• Nothing new under the heavens: MIH in the past?

      Ogden, Alan R.; Pinhasi, R.; White, W.J. (2008)
      This was to study an archaeological population of subadult teeth in 17th and 18th century skeletal material from a London (England) cemetery for enamel defects including molar-incisor-hypomineralisation (MIH).Methods: Dentitions of 45 sub-adults were examined using standard macroscopic methods and systematically recorded. A total of 557 teeth were examined with a *5 lens and photographed. Ages of the individuals were estimated from their dental crown and root development stages and not from charts that combine tooth eruption with development stages. The dental age of the individual and the approximate age of onset of enamel defects was then calculated on the basis of the chronological sequence of incremental deposition and calcification of the enamel matrix. Affected enamel was graded macroscopically as: - Mild: <30% of the tooth¿s enamel surface area visibly disrupted (this encompasses the entire range reported in most other studies), Moderate: 31-49% of the tooth¿s enamel surface area visibly disrupted and Severe: >50% of the tooth¿s enamel surface area visibly disrupted. Results: Of the total number of individuals 41 (93.2%) showed signs of enamel developmental dysplasia or MIH, 28 of them showing moderate or severe lesions of molars, primary or permanent (63.6% of the sample). Incisors and canines, though surviving much less often, showed episodes of linear hypoplasia. Conclusion:The extensive lesions seen on many of the molars displayed cuspal enamel hypoplasia (CEH). Many of these teeth also exhibited Molar Incisal Hypomineralisation (MIH).
    • Novel and established potassium channel openers stimulate hair growth in vitromodes of action in hair follicles.: implications for their

      Davies, Gareth C.; Thornton, M. Julie; Jenner, Tracey J.; Chen, Yi-Ju; Hansen, J.B.; Carr, R.D.; Randall, Valerie A. (2005)
      Although ATP-sensitive potassium (K(ATP)) channel openers, e.g., minoxidil and diazoxide, can induce hair growth, their mechanisms require clarification. Improved drugs are needed clinically. but the absence of a good bioassay hampers research. K(ATP) channels from various tissues contain subtypes of the regulatory sulfonylurea receptor, SUR, and pore-forming, K(+) inward rectifier subunits, Kir6.X, giving differing sensitivities to regulators. Therefore, the in vitro effects of established potassium channel openers and inhibitors (tolbutamide and glibenclamide), plus a novel, selective Kir6.2/SUR1 opener, NNC 55-0118, were assessed on deer hair follicle growth in serum-free median without streptomycin. Minoxidil (0.1-100 microM, p<0.001), NNC 55-0118 (1 mM, p<0.01; 0.1, 10, 100 microM, p<0.001), and diazoxide (10 microM, p<0.01) increased growth. Tolbutamide (1 mM) inhibited growth (p<0.001) and abolished the effect of 10 microM minoxidil, diazoxide and NNC 55-0118; glibenclamide (10 microM) had no effect, but prevented stimulation by 10 microM minoxidil. Phenol red stimulated growth (p<0.001), but channel modulator responses remained unaltered. Thus, deer follicles offer a practical, ethically advantageous in vitro bioassay that reflects clinical responses in vivo. The results indicate direct actions of K(ATP) channel modulators within hair follicles via two types of channels, with SUR 1 and SUR 2, probably SUR2B, sulfonylurea receptors.
    • Novel antibodies directed against the human erythropoietin receptor: creating a basis for clinical implementation

      Maxwell, P.; Melendez-Rodriguez, F.; Matchett, K.B.; Aragones, J.; Ben-Califa, N.; Jackel, H.; Hengst, L.; Lindner, H.; Bernardini, A.; Brockmeier, U.; et al. (2015)
      Recombinant human erythropoietin (rHuEPO) is an effective treatment for anaemia but concerns that it causes disease progression in cancer patients by activation of EPO receptors (EPOR) in tumour tissue have been contro- versial and have restricted its clinical use. Initial clinical studies were flawed because they used polyclonal antibodies, later shown to lack specificity for EPOR. Moreover, multiple isoforms of EPOR caused by differential splicing have been reported in cancer cell lines at the mRNA level but investigations of these variants and their potential impact on tumour progression, have been hampered by lack of suitable antibodies. The EpoCan consortium seeks to promote improved pathological testing of EPOR, leading to safer clinical use of rHuEPO, by producing well characterized EPOR antibodies. Using novel genetic and traditional peptide immunization protocols, we have produced mouse and rat monoclonal antibodies, and show that sev- eral of these specifically recognize EPOR by Western blot, immunoprecipi- tation, immunofluorescence, flow cytometry and immunohistochemistry in cell lines and clinical material. Widespread availability of these antibodies should enable the research community to gain a better understanding of the role of EPOR in cancer, and eventually to distinguish patients who can be treated safely by rHuEPO from those at increased risk from treatment.
    • Novel application of phosphonium salts as co-catalysts for the Baylis-Hillman reaction

      Karodia, Nazira; Nawaz, Wafaa; Donkor, Rachel E.; Johnson, Claire L. (2004)
    • A novel approach to crystallisation of nanodispersible microparticles by spray drying for improved tabletability

      Paluch, Krzysztof J.; Tajber, L.; Adamczyk, B.; Corrigan, O.I.; Healy, A.M. (2012-10-15)
      High-dose API powders which are to be tableted by direct compression should have high compactibility and compressibility. This note reports on a novel approach to the manufacture of crystalline powders intended for direct compaction with improved compactibility and compressibility properties. The poorly compactable API, chlorothiazide, was spray dried from a water/acetone solvent mix producing additive-free nanocrystalline microparticles (NCMPs) of median particle size 3.5 μm. Tablets compacted from NCMPs had tensile strengths ranging from 0.5 to 4.6 MPa (compared to 0.6–0.9 MPa for tablets of micronised CTZ) at compression forces ranging from 6 kN to 13 kN. NCMP tablets also had high porosities (34–20%) and large specific surface areas (4.4–4.8 m2/g). The time taken for tablets made of NCMPs to erode was not statistically longer (p > 0.05) than for tablets made of micronised CTZ. Fragmentation of NCMPs on compression was observed. The volume fraction of particles below 1 μm present in the suspension recovered after erosion of NCMP tablets was 34.8 ± 3.43%, while no nanosized particles were detected in the slurry after erosion of compacted micronised CTZ.
    • Novel Aspects of the Conduction Mechanisms of Electrolytes Containing Tetrahedral Moieties

      Kendrick, E.; Kendrick, John; Orera, A.; Panchmatia, P.; Islam, M.S.; Slater, P.R. (2010-04)
      Traditionally materials with the fluorite and perovskite structures have dominated the research in the area of oxide ion/proton conducting solid electrolytes. In such cases, the key defects are oxide ion vacancies, and conduction proceeds via a simple vacancy hopping mechanism. In recent years, there has been growing interest in alternative structure types, many of which contain tetrahedral moieties. For these new systems, an understanding of the accommodation of defects and the nature of the conduction mechanism is important for the optimisation of their conductivities, as well as to help target related structures that may display high oxide ion/proton conduction. Computer modelling studies on a range of systems containing tetrahedral moieties are presented, including apatite-type La9.33+xGe6O26+3x/2, cuspidine-type La4Ga2¿xTixO9+x/2 and La1¿xBa1+xGaO4¿x/2. The type of anion defect (vacancy or interstitial), their location and the factors affecting their incorporation are discussed. In addition, modelling data to help to understand their conduction mechanisms are presented, showing novel aspects including the important role of the tetrahedral moieties in the conduction processes
    • Novel Aspects of the Conduction Mechanisms of Electrolytes Containing Tetrahedral Moieties

      Kendrick, E.; Kendrick, John; Orera, A.; Panchmatia, P.; Islam, M.S.; Slater, P.R. (2010-09)
      Traditionally materials with the fluorite and perovskite structures have dominated the research in the area of oxide ion/proton conducting solid electrolytes. In such cases, the key defects are oxide ion vacancies, and conduction proceeds via a simple vacancy hopping mechanism. In recent years, there has been growing interest in alternative structure types, many of which contain tetrahedral moieties. For these new systems, an understanding of the accommodation of defects and the nature of the conduction mechanism is important for the optimisation of their conductivities, as well as to help target related structures that may display high oxide ion/proton conduction. Computer modelling studies on a range of systems containing tetrahedral moieties are presented, including apatite-type La9.33+xGe6O26+3x/2, cuspidine-type La4Ga2-xTixO9+x/2 and La1-xBa1+xGaO4-x/2. The type of anion defect (vacancy or interstitial), their location and the factors affecting their incorporation are discussed. In addition, modelling data to help to understand their conduction mechanisms are presented, showing novel aspects including the important role of the tetrahedral moieties in the conduction processes.
    • Novel Coronin7 interactions with Cdc42 and N-WASP regulate actin organization and Golgi morphology

      Bhattacharya, K.; Swaminathan, Karthic; Peche, V.S.; Clemen, C.S.; Knyphausen, P.; Lammers, M.; Noegel, A.A.; Rastetter, R.H. (2016-05)
      The contribution of the actin cytoskeleton to the unique architecture of the Golgi complex is manifold. An important player in this process is Coronin7 (CRN7), a Golgi-resident protein that stabilizes F-actin assembly at the trans-Golgi network (TGN) thereby facilitating anterograde trafficking. Here, we establish that CRN7-mediated association of F-actin with the Golgi apparatus is distinctly modulated via the small Rho GTPase Cdc42 and N-WASP. We identify N-WASP as a novel interaction partner of CRN7 and demonstrate that CRN7 restricts spurious F-actin reorganizations by repressing N-WASP ‘hyperactivity’ upon constitutive Cdc42 activation. Loss of CRN7 leads to increased cellular F-actin content and causes a concomitant disruption of the Golgi structure. CRN7 harbours a Cdc42- and Rac-interactive binding (CRIB) motif in its tandem β-propellers and binds selectively to GDP-bound Cdc42N17 mutant. We speculate that CRN7 can act as a cofactor for active Cdc42 generation. Mutation of CRIB motif residues that abrogate Cdc42 binding to CRN7 also fail to rescue the cellular defects in fibroblasts derived from CRN7 KO mice. Cdc42N17 overexpression partially rescued the KO phenotypes whereas N-WASP overexpression failed to do so. We conclude that CRN7 spatiotemporally influences F-actin organization and Golgi integrity in a Cdc42- and N-WASP-dependent manner.
    • Novel formation of [2M-H](+) species in positive electrospray mass spectra of indoles

      Saidykhan, Amie; Ayrton, Stephen T.; Gallagher, R.T.; Martin, William H.C.; Bowen, Richard D. (2014)
      When subjected to positive ion electrospray ionisation (ESI+) mass spectrometry (MS), indoles with a 3-alkyl substituent show a propensity to form novel [2M-H](+) 'covalently bound dimers'. This process, which appears to be initiated in the nebuliser of the instrument, is mechanistically interesting, analytically useful and potentially significant in organic synthesis. A selection of 2- and 3-substituted indoles have been synthesised and analysed by ESI-MS. The formation of the 'homo' and 'hetero' dimers of these compounds has been investigated using ESI+ mode. The mechanism of formation of the observed 'dimeric' species has been probed by synthesising authentic samples of the dimeric compounds. 'Dimeric' species corresponding to [2M-H](+) have been observed for all 3-substituted indoles studied, but not for indoles substituted in just the 2-position. By infusing equimolar mixtures of labelled and unlabelled indoles through the instrument, the expected approximately statistical mixture of homo- and heterodimeric species has been observed. Further experiments have established that this novel dimerisation occurs in the droplets formed in the nebuliser of the instrument. It has been shown that 3-substituted indoles form [2M-H](+) dimers in high abundance in the spray obtained from the nebiliser of an ESI+ instrument. The mechanism for the dimerisation does not involve the known 2M dimeric species that is readily formed in the solution-phase chemistry of indoles.
    • Novel muscle imaging in inflammatory rheumatic diseases — a focus on ultrasound shear wave elastography and quantitative MRI

      Farrow, Matthew; Biglands, J.; Alfuraih, A.M.; Wakefield, R.J.; Tan, A.L. (2020-08)
      In recent years, imaging has played an increasing role in the clinical management of patients with rheumatic diseases with respect to aiding diagnosis, guiding therapy and monitoring disease progression. These roles have been underpinned by research which has enhanced our understanding of disease pathogenesis and pathophysiology of rheumatology conditions, in addition to their key role in outcome measurement in clinical trials. However, compared to joints, imaging research of muscles is less established, despite the fact that muscle symptoms are very common and debilitating in many rheumatic diseases. Recently, it has been shown that even though patients with rheumatoid arthritis may achieve clinical remission, defined by asymptomatic joints, many remain affected by lingering constitutional systemic symptoms like fatigue, tiredness, weakness and myalgia, which may be attributed to changes in the muscles. Recent improvements in imaging technology, coupled with an increasing clinical interest, has started to ignite new interest in the area. This perspective discusses the rationale for using imaging, particularly ultrasound and MRI, for investigating muscle pathology involved in common inflammatory rheumatic diseases. The muscles associated with rheumatic diseases can be affected in many ways, including myositis—an inflammatory muscle condition, and myopathy secondary to medications, such as glucocorticoids. In addition to non-invasive visual assessment of muscles in these conditions, novel imaging techniques like shear wave elastography and quantitative MRI can provide further useful information regarding the physiological and biomechanical status of the muscle.
    • Novel nicotinamide skin-adhesive hot melt extrudates for treatment of acne

      Nasr, M.; Karandikar, H.; Abdel-Aziz, R.T.A.; Moftah, N.; Paradkar, Anant R. (Taylor and Francis, 2018-11-15)
      Hot melt extrusion is a continuous process with wide industrial applicability. Till current date, there have been no reports on the formulation of extrudates for topical treatment of dermatological diseases. The aim of the present work was to prepare and characterize medicated hot melt extrudates based on Soluplus polymer and nicotinamide, and to explore their applicability in acne treatment. The extrudates were characterized using DSC, FTIR, XRD, and DVS. The extrudates were also tested for their skin adhesion potential, ability to deposit nicotinamide in different skin layers, and their clinical efficacy in acne patients. The 10% nicotinamide extrudates exhibited amorphous nature which was reserved during storage, with no chemical interaction between nicotinamide and Soluplus. Upon contrasting the skin adhesion and drug deposition of extrudates and nicotinamide gel, it was evident that the extrudates displayed significantly higher adhesion and drug deposition reaching 4.8 folds, 5.3 folds, and 4.3 folds more in the stratum corneum, epidermis and dermis, respectively. Furthermore, the extrudates significantly reduced the total number of acne lesions in patients by 61.3% compared to 42.14% with the nicotinamide gel. Soluplus extrudates are promising topical drug delivery means for the treatment of dermatological diseases.
    • Novel Ran-RCC1 inhibitory peptide-loaded nanoparticles have anti-cancer efficacy in vitro and in vivo

      Haggag, Y.A.; Matchett, K.B.; Falconer, Robert A.; Isreb, Mohammad; Jones, Jason; Faheem, A.; McCarron, P.; El-Tanani, Mohamed (2019-02)
      The delivery of anticancer agents to their subcellular sites of action is a significant challenge for effective cancer therapy. Peptides, which are integral to several oncogenic pathways, have significant potential to be utilised as cancer therapeutics due to their selectivity, high potency and lack of normal cell toxicity. Novel Ras protein-Regulator of chromosome condensation 1 (Ran-RCC1) inhibitory peptides designed to interact with Ran, a novel therapeutic target in breast cancer, were delivered by entrapment into polyethylene glycol-poly (lactic-co-glycolic acid) PEG-PLGA polymeric nanoparticles (NPs). A modified double emulsion solvent evaporation technique was used to optimise the physicochemical properties of these peptide-loaded biodegradable NPs. The anti-cancer activity of peptide-loaded NPs was studied in vitro using Ran-expressing metastatic breast (MDA-MB-231) and lung cancer (A549) cell lines, and in vivo using Solid Ehrlich Carcinoma-bearing mice. The anti-metastatic activity of peptide-loaded NPs was investigated using migration, invasion and colony formation assays in vitro. A PEG-PLGA-nanoparticle encapsulating N-terminal peptide showed a pronounced antitumor and anti-metastatic action in lung and breast cancer cells in vitro and caused a significant reduction of tumor volume and associated tumor growth inhibition of breast cancer model in vivo. These findings suggest that the novel inhibitory peptides encapsulated into PEGylated PLGA NPs are delivered effectively to interact and deactivate Ran. This novel Ran-targeting peptide construct shows significant potential for therapy of breast cancer and other cancers mediated by Ran overexpression.
    • Novel strategies for the synthesis of unsymmetrical glycosyl disulfides

      Ribeiro Morais, Goreti; Springett, Bradley R.; Pauze, Martin; Schröder, Lisa; Northrop, Matthew; Falconer, Robert A. (2016-03)
      Novel strategies for the efficient synthesis of unsymmetrical glycosyl disulfides are reported. Glycosyl disulfides are increasingly important as glycomimetics and molecular probes in glycobiology. Sialosyl disulfides are synthesised directly from the chlorosialoside Neu5Ac2Cl, proceeding via a thiol-disulfide exchange reaction between the sialosyl thiolate and symmetrical disulfides. This methodology was adapted and found to be successfully applicable to the synthesis of unsymmetrical glucosyl disulfides under mild conditions.
    • A novel strategy for NQO1 (NAD(P)H:quinone oxidoreductase, EC 1.6.99.2) mediated therapy of bladder cancer based on the pharmacological properties of EO9.

      Choudry, Guzanfar A.; Hamilton Stewart, P.A.; Double, John A.; Krul, M.R.L.; Naylor, Brian; Flannigan, G. Michael; Shah, Tariq K.; Phillips, Roger M. (2001)
      The indolequinone EO9 demonstrated good preclinical activity but failed to show clinical efficacy against a range of tumours following intravenous drug administration. A significant factor in EO9's failure in the clinic has been attributed to its rapid pharmacokinetic elimination resulting in poor drug delivery to tumours. Intravesical administration of EO9 would circumvent the problem of drug delivery to tumours and the principal objective of this study is to determine whether or not bladder tumours have elevated levels of the enzyme NQO1 (NAD(P)H:quinone oxidoreductase) which plays a key role in activating EO9 under aerobic conditions. Elevated NQO1 levels in human bladder tumour tissue exist in a subset of patients as measured by both immunohistochemical and enzymatic assays. In a panel of human tumour cell lines, EO9 is selectively toxic towards NQO1 rich cell lines under aerobic conditions and potency can be enhanced by reducing extracellular pH. These studies suggest that a subset of bladder cancer patients exist whose tumours possess the appropriate biochemical machinery required to activate EO9. Administration of EO9 in an acidic vehicle could be employed to reduce possible systemic toxicity as any drug absorbed into the blood stream would become relatively inactive due to an increase in pH.
    • A novel theranostic strategy for MMP-14 expressing glioblastomas impacts survival

      Mohanty, S.; Chen, Z.; Li, K.; Ribeiro Morais, Goreti; Klockow, J.; Yerneni, K.; Pasani, L.; Chin, F.T.; Mitra, S.; Cheshier, S.; et al. (2017-06)
      Glioblastoma (GBM) has a dismal prognosis. Evidence from preclinical tumor models and human trials indicates the role of GBM initiating cells (GIC) in GBM drug resistance. Here, we propose a new treatment option with tumor enzyme-activatable, combined therapeutic and diagnostic (theranostic) nanoparticles, which caused specific toxicity against GBM tumor cells and GICs. The theranostic cross-linked iron oxide nanoparticles (CLIO) were conjugated to a highly potent vascular disrupting agent (ICT) and secured with a matrix-metalloproteinase (MMP-14) cleavable peptide. Treatment with CLIO-ICT disrupted tumor vasculature of MMP-14 expressing GBM, induced GIC apoptosis and significantly impaired tumor growth. In addition, the iron core of CLIO-ICT enabled in vivo drug tracking with MR imaging. Treatment with CLIO-ICT plus temozolomide achieved tumor remission and significantly increased survival of human GBM bearing mice by more than 2 fold compared to treatment with temozolomide alone. Thus, we present a novel therapeutic strategy with significant impact on survival and great potential for clinical translation.
    • A novel transflectance near infrared spectroscopy technique for monitoring hot melt extrusion

      Kelly, Adrian L.; Halsey, S.A.; Bottom, R.A.; Korde, Sachin A.; Gough, Timothy D.; Paradkar, Anant R. (2015-12-30)
      A transflectance near infra red (NIR) spectroscopy approach has been used to simultaneously measure drug and plasticiser content of polymer melts with varying opacity during hot melt extrusion. A high temperature reflectance NIR probe was mounted in the extruder die directly opposed to a highly reflective surface. Carbamazepine (CBZ) was used as a model drug, with polyvinyl pyrollidone-vinyl acetate co-polymer (PVP-VA) as a matrix and polyethylene glycol (PEG) as a plasticiser. The opacity of the molten extrudate varied from transparent at low CBZ loading to opaque at high CBZ loading. Particulate amorphous API and voids formed around these particles were found to cause the opacity. The extrusion process was monitored in real time using transflectance NIR; calibration and validation runs were performed using a wide range of drug and plasticiser loadings. Once calibrated, the technique was used to simultaneously track drug and plasticiser content during applied step changes in feedstock material. Rheological and thermal characterisations were used to help understand the morphology of extruded material. The study has shown that it is possible to use a single NIR spectroscopy technique to monitor opaque and transparent melts during HME, and to simultaneously monitor two distinct components within a formulation.
    • Novel ways to regulate T-type Ca2+ channels

      Peers, C.; Elies, Jacobo; Gamper, N. (2015)
    • Novel, High-yielding Synthesis of meso-Substituted Porphyrins via the Direct Arylation of Porphine.

      Wheelhouse, Richard T.; Shi, D-F. (2002)
      A new method for the synthesis of meso-substituted porphyrins is described: reaction of 5,10,15,20-tetrabromoporphine magnesium complex with aryl or heteroaryl boronic acids in the presence of Pd(PPh3)4 gave meso-substituted porphyrins in yields up to 70%.
    • Nuclear factor kappa B is involved in lipopolysaccharide- stimulated induction of interferon regulatory factor-1 and GAS/GAF DNA-binding in human umbilical vein endothelial cells.

      Graham, Anne M.; Bryant, C.; Liu, L.; Plevin, R.; Andrew, P.; Mackenzie, C. (2001)
      1 In this study we examined the signalling events that regulate lipopolysaccharide (LPS)-stimulated induction of interferon regulatory factor (IRF)-1 in human umbilical vein endothelial cells (HUVECS). 2 LPS stimulated a time- and concentration-dependent increase in IRF-1 protein expression, an effect that was mimicked by the cytokine, tumour necrosis factor (TNF)-¿. 3 LPS stimulated a rapid increase in nuclear factor kappa B (NFKB) DNA-binding activity. Preincubation with the NFKB pathway inhibitors, N-¿-tosyl-L-lysine chloromethyl ketone (TLCK) or pyrrolidine dithiocarbamate (PDTC), or infection with adenovirus encoding IKB¿, blocked both IRF-1 induction and NFKB DNA-binding activity. 4 LPS and TNF¿ also stimulated a rapid activation of gamma interferon activation site/gamma interferon activation factor (GAS/GAF) DNA-binding in HUVECs. Preincubation with the Janus kinase (JAK)-2 inhibitor, AG490 blocked LPS-stimulated IRF-I induction but did not affect GAS/ GAF DNA-binding. 5 Preincubation with TLCK, PDTC or infection with I¿Ba adenovirus abolished LPS-stimulated GAS/GAF DNA-binding. 6 Incubation of nuclear extracts with antibodies to RelA/p50 supershifted GAS/GAF DNA-binding demonstrating the involvement of NF¿B isoforms in the formation of the GAS/GAF complex. 7 These studies show that NF¿B plays an important role in the regulation of IRF-1 induction in HUVECs. This is in part due to the interaction of NF¿B isoforms with the GAS/GAF complex either directly or via an intermediate protein.