David A. Gaul

Nucleoside phosphorylation by the mineral schreibersite

Phosphorylation of the nucleosides adenosine and uridine by the simple mixing and mild heating of aqueous solutions of the organic compounds with synthetic analogs of the meteoritic mineral schreibersite, (Fe,Ni)3P under slightly basic conditions (pH ~9) is reported. These results suggest a potential role for meteoritic phosphorus in the origin and development of early life.

Highly-accurate metabolomic detection of early-stage ovarian cancer.

High performance mass spectrometry was employed to interrogate the serum metabolome of early-stage ovarian cancer (OC) patients and age-matched control women. The resulting spectral features were used to establish a linear support vector machine (SVM) model of sixteen diagnostic metabolites that are able to identify early-stage OC with 100% accuracy in our patient cohort. The results provide evidence for the importance of lipid and fatty acid metabolism in OC and serve as the foundation of a clinically significant diagnostic test.

Low-coordinate volatile Group 12 amides: syntheses and crystal structure determinations of dimeric {M{(CH3)2]}2}2; M=Zn, Cd and monomeric Hg{(CH3)2]}2 ☆

Anhydrous group 12 metal (Zn, Cd, Hg) dihalides react with 2 equiv. of lithium 2,2,5,5-tetramethyl-2,5-disila-1-aza-cyclopentanide Li{(CH3)2]} in Et2O to afford dimeric zinc and cadmium amide complexes {M{(CH3)2]}2}2 (M=Zn (1), M=Cd (2)), as well as the monomeric mercury derivative Hg{(CH3)2]}2 (3). All prepared complexes represent volatile solids with considerable gas-phase stability. Molecular structures determined by the single crystal X-ray diffraction technique show that zinc (1) and cadmium (2) amide examples contain three-coordinate metal atoms forming a slightly distorted M2N2-core with the bridging nitrogens, while the corresponding mercury derivative (3) consists of monomeric molecules with the central metal linearly coordinated by both nitrogen atoms.

Whole Reproductive System Non-Negative Matrix Factorization Mass Spectrometry Imaging of an Early-Stage Ovarian Cancer Mouse Model.

High-grade serous carcinoma (HGSC) is the most common and deadliest form of ovarian cancer. Yet it is largely asymptomatic in its initial stages. Studying the origin and early progression of this disease is thus critical in identifying markers for early detection and screening purposes. Tissue-based mass spectrometry imaging (MSI) can be employed as an unbiased way of examining localized metabolic changes between healthy and cancerous tissue directly, at the onset of disease. In this study, we describe MSI results from Dicer-Pten double-knockout (DKO) mice, a mouse model faithfully reproducing the clinical nature of human HGSC. By using non-negative matrix factorization (NMF) for the unsupervised analysis of desorption electrospray ionization (DESI) datasets, tissue regions are segregated based on spectral components in an unbiased manner, with alterations related to HGSC highlighted. Results obtained by combining NMF with DESI-MSI revealed several metabolic species elevated in the tumor tissue and/or surrounding blood-filled cyst including ceramides, sphingomyelins, bilirubin, cholesterol sulfate, and various lysophospholipids. Multiple metabolites identified within the imaging study were also detected at altered levels within serum in a previous metabolomic study of the same mouse model. As an example workflow, features identified in this study were used to build an oPLS-DA model capable of discriminating between DKO mice with early-stage tumors and controls with up to 88% accuracy.

Chemical encoding of risk perception and predator detection among estuarine invertebrates

Significance Chemical cues are essential to marine life, particularly for detecting predators. Despite decades of research, almost nothing is known of the molecular nature of these waterborne cues. This prevents us from assessing environmental variation and impacts of these cues and from understanding and manipulating predator–prey signaling pathways. Leveraging natural chemical variation in the urine of a predatory crab using metabolomics, the chemical profiles of urine from crabs fed different diets were revealed to be predictive of their fear-inducing potency. This pattern led us to identify the major constituents of the chemical cue used by mud crab prey to detect and avoid their predator. This investigation serves as a blueprint for investigating the molecular nature of these community-structuring waterborne cues. An effective strategy for prey to survive in habitats rich in predators is to avoid being noticed. Thus, prey are under selection pressure to recognize predators and adjust their behavior, which can impact numerous community-wide interactions. Many animals in murky and turbulent aquatic environments rely on waterborne chemical cues. Previous research showed that the mud crab, Panopeus herbstii, recognizes the predatory blue crab, Callinectus sapidus, via a cue in blue crab urine. This cue is strongest if blue crabs recently preyed upon mud crabs. Subsequently, mud crabs suppress their foraging activity, reducing predation by blue crabs. Using NMR spectroscopy- and mass spectrometry-based metabolomics, chemical variation in urine from blue crabs fed different diets was related to prey behavior. We identified the urinary metabolites trigonelline and homarine as components of the cue that mud crabs use to detect blue crabs, with concentrations of each metabolite dependent on the blue crab’s diet. At concentrations found naturally in blue crab urine, trigonelline and homarine, alone as well as in a mixture, alerted mud crabs to the presence of blue crabs, leading to decreased foraging by mud crabs. Risk perception by waterborne cues has been widely observed by ecologists, but the molecular nature of these cues has not been previously identified. Metabolomics provides an opportunity to study waterborne cues where other approaches have historically failed, advancing our understanding of the chemical nature of a wide range of ecological interactions.

MP88-01 METABOLOMIC SIGNATURES IN URINE FROM RENAL CELL CARCINOMA PATIENTS.

CONCLUSIONS: Definitive RP following SOC systemic therapy is safe and appears to be largely feasible robotically. Post-RP urinary QOL was comparable to RP for localized disease (with extrapolated benefit of avoiding symptomatic local disease progression). 25% pT0 response was seen; gene expression profiles of these patients should be sought. Despite a small sample, our analysis lends insight and support to the feasibility of the SWOG 1802 RP arm.

Abstract AS05: Metabolomic signatures in sera from early stage ovarian cancer patients

PURPOSE: Lack of symptoms as well as the deficiency of highly specific biomarkers has resulted in only a quarter of ovarian cancer cases being diagnosed in stage I. Early detection combined with conventional therapies has resulted in 5-year survival rates up to 90%, while 5-year overall survival is less than 30% for women with advanced stage ovarian cancer. An effective screening strategy for early diagnosis would be particularly advantageous for ovarian cancer patients. Investigation into characteristic metabolomic patterns for disease has the potential to detect changes in cells, tissues, and biofluids that can aid in diagnosis at an early stage. METHODS: Serum samples were collected from early-stage serous papillary or endometrioid ovarian cancer (n=26) and normal patients (n=40) and analyzed using ultra high performance liquid chromatography coupled with high resolution mass spectrometry (UPLC-MS) and tandem mass spectrometry (MS/MS). Metabolites were extracted from blood serum by precipitating proteins with methanol, lyophilization, and solvent reconstitution prior to MS analysis in both positive and negative electrospray ionization modes. Metabolic features were extracted with MZmine software. Untargeted multivariate statistical analysis employing support vector machine (SVM) learning methods, genetic algorithms and recursive feature elimination (RFE) selected a panel of metabolites that differentiates between the age-matched samples with better than 92% sensitivity and 91% specificity in all cases tested. RESULTS: Comparison of metabolic phenotypes of ovarian cancer with normal metabolic signatures revealed unique metabolite patterns for ovarian cancer. From multivariate statistical analysis, panels consisting of 17-35 metabolic features from serum samples were found to differentiate between early stage cancer and normal with very high accuracy, sensitivity, and specificity. CONCLUSIONS: Poor early diagnosis complicates collection of large patient cohorts for more detailed studies. Our preliminary work demonstrated that metabolites in serum samples may be useful for detecting early-stage ovarian cancer and support conducting larger, more focused studies. (Grant support: Marsha Rivkin Ovarian Cancer Challenge Grant; Ovarian Cancer Research Fund (OCRF)) Citation Format: David A. Gaul, Christina M. Jones, Maria Eugenia Monge, Long Q. Tran, Martin M. Matzuk, John F. McDonald*, Facundo M. Fernandez*. Metabolomic signatures in sera from early stage ovarian cancer patients [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium; Sep 8-9, 2014; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2015;21(16 Suppl):Abstract nr AS05.

Low-coordinate volatile Group 12 amides: syntheses and crystal structure determinations of dimeric {M{N[Si(CH3)2CH2CH2Si(CH 3 ) 2 ]} 2 } 2 ; M=Zn, Cd and monomeric Hg{N[Si(CH3)2CH2CH2Si(CH 3 ) 2 ]} 2

Anhydrous group 12 metal (Zn, Cd, Hg) dihalides react with 2 equiv. of lithium 2,2,5,5-tetramethyl-2,5-disila-1-aza-cyclopentanide Li{(CH3)2]} in Et2O to afford dimeric zinc and cadmium amide complexes {M{(CH3)2]}2}2 (M=Zn (1), M=Cd (2)), as well as the monomeric mercury derivative Hg{(CH3)2]}2 (3). All prepared complexes represent volatile solids with considerable gas-phase stability. Molecular structures determined by the single crystal X-ray diffraction technique show that zinc (1) and cadmium (2) amide examples contain three-coordinate metal atoms forming a slightly distorted M2N2-core with the bridging nitrogens, while the corresponding mercury derivative (3) consists of monomeric molecules with the central metal linearly coordinated by both nitrogen atoms.

Low-coordinate volatile Group 12 amides: syntheses and crystal structure determinations of dimeric {M{N[Si(CH3)2CH2CH2Si(CH3)2]}2}2; M=Zn, Cd and monomeric Hg{N[Si(CH3)2CH2CH2Si(CH3)2]}2

Anhydrous group 12 metal (Zn, Cd, Hg) dihalides react with 2 equiv. of lithium 2,2,5,5-tetramethyl-2,5-disila-1-aza-cyclopentanide Li{(CH3)2]} in Et2O to afford dimeric zinc and cadmium amide complexes {M{(CH3)2]}2}2 (M=Zn (1), M=Cd (2)), as well as the monomeric mercury derivative Hg{(CH3)2]}2 (3). All prepared complexes represent volatile solids with considerable gas-phase stability. Molecular structures determined by the single crystal X-ray diffraction technique show that zinc (1) and cadmium (2) amide examples contain three-coordinate metal atoms forming a slightly distorted M2N2-core with the bridging nitrogens, while the corresponding mercury derivative (3) consists of monomeric molecules with the central metal linearly coordinated by both nitrogen atoms.

Zinc Bis(Amide) Compounds Evaluated as Designed Precursors for Site-Selective P-type Doping of ZnSe

Zinc selenide doped with nitrogen deposited by organometallic vapor phase epitaxy (OMVPE) is one example which leads to a material that produces a blue emission. However, the effective incorporation of the nitrogen dopant into the zinc selenide lattice has not yet resulted in the demanded efficiency. One potential solution involves the design of a precursor introducing the nitrogen dopant bonded to zinc that survives the thermal decomposition process. Several new zinc bis (amide) compounds with the general formula Zn[N(R)(R′)] 2 have been synthesized. Investigations into the thermal decomposition mechanisms of these compounds have provided insight into the potential usefulness of the designed precursor in the preparation of ZnSe:N.