bluuebunny/crossref_metadata_2025 huggingface dataset:
Na+-Dependent Sources of Intra-Axonal Ca2+Release in Rat Optic Nerve duringIn VitroChemical Ischemia
Authors: Nikolaeva Maria A. , Mukherjee Ballari , Stys Peter K.
Published: October 2005

The contribution of intracellular stores to axonal Ca2+overload during chemical ischemiain vitrowas examined by confocal microscopy. Ca2+accumulation was measured by fluo-4 dextran (low-affinity dye,KD≈ 4 μm) or by Oregon Green 488 BAPTA-1 dextran (highaffinity dye,KD≈ 450 nm). Axonal Na+was measured using CoroNa Green. Ischemia in CSF containing 2 mmCa2+caused an ∼3.5-fold increase in fluo-4 emission after 30 min, indicating a large axonal Ca2+rise well into the micromolar range. Axonal Na+accumulation was enhanced by veratridine and reduced, but not abolished, by TTX. Ischemia in Ca2+-free (plus BAPTA) perfusate resulted in a smaller but consistent Ca2+increase monitored by Oregon Green 488 BAPTA-1, indicating release from intracellular sources. This release was eliminated in large part when Na+influx was reduced by replacement withN-methyl-d-glucamine (NMDG+; even in depolarizing high K+perfusate), Li+, or by the application of TTX and significantly increased by veratridine. Intracellular release also was reduced significantly by neomycin or 1-(6-[(17β-methoxyestra-1,3,5 [10]-trien-17-yl) amino] hexyl)-1H-pyrrole-2,5-dione ( U73122) (phospholipase C inhibitors), heparin [inositol trisphosphate (IP3) receptor blocker], or 7-chloro-5-(2-chlorophenyl)-1,5-dihydro-4,1-benzothiazepin-2(3H)-one (CGP37157; mitochondrial Na+/Ca2+exchange inhibitor) as well as ryanodine. CombiningCGP37157with  U73122 or heparin decreased the response more than either agent alone and significantly improved electrophysiological recovery. Our conclusion is that intra-axonal Ca2+release during ischemia in rat optic nerve is mainly dependent on Na+influx. This Na+accumulation stimulates three distinct intra-axonal sources of Ca2+: (1) the mitochondrial Na+/Ca2+exchanger driven in the Na+import/Ca2+export mode, (2) positive modulation of ryanodine receptors, and (3) promotion of IP3generation by phospholipase C.
Cooperative Glutamatergic and Cholinergic Mechanisms Generate Short-Term Modifications of Synaptic Effectiveness in Prepositus Hypoglossi Neurons
Authors: de Dios Navarro-López Juan , Delgado-García José M. , Yajeya Javier
Published: October 2005

To maintain horizontal eye position on a visual target after a saccade, extraocular motoneurons need a persistent (tonic) neural activity, called “eye-position signal,” generated by prepositus hypoglossi (PH) neurons. We have shown previouslyin vitroandin vivothat this neural activity depends, among others mechanisms, on the interplay of glutamatergic transmission and cholinergic synaptically triggered depolarization. Here, we used rat sagittal brainstem slices, including PH nucleus and paramedian pontine reticular formation (PPRF). We made intracellular recordings of PH neurons and studied their synaptic activation from PPRF neurons. Train stimulation of the PPRF area evoked a cholinergic-sustained depolarization of PH neurons that outlasted the stimulus. EPSPs evoked in PH neurons by single pulses applied to the PPRF presented a short-term potentiation (STP) after train stimulation. APV (an NMDA-receptor blocker) or chelerythrine (a protein kinase-C inhibitor) had no effect on the sustained depolarization, but they did block the evoked STP, whereas pirenzepine (an M1muscarinic antagonist) blocked both the sustained depolarization and the STP of PH neurons. Thus, electrical stimulation of the PPRF area activates both glutamatergic and cholinergic axons terminating in the PH nucleus, the latter producing a sustained depolarization probably involved in the genesis of the persistent neural activity required for eye fixation. M1-receptor activation seems to evoke a STP of PH neurons via NMDA receptors. Such STP could be needed for the stabilization of the neural network involved in the generation of position signals necessary for eye fixation after a saccade.
The Temporal Impulse Response Underlying Saccadic Decisions
Authors: Ludwig Casimir J. H. , Gilchrist Iain D. , McSorley Eugene , Baddeley Roland J.
Published: October 2005

Models of perceptual decision making often assume that sensory evidence is accumulated over time in favor of the various possible decisions, until the evidence in favor of one of them outweighs the evidence for the others. Saccadic eye movements are among the most frequent perceptual decisions that the human brain performs. We used stochastic visual stimuli to identify the temporal impulse response underlying saccadic eye movement decisions. Observers performed a contrast search task, with temporal variability in the visual signals. In experiment 1, we derived the temporal filter observers used to integrate the visual information. The integration window was restricted to the first ∼100 ms after display onset. In experiment 2, we showed that observers cannot perform the task if there is no useful information to distinguish the target from the distractor within this time epoch. We conclude that (1) observers did not integrate sensory evidence up to a criterion level, (2) observers did not integrate visual information up to the start of the saccadic dead time, and (3) variability in saccade latency does not correspond to variability in the visual integration period. Instead, our results support a temporal filter model of saccadic decision making. The temporal impulse response identified by our methods corresponds well with estimates of integration times of V1 output neurons.
Brainstem Timing: Implications for Cortical Processing and Literacy
Authors: Banai Karen , Nicol Trent , Zecker Steven G. , Kraus Nina
Published: October 2005

The search for a unique biological marker of language-based learning disabilities has so far yielded inconclusive findings. Previous studies have shown a plethora of auditory processing deficits in learning disabilities at both the perceptual and physiological levels. In this study, we investigated the association among brainstem timing, cortical processing of stimulus differences, and literacy skills. To that end, brainstem timing and cortical sensitivity to acoustic change [mismatch negativity (MMN)] were measured in a group of children with learning disabilities and normal-learning children. The learning-disabled (LD) group was further divided into two subgroups with normal and abnormal brainstem timing. MMNs, literacy, and cognitive abilities were compared among the three groups. LD individuals with abnormal brainstem timing were more likely to show reduced processing of acoustic change at the cortical level compared with both normal-learning individuals and LD individuals with normal brainstem timing. This group was also characterized by a more severe form of learning disability manifested by poorer reading, listening comprehension, and general cognitive ability. We conclude that abnormal brainstem timing in learning disabilities is related to higher incidence of reduced cortical sensitivity to acoustic change and to deficient literacy skills. These findings suggest that abnormal brainstem timing may serve as a reliable marker of a subgroup of individuals with learning disabilities. They also suggest that faulty mechanisms of neural timing at the brainstem may be the biological basis of malfunction in this group.
Postsynaptically Synthesized Prostaglandin E2 (PGE2) Modulates Hippocampal Synaptic Transmission via a Presynaptic PGE2 EP2 Receptor
Authors: Sang Nan , Zhang Jian , Marcheselli Victor , Bazan Nicolas G. , Chen Chu
Published: October 2005

Increasing evidence suggests that cyclooxygenase-2 (COX-2) is involved in synaptic transmission and plasticity, and prostaglandin E2 (PGE2) is a key molecule in COX-2-meduated synaptic modification. However, the precise mechanisms, in particular, which subtypes of PGE2 receptors (EPs) mediate the PGE2-induced synaptic response, are not clear. Recently, we demonstrated that EPs are expressed heterogeneously in the hippocampus, and EP2/4 are mainly expressed in presynaptic terminals. Here, we report that PGE2 increased synaptic stimulus-evoked amplitudes of EPSPs in hippocampal slices and frequency of miniature EPSCs (mEPSCs) in hippocampal neurons in culture. These actions were mimicked by an EP2 agonist and attenuated by protein kinase A inhibitors. Decrease of EP2 expression through silencing the EP2 gene eliminated PGE2-induced increase of the frequency of mEPSCs. COX-2 and microsomal PGE synthase-1 (mPGES-1) and mPGES-2 are present in postsynaptic dendritic spines, because they are colocalized with PSD-95 (postsynaptic density-95), a postsynaptic marker. In addition, the frequency of mEPSCs was enhanced in neurons pretreated with interleukin-1β or lipopolysaccharide, which elevated expression of COX-2 and mPGES-1 and produced PGE2, and this enhancement was inhibited by a COX-2 inhibitor that inhibited production of PGE2. Our results suggest that PGE2 synthesized by postsynaptically localized COX-2 functions as a retrograde messenger in hippocampal synaptic signaling via a presynaptic EP2 receptor.
Protease-Activated Receptor-1 and Platelet-Derived Growth Factor in Spinal Cord Neurons Are Implicated in Neuropathic Pain after Nerve Injury
Authors: Narita Minoru , Usui Aiko , Narita Michiko , Niikura Keiichi , Nozaki Hiroyuki , Khotib Junaidi , Nagumo Yasuyuki , Yajima Yoshinori , Suzuki Tsutomu
Published: October 2005

Recently, it has been reported that both thrombin-sensitive protease-activated receptor 1 (PAR-1) and platelet-derived growth factor (PDGF) are present not only in platelets, but also in the CNS, which indicates that they have various physiological functions. In this study, we evaluated whether PAR-1/PDGF in the spinal cord could contribute to the development of a neuropathic pain-like state in mice. Thermal hyperalgesia and tactile allodynia induced by sciatic nerve ligation were significantly suppressed by repeated intrathecal injection of hirudin, which is characterized as a specific and potent thrombin inhibitor. Furthermore, a single intrathecal injection of thrombin produced long-lasting hyperalgesia and allodynia, and these effects were also inhibited by hirudin in normal mice. In nerveligated mice, the increase in the binding of [35S]GTPγS to membranes of the spinal cord induced by thrombin and PAR-1-like immunoreactivity (IR) in the spinal cord were each greater than those in sham-operated mice. Thermal hyperalgesia and tactile allodynia induced by sciatic nerve ligation were also suppressed by repeated intrathecal injection of either the PDGF α receptor (PDGFRα)/Fc chimera protein or the PDGFR-dependent tyrosine kinase inhibitor AG17 [(3,5-di-tert-butyl-4-hydroxybenzylidene)-malononitrile]. Moreover, thermal hyperalgesia and tactile allodynia induced by thrombin in normal mice were virtually eliminated by intrathecal pretreatment with PDGFRα/Fc. In immunohistochemical studies, PAR-1-like IR-positive cells in the spinal dorsal horn were mostly colocated on PDGF-like IR-positive neuronal cells. These data provide novel evidence that PAR-1 and PDGF-A-mediated signaling pathway within spinal cord neurons may be directly implicated in neuropathic pain after nerve injury in mice.
Multiple and Plastic Receptors Mediate Tonic GABAAReceptor Currents in the Hippocampus
Authors: Scimemi Annalisa , Semyanov Alexey , Sperk Günther , Kullmann Dimitri M. , Walker Matthew C.
Published: October 2005

Persistent activation of GABAAreceptors by extracellular GABA (tonic inhibition) plays a critical role in signal processing and network excitability in the brain. In hippocampal principal cells, tonic inhibition has been reported to be mediated by α5-subunit-containing GABAAreceptors (α5GABAARs). Pharmacological or genetic disruption of these receptors improves cognitive performance, suggesting that tonic inhibition has an adverse effect on information processing. Here, we show that α5GABAARs contribute to tonic currents in pyramidal cells only when ambient GABA concentrations increase (as may occur during increased brain activity). At low ambient GABA concentrations, activation of δ-subunit-containing GABAAreceptors predominates. In epileptic tissue, α5GABAARs are downregulated and no longer contribute to tonic currents under conditions of raised extracellular GABA concentrations. Under these conditions, however, the tonic current is greater in pyramidal cells from epileptic tissue than in pyramidal cells from nonepileptic tissue, implying substitution of α5GABAARs by other GABAAreceptor subtypes. These results reveal multiple components of tonic GABAAreceptor-mediated conductance that are activated by low GABA concentrations. The relative contribution of these components changes after the induction of epilepsy, implying an adaptive plasticity of the tonic current in the presence of spontaneous seizures.
Identification of Nicotinic Acetylcholine Receptor Recycling and Its Role in Maintaining Receptor Density at the Neuromuscular JunctionIn Vivo
Authors: Bruneau Emile , Sutter David , Hume Richard I. , Akaaboune Mohammed
Published: October 2005

In the CNS, receptor recycling is critical for synaptic plasticity; however, the recycling of receptors has never been observed at peripheral synapses. Using a novel imaging technique, we show here that nicotinic acetylcholine receptors (AChRs) recycle into the postsynaptic membrane of the neuromuscular junction. By sequentially labeling AChRs with biotin-bungarotoxin and streptavidin-fluorophore conjugates, we were able to distinguish recycled, preexisting, and new receptor pools at synapses in living mice. Time-lapse imaging revealed that recycled AChRs were incorporated into the synapse within hours of initial labeling, and their numbers increased with time. At fully functional synapses, AChR recycling was robust and comparable in magnitude with the insertion of newly synthesized receptors, whereas chronic synaptic activity blockade nearly abolished receptor recycling. Finally, using the same sequential labeling method, we found that acetylcholinesterase, another synaptic component, does not recycle. These results identify an activity-dependent AChR-recycling mechanism that enables the regulation of receptor density, which could lead to rapid alterations in synaptic efficacy.
Tracking the Fear Engram: The Lateral Amygdala Is an Essential Locus of Fear Memory Storage
Authors: Schafe Glenn E. , Doyère Valérie , LeDoux Joseph E.
Published: October 2005

Although it is believed that different types of memories are localized in discreet regions of the brain, concrete experimental evidence of the existence of such engrams is often elusive. Despite being one of the best characterized memory systems of the brain, the question of where fear memories are localized in the brain remains a hotly debated issue. Here, we combine site-specific behavioral pharmacology with multisite electrophysiological recording techniques to show that the lateral nucleus of the amygdala, long thought to be critical for the acquisition of fear memories, is also an essential locus of fear memory storage.
Dysfunction of the Cholesterol Biosynthetic Pathway in Huntington's Disease
Authors: Valenza Marta , Rigamonti Dorotea , Goffredo Donato , Zuccato Chiara , Fenu Simone , Jamot Laure , Strand Andrew , Tarditi Alessia , Woodman Ben , Racchi Marco , Mariotti Caterina , Di Donato Stefano , Corsini Alberto , Bates Gillian , Pruss Rebecca , Olson James M. , Sipione Simonetta , Tartari Marzia , Cattaneo Elena
Published: October 2005

The expansion of a polyglutamine tract in the ubiquitously expressed huntingtin protein causes Huntington's disease (HD), a dominantly inherited neurodegenerative disease. We show that the activity of the cholesterol biosynthetic pathway is altered in HD. In particular, the transcription of key genes of the cholesterol biosynthetic pathway is severely affectedin vivoin brain tissue from HD mice and in human postmortem striatal and cortical tissue; this molecular dysfunction is biologically relevant because cholesterol biosynthesis is reduced in cultured human HD cells, and total cholesterol mass is significantly decreased in the CNS of HD mice and in brain-derived ST14A cells in which the expression of mutant huntingtin has been turned on. The transcription of the genes of the cholesterol biosynthetic pathway is regulated via the activity of sterol regulatory element-binding proteins (SREBPs), and we found an ∼50% reduction in the amount of the active nuclear form of SREBP in HD cells and mouse brain tissue. As a consequence, mutant huntingtin reduces the transactivation of an SRE-luciferase construct even under conditions of SREBP overexpression or in the presence of an exogenous N-terminal active form of SREBP. Finally, the addition of exogenous cholesterol to striatal neurons expressing mutant huntingtin prevents their death in a dose-dependent manner. We conclude that the cholesterol biosynthetic pathway is impaired in HD cells, mice, and human subjects, and that the search for HD therapies should also consider cholesterol levels as both a potential target and disease biomarker.
Vascular Development of the Brain Requires β8 Integrin Expression in the Neuroepithelium
Authors: Proctor John M. , Zang Keling , Wang Denan , Wang Rong , Reichardt Louis F.
Published: October 2005

We showed previously that loss of the integrin β8 subunit, which forms αvβ8 heterodimers, results in abnormal vascular development in the yolk sac, placenta, and brain. Animals lacking the integrin β8 (itgβ8) gene die either at midgestation, because of insufficient vascularization of the placenta and yolk sac, or shortly after birth with severe intracerebral hemorrhage. To specifically focus on the role of integrins containing the β8 subunit in the brain, and to avoid early lethalities, we used a targeted deletion strategy to deleteitgβ8only from cell types within the brain. Ablatingitgβ8from vascular endothelial cells or from migrating neurons did not result in cerebral hemorrhage. Targeted deletion ofitgβ8from the neuroepithelium, however, resulted in bilateral hemorrhage at postnatal day 0, although the phenotype was less severe than initgβ8-null animals. Newborn mice lackingitgβ8from the neuroepithelium had hemorrhages in the cortex, ganglionic eminence, and thalamus, as well as abnormal vascular morphogenesis, and disorganized glia. Interestingly, adult mice lackingitgβ8from cells derived from the neuroepithelium did not show signs of hemorrhage. We propose that defective association between vascular endothelial cells and glia lackingitgβ8is responsible for the leaky vasculature seen during development but that an unidentified compensatory mechanism repairs the vasculature after birth.
Casting Platinum Jewellery Alloys
Authors: Miller Duncan , Keraan Tauriq , Park-Ross Penny , Husemeyer Victoria , Brey Ali , Khan Irshad , Lang Candy
Published: October 2005

Comparisons are made between platinum-copper and platinum-ruthenium alloys used for jewellery to evaluate the effects of casting variables. The effects of flask temperatures, investments, and centrifugal speeds on microstructure, percentage fill, and porosity were examined over a range
of temperatures. Optimum conditions and materials for successful casting of high quality platinum jewellery alloys, using a Hot Platinum induction melting and casting machine, are described. Suitable choice of investment materials and rotational speeds produced good grid fills with Pt-5%Cu
and Pt-5%Ru alloys. Metal porosity was more difficult to control, due to the inherently chaotic nature of the casting process, but casting into a relatively cool mould minimised the probability of bad porosity for both alloys. Pt-5%Ru was found to be successful as a casting alloy when used
with induction melting technology. It displayed superior uniformity, hardness and colour, compared with cast Pt-5%Cu alloy.
Ruthenium Complexes Bearing N-Heterocyclic Carbene (NHC) Ligands
Authors: Dragutan Valerian , Dragutan Ileana , Demonceau Albert
Published: October 2005

A review of recently published aspects on ruthenium complexes with nucleophilic N-heterocyclic carbene (NHC) ligands is presented here, in continuation of a paper published in the July issue of this Journal, that covered initial work and subsequent main developments in this chemistry.
In Part II selected applications of these complexes as pre-catalysts in metathesis reactions are highlighted. Particular attention is paid to metathesis in room temperature ionic liquids as the solvents, asymmetric catalysis, and in situ generated, very active catalytic systems based on NHC-platinum
group metals. Most NHC-platinum group metal complexes are useful as highly active and selective pre-catalysts for fundamental chemical transformations.
Ruthenium-Catalysed Asymmetric Reduction of Ketones
Authors: Zanotti-Gerosa Antonio , Hems William , Groarke Michelle , Hancock Fred
Published: October 2005

The asymmetric reduction of carbonyl, C=O, groups for the production of enantiomerically pure secondary alcohols is a reaction of fundamental importance in modern synthetic chemistry. This reaction can be performed in a number of ways. Asymmetric chemocatalysis (1) and the often complementary
biocatalysis offer solutions to the stereoselective reduction of C=O groups. These two techniques have found wide industrial application (2). In the mid 1990s, two new ruthenium systems based on dihydrogen or transfer hydrogenation for asymmetric reduction of prochiral ketones were developed
by Professors Noyori and Ikariya. These systems enable catalytic asymmetric reduction to provide a route for the generation of enantiomerically pure secondary alcohols in a highly efficient, simple and economic way (3). This paper describes some robust and cost-effective chemocatalytic technology
for asymmetric ketone reduction, using ruthenium catalysts with diphosphine ligands.
Cartilage-Derived Stromal Cells: Is It a Novel Cell Resource for Cell Therapy to Regenerate Infarcted Myocardium?
Authors: Su Wenjun , Zhang Hao , Jia Zhuqing , Zhou Chunyan , Wei Yingjie , Hu Shengshou
Published: October 2005

Human cartilage is reported to contain multipotent stromal cells. We evaluated the effect of human cartilage-derived stromal cells (CDSCs) on heart function when transplanted into the infarcted myocardium of rats. CDSCs were isolated and cultured from human articular cartilage and subjected to fluorescence-activated cell sorting (FACS) analysis. The CDSCs were consistently negative for CD14, CD34, CD38, CD45, CD49f, CD104, CD105, CD106, CD117, HLA-DR, and ABCG-2, and positive for CD10, CD44, CD71, CD73, CD90, CD147, and HLA-A, -B, and -C by FACS analysis. Myocardial infarction (MI) was created in rats by ligation of the left anterior descending artery. Three weeks after MI, the CDSCs labeled with Hoechst stain were injected into the infarct and border zone. Echocardiography, histological examination, and reverse transcription-polymerase chain reaction (RT-PCR) were performed 4 weeks after cell transplantation. Echocardiography indicated that CDSC transplantation could improve heart function. The number of capillaries increased in the injection regions in the transplantation group. Histological examination showed that Hoechst-labeled CDSCs in islands within the infarcted region were stained positively for desmin and smooth muscle actin but negatively for alpha-sarcomeric actin and troponin-I. RT-PCR results indicated the expression level of collagen I, collagen III, tissue inhibitor of metalloproteinase-1, transforming growth factor-β1, and vascular endothelia growth factor were much higher in the scar tissue in the transplantation group than in the medium and control groups. Our findings suggested that CDSCs might promote angiogenesis, prevent left ventricular remodeling, and improve the heart function when transplanted into injured heart in the rat model of myocardial infarction.
Cell Cycle Features of Primate Embryonic Stem Cells
Authors: Fluckiger Anne-Catherine , Marcy Guillaume , Marchand Mélanie , Négre Didier , Cosset François-Loïc , Mitalipov Shoukhrat , Wolf Don , Savatier Pierre , Dehay Colette
Published: October 2005

Using flow cytometry measurements combined with quantitative analysis of cell cycle kinetics, we show that rhesus monkey embryonic stem cells (ESCs) are characterized by an extremely rapid transit through the G1 phase, which accounts for 15% of the total cell cycle duration. Monkey ESCs exhibit a non-phasic expression of cyclin E, which is detected during all phases of the cell cycle, and do not growth-arrest in G1 after γ-irradiation, reflecting the absence of a G1 checkpoint. Serum deprivation or pharmacological inhibition of mitogen-activated protein kinase kinase (MEK) did not result in any alteration in the cell cycle distribution, indicating that ESC growth does not rely on mitogenic signals transduced by the Ras/Raf/MEK pathway. Taken together, these data indicate that rhesus monkey ESCs, like their murine counterparts, exhibit unusual cell cycle features in which cell cycle control mechanisms operating during the G1 phase are reduced or absent.
Characterization of a Side Population of Cancer Cells from Human Gastrointestinal System
Authors: Haraguchi Naotsugu , Utsunomiya Tohru , Inoue Hiroshi , Tanaka Fumiaki , Mimori Koshi , Barnard Graham F. , Mori Masaki
Published: October 2005

A subset of stem cells, termed “side population” (SP) cells, has been identified and characterized in several mammalian tissues and cell lines. However, SP cells have never been identified or isolated from gastrointestinal cancers. We used flow cytometry and the DNA-binding dye Hoechst 33342 to isolate SP cells from various human gastrointestinal system cancer cell lines. Fifteen of sixteen cancer cell lines from the gastrointestinal system contained 0.3%–2.2% SP cells. Next, we used an oligonucleotide microarray to analyze differentially expressed genes between SP and non-SP cells of hepatoma HuH7. The expression of GATA6, which is associated with embryonic development and hepatocytic differentiation, was significantly upregulated in HuH7 SP cells. The expression of ABCG2, ABCB1, and CEACAM6, which are associated with chemoresistance, was also significantly increased in SP cells. In addition, some epithelial markers and mesenchymal markers were overexpressed in SP cells. Reverse transcription-polymerase chain reaction and immunocytochemical staining validated these results and suggested a multilineage potential for HuH7 SP cells. In hepatoma HuH7 and colorectal SW480 cell lines, SP cells showed evidence for self-renewal, generating both SP and non-SP cells. Finally, chemoresistance to anticancer agents, including doxorubicin, 5-fluorouracil, and gemcitabine, were compared between HuH7 SP and non-SP cells using an ATP bioluminescence assay. The HuH7 SP cells expressed a higher resistance to doxorubicin, 5-fluorouracil, and gemcitabine compared with non-SP cells. These findings demonstrate that cancers of the gastrointestinal system do contain SP cells that show some characteristics of so-called stem cells.
Weekly Administration of Docetaxel and Paclitaxel in Metastatic or Advanced Breast Cancer
Authors: Eniu Alexandru , Palmieri Frances M. , Perez Edith A.
Published: October 2005

Learning Objectives

After completing this course, the reader will be able to: Identify the response rates to weekly paclitaxel and docetaxel for metastatic breast cancer.Name the recommended doses of each taxane when administered weekly.Learn schemas of phase III adjuvant trials incorporating weekly taxanes.

Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit at CME.TheOncologist.com

The taxanes docetaxel (Taxotere®; Aventis Pharmaceuticals Inc., Bridgewater, NJ, http://www.aventispharma-us.com) and paclitaxel (Taxol®; Bristol-Myers Squibb, Princeton, NJ, http://www.bms.com) have significant clinical activity in metastatic breast cancer. A number of clinical trials have evaluated the tolerability and efficacy of weekly taxane administration to optimize the benefit-to-risk ratio in metastatic breast cancer. Single-agent studies with docetaxel and paclitaxel in metastatic breast cancer show clinically significant antitumor activity even in advanced, heavily pretreated, resistant, and/or refractory disease. This activity is also evident with taxane-based combination regimens. Severe hematologic and nonhematologic toxicities are infrequent, with other toxicities noted based on the dose and weekly regimen selected. Weekly docetaxel and paclitaxel regimens represent valuable therapeutic options for women with metastatic breast cancer and have entered evaluation as part of adjuvant therapy for this disease.
Topotecan as Second-Line Therapy for Ovarian Cancer: Dosage Versus Toxicity
Authors: Markman Maurie
Published: October 2005

In this issue of The Oncologist, Armstrong et al. present an analysis of the use of topotecan (Hycamtin®; GlaxoSmithKline, Philadelphia, http://www.gsk.com) in the second-line treatment of both ovarian cancer and small cell carcinoma of the lung. This cytotoxic agent has clearly been demonstrated to be a useful drug in a population of patients with both of these conditions. However, the description of the nature of the toxicity, as stated in the manuscript, must be questioned along with comments made regarding the relative toxicity of alternative cytotoxic agents frequently used in similar settings. The purpose of this discussion absolutely is not to negate the unquestioned, demonstrated usefulness of topotecan as second-line therapy in ovarian cancer but rather to point out that the U.S. Food and Drug Administration–approved dose level of 1.5 mg/m2 per day × 5 days can cause substantial and highly clinically relevant bone marrow toxicity. Whether this toxicity, which can result in a level of fatigue that may cause responding patients to discontinue treatment, should simply be labeled “excessive” rather than “cumulative” appears to be a matter of semantics rather than an important distinction. Whether delivery of a lower dose of topotecan (1 mg/m2–1.25 mg/m2 per day × 5 days) will essentially eliminate concern for the development of severe clinically relevant marrow toxicity is uncertain, but the risk will certainly be substantially reduced.
Topotecan: Weighing in When There Are Many Options
Authors: Penson Richard T. , Seiden Michael V.
Published: October 2005

The manuscript by Armstrong et al. in this issue of The Oncologist, reviewing the toxicity and efficacy of full-dose topotecan delivered as second-line therapy in individuals with small cell lung cancer or ovarian cancer, will likely serve as both the most comprehensive and the final review of this active agent delivered at the U.S. Food and Drug Administration–approved dosage and schedule. The review represents large, relative lyhomogeneous patient populations with prior platinum exposure and convincingly describes topotecan as an agent with activity that is comparable with those of all other approved drugs in this setting and a well-defined and relatively circumscribed set of toxicities. While the activity of topotecan in small cell carcinoma provides individuals with the hope for further palliation at the time of tumor recurrence, as discussed by Dr. Markman in this issue, the best use of this agent in the management of recurrent ovarian cancer is far from clear because, in part, of a growing list of approved active agents, most notably liposomal doxorubicin, gemcitabine, and weekly paclitaxel; a return to platinum; or a host of other agents such as vinorelbine, altretamine, irinotecan, docetaxel, etoposide, and others. The most pressing need is to accept that palliative therapies are designed to palliate and improve symptoms, and to move away from end points of radiologic and marker response to a focus on “clinical benefit” and clinically more meaningful end points.
Antibody-Based Therapies for Colorectal Cancer
Authors: Chung Ki Young , Saltz Leonard B.
Published: October 2005

Learning Objectives

After completing this course, the reader will be able to: Select the appropriate clinical use of cetuximab and bevacizumab in the treatment of metastatic colorectal cancer based on the currently available clinical trial data and known toxicities of each agent.Discuss the controversy over EGFR testing in colorectal cancer patients and the lack of predictive value of EGFR expression by IHC.List the relevant clinical questions regarding the use of targeted agents in colorectal cancer that remain to be addressed by clinical trials.

Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit at CME.TheOncologist.com

The recent successful development of novel monoclonal antibodies that target key components of biologic pathways has expanded the armamentarium of treatment options for patients with colorectal cancer. Two targets in particular–the process of new blood vessel development, or angiogenesis, and the epidermal growth factor receptor and its signaling pathway–are exploited by the newest monoclonal antibodies that are available for use in colorectal cancer patients. This clinical review focuses on the defining role of the two most clinically advanced novel agents, bevacizumab (Avastin®; Genentech, Inc., South San Francisco, CA, http://www.gene.com) and cetuximab (Erbitux®; ImClone Systems, Inc., New York, http://www.imclone.com), in colorectal cancer.
Combined Therapy with Weekly Irinotecan, Infusional 5-Fluorouracil and the Selective COX-2 Inhibitor Rofecoxib Is a Safe and Effective Second-Line Treatment in Metastatic Colorectal Cancer
Authors: Gasparini Giampietro , Gattuso Domenico , Morabito Alessandro , Longo Raffaele , Torino Francesco , Sarmiento Roberta , Vitale Stefano , Gamucci Teresa , Mariani Luigi
Published: October 2005

The purpose of this study was to determine the tolerability and activity of rofecoxib (Vioxx®; Merck & Co., Inc., Whitehouse Station, NJ, http://www.merck.com) combined with weekly irinotecan (Camptosar®; Pfizer Pharmaceuticals, New York, http://www.pfizer.com) and infusional 5-fluorouracil (5-FU) as second-line therapy in metastatic colorectal cancer (MCRC). Enrolled patients had previously treated metastatic disease, were aged ≥18 to ≤75 years, and had adequate performance status. A cycle of treatment consisted of i.v. irinotecan on days 1, 8, 15, and 22, rofecoxib at an oral dose of 50 mg/day, and infusional 5-FU at a fixed dose of 200 mg/m2 per day for 5 weeks followed by 3 weeks of therapy with rofecoxib alone. In the dose-finding study, the starting dose of irinotecan was 87.5 mg/m2 and further dose escalations were planned by increments of 12.5 mg/m2 up to 125 mg/m2. Forty-eight consecutive patients were enrolled in the study. Among the 15 cases enrolled in the dose-finding study, one patient experienced grade 3 reversible diarrhea as the dose-limiting toxicity, at the fourth dose level tested. Therefore, the dose of irinotecan for the phase II study was 125 mg/m2, and 33 patients were enrolled and received a total of 75 cycles. Hematological side effects were moderate, with grade 4 neutropenia recorded in only two patients. The most common nonhematological toxicity was diarrhea, occurring in 25 patients (75.8%) and considered to be of grade 3 in 12 patients (36.4%). Sixteen patients achieved partial responses (48.5%; 95% confidence interval [CI], 30.8%–66.5%), and another 10 patients (30.3%) had stable disease. The median time to progression was 7 months (95% CI, 5–12) and the median overall survival (OS) was 18 months; the 1-year estimated OS rate was 69.4%. The unique schedule tested in this study is feasible, is well-tolerated, and has promising activity in patients with MCRC after progression on oxaliplatin (Eloxatin®; Sanofi-Synthelabo Inc., New York, http://www.sanofi-synthelabo.us)-based chemotherapy.
Thalidomide in Advanced Hepatocellular Carcinoma with Optional Low-Dose Interferon-α2a upon Progression
Authors: Schwartz Jonathan D. , Sung Max , Schwartz Myron , Lehrer Deborah , Mandeli John , Liebes Leonard , Goldenberg Alec , Volm Matthew
Published: October 2005

Learning Objectives

After completing this course, the reader will be able to: Identify the etiologic factors contributing to the increasing incidence of hepatocellular carcinoma in the U.S.Explain the rationale for antiangiogenic therapeutic strategies in the treatment of hepatocellular carcinoma.Describe the clinical features associated with a particularly poor prognosis in unresectable hepatocellular carcinoma.

Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit at CME.TheOncologist.com

Purpose. To evaluate thalidomide in advanced hepatocellular carcinoma (HCC) and to evaluate combined thalidomide and low-dose interferon-α2a (IFN-α2a) after tumor progression on thalidomide. Systemic therapy is minimally effective in HCC and tumor angiogenesis is a potential therapeutic target.

Patients and Methods. Patients with unresectable HCC were eligible if they had preserved hepatic and renal function. The initial thalidomide dosage was 200 mg daily and was adjusted for toxicity. Upon progression, patients could continue thalidomide with additional low-dosage (one million units twice daily) IFN-α2a.

Results. Thirty-eight enrolled patients were predominantly hepatitis C virus infected (53%), Child-Pugh class A (79%), and Eastern Cooperative Oncology Group performance status 0–1 (92%); 60% had extrahepatic metastasis. Confirmed disease control was seen in seven patients (18%) and included one complete and one partial response (5% response rate). The median progression-free survival was 2.1 months, and median overall survival was 5.5 months. Tumor invasion of the portal vein or vena cava, large (>10 cm) tumor, and younger age were associated with shorter overall survival. Toxicity included fatigue in 74% of patients. Six patients stopped therapy because of side effects, including two patients (5%) with grade 4 arteriothrombotic events. Five patients continued thalidomide upon progression with the addition of IFN-α2a; there was no disease control and 80% had grade 3 toxicity.

Conclusions. Thalidomide is not well tolerated and confers limited disease control in advanced HCC. Combination thalidomide and low-dose IFN-α2a is neither safe nor efficacious in this population.
Paclitaxel/Carboplatin/Etoposide Versus Paclitaxel/Topotecan for Extensive-Stage Small Cell Lung Cancer: A Minnie Pearl Cancer Research Network Randomized, Prospective Phase II Trial
Authors: Greco F. Anthony , Thompson Dana S. , Morrissey Lisa H. , Erland Joan B. , Burris Howard A. , Spigel David R. , Joseph Geetha , Corso Steven W. , Spremulli Ellen , Hainsworth John D.
Published: October 2005

Purpose. To compare the combination of paclitaxel (Taxol®; Bristol-Myers Squibb, Princeton, NJ, http://www.bms.com) and topotecan (Hycamtin®; Glaxo SmithKline, Philadelphia, http://www.gsk.com) with paclitaxel, carboplatin (Paraplatin®; Bristol-Myers Squibb), and etoposide (Etopophos®, VePesid®; Bristol-Myers Squibb) in patients with previously untreated extensive-stage small cell lung cancer.

Patients and Methods. In this phase II trial, 120 patients were randomly allocated to receive either topotecan (1.5 mg/m2 i.v. days 1, 2, and 3) and paclitaxel (175 mg/m2 i.v. day 1) every 21 days orpaclitaxe l (200mg/m2 i.v. day 1), carboplatin (area under the concentration–time curve 6 i.v. day 1), and etoposide (50 mg/100 mg alternating daily by mouth days 1–10) every 21 days, each regimen for a maximum of eight cycles. The primary end points were objective response rate and time to progression.

Results. The paclitaxel–carboplatin–etoposide combination produced a significantly higher overall response rate (78% versus 48%), longer median time to progression (7.6 months versus 5.5 months), and greater number of patients free from progression at 1 year (14% versus 8%) compared with paclitaxel plus topotecan. There was no difference in overall survival. Toxicities were similar in the two treatment arms.

Conclusions. The paclitaxel–carboplatin–etoposide combination produced a superior overall response rate and time to progression in patients with extensive-stage small cell lung cancer compared with paclitaxel plus topotecan. The platinum compounds continue to be a necessary component of the initial therapy for these patients.
Multifocal Extranodal Non-Hodgkin Lymphoma: A Clinicopathologic Study of 37 Cases in Greece, a Hellenic Cooperative Oncology Group Study
Authors: Economopoulos Theofanis , Papageorgiou Sotirios , Rontogianni Dimitra , Kaloutsi Vassiliki , Fountzilas George , Tsatalas Constantinos , Pavlidis Nikolaos , Pectasides Dimitrios , Papageorgiou Efstathios , Dimopoulos Meletios
Published: October 2005

The purpose of this retrospective study was to illustrate the clinicopathological features of patients presenting with multifocal extranodal non-Hodgkin lymphoma (NHL). Among 810 patients with NHL, 37 cases (4.2%) were found to have multiple extranodal involvement (two or more sites). There were 24 men and 13 women, with a median age of 63 years. The majority of these cases (n = 26) had gastric or intestinal (GI) involvement with or without other extranodal sites. Lung along with another extranodal site was relatively common in the present series. Stratification of the 37 cases according to the International Prognostic Index (IPI) showed that 89% of the patients belonged to the high-risk groups. Diffuse large-B-cell lymphoma (DLBCL) accounted for 62%, and mucosa-associated lymphoma tissue (MALT) lymphoma accounted for 27% of all cases. After induction treatment with anthracycline-based regimens, complete remission was achieved in 21 patients (57%), partial remission was achieved in six patients (16%), and seven patients (19%) had no response, while three patients (8%) were nonevaluable. In conclusion, multifocal extranodal NHL is a heterogeneous group of diseases. The majority of them arise at various sites in the GI tract. DLBCL was the most frequent histological subtype followed by MALT lymphoma. Risk group, as defined by the IPI, was predictive of survival.
Helping Melanoma Patients Decide Whether to Choose Adjuvant High-Dose Interferon-α2b
Authors: Hurley Karen E. , Chapman Paul B.
Published: October 2005

Learning Objectives

After completing this course, the reader will be able to: Describe the benefits of adjuvant high-dose interferon-α therapy to melanoma patients.List the toxicities most commonly associated with adjuvant high-dose interferon-α therapy in melanoma patients.Assist patients with melanoma to decide whether to choose adjuvant high-dose interferon-α therapy.

Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit at CME.TheOncologist.com

High-dose interferon-α2b is a U.S. Food and Drug Administration–approved adjuvant treatment for stage III melanoma, and yet, because of its limited efficacy and well-known toxicity, it is not universally accepted by patients and oncologists. In this paper, we evaluate the benefits and risks of adjuvant high-dose interferon-α2b and try to provide a framework to help oncologists guide patients trying to decide whether to undergo adjuvant high-dose interferon therapy.
The Molecular Perspective: c-Abl Tyrosine Kinase
Authors: Goodsell David S.
Published: October 2005

Learning Objectives

After completing this course, the reader will be able to: Discuss c-Abl and Bcr-Abl and their role in cancer chemotherapy.

Access and take the CME test online and receive 1 hour of AMA PRA category 1 credit at CME.TheOncologist.com
Models for evaluating the costs of bridge failure
Authors: Wong S. M. , Onof C. J. , Hobbs R. E.
Published: October 2005

One of the key factors in evaluating the risk level of a structure such as a bridge should be an examination of the failure consequences, considering that the risk equals the probability of failure times the consequences of failure. In the present study, possible failure consequences of bridge element and system failures have been identified, and a cost-evaluation method has been adopted. The major costs involved are the rebuilding costs, traffic delay costs, access and traffic management costs, casualty costs, repair costs and some other indirect costs. However, there has been a lack of information in evaluating the casualty costs. The paper focuses on the casualty costs and presents some simple models that can be used to evaluate such costs. In addition, several case studies have been performed using the cost models, and the results are presented. Based on the case studies, empirical costs models are proposed for evaluating the total costs of element and system failures.
Refurbishment of the old Medway bridge, UK
Authors: Smith D. A.
Published: October 2005

The original Medway bridge, constructed in the 1960s, comprises 21 spans of pre-stressed concrete beams and twin three-cell box girder construction with an overall length of almost 1 km and a main span of 152·4 m. It carried both carriageways of the M2 motorway over the River Medway in Kent, UK. With the opening of the new Medway Bridge in August 2002 as part of the A2/M2 Cobham to junction 4 widening scheme for the Highways Agency, all traffic on the existing bridge was temporarily diverted giving Costain–Skanska–Mowlem joint venture (CSM) full access to the viaduct superstructure to complete the final phase of the structural refurbishment. This paper details the design of some of the final refurbishment requirements and identifies the solutions developed to overcome several problems encountered on site during the strengthening. Key items of work included replacing the entire suspended span over the river, repairing the supporting pre-stressed concrete half joints and re-assessing the approach viaducts. The work was completed under a fixed-price, design-and-build contract, which made the need for economic and buildable details all the more acute. Emphasis was placed on the development of flexible solutions to cater for anticipated variations on site.
Innovative retrofitted reinforcement techniques for masonry arch bridges
Authors: Sumon S. K.
Published: October 2005

This paper describes a series of load tests to determine the effectiveness of two innovative repair systems for masonry arch bridges containing the common defect of ring-separation. Two arches were strengthened using the Helibeam system, one using a prototype version and the other using a modified version. Two further arches were strengthened using the masonry arch repair and strengthening (MARS) system, again using a prototype and modified system. The effectiveness of the repair systems is evaluated by comparing the behaviour of the strengthened arches with an unstrengthened arch containing ring-separation. For comparison purposes, an additional test was carried out on a fully bonded arch (that is, with no ring-separation). The testing demonstrated that, following some modifications to the initial installation procedures, both retrofitted strengthening systems generated significant increases in load-carrying capacity when compared with the ring-separated and the unstrengthened arch. Some recommendations on practical limitations with particular regard to the safety of the structure during installation of the strengthening system are also given.
Wind power: a major opportunity for the UK
Authors: ffrench Randal , Bonnett Danny , Sandon James
Published: October 2005

Worldwide wind power has grown at an average rate of almost 30% over the last decade to reach 48 GW at the end of 2004. The UK now has over 1 GW installed capacity including 124 MW offshore. Wind turbines have steadily grown in size and 5 MW prototypes have been erected. The future development of wind power in Britain is likely to depend mainly on Government policy and the prices of oil and gas. This paper describes the main technical and non-technical issues facing wind power today and looks at the prospects for further UK development of wind power.