Antipollution system to remove nitrogen dioxide gas

Gas phase reaction system using anhydrous ammonia removes nitrogen dioxide. System consists of ammonia injection and mixing section, reaction section /reactor/, and scrubber section. All sections are contained in system ducting

Quantifying normal human brain metabolism using hyperpolarized [1– 13 C]pyruvate and magnetic resonance imaging

Hyperpolarized 13 C Magnetic Resonance Imaging ( 13 C-MRI) provides a highly sensitive tool to probe tissue metabolism in vivo and has recently been translated into clinical studies. We report the cerebral metabolism of intravenously injected hyperpolarized [1– 13 C]pyruvate in the brain of healthy human volunteers for the first time. Dynamic acquisition of 13 C images demonstrated 13 C-labeling of both lactate and bicarbonate, catalyzed by cytosolic lactate dehydrogenase and mitochondrial pyruvate dehydrogenase respectively. This demonstrates that both enzymes can be probed in vivo in the presence of an intact blood-brain barrier: the measured apparent exchange rate constant (k PL ) for exchange of the hyperpolarized 13 C label between [1– 13 C]pyruvate and the endogenous lactate pool was 0.012 ± 0.006 s −1 and the apparent rate constant (k PB ) for the irreversible flux of [1– 13 C]pyruvate to [ 13 C]bicarbonate was 0.002 ± 0.002 s −1 . Imaging also revealed that [1– 13 C]pyruvate, [1– 13 C]lactate and [ 13 C]bicarbonate were significantly higher in gray matter compared to white matter. Imaging normal brain metabolism with hyperpolarized [1– 13 C]pyruvate and subsequent quantification, have important implications for interpreting pathological cerebral metabolism in future studies

Carbon-Carbon bond forming reactions of organotransition metal enolate complexes

Abstract -Metal enolates play an important role in stereoselective organic synthesis. Their chemistry is affected profoundly by the metal counterion associated with the enolate fragment. In order to expand the potential of replacing main group with transition metal moieties in such species, methods have been developed for the synthesis of a number of stable, characterizable "late" transition metal ql-(C)-enolate complexes having the general structure LM-CH2COR (M = Mo, W, Re). The chemistry of these materials (e.g., functional transformations of the organic carbonyl group, transfer of the enolate moietry to organic substrates such as aldehydes and alkynes) has been investigated. The scope and mechanisms of the enolate reactions will be discussed in detail. The reaction of organic enolates with carbon electrophiles (e.g., alkyl halides, organic carbonyl compounds) gives rise to compounds containing new carbon-carbon bonds; reaction with heteroatom electrophiles results in the formation of oxidized products? There has been much interest recently in developing methods for carrying out these transformations with high stereoselectivity.3 Historically, most enolate research has focused on salts involving alkali metal anions. More recently, research efforts have been extended to enolates associated with organic cations, main group metals, and transition metals. In the transition metal area, enolates involving the so-called "early" metals (to the left of chromium, molybdenum and tungsten) have seen extensive investigationi4 in general these complexes have 0-bonded structures A in Scheme 1. This paper describes the synthesis and chemistry of middle-and late transition metal enolates, which have seen less investigation. It was our hope that such species would be more likely to have Cbound structure B, and also to react with both electrophilic and non-electrophilic species (e.g., by insertion rather than nucleophile-electrophile mechanisms). SYNTHESIS, CHARACTERIZATION AND FUNCTIONAL GROUP TRANSFORMATIONS OF TUNGSTEN AND MOLYBDENUM ENOLATES The well-known nucleophilic anionic metal salts5 Na[(qS-C5R5)(C0)3M] (M = Mo, W, R=H, Me), on treatment with a-chloroketones and esters, provide good yields of enolates 1 -8, as shown in Scheme 2. These are thermally stable complexes that may be isolated by conventional chromatographic and recrystallization methods; they have been characterized fully by elemental analysis and spectroscopic techniques. Preparation of these materials on a multi-gram scale in a one-pot procedure is possible by treatment of W(CO)6 or Mo(C0)6 with NaCp, followed by addition of the a-chlorocarbonyl compound to the resulting metal anion solution. The stability of the tungsten-carbon bond in tungsten ester enolates, fiist suggested several years ago by the work of Green and his coworkers6, has allowed us to carry out a wide range of transformations on the organic carbonyl group. Thus the reactions shown in Scheme 3 proceed in good yield, and lead to stable tungsten enolates containing ester, amide and even carboxylic acid and acid chloride functionality

Hyperpolarized13c mri of tumor metabolism demonstrates early metabolic response to neoadjuvant chemotherapy in breast cancer

Purpose: To compare hyperpolarized carbon 13 (13C) MRI with dynamic contrast material–enhanced (DCE) MRI in the detection of early treatment response in breast cancer. Materials and Methods: In this institutional review board–approved prospective study, a woman with triple-negative breast cancer (age, 49 years) underwent13C MRI after injection of hyperpolarized [1–carbon 13 {13C}]-pyruvate and DCE MRI at 3 T at baseline and after one cycle of neoadjuvant therapy. The13C-labeled lactate-to-pyruvate ratio derived from hyperpolarized13C MRI and the pharmacokinetic parameters transfer constant (Ktrans) and washout parameter (kep ) derived from DCE MRI were compared before and after treatment. Results: Exchange of the13C label between injected hyperpolarized [1-13C]-pyruvate and the endogenous lactate pool was observed, catalyzed by the enzyme lactate dehydrogenase. After one cycle of neoadjuvant chemotherapy, a 34% reduction in the13C-labeled lactate-to-pyruvate ratio resulted in correct identification of the patient as a responder to therapy, which was subsequently confirmed via a complete pathologic response. However, DCE MRI showed an increase in mean Ktrans (132%) and mean kep (31%), which could be incorrectly interpreted as a poor response to treatment. Conclusion: Hyperpolarized13C MRI enabled successful identification of breast cancer response after one cycle of neoadjuvant chemotherapy and may improve response prediction when used in conjunction with multiparametric proton MRI

Hyperpolarized 13C-MRI of Tumor Metabolism Demonstrates Early Metabolic Response to Neoadjuvant Chemotherapy in Breast Cancer

Purpose: To compare hyperpolarized carbon-13 (13C)-MRI with dynamic contrast-enhanced MRI (DCE-MRI) for detecting early treatment response in breast cancer. Materials and Methods: In this institutional review board-approved prospective study, one woman with triple-negative breast cancer (age 49) underwent 13C-MRI following injection of hyperpolarized [1-13C]pyruvate and DCE-MRI at 3 T at baseline and after a single cycle of neoadjuvant therapy. The 13C-lactate/13C-pyruvate ratio derived from hyperpolarized 13C-MRI and the pharmacokinetic parameters Ktrans and kep derived from DCE-MRI were compared, before and after treatment. Results: Exchange of the 13C-label between injected hyperpolarized [1-13C]pyruvate and the endogenous lactate pool was demonstrated, catalyzed by the enzyme lactate dehydrogenase. After one cycle of neoadjuvant chemotherapy, a 34% reduction in the 13C-lactate/13C-pyruvate ratio was shown to correctly identify the patient as a responder to therapy, which was subsequently confirmed by a complete pathologic response. However, DCE-MRI showed an increase in the pharmacokinetic parameters Ktrans (132%) and kep (31%), which could be incorrectly interpreted as a poor response to treatment. Conclusion: Hyperpolarized 13C-MRI successfully identified response in breast cancer after a single cycle of neoadjuvant chemotherapy and may improve response prediction when used in conjunction with multiparametric proton MRI.This work was supported by a Wellcome Trust Strategic Award, Cancer Research UK (CRUK; Grants C8742/A18097, C19212/ A16628, C19212/A911376, and C197/A16465), the Austrian Science Fund (Grant J4025-B26), the CRUK Cambridge Centre, the CRUK & Engineering and Physical Sciences Research Council Cancer Imaging Centre in Cambridge and Manchester, the Mark Foundation for Cancer Research and Cancer Research UK Cambridge Centre (Grant C9685/A25177), CRUK National Cancer Imaging Translational Accelerator Award, Addenbrooke’s Charitable Trust, the National Institute for Health Research Cambridge Biomedical Research Centre, Cambridge Experimental Cancer Medicine Centre, and Cambridge University Hospitals National Health Service Foundation Trust

Imaging breast cancer using hyperpolarized carbon-13 MRI.

Our purpose is to investigate the feasibility of imaging tumor metabolism in breast cancer patients using 13C magnetic resonance spectroscopic imaging (MRSI) of hyperpolarized 13C label exchange between injected [1-13C]pyruvate and the endogenous tumor lactate pool. Treatment-naïve breast cancer patients were recruited: four triple-negative grade 3 cancers; two invasive ductal carcinomas that were estrogen and progesterone receptor-positive (ER/PR+) and HER2/neu-negative (HER2-), one grade 2 and one grade 3; and one grade 2 ER/PR+ HER2- invasive lobular carcinoma (ILC). Dynamic 13C MRSI was performed following injection of hyperpolarized [1-13C]pyruvate. Expression of lactate dehydrogenase A (LDHA), which catalyzes 13C label exchange between pyruvate and lactate, hypoxia-inducible factor-1 (HIF1α), and the monocarboxylate transporters MCT1 and MCT4 were quantified using immunohistochemistry and RNA sequencing. We have demonstrated the feasibility and safety of hyperpolarized 13C MRI in early breast cancer. Both intertumoral and intratumoral heterogeneity of the hyperpolarized pyruvate and lactate signals were observed. The lactate-to-pyruvate signal ratio (LAC/PYR) ranged from 0.021 to 0.473 across the tumor subtypes (mean ± SD: 0.145 ± 0.164), and a lactate signal was observed in all of the grade 3 tumors. The LAC/PYR was significantly correlated with tumor volume (R = 0.903, P = 0.005) and MCT 1 (R = 0.85, P = 0.032) and HIF1α expression (R = 0.83, P = 0.043). Imaging of hyperpolarized [1-13C]pyruvate metabolism in breast cancer is feasible and demonstrated significant intertumoral and intratumoral metabolic heterogeneity, where lactate labeling correlated with MCT1 expression and hypoxia

The Golgin GMAP210/TRIP11 Anchors IFT20 to the Golgi Complex

Eukaryotic cells often use proteins localized to the ciliary membrane to monitor the extracellular environment. The mechanism by which proteins are sorted, specifically to this subdomain of the plasma membrane, is almost completely unknown. Previously, we showed that the IFT20 subunit of the intraflagellar transport particle is localized to the Golgi complex, in addition to the cilium and centrosome, and hypothesized that the Golgi pool of IFT20 plays a role in sorting proteins to the ciliary membrane. Here, we show that IFT20 is anchored to the Golgi complex by the golgin protein GMAP210/Trip11. Mice lacking GMAP210 die at birth with a pleiotropic phenotype that includes growth restriction, ventricular septal defects of the heart, omphalocele, and lung hypoplasia. Cells lacking GMAP210 have normal Golgi structure, but IFT20 is no longer localized to this organelle. GMAP210 is not absolutely required for ciliary assembly, but cilia on GMAP210 mutant cells are shorter than normal and have reduced amounts of the membrane protein polycystin-2 localized to them. This work suggests that GMAP210 and IFT20 function together at the Golgi in the sorting or transport of proteins destined for the ciliary membrane

Investigating orphan cytochromes P450 from Mycobacterium tuberculosis : the search for potential drug targets

Tuberculosis (TB) is a disease that the World Health Organisation (WHO) regards as a global pandemic. There is a great need for new drugs to combat this threat. Drug resistant strains of the causative agent, Mycobacterium tuberculosis (Mtb), have increased the urgency of this quest for novel anti-mycobacterial medicines. Publication of the Mtb genome sequence revealed a large number of cytochrome P450 (CYP) enzymes [Cole, S. T. et al. 1998]. These mono-oxygenase enzymes have been studied for many years and are responsible for metabolic functions in every kingdom of life. Research on the Mtb P450s to date has highlighted several of them as having critcal roles within the organism. CYP121 and CYP128 have been implicated as essential through gene knockout studies. It has been demonstrated that CYP125 is not essential for viability. However, it is part of a gene cluster highly important for Mtb infectivity and virulence. Due to the prospective importance of P450s to Mtb, this group of enzymes is under investigation as a source of novel drug targets. CYP142 was discovered as a potential drug target after it was located to a gene cluster involved in cholesterol catabolism during Mtb dormancy. As part of this PhD project, it was demonstrated that CYP142 performs an almost identical role to that reported for CYP125. These enzymes both perform C27 hydroxylation and carboxylation of the cholesterol side chain. However, variations in the level of oxidation have been identified, dependent upon the redox system with which these P450s are associated. A crystal structure of CYP142 showing high similarity in active site architecture to CYP125 supports the physiological role of CYP142 in cholesterol catabolism. Combining this with in vitro data which demonstrates that CYP142 possesses high affinity for a range of azole anti-fungal agents [Ahmad, Z. et al. 2005, 2006] supports the suggestion that it is a candidate target for the next generation of anti-mycobacterial drugs. CYP144 was highlighted as being important during the latent phase of Mtb growth, a phase that is not targeted by any of the current antimycobacterials. Work performed as part of this PhD has shown that many characteristics of CYP144 are highly comparable to those reported for other MtbP450s. CYP144 shows high affinity and specificity towards many azole molecules. Econazole, clotrimazole and miconazole have repeatedly been shown to bind to MtbP450s, including CYP144 and CYP142, with high affinity and are excellent potential candidates as novel anti-mycobacterial agents. An N-terminally truncated form of CYP144, CYP144-T, has been investigated in the pursuit of a CYP144 crystal structure. It is hoped that this will enable the elucidation of a physiological role for CYP144. Both CYP142 and CYP144 have demonstrated biochemical and biophysical characteristics that contribute to our knowledge of P450 enzymes. This PhD has established that CYP142 exhibits an equilibrium between P450 and P420 species in its CO-bound, ferrous form. A conversion from P420, and stabilisation of P450, upon substrate binding was also demonstrated. CYP144 displays unusual azole coordination characteristics when examined by EPR and removal of the CYP144 gene from Mtb increased sensitivity of the strain to clotrimazole. Studies of these enzymes has advanced knowledge of P450 and Mtb redox chemistry, established roles for the MtbP450 cohort and identified the potential of anti-mycobacterial drugs and associated targets.EThOS - Electronic Theses Online ServiceGBUnited Kingdo