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Search Results: 1 - 10 of 303041 matches for " Douglas J. Ward "
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Localized heating in nanoscale Pt constrictions measured using blackbody radiation emission
Daniel R. Ward,Naomi J. Halas,Douglas Natelson
Physics , 2008, DOI: 10.1063/1.3039060
Abstract: Using thermal emission microscopy, we investigate heating in Pt nanowires before and during electromigration. The wires are observed to reach temperatures in excess of 1000 K. This is beyond the thermal decomposition threshold for many organic molecules of interest for single molecule measurements with electromigrated nanogaps. Blackbody spectra of the hot Pt wires are measured and found to agree well with finite element modeling simulations of the electrical and thermal transport.
Is iron overload in alcohol-related cirrhosis mediated by hepcidin?
Tariq Iqbal, Azzam Diab, Douglas G Ward, Matthew J Brookes, Chris Tselepis, Jim Murray, Elwyn Elias
World Journal of Gastroenterology , 2009,
Abstract: In this case report we describe the relationship between ferritin levels and hepcidin in a patient with alcohol-related spur cell anemia who underwent liver transplantation. We demonstrate a reciprocal relationship between serum or urinary hepcidin and serum ferritin, which indicates that inadequate hepcidin production by the diseased liver is associated with elevated serum ferritin. The ferritin level falls with increasing hepcidin production after transplantation. Neither inflammatory indices (IL6) nor erythropoietin appear to be related to hepcidin expression in this case. We suggest that inappropriately low hepcidin production by the cirrhotic liver may contribute substantially to elevated tissue iron stores in cirrhosis and speculate that hepcidin replacement in these patients may be of therapeutic benefit in the future.
Increased hepcidin expression in colorectal carcinogenesis
Douglas G Ward, Keith Roberts, Matthew J Brookes, Howard Joy, Ashley Martin, Tariq Ismail, Robert Spychal, Tariq Iqbal, Chris Tselepis
World Journal of Gastroenterology , 2008,
Abstract: AIM: To investigate whether the iron stores regulator hepcidin is implicated in colon cancer-associated anaemia and whether it might have a role in colorectal carcinogenesis.METHODS: Mass spectrometry (MALDI-TOF MS and SELDI-TOF MS) was employed to measure hepcidin in urine collected from 56 patients with colorectal cancer. Quantitative Real Time RT-PCR was utilized to determine hepcidin mRNA expression in colorectal cancer tissue. Hepcidin cellular localization was determined using immunohistochemistry.RESULTS: We demonstrate that whilst urinary hepcidin expression was not correlated with anaemia it was positively associated with increasing T-stage of colorectal cancer (P < 0.05). Furthermore, we report that hepcidin mRNA is expressed in 34% of colorectal cancer tissue specimens and was correlated with ferroportin repression. This was supported by hepcidin immunoreactivity in colorectal cancer tissue.CONCLUSION: We demonstrate that systemic hepcidin expression is unlikely to be the cause of the systemic anaemia associated with colorectal cancer. However, we demonstrate for the first time that hepcidin is expressed by colorectal cancer tissue and that this may represent a novel oncogenic signalling mechanism.
Simultaneous measurements of electronic conduction and Raman response in molecular junctions
Daniel R. Ward,Naomi J. Halas,Jacob W. Ciszek,James M. Tour,Yanpeng Wu,Peter Nordlander,Douglas Natelson
Physics , 2008, DOI: 10.1021/nl073346h
Abstract: Electronic conduction through single molecules is affected by the molecular electronic structure as well as by other information that is extremely difficult to assess, such as bonding geometry and chemical environment. The lack of an independent diagnostic technique has long hampered single-molecule conductance studies. We report simultaneous measurement of the conductance and the Raman spectra of nanoscale junctions used for single-molecule electronic experiments. Blinking and spectral diffusion in the Raman response of both para-mercaptoaniline and a fluorinated oligophenylyne ethynylene correlate in time with changes in the electronic conductance. Finite difference time domain calculations confirm that these correlations do not result from the conductance modifying the Raman enhancement. Therefore, these observations strongly imply that multimodal sensing of individual molecules is possible in these mass-producible nanostructures.
齐义军, 王攀, 牛保华, 侯艳芳, 晁玮霞, WARD Douglas, JOHSON Philip J, 马远方
中国科学 生命科学 , 2011, DOI: 10.1360/052011-774
Abstract: 蛋白质糖基化修饰是哺乳动物中最为常见的一种翻译后修饰,蛋白质的寡糖侧链具有重要的生物学意义,如蛋白质分子间及细胞间相互作用、识别、肿瘤侵袭与转移等.本实验应用寡甘露糖型亲合层析柱、唾液酸型层析柱和O-连接糖蛋白亲合层析柱从血清中序列性提取寡甘露糖型、唾液酸型的N-连接糖蛋白及O-连接的糖蛋白,一维和二维电泳图谱显示血清各亚糖蛋白组图谱差异,并对富集的唾液酸型糖蛋白质组的二维电泳图谱中12个显著的差异蛋白质点进行质谱检测,鉴定出的14个蛋白均为N-连接糖蛋白.植物凝集素序列性提取血清各亚糖蛋白质组,显著减小了血清蛋白质组的复杂性和血清蛋白浓度波动范围,提高了质谱鉴定血清中对疾病诊断和疗效监测具有重要意义的生物标志物的灵敏性.
Trends in Decline of Antiretroviral Resistance among ARV-Experienced Patients in the HIV Outpatient Study: 1999–2008
Kate Buchacz,Rose Baker,Douglas J. Ward,Frank J. Palella,Joan S. Chmiel,Benjamin Young,Bienvenido G. Yangco,Richard M. Novak,John T. Brooks
AIDS Research and Treatment , 2012, DOI: 10.1155/2012/230290
Abstract: Background. Little is known about temporal trends in frequencies of clinically relevant ARV resistance mutations in HIV strains from U.S. patients undergoing genotypic testing (GT) in routine HIV care. Methods. We analyzed cumulative frequency of HIV resistance among patients in the HIV Outpatient Study (HOPS) who, during 1999–2008 and while prescribed antiretrovirals, underwent GT with plasma HIV RNA >1,000 copies/mL. Exposure ≥4 months to each of three major antiretroviral classes (NRTI, NNRTI and PI) was defined as triple-class exposure (TCE). Results. 906 patients contributed 1,570 GT results. The annual frequency of any major resistance mutations decreased during 1999–2008 (88% to 79%, ). Resistance to PIs decreased among PI-exposed patients (71% to 46%, ) as exposure to ritonavir-boosted PIs increased (6% to 81%, ). Non-significant declines were observed in resistance to NRTIs among NRTI-exposed (82% to 67%), and triple-class-resistance among TCE patients (66% to 41%), but not to NNRTIs among NNRTI-exposed. Conclusions. HIV resistance was common but declined in HIV isolates from subgroups of ARV-experienced HOPS patients during 1999–2008. Resistance to PIs among PI-exposed patients decreased, possibly due to increased representation of patients whose only PI exposures were to boosted PIs. 1. Introduction Highly active combination antiretroviral therapy (cART) has significantly improved survival and reduced the rates of AIDS-related complications among HIV-infected persons [1–3]. Emergence of HIV variants with reduced susceptibility to antiretroviral (ARV) medications can significantly limit the effectiveness and durability of treatment [3–8]. Use of ARV resistance testing to optimize cART selection has been associated with better virologic and clinical outcomes [9–11] and improved survival [12], and resistance testing is now generally recommended in the clinical management of HIV infection [13–15]. We have previously shown that use of genotypic and phenotypic testing increased in the HIV Outpatient Study (HOPS) during 1999–2006 and that the likelihood of testing varied by HIV disease severity and demographic characteristics [16]. Recent European and Canadian studies have suggested that both the prevalence [17, 18] and incidence [19, 20] of ARV resistance among HIV-infected persons have declined, due predominately to a decrease in the proportion of patients with pre-cART mono- or dual-ARV experience, and the increasing use and effectiveness of more tolerable and potent cART regimens that appear less likely to result in resistance mutations [18–22].
A Gene Optimization Strategy that Enhances Production of Fully Functional P-Glycoprotein in Pichia pastoris
Jiangping Bai, Douglas J. Swartz, Irina I. Protasevich, Christie G. Brouillette, Patina M. Harrell, Ellen Hildebrandt, Brigitte Gasser, Diethard Mattanovich, Andrew Ward, Geoffrey Chang, Ina L. Urbatsch
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0022577
Abstract: Background Structural and biochemical studies of mammalian membrane proteins remain hampered by inefficient production of pure protein. We explored codon optimization based on highly expressed Pichia pastoris genes to enhance co-translational folding and production of P-glycoprotein (Pgp), an ATP-dependent drug efflux pump involved in multidrug resistance of cancers. Methodology/Principal Findings Codon-optimized “Opti-Pgp” and wild-type Pgp, identical in primary protein sequence, were rigorously analyzed for differences in function or solution structure. Yeast expression levels and yield of purified protein from P. pastoris (~130 mg per kg cells) were about three-fold higher for Opti-Pgp than for wild-type protein. Opti-Pgp conveyed full in vivo drug resistance against multiple anticancer and fungicidal drugs. ATP hydrolysis by purified Opti-Pgp was strongly stimulated ~15-fold by verapamil and inhibited by cyclosporine A with binding constants of 4.2±2.2 μM and 1.1±0.26 μM, indistinguishable from wild-type Pgp. Maximum turnover number was 2.1±0.28 μmol/min/mg and was enhanced by 1.2-fold over wild-type Pgp, likely due to higher purity of Opti-Pgp preparations. Analysis of purified wild-type and Opti-Pgp by CD, DSC and limited proteolysis suggested similar secondary and ternary structure. Addition of lipid increased the thermal stability from Tm ~40°C to 49°C, and the total unfolding enthalpy. The increase in folded state may account for the increase in drug-stimulated ATPase activity seen in presence of lipids. Conclusion The significantly higher yields of protein in the native folded state, higher purity and improved function establish the value of our gene optimization approach, and provide a basis to improve production of other membrane proteins.
A population-based audit of ethnicity and breast cancer risk in one general practice catchment area in North London, UK: implications for practice
Michelle Ferris, Douglas F Easton, Rebecca J Doherty, Brian HJ Briggs, Michelle Newman, Ifthikhar M Saraf, Sarah Scambler, Lyndon Wagman, Michael T Wyndham, Ann Ward, Rosalind A Eeles
Hereditary Cancer in Clinical Practice , 2007, DOI: 10.1186/1897-4287-5-3-157
Abstract: Population-based cohort study.A single general practice catchment area in North London.1947 women over the age of 16 who responded to a questionnaire about ethnicity and breast cancer.Incidence of breast cancer, ethnicity.This study showed a 1.5-fold (95% CI 0.93–2.39) increase in breast cancer risk in the Ashkenazim compared with the non-Ashkenazi white population. The increased incidence was for both premenopausal and postmenopausal breast cancer (expected incidence pre:post is 1:4 whereas in the Ashkenazim it was 1:1; 51 and 52% of cases respectively). This increase was not shown in the Sephardim. Asians had a reduction in incidence (OR = 0.44; 95% CI 0.10–1.89). Results were adjusted for other risk factors for breast cancer.This study showed a 1.5-fold increase in breast cancer rates in Ashkenazim compared with the non-Jewish white population when adjusted for age (i.e. corrections were made to allow comparison of age groups) and this is not observed in the Sephardic population. The proportion of premenopausal breast cancer was just over double that of the general population. This is the first general practice population-based study in the UK to address this issue and has implications for general practitioners who care for patients from the Ashkenazi community.General practice offers the doctor the privilege of caring for individuals and their families over many episodes and sometimes for many years, allowing doctors a unique insight into the impact of health and illness on individuals' physical and psychosocial wellbeing. This study was undertaken in a GP practice in a multi-ethnic catchment area in North-West London with a high proportion of Jewish families. Within this practice there was an apparent cluster of breast cancer diagnoses in young Jewish women under 45 years, a diagnosis which had obvious medical and psychosocial consequences for both the women themselves and their young families. This also had a presumed extended impact upon the close-knit Jewish
Proteomic profiling of urine for the detection of colon cancer
Douglas G Ward, Stephen Nyangoma, Howard Joy, Emma Hamilton, Wenbin Wei, Chris Tselepis, Neil Steven, Michael JO Wakelam, Philip J Johnson, Tariq Ismail, Ashley Martin
Proteome Science , 2008, DOI: 10.1186/1477-5956-6-19
Abstract: We collected urine from 67 patients with colorectal cancer and 72 non-cancer control subjects, diluted to a constant protein concentration and generated MALDI and SELDI spectra. The intensities of 19 peaks differed significantly between cancer and non-cancer patients by both t-tests and after adjusting for confounders using multiple linear regressions. Logistic regression classifiers based on peak intensities identified colorectal cancer with up to 78% sensitivity at 87% specificity. We identified and independently quantified 3 of the discriminatory peaks using synthetic stable isotope peptides (an 1885 Da fragment of fibrinogen and hepcidin-20) or ELISA (β2-microglobulin).Changes in the urine proteome may aid in the early detection of colorectal cancer.Colorectal cancer is the third most common cancer in the developed world and the second most common cause of cancer-related death. The prognosis is clearly related to the stage at which the disease is detected and this observation has led to screening programmes using the faecal occult blood test that have resulted in a significant reduction in mortality [1]. Other stool-based approaches, such as DNA testing [2] are showing promise but blood tests, such as carcinoembryonic antigen (CEA) have been disappointing due to their low sensitivity in patients with early disease, the target population in screening programmes. The application of other serum biomarkers such as MMP-9, complement C3a des-arg and α-defensins [3-5] or proteomic approaches that seek characteristic diagnostic signatures [6] have met with limited success but have shown that, in principle, they are capable of generating sensitivities and specificities that are superior to CEA.Surface Enhanced Laser Desorption/Ionisation time-of-flight mass spectrometry (SELDI) has been widely applied to serum and plasma in attempts to discover changes in the proteome diagnostic for human cancers (reviewed in [7-9]). This methodology uses on-chip retentate chromatography
SELDI-TOF-MS determination of hepcidin in clinical samples using stable isotope labelled hepcidin as an internal standard
Douglas G Ward, Keith Roberts, Paul Stonelake, Patrick Goon, Cleidiane G Zampronio, Ashley Martin, Philip J Johnson, Tariq Iqbal, Chris Tselepis
Proteome Science , 2008, DOI: 10.1186/1477-5956-6-28
Abstract: We synthesised and re-folded hepcidin labelled with 13C/15N phenylalanine at position 9 to generate an internal standard for mass spectrometry experiments. This labelled hepcidin is 10 Daltons heavier than the endogenous peptides and does not overlap with the isotopic envelope of the endogenous hepcidin or other common peaks in human serum or urine mass spectra and can be distinguished in low resolution mass spectrometers. We report the validation of adding labelled hepcidin into serum followed by SELDI analysis to generate an improved assay for hepcidin.We demonstrate that without utilising a spiking approach the hepcidin peak height in SELDI spectra gives a good indication of hepcidin concentration. However, a stable isotope labelled hepcidin spiking approach provides a more robust assay, measures the absolute concentration of hepcidin and should facilitate inter-laboratory hepcidin comparisons.Hepcidin, a 25-residue peptide hormone, is a key regulator of iron homeostasis [1-3]. It is produced by hepatocytes and to a lesser extent by macrophages, bacteria-activated neutrophils and colorectal cancer cells [2-5]. The major stimuli for hepcidin expression include iron excess, inflammation and infection. Hepcidin exerts its biological effect at the level of cellular iron export by binding to and causing the internalisation and degradation of ferroportin [6]. Thus in macrophages; the major cell type responsible for iron recycling, the iron becomes trapped resulting in an anaemia which in the context of inflammation and infection is characterised as the anaemia of chronic disease [7].There has been intense research into how hepcidin is regulated and its role in pathologies including haematological disorders, liver disease and carcinogenesis [1,5,8]. The method most commonly employed for measuring hepcidin in serum and urine is surface enhanced laser desorption/ionisation time-of-flight mass spectrometry (SELDI) [5,9-12]. SELDI offers facile high-throughput sample prepar
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