Pulmonary capillaritis in IgA nephropathy.

Pulmonary capillaritis presenting as diffuse alveolar hemorrhage is a rare manifestation in patients with IgA nephropathy. A 20-year-old male with hemodialysis dependent, end-stage renal failure presented with recurrent hemoptysis and respiratory failure. A histologic diagnosis of pulmonary capillaritis was established by transbronchial lung biopsy.

Beta-cryptoxanthin and lung cancer in Shanghai, China--an examination of potential confounding with cigarette smoking using urinary cotinine as a biomarker for true tobacco exposure.

Diet may be a modifier of smoking-related cancer risk, with protective effects of intake of fruits and vegetables and associated antioxidants found in many observational studies. We previously reported serum beta-cryptoxanthin levels being inversely associated with smoking-related lung cancer incidence in a cohort of Chinese men. We noted, however, that serum beta-cryptoxanthin is negatively correlated with smoking.

High-frequency oscillatory ventilation for adult patients with ARDS.

High-frequency oscillatory ventilation (HFOV) is characterized by the rapid delivery of small tidal volumes (Vts) of gas and the application of high mean airway pressures (mPaws). These characteristics make HFOV conceptually attractive as an ideal lung-protective ventilatory mode for the management of ARDS, as the high mPaws prevent cyclical derecruitment of the lung and the small Vts limit alveolar overdistension. In this review, we will summarize the literature describing the use of HFOV in adult patients with ARDS.

Comparative phloem chemistry of Manchurian (Fraxinus mandshurica) and two North American ash species (Fraxinus americana and Fraxinus pennsylvanica).

Recent studies have investigated interspecific variation in resistance of ash (Fraxinus spp.) to the exotic wood-boring beetle, emerald ash borer (EAB, Agrilus planipennis). Manchurian ash (Fraxinus mandshurica) is an Asian species that has coevolved with EAB.

Community attitudes towards discriminatory practice against people with severe mental illness in Hong Kong.

Background: The existing literature on community attitudes towards people with severe mental illness (SMI) tends to be rather general and impressionistic, with apparently conflicting findings which have yet to be adequately understood.

Aims: This article undertakes to examine the community's level of tolerance towards discriminatory practice against people with SMI in three domains: family relations, employment and health care.

Methods: Structured interviews with a representative sample of 507 citizens were carried out using the computer-assisted telephone interview system (CATI).

"One-pot" methylation in glycomics application: esterification of sialic acids and permanent charge construction.

A simple and rapid "one-pot" methylation method to esterify sialic acids and construct a permanent charge was developed for N-linked glycan analysis, which combined complete nonspecific proteolytic digestion and methylation. A mixture of Asn-glycans prepared from Pronase E digestion of the glycoprotein was passed through a cation-exchange column to convert carboxylic acids to the Na+ form before being methylated with methyl iodide. Derivatives could be easily purified with a hydrophilic affinity chromatography cartridge.

Targeting AML1/ETO-histone deacetylase repressor complex: a novel mechanism for valproic acid-mediated gene expression and cellular differentiation in AML1/ETO-positive acute myeloid leukemia cells.

In t(8;21) acute myeloid leukemia (AML), the AML1/ETO fusion protein promotes leukemogenesis by recruiting class I histone deacetylase (HDAC)-containing repressor complex to the promoter of AML1 target genes. Valproic acid (VPA), a commonly used antiseizure and mood stabilizer drug, has been shown to cause growth arrest and induce differentiation of malignant cells via HDAC inhibition. VPA causes selective proteasomal degradation of HDAC2 but not other class I HDACs (i.

Analysis of nitrosamines by capillary electrospray-high-field asymmetric waveform ion mobility spectrometry-MS with programmed compensation voltage.

Emerging disinfection by-products (DBPs) in drinking water are an important public health concern. Certain DBPs, such as nitrosamines, are probable carcinogens, and exposure to halogenated DBPs may lead to birth defects. It is difficult to obtain complete separation of nitrosamines by chromatographic techniques.

Desialylation of core type 1 O-glycan in the equine embryonic capsule coincides with immobilization of the conceptus in the uterus.

During the second and third weeks of pregnancy, the equine conceptus expands rapidly while it is enclosed within a glycan capsule. Around day 16 of gestation, the conceptus loses its mobility in the uterus by a process termed 'fixation', coinciding with various changes in the capsule. Here, we compared the structure of the carbohydrate moieties expressed by the capsule during pre- and post-fixation periods.

Metabolism of GTI-2040, a phosphorothioate oligonucleotide antisense, using ion-pair reversed phase high performance liquid chromatography (HPLC) coupled with electrospray ion-trap mass spectrometry.

GTI-2040 is a 20-mer phosphorothioate oligonucleotide, which is complementary to the messenger ribonucleic acid (mRNA) of the R2 subunit of ribonucleotide reductase. This study characterized both the in vivo and in vitro metabolism of GTI-2040. A highly specific ion-pair reversed-phase electrospray ionization (IP-RP-ESI) liquid chromatography-mass spectrometry (LC-MS) method was used for the identification of GTI-2040 and metabolites from a variety of biological samples including exonuclease enzyme solutions, plasma, urine, mouse liver/kidney homogenates, and human liver microsomes.

Characterization of in vitro and in vivo hypomethylating effects of decitabine in acute myeloid leukemia by a rapid, specific and sensitive LC-MS/MS method.

DNA hypermethylation is a common finding in malignant cells and has been explored as a therapeutic target for hypomethylating agents (e.g., decitabine).

Population pharmacokinetics of humanized monoclonal antibody HuCC49deltaCH2 and murine antibody CC49 in colorectal cancer patients.

To predict the optimal time for surgery after antibody administration, the population pharmacokinetics of (125)I-HuCC49deltaCH2 and (125)I-CC49 were characterized in 55 patients with colorectal cancers. A 2-compartment linear model was used to fit the pharmacokinetic data. Model stability and performance were assessed using a visual predictive check procedure.

Single-stranded nucleic acid-induced helical self-assembly of alkynylplatinum(II) terpyridyl complexes.

Single-stranded nucleic acids, which carry multiple negative charges in an aqueous medium at near neutral pH, are found to induce the aggregation and self-assembly of the positively charged alkynylplatinum(II) terpyridyl complexes via electrostatic binding of the platinum complexes to the single-stranded nucleic acids, as revealed by the appearance of new UV-vis absorption and emission bands upon addition of single-stranded nucleic acids to a buffer solution of the complex. Changes in the intensity and pattern of circular dichroism (CD) spectroscopy are also observed, many of which are consistent with the assembly of the platinum complexes into helical structures, via metal..

Quantification of valproic acid and its metabolite 2-propyl-4-pentenoic acid in human plasma using HPLC-MS/MS.

A specific and sensitive HPLC-MS/MS method for the quantitative determination of valproic acid (VPA) and its metabolite, 2-propyl-4-pentenoic acid in human plasma has been developed, using VPA-d15 as the internal standard. The method was based on pre-column derivatization using 4-dimethylaminobenzylamine dihydrochloride. The derivatives were separated with a gradient elution and quantified by positive electrospray ionization with multiple reaction monitoring.

Enzyme specific activation of benzoquinone ansamycin prodrugs using HuCC49DeltaCH2-beta-galactosidase conjugates.

To activate prodrugs for cancer treatment, an anti-TAG-72 antibody (HuCC49DeltaCH2) was used for delivery of an activation enzyme (beta-galactosidase) to specifically activate a geldanamycin prodrug (17-AG-C2-Gal) against colon cancer. The geldanamycin prodrug 17-AG-C2-Gal was synthesized by coupling a galactose-amine derivative with geldanamycin at the C-17 position. Molecular docking with two different programs (Affinity and Autodock) showed that the prodrug (17-AG-C2-Gal) was unable to bind to Hsp90; however, the product (17-AG-C2), enzymatically cleaved by beta-galactosidase conjugate, bound to Hsp90 in a similar way as geldanamycin and 17-AG.

Cardiotoxicity of histone deacetylase inhibitor depsipeptide in patients with metastatic neuroendocrine tumors.

Purpose: This phase II study was undertaken to assess objective response and toxicity of histone deacetylase inhibitor depsipeptide in patients with neuroendocrine tumors.

Experimental Design: A total of 15 patients with metastatic neuroendocrine tumors received a 4-hour i.v.

In vivo metabolism and final disposition of a novel nonsteroidal androgen in rats and dogs.

Compound S-4 (S-3-(4-acetylamino-phenoxy)-2-hydroxy-2-methyl-N-(4-nitro-3-trifluoromethyl-phenyl)-propionamide) is a novel nonsteroidal androgen agonist that mimics many of the beneficial pharmacologic effects of testosterone with lesser effects on the prostate. S-4 demonstrated high androgen receptor binding affinity as well as anabolic specificity during in vivo pharmacologic studies in rats, identifying it as the first member of a new class of selective androgen receptor modulators. The purpose of these studies was to determine the pharmacokinetics and metabolism of S-4 in dogs.

A specific picomolar hybridization-based ELISA assay for the determination of phosphorothioate oligonucleotides in plasma and cellular matrices.

Purpose: To develop and validate an ultrasensitive and specific hybridization-based enzyme-linked immunosorbent assay method for quantification of two phosphorothioate oligonucleotides (PS ODNs) (G3139 and GTI-2040) in biological fluids.

Methods: This assay was based on hybridization of analytes to the biotin-labeled capture ODNs followed by ligation with digoxigenin-labeled detection ODN. The bound duplex was then detected by anti-digoxigenin-alkaline phosphatase using Attophos (Promega, Madison, WI, USA) as substrate.

The combination of the proteasome inhibitor bortezomib and the bcl-2 antisense molecule oblimersen sensitizes human B-cell lymphomas to cyclophosphamide.

Purpose: To determine whether the combination of the proteasome inhibitor bortezomib and the bcl-2 antisense molecule oblimersen can sensitize human lymphoma to cyclophosphamide.

Experimental Design: Cytotoxicity assays were conducted to determine if there was any additive or synergistic interaction between the combinations of bortezomib, oblimersen, and cyclophosphamide using a standard trypan blue exclusion assay. Based on these experiments, in vivo experiments in severe combined immunodeficiency beige mice were done using human lymphoma xenografts in which different schedules were explored.

High performance liquid chromatographic analysis and preclinical pharmacokinetics of the heteroarotinoid antitumor agent, SHetA2.

Background: SHetA2 {[(4-nitrophenyl)amino][2,2,4,4-tetramethylthiochroman-6-yl)amino]methane-thione], NSC 726189} is a sulfur-containing heteroarotinoid, which selectively inhibits cancer cell growth and induces apoptosis without activation of nuclear retinoic acid receptors (RARs). The objective was to develop and validate a HPLC/UV method for the determination of SHetA2, and study the pharmacokinetics of SHetA2 in the mouse.

Methods: SHetA2 and the internal standard, methylated XK469 (MeXK469) were isolated from 0.

Characterization of decomposition products and preclinical and low dose clinical pharmacokinetics of decitabine (5-aza-2'-deoxycytidine) by a new liquid chromatography/tandem mass spectrometry quantification method.

Aberrant DNA methylation patterns resulting in gene transcriptional repression are observed in numerous cancers. Decitabine, a DNA methyltransferase inhibitor, is being clinically evaluated in patients with hematologic malignancies and solid tumors. Decitabine is rather unstable and decomposes to 1-beta-D-2'-deoxyribofuranosyl-3-guanylurea under basic conditions and several additional unknown products under neutral conditions.

Pharmacokinetics of N-2-chloroethylaziridine, a volatile cytotoxic metabolite of cyclophosphamide, in the rat.

Objectives: The objectives of this study were to characterize pharmacokinetics of N-2-chloroethylaziridine (CEA) in the rat model and assess the in vivo fraction of total clearance of phosphoramide mustard (PM) that furnished CEA to circulation.

Methods: The disposition of CEA was investigated following separate intravenous (iv) administrations of PM, synthetic CEA, and their combination to the Sprague-Dawley rats. In addition, in rats receiving prodrug cyclophosphamide (CP), plasma concentrations of CP and its metabolites, 4-hydroxycyclophosphamide (HOCP), PM, and CEA, were simultaneously quantified using GC/MS and stable isotope dilution techniques.

Discovery of a daunorubicin analogue that exhibits potent antitumor activity and overcomes P-gp-mediated drug resistance.

Anthracyclines are considered to be some of the most effective anticancer drugs for cancer therapy. However, drug resistance and cardiotoxicity of anthracyclines limit their clinical application. We hypothesize that direct modifications of the sugar moiety of anthracyclines avert P-glycoprotein (P-gp) recognition and efflux, increase drug intracellular concentration in cancer cells, and thus overcome P-gp-mediated drug resistance.

A phase II study of chloroquinoxaline sulfonamide (CQS) in patients with metastatic colorectal carcinoma (MCRC).

Purpose: Phase II multicenter study investigated the efficacy and toxicity of the novel halogenated derivative of sulfaquixonaline Chloroquinoxaline Sulfonamide (CQS) in metastatic colorectal cancer.

Experimental Design: Eligible patients with metastatic or recurrent colorectal cancer received CQS at a dose schedule of 2000 mg/m2 over an hour weekly for 4 weeks every 42 days. Treatment was continued until unexpected toxicity or disease progression.