Classification of Pancreatic Ductal Adenocarcinoma Using MALDI Mass Spectrometry Imaging Combined with Neural Networks.

Despite numerous diagnostic and therapeutic advances, pancreatic ductal adenocarcinoma (PDAC) has a high mortality rate, and is the fourth leading cause of cancer death in developing countries. Besides its increasing prevalence, pancreatic malignancies are characterized by poor prognosis. Omics technologies have potential relevance for PDAC assessment but are time-intensive and relatively cost-intensive and limited by tissue heterogeneity.

MALDI-Imaging for Classification of Epithelial Ovarian Cancer Histotypes from a Tissue Microarray Using Machine Learning Methods.

Purpose: Precise histological classification of epithelial ovarian cancer (EOC) has immanent diagnostic and therapeutic consequences, but remains challenging in histological routine. The aim of this pilot study is to examine the potential of matrix-assisted laser desorption/ionization (MALDI) imaging mass spectrometry in combination with machine learning methods to classify EOC histological subtypes from tissue microarray.

Experimental Design: Formalin-fixed-paraffin-embedded tissue of 20 patients with ovarian clear-cell, 14 low-grade serous, 19 high-grade serous ovarian carcinomas, and 14 serous borderline tumors are analyzed using MALDI-Imaging.

An interactive three-dimensional digital atlas and quantitative database of human development.

Current knowledge about human development is based on the description of a limited number of embryonic specimens published in original articles and textbooks, often more than 100 years ago. It is exceedingly difficult to verify this knowledge, given the restricted availability of human embryos. We created a three-dimensional digital atlas and database spanning the first 2 months of human development, based on analysis of nearly 15,000 histological sections of the renowned Carnegie Collection of human embryonic specimens.

E-consulting in a medical specialist setting: Medicine of the future?

Objective: Today's technology provides new ways of consulting between patients and medical specialists in health care, such as videoconferencing and web-messaging. In this systematic review we assessed the effects of e-consulting between medical specialists and patients.

Methods: We searched MEDLINE, EMBASE, Psychlit and Cochrane Library for randomized clinical trials assessing the use of e-consulting methods (videoconferencing (VC) or web-messaging (WM)), as compared to conventional care (face-to-face (FF) or telephone consultations (TC)) in a medical specialist setting.

Chemical subtleties in small-molecule modulation of peptide receptor function: the case of CXCR3 biaryl-type ligands.

The G protein-coupled chemokine receptor CXCR3 plays a role in numerous inflammatory events. The endogenous ligands for the chemokine receptors are peptides, but in this study we disclose small-molecule ligands that are able to activate CXCR3. A class of biaryl-type compounds that is assembled by convenient synthetic routes is described as a new class of CXCR3 agonists.

Multicomponent synthesis of 3,6-dihydro-2H-1,3-thiazine-2-thiones.

Non-fused 3,6-dihydro-2H-1,3-thiazine-2-thiones constitute a so far rather unexplored class of compounds, with the latest report dating back more than two decades. Thiazine-2-thiones contain an endocyclic dithiocarbamate group, which is often found in pesticides, in substrates for radical chemistry and in synthetic intermediates towards thioureas and amidines. We now report the multicomponent reaction (MCR) of in situ-generated 1-azadienes with carbon disulfide.

Structure-based design, synthesis and structure-activity relationships of dibenzosuberyl- and benzoate-substituted tropines as ligands for acetylcholine-binding protein.

Using structure-based optimization procedures on in silico hits, dibenzosuberyl- and benzoate substituted tropines were designed as ligands for acetylcholine-binding protein (AChBP). This protein is a homolog to the ligand binding domain of the nicotinic acetylcholine receptor (nAChR). Distinct SAR is observed between two AChBP species variants and between the α7 and α4β2 nAChR subtype.

Preorganized frustrated Lewis pairs.

Geminal frustrated Lewis pairs (FLPs) are expected to exhibit increased reactivity when the donor and acceptor sites are perfectly aligned. This is shown for reactions of the nonfluorinated FLP tBu(2)PCH(2)BPh(2) with H(2), CO(2), and isocyanates and supported computationally.

Stereoselective synthesis of N-aryl proline amides by biotransformation-Ugi-Smiles sequence.

An efficient combination of MAO-N-catalyzed desymmetrization of cyclic meso-amines with Ugi-Smiles multicomponent chemistry produced optically pure N-aryl proline amides. This method represents the first report of a fully asymmetric Ugi-Smiles process.

Synthesis of 4-aminoquinazolines by palladium-catalyzed intramolecular imidoylation of N-(2-bromoaryl)amidines.

Compared with the widespread use of carbonylative Pd-catalyzed cross-coupling reactions, similar reactions involving isocyanide insertion are almost virgin territory. We investigated the intramolecular imidoylative cross-coupling of N-(2-bromoaryl)amidines, leading to 4-aminoquinazolines. After thorough optimization of the reaction with respect to palladium source and loading, ligand, base, temperature, and solvent, a small library of 4-aminoquinazolines was prepared to determine the scope of this method.

Palladium-catalyzed synthesis of 4-aminophthalazin-1(2H)-ones by isocyanide insertion.

Palladium-catalyzed cross-coupling of a wide range of substituted o-(pseudo)halobenzoates and hydrazines with isocyanide insertion followed by lactamization efficiently affords 4-aminophthalazin-1(2H)-ones that are difficult to obtain regioselectively by classical methods.

Role of residue 87 in the activity and regioselectivity of clozapine metabolism by drug-metabolizing CYP102A1 M11H: application for structural characterization of clozapine GSH conjugates.

In the present study, a site-saturation mutagenesis library of drug-metabolizing CYP102A1 M11H with all 20 amino acids at position 87 was applied as a biocatalyst for the production of stable and reactive metabolites of clozapine. Clozapine is an atypical antipsychotic drug in which formation of reactive metabolites is considered to be responsible for several adverse drug reactions. Reactive intermediates of clozapine can be inactivated by GSH to multiple GSH conjugates by nonenzymatic and glutathione transferase (GST)-mediated conjugation reactions.

Stability-indicating study of the anti-Alzheimer's drug galantamine hydrobromide.

Galantamine hydrobromide was subjected to different stress conditions (acidic, alkaline, thermal, photolytic and oxidative). Degradation was found to occur under acidic, photolytic and oxidative conditions, while the drug was stable under alkaline and elevated temperature conditions. A stability-indicating reversed-phase liquid chromatographic method was developed for the determination of the drug in the presence of its degradation products.

Endotoxemia decreases matching of regional blood flow and O2 delivery to O2 uptake in the porcine left ventricle.

Heterogeneity of regional coronary blood flow is caused in part by heterogeneity in O(2) demand in the normal heart. We investigated whether myocardial O(2) supply/demand mismatching is associated with the myocardial depression of sepsis. Regional blood flow (microspheres) and O(2) uptake ([(13)C]acetate infusion and analysis of resultant NMR spectra) were measured in about nine contiguous tissue samples from the left ventricle (LV) in each heart.

Hydrocortisone suppression of the fear-potentiated startle response and posttraumatic stress disorder.

This study examined the effects of oral administration of 20mg hydrocortisone on baseline and fear-potentiated startle in 63 male veterans with or without PTSD. The procedure was based on a two-session, within-subject design in which acoustic startle eyeblink responses were recorded during intervals of threat or no threat of electric shock. Results showed that the magnitude of the difference between startle responses recorded during anticipation of imminent shock compared to "safe" periods was reduced after hydrocortisone administration relative to placebo.

Asymmetric synthesis of synthetic alkaloids by a tandem biocatalysis/Ugi/Pictet-Spengler-type cyclization sequence.

We have combined the biocatalytic desymmetrization of 3,4-cis-substituted meso-pyrrolidines with an Ugi-type multicomponent reaction followed in situ by a Pictet-Spengler-type cyclization reaction sequence for the rapid asymmetric synthesis of alkaloid-like polycyclic compounds.

A highly efficient synthesis of telaprevir by strategic use of biocatalysis and multicomponent reactions.

A very short and efficient synthesis of the important drug candidate telaprevir, featuring a biocatalytic desymmetrization and two multicomponent reactions as the key steps, is presented. The classical issue of lack of stereoselectivity in Ugi- and Passerini-type reactions is circumvented. The atom economic and convergent nature of the synthetic strategy require only very limited use of protective groups.

Production and on-line acetylcholinesterase bioactivity profiling of chemical and biological degradation products of tacrine.

The present paper describes a methodology for rapid assessment of chemical and biological degradation products of tacrine and their bioactivity for acetylcholinesterase (AChE). Analysis was achieved by utilizing liquid chromatography coupled to parallel high resolution mass spectrometry and an on-line continuous-flow AChE bioassay for biochemical detection. Key advantage of the strategy described involves the straightforward chemical production of large quantities of products of which many were the same as formed during the biological degradation by cytochromes P450 (CYPs).

Synthesis and QSAR of quinazoline sulfonamides as highly potent human histamine H4 receptor inverse agonists.

Hit optimization of the class of quinazoline containing histamine H(4) receptor (H(4)R) ligands resulted in a sulfonamide substituted analogue with high affinity for the H(4)R. This moiety leads to improved physicochemical properties and is believed to probe a distinct H(4)R binding pocket that was previously identified using pharmacophore modeling. By introducing a variety of sulfonamide substituents, the H(4)R affinity was optimized.

Photohuperzine A-A new photoisomer of huperzine A: structure elucidation, formation kinetics and activity assessment.

A new photoisomer of the promising "anti-Alzheimer" drug candidate (+/-) huperzine A is described. The new substance was formed via a photoisomerization reaction and was found to be 1-amino-13-ethylidene-11-methyl-6-aza-tetracyclo-[7.3.

Scope and limitations of an efficient four-component reaction for dihydropyridin-2-ones.

A broad range of isonitrile-functionalized 3,4-dihydropyridin-2-ones could be prepared using a four-component reaction between phosphonates, nitriles, aldehydes, and isocyanoacetates. The reaction involves initial formation of a 1-azadiene intermediate which is trapped in situ by an isocyanoacetate to give the desired heterocyclic scaffold through cyclocondensation. The full scope and limitations of this four-component reaction are described.

Iridium phosphinidene complexes: a comparison with iridium imido complexes in their reaction with isocyanides.

18-Electron nucleophilic, Schrock-type phosphinidene complexes 3 [Cp*(Xy-N[triple bond]C)Ir=PAr] (Ar = Mes*, Dmp, Mes) are capable of unprecedented [1 + 2]-cycloadditions with 1 equiv of isocyanide RNC (R = Xy, Ph) to give novel iridaphosphirane complexes [Cp*(Xy-N[triple bond]C) IrPAr C=NR]. Their structures were ascertained by X-ray diffraction. Density functional theory investigations on model structures revealed that the iridaphosphirane complexes are formed from the addition of the isocyanide to 16-electron species [Cp*Ir=PAr] forming first complex 3 that subsequently reacts with another isocyanide to give the products following a different pathway than its nitrogen analogue [Cp*Ir[triple bond]Nt-Bu] 1.