bluuebunny/crossref_metadata_2025 huggingface dataset:
Isoform-specific functions of protein kinase C: the platelet paradigm
Authors: Harper M.T. , Poole A.W.
Published: November 2007

Platelets are central to haemostasis and thrombosis. Many key steps in platelet activation and aggregation are regulated by members of the PKC (protein kinase C) family. Multiple isoforms of PKC are expressed in platelets, and evidence is emerging that different isoforms play distinct roles in the platelet activation process. This may, in part, be regulated by isoform-specific interactions between PKC family members and other intracellular signalling molecules, such as tyrosine kinases, or the actin cytoskeleton regulator, VASP (vasodilator-stimulated phosphoprotein). The contributions of individual PKC isoforms can be addressed directly in platelets from knockout mouse models, which are providing key insights into the physiological function of PKC isoform diversity and can be a valuable complimentary approach to more commonly used pharmacological analyses. Using knockout mouse models, recent reports have demonstrated the importance of PKCβ and PKCθ in integrin-dependent platelet spreading, and also a novel role for PKCδ in regulating filopodial formation, highlighting the utility of such models to investigate the functions of specific PKC isoforms in a physiological process that is significant to our understanding of cardiovascular disease.
Protein kinases, from B to C
Authors: Cameron A.J. , De Rycker M. , Calleja V. , Alcor D. , Kjaer S. , Kostelecky B. , Saurin A. , Faisal A. , Laguerre M. , Hemmings B.A. , McDonald N. , Larijani B. , Parker P.J.
Published: November 2007

The PKB (protein kinase B) and PKC (protein kinase C) families display highly related catalytic domains that require a largely conserved series of phosphorylations for the expression of their optimum activities. However, in cells, the dynamics of these modifications are quite distinct. Based on experimental evidence, it is argued that the underlying mechanisms determining these divergent behaviours relate to the very different manner in which their variant regulatory domains interact with their respective catalytic domains. It is concluded that the distinct behaviours of PKB and PKC proteins are defined by the typical ground states of these proteins.
Functional PKC in vivo analysis using deficient mouse models
Authors: Leitges M.
Published: November 2007

The aim of our group is to identify PKC (protein kinase C) in vivo function by analysing individual PKC knockouts we have generated over the past few years. The general approach we are using to identify target tissues and/or defined cell populations within the mouse for further investigation is a detailed expression analysis of individual PKC isoforms. For these purposes, we have established several specific tools in the past that allow us to follow up isoform-specific PKC expression on a very precise level. Doing so, we have started to investigate PKC expression profiles under various tumour conditions in mice. As predicted, we were able to identify various PKC isoforms to be either up- or down-regulated during the development and progression of certain tumours, implying that these isoforms are substantially linked to the biology of these tumours. In order to prove this hypothesis, we then crossed relevant PKC knockout lines on the appropriate tumour background and analysed tumour growth and progression under PKC-deficient conditions. Exemplary of this approach, recent data generated with PKCα-deficient APCMin (adenomatous polyposis coli) mice identify PKCα in this system acting as a tumour suppressor instead of being a promoter as suggested from PMA data.
Study of the functional role of Bcl-2 family proteins in regulating Ca2+ signals in apoptotic cells
Authors: Lao Y. , Chang D.C.
Published: November 2007

Recently, it was found that Bcl-2 family proteins can affect the apoptotic process by modifying Ca2+ released from the ER (endoplasmic reticulum). In this review, we summarize the evidence that Bcl-2 and Bax can modulate Ca2+ mobilization from the ER to the cytosol and mitochondria. We also found evidence that both Bcl-2 and Bax can interact with IP3Rs (InsP3 receptors) to modify the Ca2+ efflux from the ER. On the basis of our findings, we suggest that Bax may interact with IP3Rs to facilitate the release of Ca2+ from the ER during apoptosis.
Lifespan regulation of conventional protein kinase C isotypes
Authors: Carmena D. , Sardini A.
Published: November 2007

Plasma membrane translocation, following allosteric binding of second messengers, initiates the signal transduction process mediated by cPKC [conventional PKC (protein kinase C)] isotypes. Mechanisms regulating the lifespan of the active enzyme such as its phosphorylation, internalization, dephosphorylation and degradation are key elements of the signalling network. The understanding of such mechanisms is essential for the design of therapeutic strategies targeting PKC isoenzymes.
Aldosterone-stimulated PKC signalling cascades: from receptor to effector
Authors: Thomas W. , McEneaney V. , Harvey B.J.
Published: November 2007

Aldosterone plays an important role in the regulation of blood pressure. The effects of this hormone have classically been described in terms of the transcriptional regulation of genes that facilitate electrolyte transport, particularly across high-resistance epithelia. The protein kinase signalling cascades that are rapidly activated in response to aldosterone are emerging as important modulators of the transcriptional response, and may serve to prime cells for the subsequent transcriptional changes. The activation of protein kinase D through an epidermal growth factor receptor transactivation pathway by aldosterone in renal cells has the potential to impact on cell trafficking events that regulate transporter activity.
Mitochondrial protein kinase Cϵ (PKCϵ): emerging role in cardiac protection from ischaemic damage
Authors: Budas G.R. , Mochly-Rosen D.
Published: November 2007

Mitochondria mediate diverse cellular functions including energy generation and ROS (reactive oxygen species) production and contribute to signal transduction. Mitochondria are also key regulators of cell viability and play a central role in necrotic and apoptotic cell death pathways induced by cardiac ischaemia/reperfusion injury. PKC (protein kinase C) ϵ plays a critical role in cardioprotective signalling pathways that protect the heart from ischaemia/reperfusion. Emerging evidence suggests that the cardioprotective target of PKCϵ resides at the mitochondria. Proposed mitochondrial targets of PKCϵ include mitoKATP (mitochondrial ATP-sensitive K+ channel), components of the MPTP (mitochondrial permeability transition pore) and components of the electron transport chain. This review highlights mitochondrial targets of PKCϵ and their possible role in cardioprotective signalling in the setting of ischaemia/reperfusion injury.
The role of abnormal trafficking of KCNE1 in long QT syndrome 5
Authors: Harmer S.C. , Tinker A.
Published: November 2007

LQTS (long QT syndrome) is an important cause of cardiac sudden death. LQTS is characterized by a prolongation of the QT interval on an electrocardiogram. This prolongation predisposes the individual to torsade-de-pointes and subsequent sudden death by ventricular fibrillation. Mutations in a number of genes that encode ion channels have been implicated in LQTS. Hereditary mutations in the α- and β-subunits, KCNQ1 and KCNE1 respectively, of the K+ channel pore IKs are the commonest cause of LQTS and account for LQTS types 1 and 5 respectively (LQT1 and LQT5). Recently, it has been shown that disease pathogenesis in LQT1 can be influenced by the abnormal trafficking of KCNQ1. In comparison, whether defective trafficking of KCNE1 plays a role in LQT5 is less well established.
The role of calcium and other ions in sorting and delivery in the late endocytic pathway
Authors: Luzio J.P. , Bright N.A. , Pryor P.R.
Published: November 2007

The passage of endocytosed receptor-bound ligands and membrane proteins through the endocytic pathway of mammalian cells to lysosomes occurs via early and late endosomes. The latter contain many luminal vesicles and are often referred to as MVBs (multivesicular bodies). The overall morphology of endosomal compartments is, in major part, a consequence of the many fusion events occurring in the endocytic pathway. Kissing events and direct fusion between late endosomes and lysosomes provide a means of delivery to lysosomes. The luminal ionic composition of organelles in the endocytic pathway is of considerable importance both in the trafficking of endocytosed ligands and in the membrane fusion events. In particular, H+ ions play a role in sorting processes and providing an appropriate environment for the action of lysosomal acid hydrolases. Na+/H+ exchangers in the endosomal membrane have been implicated in the formation of MVBs and sorting into luminal vesicles. Ca2+ ions are required for fusion events and luminal content condensation in the lysosome. Consistent with an important role for luminal Ca2+ in traffic through the late endocytic pathway, mutations in the gene encoding mucolipin-1, a lysosomal non-specific cation channel, result in abnormalities in lipid traffic and are associated with the autosomal recessive lysosomal storage disease MLIV (mucolipidosis type IV).
Regulation of T-cell migration by co-stimulatory molecules
Authors: David R. , Marelli-Berg F.M.
Published: November 2007

Migration of primed T-cells to the antigenic site is an essential event in the development of effective immunity. This process is tightly regulated in order to ensure efficient and specific responses. Most studies have focused on non-specific mediators of T-cell migration, including integrins and chemokines. However, recent studies have highlighted the key role of the T-cell receptor and co-stimulatory molecules in guiding T-cell access to antigenic tissue. Here, we review the experimental evidence for an essential contribution of co-stimulation-mediated molecular interactions regulating T-cell migration in the development of T-cell immunity and tolerance.
Mechanisms of inflammatory neurodegeneration: iNOS and NADPH oxidase
Authors: Brown G.C.
Published: November 2007

Inflammation contributes to a wide variety of brain pathologies, apparently via glia killing neurons. A number of mechanisms by which inflammatory-activated microglia and astrocytes kill neurons have been identified in culture. These include iNOS (inducible nitric oxide synthase), which is expressed in glia only during inflammation, and PHOX (phagocytic NADPH oxidase) found in microglia and acutely activated by inflammation. High levels of iNOS expression in glia cause (i) NO (nitric oxide) inhibition of neuronal respiration, resulting in neuronal depolarization and glutamate release, followed by excitotoxicity, and (ii) glutamate release from astrocytes via calcium-dependent vesicular release. Hypoxia strongly synergizes with iNOS expression to induce neuronal death via mechanism (i), because NO inhibits cytochrome oxidase in competition with oxygen. Activation of PHOX (by cytokines, β-amyloid, prion protein, ATP or arachidonate) causes microglial proliferation and inflammatory activation; thus PHOX is a key regulator of inflammation. Activation of PHOX alone causes no death, but when combined with expressed iNOS results in extensive neuronal death via peroxynitrite production.
An overview of the biological significance of endogenous gases: new roles for old molecules
Authors: Li L. , Moore P.K.
Published: November 2007

Biologically active gases that occur naturally in the body include nitric oxide (NO), carbon monoxide (CO) and hydrogen sulfide (H2S). Each of these molecules is synthesized by enzymes which have been characterized biochemically and pharmacologically, and each acts, via well-established molecular targets, to effect physiological and/or pathophysiological functions within the body. Major biological roles that appear to be common to all three gases include the regulation of vascular homoeostasis and central nervous system function. It is becoming increasingly clear that both the synthesis and the biological activity of each gas are, to some extent, regulated by the presence of the others, and as such it is necessary to consider these molecules not in isolation but acting together to control cell function. Additional, more speculative candidates for gaseous cell signalling molecules include ammonia, acetaldehyde, sulfur dioxide and nitrous oxide. Whether such molecules also play a role in regulating body function remains to be determined.
Biochemistry of oxidative stress
Authors: Halliwell B.
Published: November 2007

The terms ‘antioxidant’, ‘oxidative stress’ and ‘oxidative damage’ are widely used but rarely defined. This brief review attempts to define them and to examine the ways in which oxidative stress and oxidative damage can affect cell behaviour both in vivo and in cell culture, using cancer as an example.
Resveratrol as an antioxidant and pro-oxidant agent: mechanisms and clinical implications
Authors: de la Lastra C. Alarcón , Villegas I.
Published: November 2007

Resveratrol (3,4′,5-trihydroxystilbene) is found in various plants, including grapes, berries and peanuts. It is also present in wines, especially red wines. During the last years, it has been the focus of numerous in vitro and in vivo studies investigating its biological attributes, which include mainly antioxidant and anti-inflammatory activities, anti-platelet aggregation effect, anti-atherogenic property, oestrogen-like growth-promoting effect, growth-inhibiting activity, immunomodulation and chemoprevention. In fact, recently, it has been demonstrated that the stilbene blocks the multistep process of carcinogenesis at various stages: tumour initiation, promotion and progression. More recent results provide interesting insights into the effect of this compound on the life span of yeasts and flies, implicating the potential of resveratrol as an anti-aging agent in treating age-related human diseases. Nevertheless, depending on the concentration of the phytoalexin and the cell type, it has also been shown that resveratrol can exhibit pro-oxidant properties, leading to oxidative breakage of cellular DNA in the presence of transition metal ions such as copper. Recently, it has been proposed that such a pro-oxidant action could be a common mechanism for anticancer and chemopreventive properties of plant polyphenols. The present paper is intended to provide the reader up-to-date information on the antioxidant and pro-oxidant properties of resveratrol and its clinical implications.
Systemic inflammation and stroke: aetiology, pathology and targets for therapy
Authors: McColl B.W. , Allan S.M. , Rothwell N.J.
Published: November 2007

There is growing evidence that systemic inflammation is involved in multiple aspects of stroke aetiology and pathology. In the present review, we provide an overview of these roles and, in particular, outline recent evidence that the underlying systemic inflammatory profile can critically alter the response to ischaemic brain injury. We also highlight the need for stroke models to more adequately account for the involvement of underlying systemic inflammation.
Neurodegeneration in models of Gram-positive bacterial infections of the central nervous system
Authors: Neher J.J. , Brown G.C.
Published: November 2007

Gram-positive bacterial infections of the central nervous system, such as meningitis, induce an extensive inflammatory response, which in turn may damage neurons. LTA (lipoteichoic acid) is a component of the Gram-positive bacterial cell wall that induces glial inflammatory activation in vitro and in vivo. It does so by binding to Toll-like receptor-2 on microglia and astrocytes, rapidly activating ERK1/2 (extracellular-signal-regulated kinase 1/2) and p38 MAPKs (mitogen-activated protein kinases), causing NF-κB (nuclear factor κB) activation and leading to the production of pro-inflammatory cytokines and expression of inducible nitric oxide synthase (in synergy with muramyl dipeptide). LTA-activated microglia kill co-cultured neurons apparently via nitric oxide, superoxide and peroxynitrite, which may induce apoptosis of neurons that are then phagocytosed by microglia.
Insulin action on the liver in vivo
Authors: Cherrington A.D. , Moore M.C. , Sindelar D.K. , Edgerton D.S.
Published: November 2007

Insulin has a potent inhibitory effect on hepatic glucose production by direct action at hepatic receptors. The hormone also inhibits glucose production by suppressing both lipolysis in the fat cell and secretion of glucagon by the α-cell. Neural sensing of insulin levels appears to participate in control of hepatic glucose production in rodents, but a role for brain insulin sensing has not been documented in dogs or humans. The primary effect of insulin on the liver is its direct action.
Homocysteine metabolism in diabetes
Authors: Wijekoon E.P. , Brosnan M.E. , Brosnan J.T.
Published: November 2007

An increase in the plasma level of Hcy (homocysteine), an intermediate in the catabolism of methionine, has been identified as a risk factor for many diseases including CVD (cardiovascular disease). CVD is the major cause of death in patients with diabetes mellitus. Therefore the study of Hcy metabolism in diabetes mellitus has been a major focus of current research. Studies conducted in our laboratory were able to show that in both Type 1 and Type 2 diabetes with no renal complications, the plasma Hcy levels were lower than in controls. In Type 1 diabetes, increased activities of the trans-sulfuration enzymes were the major cause for the reduction in plasma Hcy. In Type 2 diabetes, BHMT (betaine:homocysteine methyltransferase) was also observed to play a major role in the increased catabolism of Hcy in addition to the trans-sulfuration enzymes. We were also able to demonstrate the direct effect of insulin and the counter-regulatory hormones on the regulation of cystathionine β-synthase and BHMT, which accounts for the changes in the activities of these two enzymes seen in diabetes mellitus.
Long-chain fatty acid sensing in the gastrointestinal tract
Authors: McLaughlin J.
Published: November 2007

The gastrointestinal tract actively responds to the presence of nutrients in the lumen, and there is a high level of specificity to these responses. This specificity exists for different nutrient types and anatomical regions, with physiologically appropriate target end-organ responses. This review will journey from outlining the effects of dietary fat on digestive function and feeding behaviour to the evidence for lipid sensory cells, particularly the enteroendocrine system, in the epithelium. It will also outline potential molecular bases for these mechanisms. This will deal exclusively with issues specific to fatty acid sensing and not the emergent acid pH-sensing mechanisms that may also be activated in the presence of free fatty acids.
Early life programming of energy balance
Authors: Cripps R.L. , Archer Z.A. , Mercer J.G. , Ozanne S.E.
Published: November 2007

Obesity prevalence is increasing worldwide, leading to increased morbidity, mortality and health care costs due to its role as a key risk factor in many diseases. Early life growth and nutrition has been implicated in determining susceptibility to obesity in both childhood and adulthood; however, the mechanisms underlying this link are poorly understood. A variety of animal models have been established to try and uncover the developmental programming effects of maternal early life nutrition on energy balance regulation and the mechanisms behind them.
Synaptic memory mechanisms: Alzheimer's disease amyloid β-peptide-induced dysfunction
Authors: Rowan M.J. , Klyubin I. , Wang Q. , Hu N.W. , Anwyl R.
Published: November 2007

There is growing evidence that mild cognitive impairment in early AD (Alzheimer's disease) may be due to synaptic dysfunction caused by the accumulation of non-fibrillar, oligomeric Aβ (amyloid β-peptide), long before widespread synaptic loss and neurodegeneration occurs. Soluble Aβ oligomers can rapidly disrupt synaptic memory mechanisms at extremely low concentrations via stress-activated kinases and oxidative/nitrosative stress mediators. Here, we summarize experiments that investigated whether certain putative receptors for Aβ, the αv integrin extracellular cell matrix-binding protein and the cytokine TNFα (tumour necrosis factor α) type-1 death receptor mediate Aβ oligomer-induced inhibition of LTP (long-term potentiation). Ligands that neutralize TNFα or genetic knockout of TNF-R1s (type-1 TNFα receptors) prevented Aβ-triggered inhibition of LTP in hippocampal slices. Similarly, antibodies to αv-containing integrins abrogated LTP block by Aβ. Protection against the synaptic plasticity-disruptive effects of soluble Aβ was also achieved using systemically administered small molecules targeting these mechanisms in vivo. Taken together, this research lends support to therapeutic trials of drugs antagonizing synaptic plasticity-disrupting actions of Aβ oligomers in preclinical AD.
How do mammalian mitochondria synthesize proteins?
Authors: Rorbach J. , Soleimanpour-Lichaei R. , Lightowlers R.N. , Chrzanowska-Lightowlers Z.M.A.
Published: November 2007

Mitochondria contain their own genome that is expressed by nuclear-encoded factors imported into the organelle. This review provides a summary of the current state of knowledge regarding the mechanism of protein translation in human mitochondria and the factors involved in this process.
Using systems biology to define the essential biological networks responsible for adaptation to endurance exercise training
Authors: Keller P. , Vollaard N. , Babraj J. , Ball D. , Sewell D.A. , Timmons J.A.
Published: November 2007

We predict that RNA level regulation is as diverse and powerful as protein level regulation when considering physiological adaptation. Non-coding RNA molecules, such as miRNAs (microRNAs), have emerged as a powerful mechanism for post-transcriptional regulation of mRNA. In an effort to define the role of miRNA in human skeletal-muscle biology, we have initiated profiling of muscle RNA before and after endurance exercise training. The robust molecular phenotype of muscle is established using unbiased analysis strategies of the raw data, reflecting the statistical power of gene ontology and network analysis. We can thus determine the structural features of the skeletal-muscle transcriptome, identify discrete networks activated by training and utilize bioinformatics predictions to establish the interaction between non-coding RNA modulation and Affymetrix expression profiles.
Effect of exercise and insulin on SREBP-1c expression in human skeletal muscle: potential roles for the ERK1/2 and Akt signalling pathways
Authors: Boonsong T. , Norton L. , Chokkalingam K. , Jewell K. , Macdonald I. , Bennett A. , Tsintzas K.
Published: November 2007

SREBP-1c (sterol-regulatory-element-binding protein 1c) is a transcription factor that regulates genes associated with glucose and fatty acid metabolism and exhibits responsiveness to insulin and exercise. We have examined the effects of exercise on basal and insulin-mediated changes in the activation (phosphorylation) of the signalling molecules involved in the regulation of SREBP-1c and related them to changes in the expression of SREBP-1c in human skeletal muscle. Eight healthy men performed one-legged cycling for 90 min; 24 h later a hyperinsulinaemic euglycaemic clamp for 4 h was performed. Muscle biopsies were obtained from the rested (control) leg and the exercised leg immediately after exercise and before and after the insulin clamp. Immediately after exercise, phosphorylation of ERK (extracellular-signal-regulated kinase) 1, ERK2 and Akt (protein kinase B) was higher in the exercised than the control leg. SREBP-1c mRNA content was not affected by exercise, whereas its protein level was lower in the exercised than the control leg and returned to pre-exercise levels 24 h later. Similarly, SREBP-1c mRNA content was ∼1.5-fold higher in the exercised than the control leg 24 h after exercise. Insulin infusion up-regulated SREBP-1c mRNA level ∼2-fold, but did not affect its protein level. Phosphorylation of Akt also increased in response to insulin clamp, whereas phospho-ERK1 and -ERK2 levels were unchanged. Neither exercise nor insulin affected STAT3 (signal transducer and activator of transcription 3) or p38 MAPK (mitogen-activated protein kinase) phosphorylation. These findings suggest that exercise-induced changes in muscle SREBP-1c expression might be mediated by the activation of the ERK1/2 pathway, whereas Akt might be a positive regulator of SREBP-1c in human skeletal muscle under insulin-stimulated conditions.
mVps34 is activated by an acute bout of resistance exercise
Authors: MacKenzie M.G. , Hamilton D.L. , Murray J.T. , Baar K.
Published: November 2007

Resistance-exercise training results in a progressive increase in muscle mass and force production. Following an acute bout of resistance exercise, the rate of protein synthesis increases proportionally with the increase in protein degradation, correlating at 3 h in the starved state. Amino acids taken immediately before or immediately after exercise increase the post-exercise rate of protein synthesis. Therefore a protein that controls protein degradation and amino acid-sensitivity would be a potential candidate for controlling the activation of protein synthesis following resistance exercise. One such candidate is the class III PI3K (phosphoinositide 3-kinase) Vps34 (vacuolar protein sorting mutant 34). Vps34 controls both autophagy and amino acid signalling to mTOR (mammalian target of rapamycin) and its downstream target p70 S6K1 (S6 kinase 1). We have identified a significant increase in mVps34 (mammalian Vps34) activity 3 h after resistance exercise, continuing for at least 6 h, and propose a mechanism whereby mVps34 could act as an internal amino acid sensor to mTOR after resistance exercise.
Towards new tuberculosis drugs
Authors: Cole S.T. , Alzari P.M.
Published: November 2007

The need for better drugs to treat tuberculosis has never been greater. Despite insufficient funding for discovery research, intensive efforts have been made to find and develop new lead compounds capable of reducing the duration of the present treatment known as DOTS (directly observed therapy short course), from 6 to under 4 months. This minireview describes the progress achieved during the last 5 years and highlights some of the successes without neglecting the problems.
Cancer genetics: mouse models of intestinal cancer
Authors: Clarke A.R.
Published: November 2007

The capacity to model cancer within the mouse has advanced significantly in recent years. Perhaps the most notable technical gains have been in the development of techniques that allow the temporal and spatial control of gene expression, so that it is now possible to regulate target genes in the tissue of choice and at a given time [Maddison and Clarke (2005) J. Pathol. 205, 181–193; Shaw and Clarke (2007) DNA Repair 6, 1403–1412; Marsh and Clarke (2007) Expert Rev. Anticancer Ther. 7, 519–531]. We have used these approaches to study tumorigenesis in the murine intestine. Loss of function of the tumour-suppressor gene Apc (adenomatous polyposis coli) has been associated with the development of both human and murine neoplasia, principally those of the intestinal epithelium. However, as Apc has been implicated in multiple cellular functions, the precise mechanisms underlying these associations remain somewhat unclear. I review here the use of an inducible strategy to co-ordinately delete genes from the adult murine epithelium. This approach has allowed a characterization of the direct consequences of inactivation of gene function. For Apc, these include failure in the differentiation programme, failure to migrate, aberrant proliferation and the aberrant induction of apoptosis. Transcriptome analysis of this model has also identified potential new targets for therapeutic intervention, such as Sparc (secreted protein acidic and rich in cysteine), deficiency of which, we have now shown, suppresses adenoma formation. Finally, we have been able to address how other genes modulate the consequences of Apc loss. Thus we show that there is little effect following loss of cyclin D1, Tcf-1 and p53, but that there are marked differences following loss of either c-Myc or Mbd2. The models therefore allow us to define the earliest events associated with carcinogenesis in the intestine.
Characterization of cancer stem cells in chronic myeloid leukaemia
Authors: Jørgensen H.G. , Holyoake T.L.
Published: November 2007

CML (chronic myeloid leukaemia) is a myeloproliferative disease that originates in an HSC (haemopoietic stem cell) as a result of the t(9;22) translocation, giving rise to the Ph (Philadelphia chromosome) and bcr-abl oncoprotein. The disease starts in CP (chronic phase), but as a result of genomic instability, it progresses over time to accelerated phase and then to BC (blast crisis), becoming increasingly resistant to therapy. bcr-abl is a constitutively active tyrosine kinase that has been targeted by TKIs (tyrosine kinase inhibitors), including IM (imatinib mesylate), nilotinib and dasatinib. We have developed various flow cytometry techniques to enable us to isolate candidate CML stem cells from CP patients at diagnosis that efflux Hoechst dye, express CD34, lack CD38 and are cytokine-non-responsive in culture over periods of up to 12 days in growth factors. These stem cells have been shown to regenerate bcr-abl-positive haemopoiesis in immunocompromised mice upon transplantation. We previously demonstrated that IM was antiproliferative for CML stem cells but did not induce apoptosis. Clinical experience now confirms that IM may not target CML stem cells in vivo with few patients achieving complete molecular remission and relapse occurring rapidly upon drug withdrawal. Our recent efforts have focused on understanding why CML stem cells are resistant to IM and on trying to find novel ways to induce apoptosis of this population. We have shown that CML stem cells express very high levels of functional wild-type bcr-abl; no kinase domain mutations have been detected in the stem cell population. Dasatinib, a more potent multitargeted TKI than IM, inhibits bcr-abl activity more efficiently than IM but still does not induce apoptosis of the stem cell population. Most recently, we have tested a number of novel drug combinations and found that FTIs (farnesyl transferase inhibitors) have activity against CML. BMS-214662 is the most effective of these and induces apoptosis of phenotypically and functionally defined CML stem cells in vitro, as a single agent and in combination with IM or dasatinib. The effect against CML stem cells is selective with little effect on normal stem cells. The drug is also effective against BC CML stem cells and equally effective against wild-type and mutant bcr-abl, including the most resistant mutant T315I. In association with apoptosis, there is activation of caspase 8 and caspase 3, inhibition of the MAPK pathway, IAP-1 (inhibitor of apoptosis protein-1), NF-κB (nuclear factor κB) and iNOS (inducible nitric oxide synthase). Furthermore, BMS-214662 synergizes with MEK1/2 [MAPK (mitogen-activated protein kinase)/ERK (extracellular-signal-regulated kinase) kinase 1/2] inhibitors, suggesting a second mechanism other that RAS inhibition for induction of apoptosis. Our intentions are now to explore the activity of BMS-214662 in other cancer stem cell disorders and to move this preclinical work to a clinical trial combining dasatinib with BMS-214662 in CML.
DNA replication-associated lesions: importance in early tumorigenesis and cancer therapy
Authors: Petermann E. , Helleday T.
Published: November 2007

DNA lesions resulting from impaired progression of replication forks are implicated in genetic instability and tumorigenesis. Because the cellular response to these lesions poses an important tumorigenesis barrier, the responsible signalling and repair pathways are often mutated or inactive in tumours. Here, we discuss how such deficiencies can in turn be exploited for cancer therapy.
Dietary meat, endogenous nitrosation and colorectal cancer
Authors: Kuhnle G.G.C. , Bingham S.A.
Published: November 2007

Colorectal cancer is the third most common cancer in developed countries such as the U.K., but incidence rates around the world vary approx. 20-fold. Diet is thought to be a key factor determining risk: red and processed meat, but not white meat or fish, are associated with an increased risk of colorectal cancer. The endogenous formation of N-nitroso compounds is a possible explanation because red and processed meat, but not white meat or fish, cause a dose-dependent increase in faecal ATNCs (apparent total N-nitroso compounds) and the formation of nitroso-compound-specific DNA adducts in humans. Red meat is particularly rich in haem which has been found to promote the endogenous formation of ATNC. Nitrosyl haem and nitroso thiols have been identified as major constituents of both faecal and ileal ATNC with a significant increase in the formation of these compounds following a diet rich in red meat. In vitro incubations show that, under simulated gastric conditions, nitroso thiols are the main species of nitroso compound formed, suggesting that acid-catalysed thionitrosation is the initial step in the endogenous formation of nitroso compounds. Nitrosyl haem and other nitroso compounds can then form under the alkaline and reductive conditions of the small and large bowel.
Determining the efficacy of dietary phytochemicals in cancer prevention
Authors: Manson M.M. , Foreman B.E. , Howells L.M. , Moiseeva E.P.
Published: November 2007

Accumulating data suggest that dietary phytochemicals have the potential to moderate deregulated signalling or reinstate checkpoint pathways and apoptosis in damaged cells, while having minimal impact on healthy cells. These are ideal characteristics for chemopreventive and combination anticancer strategies, warranting substantial research effort into harnessing the biological activities of these agents in disease prevention and treatment. However, this requires further investigation into their mode of action and novel approaches to the development of reliable biomarkers.
Are multiple checkpoint mediators involved in a checkpoint linking histone gene expression with DNA replication?
Authors: Müller B. , Blackburn J. , Feijoo C. , Zhao X. , Smythe C.
Published: November 2007

In metazoans, accurate replication of chromosomes is ensured by the coupling of DNA synthesis to the synthesis of histone proteins. Expression of replication-dependent histone genes is restricted to S-phase by a combination of cell cycle-regulated transcriptional and post-transcriptional control mechanisms and is linked to DNA replication by a poorly understood mechanism involving checkpoint kinases [Su, Gao, Schneider, Helt, Weiss, O'Reilly, Bohmann and Zhao (2004) EMBO J. 23, 1133–1143; Kaygun and Marzluff (2005) Nat. Struct. Mol. Biol. 12, 794–800]. Here we propose a model for the molecular mechanisms that link these two important processes within S-phase, and propose roles for multiple checkpoints in this mechanism.
O-glycan regulation of apoptosis and proliferation in colorectal cancer cell lines
Authors: Patsos G. , Robbe-Masselot C. , Klein A. , Hebbe-Viton V. , Martin R. San , Masselot D. , Graessmann M. , Paraskeva C. , Gallagher T. , Corfield A.
Published: November 2007

Cell growth pathways are mediated through protein–glycan interactions including O-glycosylation. Investigation of these growth pathways can be carried out using appropriate inhibitors to identify stage-specific events. We have adopted this approach to study a group of benzyl-O-N-acetyl-D-galactosamine analogues in human colorectal cancer cell lines. Exposure to O-glycan inhibitors resulted in the induction of apoptosis, a block in proliferation, accumulation of intracellular aryl-glycans and changes in related genes as detected by gene array. Colorectal cancer cell lines susceptible to the inhibitors showed growth arrest with all compounds. However, a differential action of each inhibitor was detected in the pattern of genes affected and in the structure of aryl-glycans formed.
Toll-like receptor 4 regulates colitis-associated adenocarcinoma development in interleukin-10-deficient (IL-10−/−) mice
Authors: Zhang R. , Li Y. , Beck P.L. , McCafferty D.-M.
Published: November 2007

Chronic inflammatory conditions such as ulcerative colitis and Crohn's disease are associated with an increased risk of developing adenocarcinoma. It has been hypothesized that this increased risk may be related to soluble mediators present in the inflammatory environment and that factors involved in exacerbating the inflammatory response could increase the risk of developing colitis-associated cancer. There is a growing body of evidence from both clinical studies and animal models which suggests that colitis occurs due to an aberrant immune response to enteric flora in genetically susceptible individuals. It is well documented that bacterial toxins such as endotoxin have potent pro-inflammatory effects through activation of TLR4 (Toll-like receptor 4) and therefore this molecule could potentially play a prominent role in the initiation/exacerbation of colitis and adenocarcinoma development. Using genetic mutant mice, we have examined the role of TLR4 in a spontaneously developing mouse model of colitis-associated adenocarcinoma: the IL-10−/− (interleukin-10-deficient) mouse. Surprisingly, our evidence suggests that the absence of TLR4 promotes colitis-associated adenocarcinoma in IL-10−/− mice. TLR4-dependent chemokine induction may play a part in modulating the development of colitis-associated neoplasia through altered leucocyte recruitment.
Combination of indomethacin and statin compared with indomethacin and placebo in patients with a first episode of acute pericarditis: preliminary findings
Authors: Di Pasquale Pietro , Cannizzaro Sergio , Fasullo Sergio , Ganci Filippo , Marenghini Giorgio , Scalzo Sebastiano , Giambanco Francesco , Vitale Giuseppe , Polizzi Giovanni , Paterna Salvatore
Published: November 2007

The aim of the present study was to evaluate the safety and efficacy of the combination of indomethacin and statin compared with indomethacin plus placebo in patients with a first episode of pericarditis. A total of 55 consecutive patients with acute pericarditis were randomized in a double-blind manner into two groups: group 1 (statin group) was treated with 150 mg of indomethacin plus 10 mg of rosuvastatin, and group 2 (placebo group) was treated with 150 mg of indomethacin plus placebo. Both groups received treatment up to the normalization of inflammation markers and for the following week. Clinical and laboratory assessments [white cell count, ESR (erythrocyte sedimentation rate) and CRP (C-reactive protein), troponin I, creatine kinase and brain natriuretic peptide plasma levels], ECG and echocardiogram were performed at baseline and daily up to discharge. All of the patients were followed as outpatients for 3 months to evaluate any recurrence of pericarditis. The two groups were similar in age, sex and laboratory parameters [group 1 (the statin group), n=28 patients; gender, 18 male and ten female; and age, 29.5±5.7 years; group 2 (placebo group), n=27 patients; gender, 16 male/11 female; and age, 29.2±4.8 years]. The statin group, when compared with the placebo group, had a significantly faster reduction in CRP values (5.0±1.0 compared with 6.0±2.0 days respectively; P=0.022), ST segment normalization (3.5±1.0 compared with 4.5±1.0 days respectively; P=0.001), pericardial effusion (4.5±1.0 compared with 5.5±1.0 days respectively; P=0.001) and ESR (5.0±1 compared with 6.0±2 days respectively; P=0.022). Our results show that the combination of statin and indomethacin treatment in patients with acute pericarditis is feasible, with a significant reduction in inflammatory markers and a favourable trend in hospitalization time (5.5±2.0 compared with 6.5±2.0 days respectively; P=0.069). However, these preliminary findings require further studies in a larger sample of patients.
Reduced body mass index is associated with increased angiotensin II in young women with postural tachycardia syndrome
Authors: Stewart Julian M. , Taneja Indu , Medow Marvin S.
Published: November 2007

Altered peripheral haemodynamics, decreased cardiac output, decreased blood volume and increased AngII (angiotensin II) have been reported in POTS (postural tachycardia syndrome). Recent findings indicate that BMI (body mass index) may be reduced. In the present study, we investigated the hypothesis that reduced BMI is associated with haemodynamic abnormalities in POTS and that this is related to AngII. We studied 52 patients with POTS, aged 14–29 years, compared with 36 control subjects, aged 14–27 years. BMI was not significantly reduced on average in the POTS patients, but was reduced in patients with decreased peripheral blood flow. POTS patients were then subdivided on the basis of BMI, and supine haemodynamics were measured. There was no difference in blood volume or cardiac output once BMI or body mass were accounted for. When POTS patients with BMI <50th percentile were compared with controls, calf blood flow [1.63±0.31 compared with 3.58±0.67 ml−1·min−1·(100 ml of tissue)−1] and maximum venous capacity (3.87±0.32 compared with 4.98±0.36 ml/100 ml of tissue) were decreased, whereas arterial resistance [56±0.5 compared with 30±4 mmHg·ml−1·min−1·(100 ml of tissue)−1] and venous resistance [1.23±0.17 compared with 0.79±0.11 mmHg·ml−1·min−1·(100 ml of tissue)−1] were increased. Similar findings were also observed when POTS patients with BMI <50th percentile were compared with POTS patients with BMI >50th percentile. There was no relationship between blood flow, resistance or maximum venous capacity with BMI in control subjects. BMI was inversely related to plasma AngII concentrations in those POTS patients with decreased peripheral blood flow, consistent with cachectic properties of the octapeptide. Patients with low-flow POTS had decreased body mass, but decreased body mass alone cannot account for findings of peripheral vasoconstriction. In conclusion, the findings suggest that reduced body mass relates to increased plasma AngII.
New ab initio potential energy surfaces for the F+H2 reaction
Authors: Li Guoliang , Werner Hans-Joachim , Lique François , Alexander Millard H.
Published: November 2007

We present the results of new ab initio calculations of the three FH2 potential energy surfaces (PESs) which are necessary for a complete description of the F+H2 reaction. These are the result of high-precision multireference configuration-interaction calculations, with an additional scaling of the external correlation energy. The results of these calculations have been fitted to a multiparameter form for use in subsequent quantum scattering calculations. With a scaling factor of s=1.078, the calculated exoergicity agrees nearly exactly with experimentally determined values. With a slightly reduced scaling factor of s=1.05, the fitted PESs give excellent agreement with the position and modulation depth of the F+HD→FH+D transition state resonance observed by Skodje et al. [J. Chem. Phys. 112, 4536 (2000)]. This suggests that these new PESs can be used with confidence in the simulation of the reactivity of the ground and excited spin-orbit states of the F atom in reactions with H2.
Modeling the nonlinear large deformation kinetics of volume phase transition for the neutral thermosensitive hydrogels
Authors: Wang Xiaogui
Published: November 2007

By regarding the neutral thermosensitive hydrogel as a biphasic mixture media, an incompressible deformable porous solid skeleton, and an incompressible interstitial fluid phase saturating the interconnected space, a novel biphasic mixture theory for modeling the nonlinear large deformation kinetics of the volume phase transition was developed from the first law of thermodynamics and the continuum mixture theory. The governing equations consist of the saturated continuity equation, the momentum equations of the fluid, and the momentum equations of the bulk hydrogel. The explicit expressions of the constitutive relationships, which are capable of characterizing the nonlinear large deformation kinetics of the volume phase transition of the N-isopropylacrylamide thermosensitive hydrogels, were derived from the Helmholtz free energy formed by the elastic and mixing contributions. Both the governing equations and the constitutive relationships are in the Lagrangian framework, and special attention was paid to the deformable porous solid skeleton.
Nearest-neighbor oxygen distances in liquid water and ice observed by x-ray Raman based extended x-ray absorption fine structure
Authors: Bergmann Uwe , Di Cicco Andrea , Wernet Philippe , Principi Emiliano , Glatzel Pieter , Nilsson Anders
Published: November 2007

We report the nearest-neighbor oxygen-oxygen radial distribution function (NN O–O RDF) of room temperature liquid water and polycrystalline ice Ih (−16.8°C) obtained by x-ray Raman based extended x-ray absorption fine structure (EXAFS) spectroscopy. The spectra of the two systems were taken under identical experimental conditions using the same procedures to obtain the NN O–O RDFs. This protocol ensured a measurement of the relative distance distribution with very small systematic errors. The NN O–O RDF of water is found to be more asymmetric (tail extending to longer distances) with longer average distance (2.81Å for water and 2.76Å for ice) but a slightly shorter peak position (2.70Å for water and 2.71Å for ice). The refinement also showed a small but significant contribution from the linear O–H–O multiple scattering signal. The high sensitivity to short range distances of the EXAFS probe will set further restrictions to the range of possible models of liquid water.
A spherical model with directional interactions. I. Static properties
Authors: Zaccarelli Emanuela , Sciortino Francesco , Tartaglia Piero
Published: November 2007

We introduce a simple spherical model whose structural properties are similar to the ones generated by models with directional interactions, by employing a binary mixture of large and small hard spheres, with a square-well attraction acting only between particles of different sizes. The small particles provide the bonds between the large ones. With a proper choice of the interaction parameters, as well as of the relative concentration of the two species, it is possible to control the effective valence. Here we focus on a specific choice of the parameters which favors tetrahedral ordering and study the equilibrium static properties of the system in a large window of densities and temperatures. Upon lowering the temperature we observe a progressive increase in local order, accompanied by the formation of a four-coordinated network of bonds. Three different density regions are observed: At low density the system phase separates into a gas and a liquid phase; at intermediate densities a network of fully bonded particles develops; at high densities—due to the competition between excluded volume and attractive interactions—the system forms a defective network. The very same behavior has been previously observed in numerical studies of nonspherical models for molecular liquids, such as water, and in models of patchy colloidal particles. Different from these models, theoretical treatments devised for spherical potentials, e.g., integral equations and ideal mode coupling theory for the glass transition, can be applied in the present case, opening the way for a deeper understanding of the thermodynamic and dynamic behavior of low valence molecules and particles.