Multicomponent analysis of the pancreatic adenocarcinoma progression model using a pancreatic intraepithelial neoplasia tissue microarray.

A multistep model for pancreatic adenocarcinoma has been proposed recently. In this model, well-defined, noninvasive ductal lesions are recognized as precursors of invasive cancer and have been classified under the nomenclature of pancreatic intraepithelial neoplasia, or PanIN. Increasing evidence suggests that PanINs represent true neoplasms of the pancreatic ductal epithelium, accumulating histologic and genetic abnormalities in their progression toward invasive cancer.

Florid von Brunn nests mimicking urothelial carcinoma: a morphologic and immunohistochemical comparison to the nested variant of urothelial carcinoma.

Florid von Brunn nests may mimic the nested variant of urothelial carcinoma. We examined formalin-fixed, paraffin-embedded tissue from 21 cases of florid von Brunn nests and 11 cases of nested variant of urothelial carcinoma. Morphologic features were recorded in detail.

Sustained response initiation is required for T cell clonal expansion but not for effector or memory development in vivo.

The factors determining whether an immune response is productive are poorly understood. To understand the circumstances affecting the early stage of the immune response which determine whether memory is generated, the CD8 T cell response was mapped in detail following immunization with live or heat-killed bacteria. Our results demonstrate that even in response to a weak immunogen, functional memory cell development is linked to effector cell induction in lymphoid and nonlymphoid tissues.

Hypermethylation of the human glutathione S-transferase-pi gene (GSTP1) CpG island is present in a subset of proliferative inflammatory atrophy lesions but not in normal or hyperplastic epithelium of the prostate: a detailed study using laser-capture microdissection.

Somatic inactivation of the glutathione S-transferase-pi gene (GSTP1) via CpG island hypermethylation occurs early during prostate carcinogenesis, present in approximately 70% of high-grade prostatic intraepithelial neoplasia (high-grade PIN) lesions and more than 90% of adenocarcinomas. Recently, there has been a resurgence of the concept that foci of prostatic atrophy (referred to as proliferative inflammatory atrophy or PIA) may be precursor lesions for the development of prostate cancer and/or high-grade PIN. Many of the cells within PIA lesions contain elevated levels of GSTP1, glutathione S-transferase-alpha (GSTA1), and cyclooxygenase-II proteins, suggesting a stress response.

Pressor response to intravenous tyramine in healthy subjects after safinamide, a novel neuroprotectant with selective, reversible monoamine oxidase B inhibition.

Safinamide is a novel neuroprotectant combining sodium and calcium channel blocking properties with selective, reversible monoamine oxidase type B (MAO B) inhibition. Phase 1 studies have demonstrated that in healthy volunteers, the ED50 (a dose that inhibits enzyme activity by 50% in 50% of treated subjects) for MAO B inhibition is 87.5 microg/kg/day orally, and that no MAO A inhibition occurs after 10-mg/kg oral dosing.

Alpha-methylacyl-CoA racemase: a variably sensitive immunohistochemical marker for the diagnosis of small prostate cancer foci on needle biopsy.

Expression of the alpha-methylacyl-CoA racemase (AMACR) gene has recently been demonstrated by several groups to be markedly elevated in prostate cancer cells with little expression in benign prostate tissue and has been suggested as a molecular marker of prostate cancer on needle biopsy. There is scant data, however, as to the sensitivity and specificity of AMACR in the diagnosis of small foci of cancer on needle biopsy. A total of 209 needle biopsies of the prostate with small foci (<5% of a core) of prostatic adenocarcinoma were identified.

Induction of tumor cell apoptosis in vivo increases tumor antigen cross-presentation, cross-priming rather than cross-tolerizing host tumor-specific CD8 T cells.

Cross-presentation of cell-bound Ags from established, solid tumors to CD8 cells is efficient and likely to have a role in determining host response to tumor. A number of investigators have predicted that when tumor Ags are derived from apoptotic cells either no response, due to Ag "sequestration," or CD8 cross-tolerance would ensue. Because the crucial issue of whether this happens in vivo has never been addressed, we induced apoptosis of established hemagglutinin (HA)-transfected AB1 tumors in BALB/c mice using the apoptosis-inducing reagent gemcitabine.

Intermediate cells in human prostate epithelium are enriched in proliferative inflammatory atrophy.

Within the human prostate epithelium four cell populations can be discriminated based on their expression of keratins (K). Basal cells express high levels of K5 and K14, as well as p63, whereas they have very low levels of androgen receptor, prostate-specific antigen (PSA), K8, and K18. Luminal secretory cells lack p63, K5, and K14 but express high levels of K8, K18, androgen receptor, and PSA.

Enantioselective analytical methods in pharmacokinetics with specific reference to genetic polymorphic metabolism.

The new trend towards developing enantiospecific drugs has increased the interest in enantiospecific pharmacokinetics of chiral drugs, mainly in the case where only one of the two enantiomers is responsible for the pharmacological activity. Enantiospecific bioassays are also useful in investigating the pharmacokinetic behaviour of the two enantiomers when a given drug is marketed as racemate. The stability of the stereogenic centre in vitro and in vivo, as far as unidirectional and bidirectional inversions are concerned, is another reason for requiring stereospecific assay and bioassay.

Telomere shortening is an early somatic DNA alteration in human prostate tumorigenesis.

Chromosomal instability appears to be key to the pathogenesis of malignant transformation in human cancers, yet the precise molecular mechanisms underlying chromosomal rearrangements remain largely unknown. Telomeres stabilize and protect the ends of chromosomes, but shorten because of cell division and/or oxidative damage. Critically short telomeres, in the setting of abrogated DNA damage checkpoints, have been shown to cause chromosomal instability in vitro and in animal models, leading to an increased cancer incidence as a result of chromosome fusions, subsequent breakage, and rearrangement.

Elevated Skp2 protein expression in human prostate cancer: association with loss of the cyclin-dependent kinase inhibitor p27 and PTEN and with reduced recurrence-free survival.

The F-box protein Skp2 (Fbl1) is a positive regulator of G1-S transition and promotes ubiquitin-mediated proteolysis of the cyclin-dependent kinase inhibitor p27. Its overexpression has been implicated in cell transformation and oncogenesis in both in vitro and in vivo models. In this study, we investigated its role in human prostate cancer progression.

Bioequivalence of ticlopidine hydrochloride administered in single dose to healthy volunteers.

Ticlopidine hydrochloride (CAS 55142-85-3) is an inhibitor of platelet aggregation used in the management and prevention of thromboembolic disorders.A new formulation of ticlopidine hydrochloride (test) was compared to the reference Tiklid, present in the market, in order to assess their bioequivalence and to register the new formulation as a generic according to the Abbreviated New Drug Application (ANDA) procedure.Twenty-four healthy male volunteers were treated with the two formulations (one tablet containing 250mg of active ingredient) according to a single-dose, balanced, crossover, double-blind design with a washout between the two study periods.

Telomere shortening is nearly universal in pancreatic intraepithelial neoplasia.

A multistep model of carcinogenesis has recently been proposed for pancreatic ductal adenocarcinomas. In this model, noninvasive precursor lesions in the pancreatic ductules accumulate genetic alterations in cancer-associated genes eventually leading to the development of an invasive cancer. The nomenclature for these precursor lesions has been standardized as pancreatic intraepithelial neoplasia or PanIN.

Migration of primary and memory CD8 T cells.

Our results indicate that a substantial proportion of the antimicrobial CD8 and CD4 T cell response is focused in non-lymphoid tissues. This finding makes teleological sense since maximum protection against infection is better served by the widespread presence of effector and memory cells. In the case of CD8 T cells, it appears that irrespective of the site at which initial activation of naive cells occurs, the end result is production of effector cells with broad migratory capabilities.

Integrin alpha(v) and coxsackie adenovirus receptor expression in clinical bladder cancer.

Objectives: To evaluate the expression of the coxsackie and adenovirus receptor (CAR) and alpha(v) integrins in clinical specimens of bladder cancer to determine the susceptibility to adenoviral gene therapy. Efficient adenovirus-based gene therapy requires binding of the virus to CAR and involves the alpha(v) integrins. Studies on bladder cancer cell lines have shown that low adenoviral transduction rates were associated with low-level expression of CAR.

Inadequate formalin fixation decreases reliability of p27 immunohistochemical staining: probing optimal fixation time using high-density tissue microarrays.

Immunohistochemical analysis of molecular targets in clinical tissues is increasingly becoming central to our ability to render diagnoses, to predict prognosis, to select patients for appropriate therapies, and to provide surrogate end points for therapeutic monitoring. For example, reduction of immunohistochemical staining for the cyclin-dependent kinase inhibitor p27(Kip1) has been proposed as a potential prognostic biomarker in prostate, breast, and gastrointestinal tumors. We observed that with our standard formalin fixation in rapidly processed (same-day) radical prostatectomy specimens, there is often a gradient of p27(Kip1) staining in normal prostate epithelium, with more staining near the periphery and less staining toward the center of the sample.

Proteolytic balance in patients with multiple sclerosis during interferon treatment.

Multiple sclerosis (MS) is a progressive, inflammatory, demyelinating disease. An altered cytokine network has been reported to occur during the disease, and its pathogenetic role has been hypothesized. To date, interferon-beta (IFN-beta) is the most effective and reliable therapy in the majority of MS patients, although the mechanisms underlying its therapeutic effects are not fully understood.

Pharmacokinetic and pharmacodynamic comparative study of zofenopril and enalapril in healthy volunteers.

Zofenopril calcium (CAS 81938-43-4) is a new angiotensin converting enzyme (ACE) inhibitor, which in addition to the typical activity of the class, proved to possess a specific cardioprotective effect due also to the presence of the sulfhydryl group. In this trial zofenopril calcium and enalapril maleate (CAS 76095-16-4) were given to 20 healthy volunteers of both sexes in repeated dose regiment at two dose levels: 30 mg and 60 mg zofenopril calcium and 10 mg and 20 mg enalapril maleate. The study was conducted according to a two-period, two-sequence, crossover design, with washout.

Tissue-level regulation of Th1 and Th2 primary and memory CD4 T cells in response to Listeria infection.

Ag-specific Th1 and Th2 cytokine-producing CD4 T cells were quantitated in secondary lymphoid and tertiary tissues following oral Listeria monocytogenes infection. Although the response to Listeria was previously believed to be predominantly Th1 like, CD4 T cells producing IL-4 or IL-5 comprised a substantial proportion of the overall primary and memory response. The frequency of IFN-gamma-, IL-4-, or IL-5-producing primary effector or memory CD4 T cells was significantly higher in lung, liver, and intestinal lamina propria (LP) as compared with spleen and lymph node.

Pharmacokinetic behaviour of antithrombin III following intravenous infusion in healthy volunteers.

Antithrombin III (CAS 52014-67-2) is produced from plasma of healthy donors and is purified from any detectable agent of transmissible infection. This drug is used in therapy by i.v.

Alpha-methylacyl-CoA racemase: a new molecular marker for prostate cancer.

Identification of genes that are dysregulated in association with prostate carcinogenesis can provide disease markers and clues relevant to disease etiology. Of particular interest as candidate markers of disease are those genes that are frequently overexpressed. In this study, we describe a gene, alpha-methylacyl-CoA racemase (AMACR), whose expression is consistently up-regulated in prostate cancer.