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Biomedical subjects

A R Miller

Publications and source records attributed to A R Miller.

At least 37 records · Page 2Linked to original sources
PubMed1998

Neoadjuvant chemoradiation for adenocarcinoma of the pancreas.

Pancreaticoduodenectomy is performed on carefully selected patients as part of a protocol-based clinical research program emphasizing the importance of multimodality management for patients with potentially resectable adenocarcinoma of the pancreatic head. Treatment schemas emphasize the importance of minimizing toxicity and treatment duration, while attempting to improve therapeutic efficacy. Cytotoxicity is enhanced by combining radiation therapy with more potent radiation-sensitizing agents. Because of the high incidence of liver metastases, systemic therapy is continued after chemoradiation and surgery with systemic agents of low toxicity directed at specific molecular events involved in pancreatic tumorigenesis such as inhibition of angiogenesis, induction of apoptosis, or arrest of the cell cycle.

Adenocarcinoma↗
PubMed1998

Reversible ischemic neurologic deficit after ECT.

We report the case of a 58-year-old woman with depression and hypertension in whom aphasia, right-sided hemiparesis, and a possible right visual field defect were identified during recovery from right unilateral electroconvulsive therapy (ECT). The neurologic deficits resolved over a 3-day period; the patient was diagnosed with a reversible ischemic neurologic deficit (RIND). Review of the patient literature suggests that such cerebrovascular events in the setting of ECT are extremely rare and possibly decreasing in frequency. Reasons for such a decrease may include improved screening for predisposing cardiovascular conditions and the widespread use of neuromuscular blockade, ventilatory support, and cardiovascular monitoring during the procedure. Prompt recognition of cerebrovascular events is important to prevent complications such as cerebral edema, seizures, and aspiration, as well as to use new treatments for stroke.

Ancrod↗
PubMed1997

"Profile" analysis of the personality characteristics of child molesters using the MMPI-2.

Identification of child sexual molesters has been attempted for at least half a century without success. This is due, in part, to the heterogeneity of child molesters. Child sexual molesters were studied in three ways. First, a discriminant function analysis was conducted to evaluate how well the MMPI-2 would distinguish child molesters from controls. Hit rates of 81% and 88% were found for clinical scales alone and the clinical and supplemental scales, respectively. Second, a cluster analysis of MMPI-2 data identified four groups that resembled clusters found previously with the MMPI. Third, when followed in treatment, all subgroups achieved significant progress ratings and no significant difference in treatment progress was found between clusters.

Adolescent↗
PubMed1997

Transduction of murine and human tumors using recombinant adenovirus vectors.

BACKGROUND: Most cytokine-based cancer gene therapy clinical trials have used labor-intensive, retrovirus-mediated strategies resulting in unpredictable gene expression. Recombinant AdV vectors were evaluated for easier, more reproducible gene transfer into 12 human melanoma, 2 murine fibrosarcomas, and 8 other tumor cell lines. METHODS: AdV vectors contained a reporter (Escherichia coli beta-galactosidase or firefly luciferase) or cytokine gene (human interleukin-2 [IL-2] or IL-7). Transduction efficiencies and expression levels were assessed by histochemical staining, flow cytometry, polymerase chain reaction, fluorometry, and enzyme-linked immunosorbent assay. Tumorigenicity was determined by subcutaneous injection of cells into syngeneic mice. RESULTS: All cell lines studied were transduced with AdV. Most cell lines exhibited 100% transduction efficiencies (by flow cytometry) at multiplicities of infection (MOI) epsilon 10. Gene expression correlated linearly with MOI, but a cytopathic effect was observed at MOI > 100 with all vectors. Nanogram gene expression levels were routinely achieved. Irradiation (30 Gy) minimally affected expression levels. Tumorigenicity of AdV-IL-2-transduced fibrosarcoma cells in mice was inversely related to IL-2 production. A majority of mice that rejected their tumor challenge were immune to tumor rechallenge. CONCLUSIONS: E1-deleted AdV vectors may prove useful in generating tumor vaccines ex vivo with high, transient cytokine expression levels.

Adenoviridae↗
PubMed1997

Multifunctional cytokine expression by human mast cells: regulation by T cell membrane contact and glucocorticoids.

Human mast cells readily release a variety of mediators, including cytokines, in response to IgE receptor crosslinking, but the mechanisms governing the expression of cytokines are still unclear. Using a human mast cell line, HMC-1, we show expression of cytokine transcripts as early as 2 h after activation with ionomycin and phorbol myristate acetate (PMA). Resting HMC-1 cells expressed transcripts for interleukin-1 receptor antagonist (IL-1RA), IL-2, IL-4, IL-5, GM-CSF, and weakly for IL-8, and stimulation with ionomycin and PMA induced additional transcripts for IL-6 and IL-13 and upregulated expression of IL-8 transcripts. HMC-1 cells secreted IL-4, IL-8, and GM-CSF protein after activation and dexamethasone significantly inhibited the production of these cytokines. Of significance is the finding that the addition of membranes purified from activated T cells to mast cell cultures induced transcripts selectively for IL-8 and none for other proinflammatory cytokines. Flow cytometry revealed that resting HMC-1 cells express CD40, a molecule involved in contact-dependent signaling of monocytes and B cells by T cells. However, activation of HMC-1 by anti-CD40 antibody did not induce IL-8 gene expression or protein production. This study demonstrates that human mast cells are capable of expressing multiple cytokines that can be inhibited by glucocorticoids. It also raises the possibility that T cells may activate mast cell cytokine synthesis by novel contact-dependent mechanisms. This phenomenon of T cell regulation of mast cell function requires further study.

Anti-Inflammatory Agents↗
PubMed1997

A new technique for removal of intraarticular bullet fragments from the femoral head.

Removal of foreign bodies from a joint usually involves an extensive surgical approach. The necessity for intraarticular bullet removal has been well documented in the literature. The conventional approach for bullet extraction usually requires an open arthrotomy, arthroscopic removal or, in most cases, a combination of the two. This report involves a previously undocumented technique for bullet removal from the hip. A Synthes DHS Triple Reamer was inserted through a limited lateral incision over a guide pin that had been placed under fluoroscopic guidance. The tip of the guide pin was positioned in contact against the bullet fragments in both the anteroposterior and lateral planes. The fragments were then removed through the reamed canal. This technique allows for bullet removal without the inherent risks associated with an open arthrotomy and without the special skills required for hip arthroscopy. It is relatively easy to perform and may prove to be a valuable tool in the arsenal of orthopedists who deal with specific gunshot wounds to the hip region.

Adult↗
PubMed1996

Cytokine priming reduces dependence on TNF-R2 for TNF-alpha-mediated induction of macrophage nitric oxide generation.

In the presence of interferon-gamma (IFN-gamma), human tumor necrosis factor-alpha (Hu-TNF-alpha), which binds to murine TNF-alpha receptor type 1 (TNF-R1) but not to murine TNF-R2, was effective in inducing nitric oxide (NO) production in spleen-derived macrophages (M phi), albeit at concentrations 12.5-fold greater than those required by murine TNF-alpha (Mu-TNF-alpha), to achieve the same result. Addition of anti-TNF-R1 completely inhibited the Mu-TNF-alpha-mediated induction of NO, demonstrating that TNF-R1 is critical to the IFN-gamma-dependent TNF-alpha-mediated induction of M phi effector function. However, treatment with anti-TNF-R2 resulted in a partial inhibition of M phi activation. Spleen-derived M phi were more dependent on TNF-R2 than RAW 264.7 or peritoneal M phi based on their responsiveness to Hu-TNF-alpha. Priming of spleen-derived M phi with either IFN-gamma or granulocyte-macrophage colony-stimulating factor (GM-CSF) heightened the maximal responses to both TNF-alpha species and increased the overall effectiveness of Hu-TNF-alpha without increasing expression of either TNF-alpha receptor. The dependence of spleen-derived M phi on both TNF-alpha receptors for signaling the induction of effector function supports an active signaling role for TNF-R2 in its synergy with TNF-R1 rather than a passive ligand passing role.

Animals↗
PubMed1994

Cytokine-mediated gene therapy for cancer.

BACKGROUND: Significant interest has been generated in the gene therapy of cancer. One strategy involves tumor-directed cytokine gene transfer and its effects on tumor immunobiology. METHODS: The authors review the current literature pertaining to cytokine gene therapy of cancer and provide a description of gene transfer methods currently being evaluated. RESULTS: Several cytokine gene transfer models have been described involving at least 12 different cytokines. The introduction of cytokine genes into experimental animal tumors improves their ability to be recognized and destroyed by the host immune system. Certain cytokines will regulate phenotypic properties such as major histocompatibility complex antigens, immunosuppressive peptides, protooncogenes or endogenous cytokine production. Cytokine-transduced tumors attract an inflammatory exudate in vivo that generally results in tumor destruction. The nature of the infiltrate (lymphocytic, mononuclear, granulocytic) cannot always be predicted from the known biological properties of each cytokine. Untransduced bystander tumor cells are usually also destroyed. Some, but not all, cytokine transductions result in the generation of systemic major histocompatibility complex-restricted, tumor immunity. It has been hypothesized that the local continuous production of cytokines by tumor cells provides an optimal microenvironment for antigen recognition and the generation of T-cell immunity. CONCLUSIONS: These experimental observations hold promise for the clinical application of genetically engineered tumor vaccines.

Animals↗
PubMed1994

Effect of high- versus moderate-intensity exercise on lymphocyte subpopulations and proliferative response.

The effect of 45 min of high- (80% VO2max) versus moderate- (50% VO2max) intensity treadmill exercise on circulating leukocyte and lymphocyte subpopulations, catecholamine and cortisol concentrations, and the mitogen-stimulated lymphocyte proliferative response was investigated in 10 well-conditioned (mean VO2max 66.0 +/- 1.9 ml/kg/min), young males (mean age 22.1 +/- 1.3 yrs). Blood samples were taken before and immediately after exercise, with three more samples taken during 3.5 h of recovery. Treatment order on the treadmill (graded walking at 7.3 +/- 0.1 km/h, 6.5 +/- 0.6% grade, versus level running at 16.1 +/- 0.3 km/h) was counterbalanced, with subjects acting as their own controls and results analyzed using a 2 x 5 repeated measures ANOVA. The concanavalin A- (Con A) stimulated lymphocyte proliferative response was decreased at 1 h and 2 h post-exercise relative to baseline levels following both exercise-intensity conditions. However, when adjusted on a per-T cell (CD3+) basis to account for the change in number of T cells in the in vivo assay, only the high-intensity exercise condition was associated with a 1-h post-exercise decrease (21%, p = 0.05) in the proliferative response relative to baseline. Exercise at 80% versus 50% VO2max resulted in significantly greater increases in cortisol and epinephrine concentrations, providing a physiological rationale for the immediate-post-exercise lymphocytosis, 1- to 3.5-h lymphocytopenia, and the decrease in Con A-stimulated lymphocyte proliferative response (per CD3+ cell) that occurred in greater measure following high-intensity exercise.

Adolescent↗
PubMed1994

Retroviral-mediated gene transfer into rat experimental liver transplant.

Replication-defective retroviral vectors were used for ex vivo gene transfer into rat liver grafts under conditions mimicking clinical liver transplantation. Supernatant containing single- and double-gene vectors encoding for either the human IL-7 and/or neomycin phosphotransferase genes were used to perfuse the liver grafts during cold ischemia before transplantation. Whole liver grafts were perfused with vector supernatant or medium only. Reduced-size liver grafts (50% hepatectomy) were similarly perfused either immediately after reduction or 24 hr later after induction of active hepatocyte division. After transplantation of these grafts in orthotopic position, the liver tissue was removed at specified intervals, and genomic DNA and mRNA were examined for proviral sequences and expression. Stable integration of the proviral sequences was detected only in reduced-size grafts transplanted 24 hr after hepatectomy. Proviral message of both neomycin phosphotransferase and human IL-7 were present up to 21 days after transduction. This study demonstrates efficient ex vivo gene transfer to donor liver grafts. Gene transfer to livers before transplantation carries the potential to modulate immunogenicity and alter the antigraft immune response.

Animals↗
PubMed1994

Staphylococcal glycocalyx activates macrophage prostaglandin E2 and interleukin 1 production and modulates tumor necrosis factor alpha and nitric oxide production.

We have examined the effect of staphylococcal glycocalyces on the ability of murine peritoneal macrophages to produce prostaglandin E2 (PGE2) and the inflammatory cytokines interleukin 1 (IL-1) and tumor necrosis factor alpha (TNF-alpha) and to generate nitric oxide. Glycocalyx partially purified under endotoxin-free conditions from defined liquid medium cultures of Staphylococcus lugdunensis or Staphylococcus epidermidis was a strong stimulator of PGE2 and IL-1 production. The addition of 10 to 100 micrograms of glycocalyx per ml induced levels of IL-1 and PGE2 production similar to that induced by 0.1 to 1 micrograms of Escherichia coli lipopolysaccharide (LPS) per ml. In contrast, glycocalyx induced ninefold less TNF-alpha and three- to fourfold less nitrite than LPS. A modulatory effect was suggested by the observation that the amount of TNF-alpha and nitrite generated remained constant whether the macrophages were stimulated with 10 or 100 micrograms of glycocalyx per ml. A selective modulation of macrophage activation was confirmed by the demonstration that costimulation of macrophages with both glycocalyx and LPS resulted in a reduction in TNF-alpha and nitrite generation relative to stimulation with LPS alone even though costimulation had no effect on PGE2 production and increased IL-1 production. Involvement of PGE2 in this modulatory effect was suggested by the ability of indomethacin to augment glycocalyx-stimulated TNF-alpha production and to reverse the inhibitory effect of glycocalyx on LPS induction of TNF-alpha production. However, the inability of indomethacin to reverse the inhibitory effect of glycocalyx on LPS-induced nitric oxide generation suggests that the selective modulation of macrophage function by glycocalyx may be more complex than increased sensitivity to PGE2 feedback inhibition.

Animals↗
PubMed1993

Transduction of human melanoma cell lines with the human interleukin-7 gene using retroviral-mediated gene transfer: comparison of immunologic properties with interleukin-2.

Two human melanoma cell lines were transduced with the human interleukin (IL)-7 and IL-2 genes using retroviral-mediated gene transfer. Stable, high-level cytokine expression was achieved. The in vitro growth of transduced tumors was unaltered. Neither of the IL-2-transduced melanoma cell lines grew in athymic mice, whereas one IL-7-transduced melanoma line showed retarded in vivo growth. This is consistent with animal studies suggesting a predominantly T-cell response to IL-7-transduced tumors and a more nonspecific response to IL-2-transduced tumors. Both IL-7- and IL-2-transduced melanoma cell lines could induce cytotoxic lymphocytes in mixed lymphocyte-tumor cultures. The expression of putative melanoma antigens (MAGE)-1 and MAGE-3 was unaltered by cytokine transduction. In one cell line, IL-7 transduction resulted in a marked inhibition of the immunosuppressive peptide transforming growth factor (TGF)beta 1. The results allow a comparison of immunobiologic properties of IL-7- and IL-2-transduced human melanoma cell lines in consideration of their use in genetically engineered tumor vaccines. IL-7 transduction results in stable cytokine expression and phenotypic alterations that appear to be favorable for enhanced immunogenicity and it deserves clinical testing.

Animals↗