antibodies; novel types of antibody-based therapeutics; and novel uses for these agents as modulators of the host immune system or other aspects of host-tumor interaction. Research in each of these areas will be reviewed.

Alemtuzumab↗

PubMed1999

Differential targeting of protein kinase CK2 to the nuclear matrix upon transient overexpression of its subunits.

Modest dysregulation of CK2 has been shown to enhance the oncogenic potential in transgenic models of cancer. Since nuclear matrix serves as an anchor for CK2 and plays a key role in growth-related activities, we examined the effects of CK2 overexpression on its signaling to the nuclear matrix. Expression plasmids pCI-CK2alpha, pCI-CK2beta, and the bicistronic pCI-CK2alphabeta containing full length cDNAs encoding the various subunits were employed to transiently transfect two cell lines, BPH-1 and COS-1. Cytosol from transfected BPH-1 cells containing alpha or beta or alpha + beta or alphabeta showed a modest increase in CK2 activity by 26%, 1%, 20%, and 17%, respectively, over that in the controls transfected with pCI vector. However, the corresponding increase in CK2 activity in the NM fraction was 156%, 8%, 147%, and 152%, respectively. Immunoblot analysis of the CK2 in the NM accorded with these data. Similar results were obtained with COS-1 cells or other expression vectors. The results suggest that moderate overexpression of CK2 in the cells evokes a differential several-fold enhancement in NM associated CK2 relative to that in the cytosol. This process may have a bearing on the functional signaling of this kinase in relation to its possible role in oncogenesis.

Androgen-Binding Protein↗

PubMed1999

Nuclear matrix targeting of the protein kinase CK2 signal as a common downstream response to androgen or growth factor stimulation of prostate cancer cells.

Protein kinase CK2, a messenger-independent serine/threonine kinase, has been implicated in cell growth. Androgenic stimulus in rat prostate modulates its association with nuclear matrix (NM) and chromatin. Because the growth of human prostate carcinoma cells is influenced by androgens and/or growth factors, we determined the nature of CK2 signaling in the NM in response to androgen and growth factor stimuli. Androgen-sensitive LNCaP and androgen-insensitive PC-3 cells were cultured in media to regulate their growth in the presence of 5alpha-dihydrotestosterone (5alpha-DHT) or growth factors (epidermal growth factor, keratinocyte growth factor, and transforming growth factor alpha). The activity of CK2 was measured in the cytosolic and NM fractions isolated from these cells after treatment with growth stimuli. The changes in CK2 in various fractions were also confirmed by immunoblotting with a specific antibody. LNCaP cells responded to both 5alpha-DHT and growth factors for growth. The presence of these agents in the culture medium evoked a translocation of CK2 to the NM from the cytosol. The PC-3 cells did not respond to 5alpha-DHT for growth but did respond to growth factors. Under these conditions, there was also a translocation of CK2 to the NM concomitant with a decrease in the cytosolic fraction. These results suggest that CK2 translocation to the NM occurs in response to various growth stimuli in cells in culture. Thus, CK2 is a common downstream signal transducer in response to diverse growth stimuli that may relate to the pathobiology of prostate cancer cells.

Adenocarcinoma↗

PubMed1999

Modulation of nuclear matrix protein phosphorylation by histones: possible involvement of NM-associated protein kinase CK2 activity.

Nuclear matrix (NM), a proteinaceous network of filaments, dictates nuclear morphology and the structure/function of DNA. Phosphorylation of NM proteins is a potential signal for regulating matrix functions. Histones also are intimately involved in DNA structure and transcription. Here, we report that various histones enhanced 32P incorporation into certain NM proteins. Modulation of NM protein phosphorylation by histones is mediated through regulation of protein kinase CK2, a messenger-independent serine/threonine kinase, which is significantly associated with the NM. The stimulatory effect of histones was mitigated by prior incubation of histones with DNA in the reaction. Phosphorylation of NM proteins was extensively reduced when an excess of the CK2-specific peptide substrate was included in the phosphorylation reaction as a competitor. Also, enhancement in the NM-associated CK2 activity by histones was blocked by inhibitors of CK2. Histone H1 effect appeared to be mediated mainly by charge effect since a stretch of polylysine induced a similar effect. Various histones also differentially affected the autophosphorylation of NM-associated CK2 subunits. This may contribute to the observed effects of histones on the NM, resulting in an enhancement and differential pattern of NM protein phosphorylation. Such a regional modification of NM protein phosphorylation might influence the nuclear functions that require histone displacement, namely, replication and transcription.

Animals↗

PubMed1999

Apoptosis and growth inhibition of head and neck tumor cell line induced by epidermal growth factor receptor tyrosine kinase inhibitor.

Overexpression of the epidermal growth factor (EGF) receptor, a hallmark of aerodigestive squamous cell carcinoma of the head and neck (SCCHN), correlates with aggressive tumor behavior. There is evidence that SCCHN cells auto-activate their EGF receptors. The receptor has therefore attracted interest as a potential therapeutic target. We tested the in vitro therapeutic efficacy of PD153035--a potent, specific inhibitor of the tyrosine kinase intrinsic to the EGF receptor--by employing a well-characterized cell line derived from human gingival SCCHN. DNA-synthesis and cell number were assayed for growth-inhibitory effects, phosphorylation of the EGF receptor was quantitated by immunoblot, and cell apoptosis was detected by terminal deoxytransferase (TdT)-mediated deoxyuridine triphosphate (dUTP)-biotin nick end labeling (TUNEL) in situ assay. PD153035, at nanomolar concentrations, inhibited autophosphorylation of the EGF receptor induced by EGF stimulation and the inhibition occurred in a dose-dependent manner. Under the same conditions, PD153035 inhibited cell growth, and induced apoptosis of SCCHN cells in vitro. We conclude that selective inhibition of the EGF receptor tyrosine kinase completely abolishes EGF receptor phosphorylation resulting from receptor stimulation, and results in growth inhibition and apoptosis of SCCHN cells in vitro. By inducing cytostasis and apoptosis, this new class of inhibitors may be of therapeutic value against SCCHN.

Apoptosis↗

PubMed1999

Role of protein kinase CK2 in phosphorylation nucleosomal proteins in relation to transcriptional activity.

Protein kinase CK2 undergoes rapid translocation to nuclear matrix and nucleosomes on androgenic stimulation of growth in prostatic epithelial cells. Further, CK2 appears to be regulated differentially in the transcriptionally active and inactive nucleosomes. We have investigated the role of CK2 in phosphorylation of nucleosome-associated proteins in the transcriptionally active and inactive nucleosomes that were isolated from ventral prostate subjected to different androgenic status in vivo. Proteins associated with these nucleosomes were phosphorylated via the intrinsic protein kinase activity, using [gamma-32P]ATP in the absence and presence of GTP. Several proteins appear to be potential substrates for CK2 associated with the nucleosomes. Among them are proteins that are differentially associated with the transcriptionally active and inactive nucleosomes. Phosphorylation of several of these proteins is modulated depending not only on their sites of association (i.e., active vs. inactive nucleosomes) but also on the state of transcriptional activity. Differential phosphorylation of specific proteins by CK2 associated with the active and inactive nucleosomes may be pertinent to the process of transcription regulation.

Animals↗

PubMed1998

Dynamics of protein kinase CK2 association with nucleosomes in relation to transcriptional activity.

Protein kinase CK2 has been implicated in control of cell growth and proliferation. Since growth stimuli evoke its preferential association with chromatin and nuclear matrix, we examined the dynamics of CK2 in nucleosomes fractionated on the basis of their transcriptional activity in the rat prostate. In this model, androgens induce expression of androgen-dependent genes but inhibit the androgen-repressed genes, whereas absence of androgens has the reverse effect. The level of CK2 was higher in the active than in inactive nucleosomes from normal prostate. Differential alterations in the levels of CK2 activity in the transcriptionally active versus inactive nucleosomes were evoked by androgen deprivation or administration. Comparison of the distribution of CK2 in active and inactive nucleosomes under varying androgenic conditions showed that the relative CK2 activity intrinsic to the transcriptionally active nucleosomes remained fairly stable, concordant with gene activity specific to the androgenic status. However, CK2 associated with inactive nucleosomes declined to a minimal level on androgen deprivation but increased rapidly on androgen administration (reflecting expression of multiple androgen-dependent genes). We suggest a role for CK2 in promoting the conformational transition of inactive nucleosomes to the active form and in the function of transcriptionally active nucleosomes.

Androgens↗

PubMed1998

Mechanism of protein kinase CK2 association with nuclear matrix: role of disulfide bond formation.

Nuclear matrix (NM) appears to be an intranuclear locale for significant and dynamic association of the ubiquitous multifunctional messenger-independent serine/threonine protein kinase CK2 that has been implicated in growth control [Tawfic et al. (1996): J Cell Biochem 61:165-171]. We have examined the nature of the association of CK2 with the NM. Nuclei prepared in the presence of a sulfhydryl-blocking reagent such as iodoacetamide demonstrate a reduction in the amount of CK2 associated with the NM to less than 5% of the control. On the other hand, when nuclei are treated with the sulfhydryl crosslinking reagent sodium tetrathionate, NM-associated CK2 increases severalfold. Treatment of nuclei with sodium tetrathionate followed by 2-mercaptoethanol blocks this increase. Nuclei isolated from rat liver and prostate behaved similarly, suggesting an identical mode of association of CK2 with the NM regardless of the organ. These results indicate a role of sulfhydryl interactions such that NM anchoring of CK2 occurs via its beta subunit, which contains several vicinal cysteine residues. Further, various sulfhydryl-blocking reagents inhibited CK2 activity in a concentration-dependent manner, and the inhibitory effect was reversed by agents such as dithiothreitol, implying that cysteine residues in the CK2 play a role in its catalytic activity.

Animals↗

PubMed1998

Hybrid tumors or salivary gland tumors sharing common differentiation pathways? Reexamining adenoid cystic and epithelial-myoepithelial carcinomas.

Three adenoid cystic carcinomas and two epithelial-myoepithelial carcinomas, which focally shared common histologic features, were studied to examine the common differentiation pathways manifested by these tumors and to discuss criteria for hybrid salivary gland tumors. Regions of the adenoid cystic carcinomas had cellular features ranging from simple clear cell change of basal/myoepithelial cells to combined clear cells and prominent ductal structures mimicking epithelial-myoepithelial carcinoma. Conversely, two epithelial-myoepithelial carcinomas had adenoid cystic carcinoma-like regions caused by the formation of "pseudocysts"; this resulted in a focal cribriform pattern. Electron microscopy of two additional but typical epithelial-myoepithelial carcinomas revealed both excess basal lamina at the margins of cellular nests and widened intercellular spaces containing reduplicated basal lamina and accumulations of glycosaminoglycans; these ultrastructural features were identical to those seen in adenoid cystic carcinomas. The five current cases are not examples of hybrid tumors, but they demonstrate the effects of gene expression and the resulting differentiation of synthetic products and tumor cells that are generally restricted to one or the other of these two tumor types by as-yet-unknown means. To avoid misdiagnosis and its prognostic implications, adenoid cystic carcinoma-like regions in epithelial-myoepithelial carcinoma and epithelial-myoepithelial-like regions in adenoid cystic carcinoma should be recognized simply as anomalous differentiation.

Adult↗

PubMed1998

DNA content is an independent prognostic indicator in endometrial adenocarcinoma. A Gynecologic Oncology Group study.

The identification of prognostic variables is an important aspect of managing and counseling women with endometrial adenocarcinoma. The surgical stage, age, cell type, depth of myometrial invasion, and histologic grade have all been previously demonstrated to be related to prognosis. Several reports have indicated that tumor ploidy as determined by flow cytometry with fresh or fixed cells removed from paraffin blocks of endometrial adenocarcinomas can contribute to the assessment of prognosis. To verify the significance of DNA content in endometrial adenocarcinoma, we conducted an historical cohort study on a subgroup of women from a Gynecologic Oncology Group (GOG) protocol of early clinical stage disease. Flow cytometry was performed at one facility on cells extracted from blocks obtained from several GOG member institutions. Blocks were submitted for 293 of 933 eligible patients. Ninety-two histograms were of good quality, with 55 interpreted as diploid and 37 as aneuploid. One hundred sixty-two histograms were technically suboptimal, of which 137 were considered probably diploid, 13 probably aneuploid, and 12 unacceptable due to high background noise. Of the commonly accepted prognostic variables, only depth of invasion was significantly related to the ploidy status. There was no discernable difference in survival between patients with diploid and patients with probable diploid and probable aneuploid tumor types. Incorporation of the flow cytometry data into a proportional hazards regression model adjusted for age and surgical stage revealed a significant increased risk of disease-related death (relative risk, 4.1; 95% confidence interval, 2.3 to 7.3) for patients with aneuploid tumor type as compared to patients with diploid tumor type. This study confirms the prognostic significance of ploidy determination by flow cytometry and also indicates some of the difficulties of retrospectively applying this technology to cooperative group studies.

Adenocarcinoma↗

PubMed1998

Hemangioendothelioma of the cavernous sinus: case report.

OBJECTIVE AND IMPORTANCE: Hemangioendothelioma is an uncommon vascular neoplasm, and its intracranial occurrence is extremely rare. The occurrence of such a tumor within the cavernous sinus has not been reported previously. CLINICAL PRESENTATION: We report a 36-year-old woman who presented with right-sided retro-orbital pain and diplopia caused by a right sixth nerve paresis. Magnetic resonance imaging revealed a lesion within the right inferior cavernous sinus. INTERVENTION: The tumor was excised completely via an orbitozygomatic approach. CONCLUSION: Hemangioendothelioma is a rare, indolent vascular tumor, and its characteristics are reviewed. The need for complete excision is emphasized, and the advantages of the orbitozygomatic approach for the removal of tumors of the cavernous sinus is discussed.

Adult↗