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Biomedical subjects

J T Phillips

Publications and source records attributed to J T Phillips.

18 recordsLinked to original sources
PubMed2006

Lactate dehydrogenase-B is silenced by promoter hypermethylation in human prostate cancer.

In order to identify novel candidates associated with prostate cancer metastasis, we compared the proteomic profile of the poorly metastatic human prostate cancer cell line LNCaP, with its highly metastatic variant LNCaP-LN3, by two-dimensional gel electrophoresis. A major protein spot (pI of 5.9 and molecular weight of 37 kDa) was seen in LNCaP cells, but not in LNCaP-LN3 cells and was identified as lactate dehydrogenase-B (LDHB), by tandem mass spectrometry. Furthermore, enzyme kinetic assays and zymography showed a higher LDH enzyme activity in LNCaP cells compared with LNCaP-LN3. Bisulphite-modified DNA sequencing showed promoter hypermethylation in LNCaP-LN3 cells but not in LNCaP, Du145, PC3, CWR22 or BPH45 cells. Treatment of LNCaP-LN3 cells with 5'-azacytidine caused re-expression of LDHB transcripts. In tissues, LDHB promoter hypermethylation occurred at a higher frequency in prostate cancer, 14/ 31 (45%), compared to adjacent nonmalignant or benign tissue, 2/19 (11%) (P < 0.025). Immunohistochemistry showed a higher frequency of LDHB expression in benign or non-malignant tissues, 59/ 73 (81%), compared to cancer cases, 3/53 (6%) (P < 0.001). Absent LDHB expression was also seen in 7/7 (100%) cases of metastatic cancer in bone. Our data are the first to show loss of LDHB expression in prostate cancer, the mechanism of which appears to involve promoter hypermethylation.

Amino Acid Sequence↗
PubMed2005

Characterizing the mechanisms of progression in multiple sclerosis: evidence and new hypotheses for future directions.

Major advancements have been achieved in our ability to diagnose multiple sclerosis (MS) and to commence treatment intervention with agents that can favorably affect the disease course. Although MS exacerbations and the emergence of disability constitute the more conspicuous aspects of the disease process, evidence has confirmed that most of the disease occurs on a constitutive and occult basis. Disease-modifying therapies appear to be modest in the magnitude of their treatment effects, particularly in the progressive stage of the disease. Therapeutic strategies currently used for MS primarily target the inflammatory cascade. Several potential mechanisms appear to be involved in the progression of MS. Characterizing these mechanisms will result in a better understanding of the various forms of the disorder and how to effectively treat its clinical manifestations. It is our objective within this 2-part series on progression in MS to offer both evidence-based observations and hypothesis-driven expert perspectives on what constitutes the cause of progression in MS. We have chosen areas of inquiry that appear to have been most productive in helping us to better conceptualize the landscape of what MS looks like pathologically, immunologically, neuroscientifically, radiographically, and genetically. We have attempted to advance hypotheses focused on a deeper understanding of what contributes to the progression of this illness and to illustrate new technical capabilities that are catalyzing novel research initiatives targeted at achieving a more complete understanding of progression in MS.

Disease Progression↗
PubMed2004

Disease modifying agent related skin reactions in multiple sclerosis: prevention, assessment, and management.

BACKGROUND: The objective for this article is to highlight some of the adverse skin manifestations associated with injectable disease modifying therapy for multiple sclerosis (MS). Early identification and intervention can often lead to minimal consequences and prolonged patient tolerance and compliance with these agents. At the University of Texas Southwestern Medical Center at Dallas and Texas Neurology in Dallas we actively follow approximately 5000 MS patients. The majority of our patients with relapsing-remitting MS (RRMS) or secondary progressive MS (SPMS) are treated with one of the currently available disease modifying agents (DMAs). Our experience with these patients, and the challenges they face in continuing long-term treatment, constitutes the basis of our proposed treatment strategies. CONCLUSION: Skin reactions in response to injectable DMA therapy in MS are generally mild. However, some reactions can evolve into potentially serious lesions culminating in infection, necrosis, and in some circumstances requiring surgical repair.

Adjuvants, Immunologic↗
PubMed2004

An open-label safety and drug interaction study of natalizumab (Antegren) in combination with interferon-beta (Avonex) in patients with multiple sclerosis.

In this open-label drug-interaction trial, we studied 38 patients with relapsing-remitting multiple sclerosis (MS) who received 3.0 or 6.0 mg/kg of natalizumab as a single intravenous (i.v.) infusion during stable treatment with intramuscular (i.m.) interferon beta-1a 30 microg (IFNbeta-1a; Avonex). To assess the pharmacokinetic (PK) interaction of natalizumab and IFNbeta-1a, serum concentration-time data for both agents were collected and analysed. Biologic response markers of IFNbeta-1a activity, beta2-microglobulin and neopterin, were also assessed to determine effects of natalizumab on IFNbeta-1a pharmacodynamics (PD). Further, safety and immunogenicity were evaluated. The combination of drug therapies was well tolerated. Although natalizumab serum concentrations (and corresponding PK exposure measures) appeared to be somewhat elevated in the presence of IFNbeta-1a, when compared to the same dose (6.0 mg/kg) administered alone in a concurrent comparator study, the differences were generally small and unlikely to be clinically relevant. In general, natalizumab had no apparent clinically relevant effects on the PK or PD properties of IFNbeta-1a. The presence of antibodies to IFNbeta-1a and natalizumab was relatively low. Overall, the study provided safety, immunogenicity, PK and PD data to support a combination strategy for the use of natalizumab and IFNbeta-1a in the treatment of patients with relapsing-remitting MS. A large clinical study is currently in progress to evaluate the efficacy and long-term safety of this combination drug therapy.

Adjuvants, Immunologic↗
PubMed2003

The utility of MRI in suspected MS [RETIRED]: report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology.

Advancements in imaging technologies and newly evolving treatments offer the promise of more effective management strategies for MS. Until recently, confirmation of the diagnosis of MS has generally required the demonstration of clinical activity that is disseminated in both time and space. Nevertheless, with the advent of MRI techniques, occult disease activity can be demonstrated in 50 to 80% of patients at the time of the first clinical presentation. Prospective studies have shown that the presence of such lesions predicts future conversion to clinically definite (CD) MS. Indeed, in a young to middle-aged adult with a clinically isolated syndrome (CIS), once alternative diagnoses are excluded at baseline, the finding of three or more white matter lesions on a T2-weighted MRI scan (especially if one of these lesions is located in the periventricular region) is a very sensitive predictor (>80%) of the subsequent development of CDMS within the next 7 to 10 years. Moreover, the presence of two or more gadolinium (Gd)-enhancing lesions at baseline and the appearance of either new T2 lesions or new Gd enhancement on follow-up scans are also highly predictive of the subsequent development of CDMS in the near term. By contrast, normal results on MRI at the time of clinical presentation makes the future development of CDMS considerably less likely.

Adult↗
PubMed2002

Quantitative oculographic characterisation of internuclear ophthalmoparesis in multiple sclerosis: the versional dysconjugacy index Z score.

BACKGROUND: There is a poor correlation between multiple sclerosis disease activity, as measured by magnetic resonance imaging, and clinical disability. OBJECTIVE: To establish oculographic criteria for the diagnosis and severity of internuclear ophthalmoparesis (INO), so that future studies can link the severity of ocular dysconjugacy with neuroradiological abnormalities within the dorsomedial brain stem tegmentum. METHODS: The study involved 58 patients with multiple sclerosis and chronic INO and 40 normal subjects. Two dimensional infrared oculography was used to derive the versional dysconjugacy index (VDI)-the ratio of abducting to adducting eye movements for peak velocity and acceleration. Diagnostic criteria for the diagnosis and severity of INO were derived using a Z score and histogram analysis, which allowed comparisons of the VDI from multiple sclerosis patients and from a control population. RESULTS: For a given saccade, the VDI was typically higher for acceleration v velocity, whereas the Z scores for velocity measures were always higher than values derived from comparable acceleration VDI measures; this was related to the greater variability of acceleration measures. Thus velocity was a more reliable measure from which to determine Z scores and thereby the criteria for INO and its level of severity. The mean (SD) value of the VDI velocity derived from 40 control subjects was 0.922 (0.072). The highest VDI for velocity from a normal control subject was 1.09, which was 2.33 SD above the normal control mean VDI. We therefore chose 2 SD beyond this value (that is, a Z score of 4.33) as the minimum criterion for the oculographic confirmation of INO. Of patients thought to have unilateral INO on clinical grounds, 70% (16/23) were found to have bilateral INO on oculographic assessment. CONCLUSIONS: INO can be confirmed and characterised by level of severity using Z score analysis of quantitative oculography. Such assessments may be useful for linking the level of severity of a specific clinical disability with neuroradiological measures of brain tissue pathology in multiple sclerosis.

Case-Control Studies↗
PubMed1996

Polypharmacy in multiple sclerosis.

The goal of this article is to describe therapeutic approaches to multiple sclerosis (MS) which may be applicable to other human conditions such as epilepsy. Polypharmacy is very commonly employed in MS and it is likely to increase in the future. This paper is written with the premise that therapeutic principles and practices underlying the care of patients with MS may be useful for the treatment of people with epilepsy. We will point out some of the analogies between MS and epilepsy and we will describe the polypharmacy approach employed to treat patients with MS. We will review current information as to the etiology and pathogenesis of MS and describe potential therapeutic targets derived from this knowledge. We will identify or suggest certain therapeutic principles underlying polypharmacy in MS which may be relevant to epilepsy or other conditions. Finally, we will describe some of the obstacles to expanding rational polypharmacy and how we might overcome these problems.

Brain↗
PubMed1995

Modification of acute experimental autoimmune encephalomyelitis in the Lewis rat by oral administration of type 1 interferons.

The effect of orally administered type 1 interferons on the severity of acute experimental autoimmune encephalomyelitis (EAE), a T cell-mediated autoimmune disease, was examined by inoculation of Lewis rats with guinea pig myelin basic protein (GPMBP) and complete Freund's adjuvant. Rats were fed either rat species-specific or human recombinant type 1 interferon (IFN) or mock IFN daily for 7 days preceding immunization and for 21 days thereafter. There was a significant decrease in the clinical score and inflammatory foci in animals fed 5000 units IFN compared with mock-treated animals. There was a significant decrease in clinical score and number of inflammatory foci in spinal cord in animals fed orally 5000 units human recombinant IFN-alpha PO compared with SC 5000 units recombinant human IFN-alpha. Oral administration of type 1 interferon, as opposed to subcutaneous administration, inhibited the secretion of IFN-gamma from ConA-activated draining popliteal lymph node cells compared with mock-fed animals. These experiments demonstrate that acute EAE is more effectively inhibited by equivalent amounts of orally in contrast to parenterally administered IFN-alpha. These results suggest that type 1 IFNs are active by the oral route and have significant clinical and histologic effects in acute autoimmune disease.

Administration, Oral↗
PubMed1993

A clinical therapeutic trial of cyclosporine in myasthenia gravis.

We randomly assigned 39 patients with steroid-dependent generalized myasthenia gravis to treatment with cyclosporine (5 mg/kg per body weight in divided doses) or placebo. Duration of treatment was 6 months. Patients were evaluated monthly. Primary measures of efficacy were quantified strength testing, antihuman acetylcholine receptor antibody titer, and dosage of corticosteroid medication. At the end of the study, patients in the cyclosporine group had significantly greater improvement in strength (p = 0.004) and a reduction in antireceptor antibody titer (p = 0.01). Percentage reduction of steroid medication was greater in the cyclosporine group, although the difference was not statistically significant (p = 0.12). There were no treatment failures, and there was one drug failure in the cyclosporine group. In the placebo group, there were three treatment failures. No significant nephrotoxicity was noted at this dosage during the first 6 months. During the subsequent 18 months of open-label therapy, continued reduction in steroid dosage occurred. Cumulative side effects, however, caused 35% of patients to discontinue the medication; 10% did so secondary to slowly progressive nephrotoxicity.

Adult↗
PubMed1993

Prolactin receptor expression by lymphoid tissues in normal and immunized rats.

Prolactin receptor (PRLr) expression and distribution in thymus, spleen, bone marrow, lymph nodes, and peripheral blood lymphocytes from young adult Lewis rats are analyzed using single-color flow cytometry and a well-characterized monoclonal antibody directed against the rat liver PRLr. The in vivo effects of regional immunization on PRLr expression are also examined. PRLr is found to be widely distributed among cells of the immune system and demonstrates lymphoid tissue-specific patterns of expression. Footpad immunization caused the rapid, but transient, induction of PRLr expression in the draining lymph node, with only modest effects on PRLr expression in other distant lymphoid tissues. These studies indicate that PRL may be capable of direct interaction with the immune system through differential expression of the PRL cell surface receptor on select lymphoid target cell populations.

Animals↗
PubMed1993

Prolactin stimulates proliferation of cultured human keratinocytes.

The effect of the pituitary hormone prolactin on in vitro proliferation of human keratinocytes has been studied. Cell proliferation was determined by [3H] thymidine incorporation and cell enumeration in culture. Physiologic concentrations of prolactin markedly stimulated proliferation of newborn foreskin keratinocytes in serum-free medium. In addition, it was able to replace almost completely the growth-promoting effects of bovine pituitary extract, a commonly added supplement for keratinocyte culture. This activity was also evident in the absence of epidermal growth factor, but required the presence of insulin. Radioligand-binding studies confirmed the expression of specific prolactin binding sites (Kd 8.9 nM; 1350 sites per cell) on freshly procured keratinocyte membranes. These results extend its hormonal influences to include regulation of in vitro proliferation of human keratinocytes, and suggest the possibility of a completely defined growth medium for keratinocytes.

Binding Sites↗
PubMed1992

Adoptive transfer of experimental allergic encephalomyelitis using serum-free, chemically defined in vitro culture conditions.

Enhanced adoptive transfer of experimental allergic encephalomyelitis (EAE) in rats requires in vitro culture of encephalitogen-sensitized donor spleen cells with either myelin basic protein or T-cell mitogen for 18-72 h prior to transfer to unimmunized recipients. The required in vitro culture period offers an opportunity to address in detail cellular and molecular immunoregulatory processes involved in the development of EAE. Conventional culture conditions using fetal bovine serum may impose analytical limitations due to the chemical complexity of the media. To permit better definition of the chemical events associated with the development of EAE, we report the successful adoptive transfer of EAE in Lewis rats using completely chemically defined, serum-free culture conditions.

Animals↗
PubMed1987

Preliminary results of a double-blind, randomized, placebo-controlled trial of cyclosporine in myasthenia gravis.

We randomly assigned 20 patients with progressively worsening generalized myasthenia gravis of recent onset whose illness was not controlled by anticholinesterase therapy to treatment with either cyclosporine (6 mg per kilogram of body weight per day) or placebo. Patients who had been treated with thymectomy, steroids, or other immunosuppressive agents were excluded. The duration of treatment was 12 months. Disease activity was assessed by quantified strength testing and by measurements of antihuman acetylcholine-receptor antibody. Patients were assessed at 6 months and 12 months, or at the following early end points: drug failure (doubling of creatinine), treatment failure (respiratory or swallowing difficulty), or protocol violation (stopping medication for more than five days). At six months, patients in the cyclosporine group had had significantly more objective improvement in strength; one early end point had been reached (drug failure; no treatment failures). In the placebo group, three early end points had been reached (all treatment failures). The decline in titers of acetylcholine-receptor antibody was larger in the treated group, although the difference was not statistically significant. At the end of the study (after 12 months of treatment or arrival at an earlier end point), improvement in strength and reduction in titers of anti-receptor antibody continued to be greater in the cyclosporine group. Nephrotoxicity occurred in three patients receiving cyclosporine but was nonprogressive with a reduction in dosage and reversible with discontinuation of the drug. These results are preliminary and need confirmation, but we conclude that cyclosporine is probably an effective therapy in some patients with myasthenia gravis.

Adult↗
PubMed1981

The biochemical characterization of Syrian hamster cell-surface alloantigens. II. Immunochemical relationships between cell-surface alloantigens and class II MHC homologues.

Immunochemical comparisons between hamster cell-surface p39/p29 alloantigens and putative MHC class I and II products indicate that p39/p29 alloantigens are probable class II products. Both p39/p29 alloantigens and class II homologues have varying expression in hamster lymphoid tissues and are absent from fibroblasts. In addition, analysis by nonequilibrium pH gradient electrophoresis demonstrates similar, although nonidentical, alloantigen and class II homologous charge profiles. This observation could reflect multiple class II subregions within the hamster MHC. These data therefore suggest an immunochemical description of the hamster MHC which is compatible with MHC models proposed for other mammalian species.

Animals↗
PubMed1981

Immunochemical characterization of Syrian hamster major histocompatibility complex homologues.

Based primarily on studies in mice and man, the organization and gene-product structures of the mammalian major histocompatibility complex (MHC) are thought to be extensively conserved. However, attempts to generalize from the specific observations of other species to Syrian hamsters have not been completely successful. Previous studies in hamsters have suggested abnormal structure, expression, and/or function of the putative hamster MHC and its products. Characterization of hamster MHC gene-products is therefore of interest. This study concerns the identification and characterization of hamster cell-surface glycoproteins homologous to MHC products of man and mouse. Utilizing radioimmunoprecipitation and serologic techniques, these molecules have been characterized with regard to molecular weight, tissue distribution and immunochemical homology to human and murine class I and II MHC products. In addition, alloantisera raised between histoincompatible hamster strains have been similarly used to identify cell-surface alloantigens of this species. The alloantisera detect cell-surface hamster molecules with immunochemical properties and tissue distribution resembling MHC class II rather than class I products. Thus, in contrast to other species, hamsters appear not to express extensively polymorphic major transplantation antigens of the class I type. Some hamster alloantigens are apparently homologous of Ia determinants since their genes are linked to Hm-1. However, other alloantigens with similar molecular weights are seemingly encoded by genes unlinked to the hamster MHC. These data support the hypothesis that the hamster MHC contains genes which encode for molecular products similar to those described in man and mouse, but that the organization and/or expression of these genes may be atypical.

Absorption↗
PubMed1981

Biochemical characterization of Syrian hamster cell surface alloantigens. III. Hamster alloantisera immunoprecipitate class II-like, but not class I-like, molecules.

Twelve hamster alloantisera, recently produced by mutual immunizations of domestic inbred strains and recently wild, partially inbred lines, identify two cell surface molecules, 29 and 39 kilodaltons, expressed by hamster lymphohematopoietic cells. Their expression on lymph node and spleen cells suggests that hamster T cells display cell surface class II homologues. None of the alloantisera identify putative hamster homologues of class I MHC molecules. The data are consistent with the hypothesis that hamsters possess a chromosomal region, tentatively designated Hm-1, that comprises genetic loci encoding alloantigens detectable by mixed lymphocyte reactivity and by serology, a region that resembles the I region of murine H-2.

Animals↗