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Biomedical subjects

Scott Patterson

Publications and source records attributed to Scott Patterson.

8 recordsLinked to original sources
PubMed2006

Hypomorphic promoter mutation in PIGM causes inherited glycosylphosphatidylinositol deficiency.

Attachment to the plasma membrane by linkage to a glycosylphosphatidylinositol (GPI) anchor is a mode of protein expression highly conserved from protozoa to mammals. As a clinical entity, deficiency of GPI has been recognized as paroxysmal nocturnal hemoglobinuria, an acquired clonal disorder associated with somatic mutations of the X-linked PIGA gene in hematopoietic cells. We have identified a novel disease characterized by a propensity to venous thrombosis and seizures in which deficiency of GPI is inherited in an autosomal recessive manner. In two unrelated kindreds, a point mutation (c --> g) at position -270 from the start codon of PIGM, a mannosyltransferase-encoding gene, disrupts binding of the transcription factor Sp1 to its cognate promoter motif. This mutation substantially reduces transcription of PIGM and blocks mannosylation of GPI, leading to partial but severe deficiency of GPI. These findings indicate that biosynthesis of GPI is essential to maintain homeostasis of blood coagulation and neurological function.

Amino Acid Sequence↗
PubMed2006

Natural killer T cells and haemopoiesis.

Invariant natural killer T (iNKT) cells are a small but powerful subset of regulatory T cells involved in the modulation of a variety of normal and pathological immune responses. In contrast to conventional or other types of regulatory T cells, they are activated by glycolipid and phospholipid ligands that are presented to them by the non-polymorphic, major histocompatibility complex class I-like molecule CD1d. The in-depth understanding of their function has resulted in successful, iNKT cell-centred experimental therapeutic interventions including prevention of graft-versus-host disease and anti-leukaemia effects. Extending these successes into the clinical arena will require better understanding of their contribution to the pathogenesis of human, including haematological, diseases.

Antigen-Presenting Cells↗
PubMed2005

Regulation of hematopoiesis in vitro and in vivo by invariant NKT cells.

Invariant natural killer T cells (iNKT cells) are a small subset of immunoregulatory T cells highly conserved in humans and mice. On activation by glycolipids presented by the MHC-like molecule CD1d, iNKT cells promptly secrete T helper 1 and 2 (Th1/2) cytokines but also cytokines with hematopoietic potential such as GM-CSF. Here, we show that the myeloid clonogenic potential of human hematopoietic progenitors is increased in the presence of glycolipid-activated, GM-CSF-secreting NKT cells; conversely, short- and long-term progenitor activity is decreased in the absence of NKT cells, implying regulation of hematopoiesis in both the presence and the absence of immune activation. In accordance with these findings, iNKT-cell-deficient mice display impaired hematopoiesis characterized by peripheral-blood cytopenias, reduced marrow cellularity, lower frequency of hematopoietic stem cells (HSCs), and reduced early and late hematopoietic progenitors. We also show that CD1d is expressed on human HSCs. CD1d-expressing HSCs display short- and long-term clonogenic potential and can present the glycolipid alpha-galactosylceramide to iNKT cells. Thus, iNKT cells emerge as the first subset of regulatory T cells that are required for effective hematopoiesis in both steady-state conditions and under conditions of immune activation.

Animals↗
PubMed2005

Human invariant NKT cells are required for effective in vitro alloresponses.

NKT cells are a small subset of regulatory T cells conserved in humans and mice. In humans they express the Valpha24Jalpha18 invariant chain (hence invariant NKT (iNKT) cells) and are restricted by the glycolipid-presenting molecule CD1d. In mice, iNKT cells may enhance or inhibit anti-infectious and antitumor T cell responses but suppress autoimmune and alloreactive responses. We postulated that iNKT cells might also modulate human alloreactive responses. Using MLR assays we demonstrate that in the presence of the CD1d-presented glycolipid alpha-galactosylceramide (alphaGC) alloreactivity is enhanced (37 +/- 12%; p < 0.001) in an iNKT cell-dependent manner. iNKT cells are activated early during the course of the MLR, presumably by natural ligands. In MLR performed without exogenous ligands, depletion of iNKT cells significantly diminished the alloresponse in terms of proliferation (58.8 +/- 24%; p < 0.001) and IFN-gamma secretion (43.2 +/- 15.2%; p < 0.001). Importantly, adding back fresh iNKT cells restored the reactivity of iNKT cell-depleted MLR to near baseline levels. CD1d-blocking mAbs equally reduced the reactivity of the iNKT cell-replete and -depleted MLR compared with IgG control, indicating that the effect of iNKT cells in the in vitro alloresponse is CD1d-dependent. These findings suggest that human iNKT cells, although not essential for its development, can enhance the alloreactive response.

Antigens, CD1↗
PubMed2004

Endozepine stupor: disease or deception? A critical review.

Presentation of patients with recurrent stupor associated with apparently elevated levels of an endogenous benzodiazepine-like agent, endozepine-4, has been reported from several centers, and a new syndrome, endozepine stupor has been proposed. We recently reported a case with typical features of this syndrome, which proved to be an example of surreptitious administration of exogenous benzodiazepine. This and other examples of clandestine drug use, together with uncertainties about the validity of tests used to distinguish exogenous and endogenous benzodiazepines, prompted us to undertake a reappraisal of this clinical syndrome.

Benzodiazepines↗
PubMed2003

Kullback-Leibler divergence for evaluating bioequivalence.

In this paper we propose a methodology for evaluating the bioequivalence of two formulations of a drug that encompasses not only average bioequivalence (ABE), but also the more recently introduced measures of population bioequivalence (PBE) and individual bioequivalence (IBE). The latter two measures are concerned with prescribability (PBE) and switchability (IBE). The main idea is to use the Kullback-Leibler divergence (KLD) as a measure of discrepancy between the distributions of the two formulations. Two formulations are declared bioequivalent if the upper bound of a level-alpha confidence interval for the KLD is less than a given goalpost to be set by a regulator. This new methodology overcomes many of the disadvantages of the corresponding measures recommended by the FDA. In particular the KLD: (i) possesses the natural hierarchical property that IBE => PBE => ABE; (ii) satisfies the properties of a true distance metric; (iii) is invariant to monotonic transformations of the data; (iv) generalizes easily to the multivariate case where equivalence on more than one parameter (for example, AUC, C(max) and T(max)) is required; and (v) is applicable over a wide range of distributions of the response variable (for example, those in the exponential family). The performance of the KLD relative to the metric proposed in guidance by the FDA for the evaluation of individual bioequivalence is evaluated using a simulation study. Previously published retrospective analyses using the FDA-proposed metric are contrasted with those based on the KLD. It is concluded that the KLD is a viable alternative to the FDA-proposed metric and that its mathematical and statistical properties make it a readily interpretable measure of the differences between formulations.

Area Under Curve↗
PubMed2002

Selecting targets for therapeutic validation through differential protein expression using chromatography-mass spectrometry.

The identification of potential targets for therapeutic intervention can be accomplished on a systematic basis by a variety of techniques that include quantitative analysis of gene-specific mRNA levels and expressed proteins in normal and diseased cells. Differences in the expression levels of nucleic acid and protein gene products could suggest protein drug targets that are directly causative of disease, or reveal biochemical pathways that could be modulated by therapeutic molecules. Any effort based on mRNA or protein expression level comparisons could be confounded by a number of factors: level in steady-state may not be correlated with actual encoded protein levels; differentially expressed protein levels might be a result of disease process, and not causative of the process, and therapeutic intervention based on such a difference will be unproductive and the differential expression of mRNA or protein may be the result of biological variation unrelated to the disease process under study. In order to address these possibly confounding factors, it is necessary to validate potential targets by establishing their firm association with disease, and their minimal distribution in non-diseased tissues of any type. This requirement suggests that emphasis on true and reproducible quantitation of protein expression levels in a variety of samples will be an effective and highly efficient method of generating drug targets with a high degree of utility. To achieve this aim, we have established an industrial-scale proteomics-based discovery platform consisting of cell biology, protein chemistry, and mass spectrometry technical groups together with bioinformatics groups. The analytical method used for quantitation employs isotope labeling for differential analysis (ICATTM, Applied Biosystems, Inc.). With this technique, tryptic peptides are generated from labeled proteins that have been specifically captured from various subcellular locations or protein families. The resulting peptides are identified and quantified by mass spectrometry. To evaluate this approach on a large-scale, we have applied it to a study of continuous cell lines derived from human pancreatic adenocarcinomas. We have been able to establish processes for target discovery for small molecule drug targets as well as therapeutic antibody target identification for cell surface proteins. In addition, we have developed a process for identification of serum markers of this disease based upon standardized fractionation procedures. The results of these analyses will be presented together with the some of the issues from both the wet and dry (computational) lab that need to be addressed in such an undertaking.

Biomarkers, Tumor↗