Genetic alterations in primary melanoma in Taiwan.

BACKGROUND: Acral melanoma (AM) is the most common histopathological subtype of malignant melanoma in Asians. However, differences in the mutational profiles underlying AM and nonacral cutaneous melanoma (NAM) in Asians are not well understood. OBJECTIVES: To augment the understanding of the prevalence, patterns and associations of various mutations between different subtypes of melanoma. METHODS: We performed comprehensive genomic profiling of 409 cancer-associated genes, using next-generation sequencing, in 66 primary melanomas comprised of 45 AMs and 21 NAMs. RESULTS: Most of the AMs (n = 27/45; 60%), but only five of 21 (24%) NAMs, were triple wild-type (triple-WT) tumours. Compared with AMs, NAMs exhibited a significantly higher frequency of BRAF mutations. The frequencies of NRAS/KRAS mutations, cell-cycle aberrations, copy number gains in BIRC2, BIRC3 and BIRC5, and gains of receptor tyrosine kinase genes were significantly higher in AMs. Ulceration was found at significantly higher rates in the AMs and NAMs with cell-cycle aberrations and gains of receptor tyrosine kinase genes. Notably, cell-cycle aberrations and copy number gains in BIRC2, BIRC3 and BIRC5 were significantly associated with poor melanoma-specific survival in the 66 patients with melanoma and especially in the 45 patients with AM. Multivariate analysis showed that lymph node metastasis and cell-cycle aberrations were independent prognostic factors of melanoma-specific survival. CONCLUSIONS: This study strengthens our understanding of the patterns and clinical associations of oncogenic mutations in AMs and NAMs in Asians. What's already known about this topic? Mutation frequencies of driver genes vary between melanoma subtypes. Acral melanoma is the most common subtype of melanoma in Asians. KIT mutations and copy number variations occur more frequently in the acral subtype of melanoma than in the nonacral subtype What does this study add? NRAS/KRAS mutations, cell-cycle aberrations, copy number gains in BIRC2, BIRC3 and BIRC5, and amplifications of receptor tyrosine kinase genes were significantly enriched in acral melanoma and could be potential targets for treatment. Melanomas with cell-cycle aberrations and gains in receptor tyrosine kinase genes were significantly more likely to contain ulceration. What is the translational message? Cell-cycle aberrations and copy number gains in BIRC2, BIRC3 and BIRC5 were significantly associated with poor melanoma-specific survival. These observations should be explored further for future drug development.

The metabolome profiling and pathway analysis in metabolic healthy and abnormal obesity.

OBJECTIVES: Mechanisms of the development of abnormal metabolic phenotypes among obese population are not yet clear. In this study, we aimed to screen metabolomes of both healthy and subjects with abnormal obesity to identify potential metabolic pathways that may regulate the different metabolic characteristics of obesity. METHODS: We recruited subjects with body mass index (BMI) over 25 from the weight-loss clinic of a central hospital in Taiwan. Metabolic healthy obesity (MHO) is defined as without having any form of hyperglycemia, hypertension and dyslipidemia, while metabolic abnormal obesity (MAO) is defined as having one or more abnormal metabolic indexes. Serum-based metabolomic profiling using both liquid chromatography-mass spectrometry and gas chromatography-mass spectrometry of 34 MHO and MAO individuals with matching age, sex and BMI was performed. Conditional logistic regression and partial least squares discriminant analysis were applied to identify significant metabolites between the two groups. Pathway enrichment and topology analyses were conducted to evaluate the regulated pathways. RESULTS: A differential metabolite panel was identified to be significantly differed in MHO and MAO groups, including L-kynurenine, glycerophosphocholine (GPC), glycerol 1-phosphate, glycolic acid, tagatose, methyl palmitate and uric acid. Moreover, several metabolic pathways were relevant in distinguishing MHO from MAO groups, including fatty acid biosynthesis, phenylalanine metabolism, propanoate metabolism, and valine, leucine and isoleucine degradation. CONCLUSION: Different metabolomic profiles and metabolic pathways are important for distinguishing between MHO and MAO groups. We have identified and discussed the key metabolites and pathways that may prove important in the regulation of metabolic traits among the obese, which could provide useful clues to study the underlying mechanisms of the development of abnormal metabolic phenotypes.

Hand warmer related corrosive injury.

INTRODUCTION: Corrosive injury of the esophagus and stomach is never been reported after intoxication of hand warmers. Herein we reported a case that had grade IIA corrosive injury found by endoscopic examination. CASE REPORT: An 84 year-old woman with a history of dementia ingested the contents of hand warmers. She had radiopaque patches in the stomach and duodenum. Upper endooscopic examination revealed corrosive injury of the esophagus and stomach. She recovered with the use of deferoxamine and proton pump inhibitor (PPI). DISCUSSION: The hand warmer contains activated charcoal, salt, and vermiculite, and 50% of iron powder. In previous literature, ingestions of one hand warmer packet or less are considered less toxic. But in our case, corrosive injury of the esophagus and stomach is obvious. CONCLUSION: It appears that significant toxicity will occur after ingestion of one hand warmer packet. Appropriate gastrointestinal decontamination and aggressive management are needed for all patients who are hand warmers intoxicated.

Prediction and mechanistic interpretation of human oral drug absorption using MI-QSAR analysis.

Membrane-interaction [MI]-QSAR analysis, which includes descriptors explicitly derived from simulations of solutes [drugs] interacting with phospholipid membrane models, was used to construct QSAR models for human oral intestinal drug absorption. A data set of 188 compounds, which are mainly drugs, was divided into a parent training set of 164 compounds and a test set of 24 compounds. Stable, but not highly fit [R2 = 0.68] MI-QSAR models could be built for all 188 compounds. However, the relatively large number [47] of drugs having 100% absorption, as well as all zwitterionic compounds [11], had to be eliminated from the training set in order to construct a linear five-term oral absorption diffusion model for 106 compounds which was both stable [R2 = 0.82, Q2 = 0.79] and predictive given the test set compounds were predicted with nearly the same average accuracy as the compounds of the training set. Intermolecular membrane-solute descriptors are essential to building good oral absorption models, and these intermolecular descriptors are displaced in model optimizations and intramolecular solute descriptors found in published oral absorption QSAR models. A general form for all of the oral intestinal absorption MI-QSAR models has three classes of descriptors indicative of three thermodynamic processes: (1) solubility and partitioning, (2) membrane-solute interactions, and (3) flexibility of the solute and/or membrane. The intestinal oral absorption MI-QSAR models were compared to MI-QSAR models previously developed for Caco-2 cell permeation and for blood-brain barrier penetration. The MI-QSAR models for all three of these ADME endpoints share several common descriptors, and suggest a common mechanism of transport across all three barriers. A further analysis of these three types of MI-QSAR models has been done to identify descriptor-term differences across these three models, and the corresponding differences in thermodynamic transport behavior of the three barriers.

Selective cytotoxicity of azatyrosinamides against ras-transformed NIH 3T3 cells.

This study aims to develop novel azatyrosinamide compounds structurally modified from ras-specific antioncogenic azatyrosine. Analogues 4-15 were prepared and their inhibition on the growth of wild-type and ras-transformed NIH 3T3 cell lines was compared. Compound 12 was found to be the most active with IC50 16.5+/-2.2 microM which is 458-fold more potent than that of azatyrosine. The selective toxicity, defined as IC(50 wild-type)/IC(50 ras-transformed) for this compound was 138.5.

A least-squares error minimization approach in the determination of ferric ion diffusion coefficient of Fricke-infused dosimeter gels.

A least-squares error minimization approach was adopted to assess ferric ion diffusion coefficient of Fricke-agarose gels. Ferric ion diffusion process was modeled as a Gaussian-shaped degradation kernel operating on an initial concentration distribution. Diffusion coefficient was iteratively determined by minimizing the error function defined as the difference between the theoretically calculated and the experimentally measured dose distributions. A rapid MR image-based differential gel dosimetry technique that time resolves the evolution of the ferric ion diffusion process minimizes smearing of the dose distribution. Our results showed that for a Fricke-agarose gel contained 1 mM ammonium ferrous sulfate, 1% agarose, 1 mM sodium chloride, and 50 mM sulfuric acid, its ferric ion diffusion coefficient is (1.59 +/- 0.28) x 10(-2) cm2 h(-1) at room temperature. This value falls within the 1.00-2.00 x 10(-2) cm2 h(-1) range previously reported under varying gelling ingredients and concentrations. This method allows a quick, nondestructive evaluation of the ferric ion diffusion coefficient that can be used in conjunction with the in situ gel dosimetry experiment to provide a practical diffusion characterization of the dosimeter gel.

4D-fingerprints, universal QSAR and QSPR descriptors.

An elusive goal in the field of chemoinformatics and molecular modeling has been the generation of a set of descriptors that, once calculated for a molecule, may be used in a wide variety of applications. Since such universal descriptors are generated free from external constraints, they are inherently independent of the data set in which they are employed. The realization of a set of universal descriptors would significantly streamline such chemoinformatics tasks as virtual high-throughout screening (VHTS) and toxicity profiling. The current study reports the derivation and validation of a potential set of universal descriptors, referred to as the 4D-fingerprints. The 4D-fingerprints are derived from the 4D-molecular similarity analysis. To evaluate the applicability of the 4D-fingerprints as universal descriptors, they are used to generate descriptive QSAR models for 5 independent training sets. Each of the training sets has been analyzed previously by several varying QSAR methods, and the results of the models generated using the 4D-fingerprints are compared to the results of the previous QSAR analyses. It was found that the models generated using the 4D-fingerprints are comparable in quality, based on statistical measures of fit and test set prediction, to the previously reported models for the other QSAR methods. This finding is particularly significant considering the 4D-fingerprints are generated independent of external constraints such as alignment, while the QSAR methods used for comparison all require an alignment analysis.

The role of dose distribution gradient in the observed ferric ion diffusion time scale in MRI-Fricke-infused gel dosimetry.

Ferric ion diffusion is a detrimental factor in MRI-Fricke-infused gel dosimetry. In this study, a novel approach involving MR image subtraction and a fast image-based dosimetry technique to study ferric ion diffusion effects is presented. The fast image-based approach allows studying dose profile degradation within minutes post-irradiation. The relationship between the rate of dose profile deterioration and dose distribution gradients can be elucidated with the improved imaging temporal resolution also. Our results showed that for a dose distribution with gradient 4 Gy/mm or higher, ferric ion diffusion causes apparent dose profile degradation in 0.5-1 h post-irradiation. For a gradual dose gradient change of 2.1 Gy/mm or smaller, dose profile degradation appears insignificant for a two-hour elapsed diffusion time. These observations agree well with the theoretical analysis of a square dependence between dose profile degradation and dose distribution gradient. Because all stereotactic radiosurgery procedures produce steep dose distributions and because the ideal "snapshot" of MR scanning cannot be achieved, knowledge of the ferric ion diffusion time scale is important in experimental designs in order to avoid potential measurement errors in MRI-Fricke-agarose gel dosimetry.

Seminal plasma zinc levels and sperm motion characteristics in infertile samples.

BACKGROUND: Zinc (Zn) in seminal plasma stabilizes the cell membrane and nuclear chromatin of spermatozoa. It may also have an antibacterial function. However, extremely high concentrations of Zn (10 to 100 x the normal range) may inhibit sperm motility and the function of the mannose receptor on the sperm head. In this study, we analyzed the correlation between Zn levels in seminal plasma and the characteristics of semen as measured by conventional and computer aided sperm analysis (CASA). METHODS: One hundred fifteen infertile couples were recruited for conventional semen analysis and CASA from December 1995 through January 1996, and Zn levels in semen samples were determined by flame atomic absorption spectroscopy (AAS). RESULTS: A good correlation in a positive direction (r = 0.73, p = 0.0001) was noted between the total amount of Zn per ejaculate and the Zn concentration. The Zn concentration in seminal plasma was negatively correlated with the seminal pH (r = -0.35, p = 0.0081). There was no significant correlation between the total amount of Zn per ejaculate and sperm characteristics, including sperm count, motility (% sperm count), progressive motility (% motility), rapid motility (% motility), average path velocity (VAP, microns/s), straight-line velocity (VSL, microns/s), curvilinear velocity (VCL, microns/s), amplitude of lateral head displacement (ALH, microns), beat/cross frequency (BCF, beats/s), straightness (STR), and linearity (LIN). There was also no significant correlation between the Zn concentration in seminal plasma and the above sperm characteristics. CONCLUSION: The characteristics of semen as determined by conventional semen analysis or CASA bore no correlation with total seminal Zn amount or Zn concentrations in the ejaculates. Routine determination of the Zn concentration in seminal plasma offers no advantages in infertility work-ups.

Carcinosarcoma of the renal pelvis: a case report with immunohistochemical study.

The clinicopathologic feature of one carcinosarcoma of the renal pelvis is reported. The tumor occurred in a 51-year-old woman with a long standing history of renal calculi. The epithelial component was consistent with squamous cell carcinoma, whereas the sarcomatous component was composed of pleomorphic spindle cells. The immunohistochemical studies demonstrated obvious epithelial and mesenchymal reactivity respectively. The tumor progressed rapidly with widespread metastases and the patient died one month after operation.