Showing papers by "University of Leicester published in 2002"

The amount of carbon released from peat and forest fires in Indonesia during 1997

Abstract: Tropical peatlands are one of the largest near-surface reserves of terrestrial organic carbon, and hence their stability has important implications for climate change1,2,3. In their natural state, lowland tropical peatlands support a luxuriant growth of peat swamp forest overlying peat deposits up to 20 metres thick4,5. Persistent environmental change—in particular, drainage and forest clearing—threatens their stability2, and makes them susceptible to fire6. This was demonstrated by the occurrence of widespread fires throughout the forested peatlands of Indonesia7,8,9,10 during the 1997 El Nino event. Here, using satellite images of a 2.5 million hectare study area in Central Kalimantan, Borneo, from before and after the 1997 fires, we calculate that 32% (0.79 Mha) of the area had burned, of which peatland accounted for 91.5% (0.73 Mha). Using ground measurements of the burn depth of peat, we estimate that 0.19–0.23 gigatonnes (Gt) of carbon were released to the atmosphere through peat combustion, with a further 0.05 Gt released from burning of the overlying vegetation. Extrapolating these estimates to Indonesia as a whole, we estimate that between 0.81 and 2.57 Gt of carbon were released to the atmosphere in 1997 as a result of burning peat and vegetation in Indonesia. This is equivalent to 13–40% of the mean annual global carbon emissions from fossil fuels, and contributed greatly to the largest annual increase in atmospheric CO2 concentration detected since records began in 1957 (ref. 1).

The Proinflammatory CD14+CD16+DR++ Monocytes Are a Major Source of TNF

Abstract: In human blood two monocyte populations can be distinguished, i.e., the CD14(++)CD16(-)DR(+) classical monocytes and the CD14(+)CD16(+)DR(++) proinflammatory monocytes that account for only 10% of all monocytes. We have studied TNF production in these two types of cells using three-color immunofluorescence and flow cytometry on whole peripheral blood samples stimulated with either LPS or with the bacterial lipopeptide S-(2,3-bis(palmitoyloxy)-(2-RS)-propyl)-N-palmitoyl-(R)-Cys-(S)-Ser-(S)-Lys(4)-OH,trihydrochloride (Pam3Cys). After stimulation with LPS the median fluorescence intensity for TNF protein was 3-fold higher in the proinflammatory monocytes when compared with the classical monocytes. After stimulation with Pam3Cys they almost exclusively responded showing 10-fold-higher levels of median fluorescence intensity for TNF protein. The median fluorescence intensity for Toll-like receptor 2 cell surface protein was found 2-fold higher on CD14(+)CD16(+)DR(++) monocytes, which may explain, in part, the higher Pam3Cys-induced TNF production by these cells. When analyzing secretion of TNF protein into the supernatant in PBMCs after depletion of CD16(+) monocytes we found a reduction of LPS-induced TNF by 28% but Pam3Cys-induced TNF was reduced by 64%. This indicates that the minor population of CD14(+)CD16(+) monocytes are major producers of TNF in human blood.

IARC Monographs on the evaluation of carcinogenic risks to humans: Some traditional herbal medicines, some mycotoxins, naphthalene and styrene

Abstract: Members Ahti Anttila, Finnish Cancer Registry, Institute for Statistical and Epidemiological Cancer Research, Liisankatu 21 B, 00170 Helsinki, Finland Ramesh V. Bhat, National Institute of Nutrition, Indian Council of Medical Research, Jamai-Osmania PO, Hyderabad-500 007 AP, India James A. Bond, Chemico-Biological Interactions, Toxcon, 5505 Frenchmans Creek, Durham, NC 27713, USA Susan J. Borghoff, CIIT Centers for Health Research, 6 Davis Drive, Box 12137, Research Triangle Park, NC 27709-2127, USA F. Xavier Bosch, Epidemiology Unit and Cancer Registry, Catalan Institute of Oncology, Av. Gran via s/n, Km. 2.7, 08907 L’Hospitalet del Llobregat, Spain Gary P. Carlson, School of Health Sciences, 1338 Civil Engineering Building, Purdue University, West Lafayette, IN 47907-1338, USA Marcel Castegnaro, Les Collanges, 07240 Saint-Jean-Chambre, France George Cruzan, ToxWorks, 1153 Roadstown Road, Bridgeton, NJ 08302-6640, USA Wentzel C.A. Gelderblom, Programme on Mycotoxins and Experimental Carcinogenesis, Medical Research Council (MRC), PO Box 19070, Tygerberg, South Africa 7505 Ulla Hass, Institute of Food Safety and Toxicology, Morkhoj Bygade 19, 2860 Soborg, Denmark Sara H. Henry, 5100 Paint Branch Parkway, College Park, MD 20740-3835, USA Ronald A. Herbert, Laboratory of Experimental Pathology, National Institute of Environmental Health Sciences, PO Box 12233, Mail Drop B3-08, Research Triangle Park, NC 27709-2233, USA Marc Jackson, Integrated Laboratory Systems, Inc., PO Box 13501, Research Triangle Park, NC 27709, USA IARC WORKING GROUP ON THE EVALUATION OF CARCINOGENIC RISKS TO HUMANS: SOME TRADITIONAL HERBAL MEDICINES, SOME MYCOTOXINS, NAPHTHALENE AND STYRENE

A novel Epac-specific cAMP analogue demonstrates independent regulation of Rap1 and ERK.

Abstract: cAMP is involved in a wide variety of cellular processes that were thought to be mediated by protein kinase A (PKA)1. However, cAMP also directly regulates Epac1 and Epac2, guanine nucleotide-exchange factors (GEFs) for the small GTPases Rap1 and Rap2 (refs 2,3). Unfortunately, there is an absence of tools to discriminate between PKA- and Epac-mediated effects. Therefore, through rational drug design we have developed a novel cAMP analogue, 8-(4-chloro-phenylthio)-2′-O-methyladenosine-3′,5′-cyclic monophosphate (8CPT-2Me-cAMP), which activates Epac, but not PKA, both in vitro and in vivo. Using this analogue, we tested the widespread model that Rap1 mediates cAMP-induced regulation of the extracellular signal-regulated kinase (ERK)4,5. However, both in cell lines in which cAMP inhibits growth-factor-induced ERK activation and in which cAMP activates ERK, 8CPT-2Me-cAMP did not affect ERK activity. Moreover, in cell lines in which cAMP activates ERK, inhibition of PKA and Ras, but not Rap1, abolished cAMP-mediated ERK activation. We conclude that cAMP-induced regulation of ERK and activation of Rap1 are independent processes.

Guidelines for the Design and Statistical Analysis of Experiments Using Laboratory Animals

Abstract: For ethical and economic reasons, it is important to design animal experiments well, to analyze the data correctly, and to use the minimum number of animals necessary to achieve the scientific objectives---but not so few as to miss biologically important effects or require unnecessary repetition of experiments. Investigators are urged to consult a statistician at the design stage and are reminded that no experiment should ever be started without a clear idea of how the resulting data are to be analyzed. These guidelines are provided to help biomedical research workers perform their experiments efficiently and analyze their results so that they can extract all useful information from the resulting data. Among the topics discussed are the varying purposes of experiments (e.g., exploratory vs. confirmatory); the experimental unit; the necessity of recording full experimental details (e.g., species, sex, age, microbiological status, strain and source of animals, and husbandry conditions); assigning experimental units to treatments using randomization; other aspects of the experiment (e.g., timing of measurements); using formal experimental designs (e.g., completely randomized and randomized block); estimating the size of the experiment using power and sample size calculations; screening raw data for obvious errors; using the t-test or analysis of variance for parametric analysis; and effective design of graphical data.

The role of mitochondrial factors in apoptosis: a Russian roulette with more than one bullet.

Abstract: Mitochondria are 'life-essential' organelles for the production of metabolic energy in the form of ATP. Paradoxically mitochondria also play a key role in controlling the pathways that lead to cell death. This latter role of mitochondria is more than just a 'loss of function' resulting in an energy deficit but is an active process involving different mitochondrial proteins. Cytochrome c was the first characterised mitochondrial factor shown to be released from the mitochondrial intermembrane space and to be actively implicated in apoptotic cell death. Since then, other mitochondrial proteins, such as AIF, Smac/DIABLO, endonuclease G and Omi/HtrA2, were found to undergo release during apoptosis and have been implicated in various aspects of the cell death process. Members of the Bcl-2 protein family control the integrity and response of mitochondria to apoptotic signals. The molecular mechanism by which mitochondrial intermembrane space proteins are released and the regulation of mitochondrial homeostasis by Bcl-2 proteins is still elusive. This review summarises and evaluates the current knowledge concerning the complex role of released mitochondrial proteins in the apoptotic process.

The proteasome: a novel target for cancer chemotherapy.

Abstract: The ubiquitin-proteasome system is an important regulator of cell growth and apoptosis. The potential of specific proteasome inhibitors to act as novel anti-cancer agents is currently under intensive investigation. Several proteasome inhibitors exert anti-tumour activity in vivo and potently induce apoptosis in tumour cells in vitro, including those resistant to conventional chemotherapeutic agents. By inhibiting NF-κB transcriptional activity, proteasome inhibitors may also prevent angiogenesis and metastasis in vivo and further increase the sensitivity of cancer cells to apoptosis. Proteasome inhibitors also exhibit some level of selective cytotoxicity to cancer cells by preferentially inducing apoptosis in proliferating or transformed cells or by overcoming deficiencies in growth-inhibitory or pro-apoptotic molecules. High expression of oncogene products like c-Myc also makes cancer cells more susceptible to proteasome inhibitor-induced apoptosis. The induction of apoptosis by proteasome inhibitors varies between cell types but often occurs following an initial accumulation of short-lived proteins such as p53, p27, pro-apoptotic Bcl-2 family members or activation of the stress kinase JNK. These initial events often result in a perturbation of mitochondria with concomitant release of cytochrome c and activation of the Apaf-1 containing apoptosome complex. This results in activation of the apical caspase-9 followed by activation of effector caspases-3 and -7, which are responsible for the biochemical and morphological changes associated with apoptosis.

A meta-analysis of 50 years of ruptured abdominal aortic aneurysm repair

Abstract: Background: Operative repair of ruptured abdominal aortic aneurysm (RAAA) is associated with a high mortality rate but reported figures vary widely. The aim of this study was to estimate the operative mortality of RAAA repair and determine how it has changed over time. Methods: A meta-analysis of all English language literature quoting figures for operative mortality of RAAA repair. Results: The pooled estimate for the overall operative mortality rate of RAAA repair from 1955 to 1998 was 48 (95 per cent confidence interval 46 to 50) per cent. Meta-regression analysis of operative mortality over time demonstrated a constant reduction of approximately 3·5 per cent per decade (1954–1997) with an operative mortality rate estimate for the year 2000 of 41 per cent. Seventy-seven studies reported intraoperative mortality but, while this appears to have remained constant over time, there was evidence of the presence of publication bias in the subgroup of papers reporting this outcome. There was no evidence of publication bias for the overall operative mortality outcome. Conclusion: Contrary to the conclusion of recent studies, this paper demonstrates a gradual reduction with time in the operative mortality rate of RAAA repair. © 2002 British Journal of Surgery Society Ltd

Metabolism of the Cancer Chemopreventive Agent Curcumin in Human and Rat Intestine

Abstract: Curcumin, the yellow pigment in turmeric, prevents malignancies in the intestinal tract of rodents. It is under clinical evaluation as a potential colon cancer chemopreventive agent. The systemic bioavailability of curcumin is low, perhaps attributable, at least in part, to metabolism. Indirect evidence suggests that curcumin is metabolized in the intestinal tract. To investigate this notion further, we explored curcumin metabolism in subcellular fractions of human and rat intestinal tissue, compared it with metabolism in the corresponding hepatic fractions, and studied curcumin metabolism in situ in intact rat intestinal sacs. Analysis by high-performance liquid chromatography, with detection at 420 or 280 nm, permitted characterization of curcumin conjugates and reduction products. Chromatographic inferences were corroborated by mass spectrometry. Curcumin glucuronide was identified in intestinal and hepatic microsomes, and curcumin sulfate, tetrahydrocurcumin, and hexahydrocurcumin were found as curcumin metabolites in intestinal and hepatic cytosol from humans and rats. The extent of curcumin conjugation was much greater in intestinal fractions from humans than in those from rats, whereas curcumin conjugation was less extensive in hepatic fractions from humans than in those from rats. The curcumin-reducing ability of cytosol from human intestinal and liver tissue exceeded that observed with the corresponding rat tissue by factors of 18 and 5, respectively. Curcumin sulfate was identified in incubations of curcumin with intact rat gut sacs. Curcumin was sulfated by human phenol sulfotransferase isoenzymes SULT1A1 and SULT1A3. Equine alcohol dehydrogenase catalyzed the reduction of curcumin to hexahydrocurcumin. The results show that curcumin undergoes extensive metabolic conjugation and reduction in the gastrointestinal tract and that there is more metabolism in human than in rat intestinal tissue. The pharmacological implications of the intestinal metabolism of curcumin should be taken into account in the design of future chemoprevention trials of this dietary constituent.

NGOs, civil society and democratization: a critical review of the literature

Abstract: One of the most striking features of the anglophone literature on NGOs is the diversity of NGO sectors and their contributions to civil society and democracy; yet, exploration of this complexity is often eschewed in favour of a normative approach in which the apparently mutually enhancing relationship between NGOs, civil society and the state is underpinned by liberal democratic assumption rather than an engagement with wider debates about the politics of development. Following a critique of this approach to NGOs, civil society and democracy, the paper argues that the role of NGOs in the politics of development is far more complex than much of the NGO literature would suggest, and calls for a more contextualized and less value-laden approach to the understanding of the political role of NGOs.

Succinct indexable dictionaries with applications to encoding k-ary trees and multisets

Abstract: We consider the indexable dictionary problem which consists in storing a set S ⊆ {0,…, m - 1} for some integer m, while supporting the operations of rank(x), which returns the number of elements in S that are less than x if x e S, and -1 otherwise; and select(i) which returns the i-th smallest element in S.We give a structure that supports both operations in O(1) time on the RAM model and requires B(n,m) + o(n) + O(lg lg m) bits to store a set of size n, where B(n,m) = ⌈lg (nm)⌉ is the minimum number of bits required to store any n-element subset from a universe of size m. Previous dictionaries taking this space only supported (yes/no) membership queries in O(1) time. In the cell probe model we can remove the O(lg lg m) additive term in the space bound, answering a question raised by Fich and Miltersen, and Pagh.We also present two applications of our dictionary structure:• An information-theoretically optimal representation for k-ary cardinal trees (aka k-ary tries). Our structure uses C(n,k) + o(n + lg k) bits to store a k-ary tree with n nodes and can support parent, i-th child, child labeled i, and the degree of a node in constant time, where C(n,k) is the minimum number of bits to store any n-node k-ary tree. Previous space efficient representations for cardinal k-ary trees required C(n,k) + Ω(n) bits.• An optimal representation for multisets where (appropriate generalisations of) the select and rank operations can be supported in O(1) time. Our structure uses B(n, m + n) + o(n) + O(lg lg m) bits to represent a multiset of size n from an m element set; the first term is the minimum number of bits required to represent such a multiset.

Prevalence of faecal incontinence in adults aged 40 years or more living in the community

Abstract: Background: Prevalence studies of faecal incontinence in the general population are rare and the impact of faecal incontinence on quality of life has not been previously addressed. Aims: To establish the prevalence of faecal incontinence in adults in terms of frequency of leakage, degree of soiling, and level of impact on quality of life. Methods: In a cross sectional postal survey, 15 904 adults aged 40 years or more (excluding residents of nursing and residential homes) were selected randomly by household from the Leicestershire Health Authority patient register. Participants were asked to complete a confidential health questionnaire. Major faecal incontinence was defined as soiling of underwear or worse with a frequency of several times a month or more. Respondents were also asked if bowel symptoms had an impact on their quality of life. Results: From a total sample of 10 116 respondents, 1.4% reported major faecal incontinence and 0.7% major faecal incontinence with bowel symptoms that had an impact on quality of life. Major faecal incontinence was significantly associated with a lot of impact on quality of life (odds ratio 12.4, 95% confidence interval 7.5–20.6). Incontinence was more prevalent and more severe in older people but there was no significant difference between men and women. Conclusions: This study has confirmed that faecal incontinence is a fairly common symptom, particularly in older people. Faecal incontinence in men has received little attention in the past and the results from this study indicate that it is as much of a problem in men as it is in women while the level of unmet need in this group is high. Estimates of need for health care for this symptom should be multidimensional and assess both the severity of symptoms and the impact it has on quality of life.

X-ray background measurements with XMM-Newton EPIC

Abstract: We discuss the methods used to compile a high signal-to-noise dataset representative of both the instrumental and cosmic background signal measured at high galactic latitude by the XMM-Newton EPIC cameras. The characteristics of the EPIC background are described and the potential applications of the de- rived dataset in general science analysis are outlined. In the case of the cosmic X-ray background, the tran- sition between a hard power-law spectrum (due to the integrated emission of unresolved, largely extragalac- tic, point sources) and a softer thermal spectrum (produced by hot plasma associated with the Galactic plane and halo) is unambiguously detected around 1 keV. We derive a value for the intensity of the power-law component of 2:15 0:26 10 11 erg cm 2 s 1 deg 2 in the 2{10 keV band (normalisation at 1 keV of 11.1 photons cm 2 s 1 sr 1 keV 1 ). The implication is that recent, very deep Chandra observations have re- solved70{90% of the 2{10 keV background into discrete sources. Our measurement is towards the higher end of the range of quoted background normalisations.

X-Ray spectral variability and rapid variability of the soft X-ray spectrum Seyfert 1 galaxies Arakelian 564 and Ton S180

Abstract: The bright, soft X-ray spectrum Seyfert 1 galaxies Ark 564 and Ton S180 were monitored for 35 days and 12 days, respectively, with ASCA and RXTE (and EUVE for Ton S180). These represent the most intensive X-ray monitoring of any such soft-spectrum Seyfert 1 to date. Light curves were constructed for Ton S180 in six bands spanning 0.1-10 keV and for Ark 564 in five bands spanning 0.7-10 keV. The short-timescale (hours-days) variability patterns were very similar across energy bands, with no evidence of lags between any of the energy bands studied. The fractional variability amplitude was almost independent of energy band, unlike hard-spectrum Seyfert 1 galaxies, which show stronger variations in the softer bands. It is difficult to simultaneously explain soft Seyfert galaxies stronger variability, softer spectra, and weaker energy dependence of the variability relative to hard Seyfert galaxies. There was a trend for soft- and hard-band light curves of both objects to diverge on the longest timescales probed (~weeks), with the hardness ratio showing a secular change throughout the observations. This is consistent with the fluctuation power density spectra that showed relatively greater power on long timescales in the softest bands. The simplest explanation of all of these is that two continuum emission components are visible in the X-rays: a relatively hard, rapidly variable component that dominates the total spectrum and a slowly variable soft excess that only shows up in the lowest energy channels of ASCA. Although it would be natural to identify the latter component with an accretion disk and the former with a corona surrounding it, a standard thin disk could not get hot enough to radiate significantly in the ASCA band, and the observed variability timescales are much too short. It also appears that the hard component may have a more complex shape than a pure power law. The most rapid factor of 2 flares and dips occurred within ~1000 s, in Ark 564 and a bit more slowly in Ton S180. The speed of the luminosity changes rules out viscous or thermal processes and limits the size of the individual emission regions to 15 Schwarzschild radii (and probably much less), that is, to either the inner disk or small regions in a corona.

Neoproterozoic to Paleozoic Geology of the Altai Orogen, NW China: New Zircon Age Data and Tectonic Evolution

Abstract: We present a synthesis and a new account of the geological and tectonic history of the terranes of the Chinese Paleozoic Altai orogen together with new, single zircon ages for granitic and rhyodacitic rocks. A central terrane consists of Neoproterozoic to Silurian, amphibolite facies, metasedimentary rocks, and abundant Devonian‐Carboniferous granites. The presence of Precambrian basement is indicated by Sinian fossils, our xenocryst ages, and published Nd mean crustal residence ages of granites. Felsic arc‐type lavas on the southern margin of the terrane have a mean 207Pb/206Pb zircon age of 505 Ma, reflecting the time of arc volcanism, and the presence of xenocysts with ages between 614 and 921 Ma suggests derivation by intracrustal melting. Accordingly, we suggest that a Cambro‐Ordovician continental magmatic arc was built on the southern margin of the central terrane by northward subduction. A low‐grade Ordovician Andean‐type arc with a continental basement is situated above a normal fault on...

Ventilation and health in non-industrial indoor environments: report from a European multidisciplinary scientific consensus meeting (EUROVEN).

Abstract: Scientific literature on the effects of ventilation on health, comfort, and productivity in non-industrial indoor environments (offices, schools, homes, etc.) has been reviewed by a multidisciplinary group of European scientists, called EUROVEN, with expertise in medicine, epidemiology, toxicology, and engineering. The group reviewed 105 papers published in peer-reviewed scientific journals and judged 30 as conclusive, providing sufficient information on ventilation, health effects, data processing, and reporting, 14 as providing relevant background information on the issue, 43 as relevant but non-informative or inconclusive, and 18 as irrelevant for the issue discussed. Based on the data in papers judged conclusive, the group agreed that ventilation is strongly associated with comfort (perceived air quality) and health [Sick Building Syndrome (SBS) symptoms, inflammation, infections, asthma, allergy, short-term sick leave], and that an association between ventilation and productivity (performance of office work) is indicated. The group also concluded that increasing outdoor air supply rates in non-industrial environments improves perceived air quality; that outdoor air supply rates below 25 l/s per person increase the risk of SBS symptoms, increase short-term sick leave, and decrease productivity among occupants of office buildings; and that ventilation rates above 0.5 air changes per hour (h-1) in homes reduce infestation of house dust mites in Nordic countries. The group concluded additionally that the literature indicates that in buildings with air-conditioning systems there may be an increased risk of SBS symptoms compared with naturally or mechanically ventilated buildings, and that improper maintenance, design, and functioning of air-conditioning systems contributes to increased prevalence of SBS symptoms.

Presynaptic Mitochondrial Calcium Sequestration Influences Transmission at Mammalian Central Synapses

Abstract: Beyond their role in generating ATP, mitochondria have a high capacity to sequester calcium. The interdependence of these functions and limited access to presynaptic compartments makes it difficult to assess the role of sequestration in synaptic transmission. We addressed this important question using the calyx of Held as a model glutamatergic synapse by combining patch-clamp with a novel mitochondrial imaging method. Presynaptic calcium current, mitochondrial calcium concentration ([Ca2+]mito, measured using rhod-2 or rhod-FF), cytoplasmic calcium concentration ([Ca2+]cyto, measured using fura-FF), and the postsynaptic current were monitored during synaptic transmission. Presynaptic [Ca2+]cytorose to 8.5 ± 1.1 μm and decayed rapidly with a time constant of 45 ± 3 msec; presynaptic [Ca2+]mito also rose rapidly to >5 μm but decayed slowly with a half-time of 1.5 ± 0.4 sec. Mitochondrial depolarization with rotenone and carbonyl cyanide p -trifluoromethoxyphenylhydrazone abolished mitochondrial calcium rises and slowed the removal of [Ca2+]cyto by 239 ± 22%. Using simultaneous presynaptic and postsynaptic patch clamp, combined with presynaptic mitochondrial and cytoplasmic imaging, we investigated the influence of mitochondrial calcium sequestration on transmitter release. Depletion of ATP to maintain mitochondrial membrane potential was blocked with oligomycin, and ATP was provided in the patch pipette. Mitochondrial depolarization raised [Ca2+]cyto and reduced transmitter release after short EPSC trains (100 msec, 200 Hz); this effect was reversed by raising mobile calcium buffering with EGTA. Our results suggest a new role for presynaptic mitochondria in maintaining transmission by accelerating recovery from synaptic depression after periods of moderate activity. Without detectable thapsigargin-sensitive presynaptic calcium stores, we conclude that mitochondria are the major organelle regulating presynaptic calcium at central glutamatergic terminals.

The cancer preventative agent resveratrol is converted to the anticancer agent piceatannol by the cytochrome P450 enzyme CYP1B1

Abstract: Resveratrol is a cancer preventative agent that is found in red wine. Piceatannol is a closely related stilbene that has antileukaemic activity and is also a tyrosine kinase inhibitor. Piceatannol differs from resveratrol by having an additional aromatic hydroxy group. The enzyme CYP1B1 is overexpressed in a wide variety of human tumours and catalyses aromatic hydroxylation reactions. We report here that the cancer preventative agent resveratrol undergoes metabolism by the cytochrome P450 enzyme CYP1B1 to give a metabolite which has been identified as the known antileukaemic agent piceatannol. The metabolite was identified by high performance liquid chromatography analysis using fluorescence detection and the identity of the metabolite was further confirmed by derivatisation followed by gas chromatography–mass spectrometry studies using authentic piceatannol for comparison. This observation provides a novel explanation for the cancer preventative properties of resveratrol. It demonstrates that a natural dietary cancer preventative agent can be converted to a compound with known anticancer activity by an enzyme that is found in human tumours. Importantly this result gives insight into the functional role of CYP1B1 and provides evidence for the concept that CYP1B1 in tumours may be functioning as a growth suppressor enzyme. British Journal of Cancer (2002) 86, 774–778. DOI: 10.1038/sj/bjc/6600197 www.bjcancer.com © 2002 Cancer Research UK

Chemopreventive Efficacy and Pharmacokinetics of Curcumin in the Min/+ Mouse, a Model of Familial Adenomatous Polyposis

Abstract: Curcumin, the major yellow pigment in turmeric, prevents the development of adenomas in the intestinal tract of the C57Bl/6J Min/+ mouse, a model of human familial APC. To aid the rational development of curcumin as a colorectal cancer-preventive agent, we explored the link between its chemopreventive potency in the Min/+ mouse and levels of drug and metabolites in target tissue and plasma. Mice received dietary curcumin for 15 weeks, after which adenomas were enumerated. Levels of curcumin and metabolites were determined by high-performance liquid chromatography in plasma, tissues, and feces of mice after either long-term ingestion of dietary curcumin or a single dose of [(14)C]curcumin (100 mg/kg) via the i.p. route. Whereas curcumin at 0.1% in the diet was without effect, at 0.2 and 0.5%, it reduced adenoma multiplicity by 39 and 40%, respectively, compared with untreated mice. Hematocrit values in untreated Min/+ mice were drastically reduced compared with those in wild-type C57Bl/6J mice. Dietary curcumin partially restored the suppressed hematocrit. Traces of curcumin were detected in the plasma. Its concentration in the small intestinal mucosa, between 39 and 240 nmol/g of tissue, reflects differences in dietary concentration. [(14)C]Curcumin disappeared rapidly from tissues and plasma within 2-8 h after dosing. Curcumin may be useful in the chemoprevention of human intestinal malignancies related to Apc mutations. The comparison of dose, resulting curcumin levels in the intestinal tract, and chemopreventive potency suggests tentatively that a daily dose of 1.6 g of curcumin is required for efficacy in humans. A clear advantage of curcumin over nonsteroidal anti-inflammatory drugs is its ability to decrease intestinal bleeding linked to adenoma maturation.

A novel interaction between lamin A and SREBP1: implications for partial lipodystrophy and other laminopathies

Abstract: The gene encoding nuclear lamins A and C is mutated in at least three inherited disorders. Two of these, Emery-Dreifuss muscular dystrophy (EDMD-AD) and a form of dilated cardiomyopathy (CMD1A), involve muscle defects, and the other, familial partial lipodystrophy (FPLD), involves loss of subcutaneous adipose tissue. Mutations causing FPLD, in contrast to those causing muscle disorders, are tightly clustered within the C-terminal domain of lamin A/C. We investigated the expression and subcellular localization of FPLD lamin A mutants and found no abnormalities. We therefore set out to identify proteins interacting with the C-terminal domain of lamin A by screening a mouse 3T3-L1 adipocyte library in a yeast two-hybrid interaction screen. Using this approach, the adipocyte differentiation factor, sterol response element binding protein 1 (SREBP1) was identified as a novel lamin A interactor. In vitro glutathione S-transferase pull-down and in vivo co-immunoprecipitation studies confirmed an interaction between lamin A and both SREBP1a and 1c. A binding site for lamin A was identified in the N-terminal transcription factor domain of SREBP1, between residues 227 and 487. The binding of lamin A to SREBP1 was noticeably reduced by FPLD mutations. Interestingly, one EDMD-AD mutation also interfered with the interaction between lamin A and SREBP1. Whilst the physiological relevance of this interaction has yet to be elucidated, these data raise the intriguing possibility that fat loss seen in laminopathies may be caused, at least in part, by reduced binding of the adipocyte differentiation factor SREBP1 to lamin A.