bluuebunny/crossref_metadata_2025 huggingface dataset:
Establishment of Broad‐leaved Thickets in Serengeti, Tanzania: The Influence of Fire, Browsers, Grass Competition, and Elephants1
Authors: Sharam Gregory , Sinclair A. R. E. , Turkington Roy
Published: July 2006

The role ofEuclea divinorumin the establishment of broad‐leaved thickets was investigated in Serengeti National Park, Tanzania. Thickets are declining due to frequent fires, but have not reestablished when fires have been removed. Seedlings ofE. divinorum, a fire‐resistant tree, were found in grassland adjacent to thickets and as thicket canopy trees and may function to facilitate thicket establishment. Seedlings of thicket species were abundant underE. divinorumcanopy trees but not in the grassland, indicating thatE. divinorumcan facilitate forest establishment. We examinedE. divinorumestablishment in grassland by measuring survival and growth of seedlings with respect to fire, browsers, elephants, and competition with grass. Seedling survival was reduced by fire (50%), browsers (70%), and competition with grass (50%), but not by elephants. Seedling growth rate was negative unless both fire and browsers, or grass was removed. Establishment of thickets viaE. divinorumis not occurring under the current conditions in Serengeti of frequent fires, abundant browsers, and dense grass in riparian areas. Conditions that allowed establishment may have occurred in 1890–1920s during a rinderpest epizootic, and measurements of thicket canopy trees suggest they established at that time.
African elephantsLoxodonta africanaand human‐elephant interactions: implications for conservation
Authors: LEE P. C. , GRAHAM M. D.
Published: July 2006

African elephants face an uncertain future. Politics, war, sustained media campaigns, corrupt, weak or absent institutions supporting conservation, land‐use planning or general governance, and greed are all bringing elephants into direct conflict with humans. Although elephant populations have declined considerably relative to their historical size and range, human populations have expanded to occupy and intensively use remaining elephant areas. Strategies to minimize perceptions of conflict and the implementation of land‐use planning with biodiversity protection as its goal could help to sustain at least some populations of elephants. Here, we review threats to elephants, with an emphasis on those resulting from human perceptions of conflict, and suggest some mechanisms for grappling with these threats.
Aspects of the reproductive biology and breeding management of Asian and African elephants Elephas maximus and Loxodonta africana
Authors: HILDEBRANDT T. B. , GÖRITZ F. , HERMES R. , REID C. , DEHNHARD M. , BROWN J. L.
Published: July 2006

Elephants possess many unique qualities, including some that relate directly to their reproductive biology. Thus, comparative studies on elephants provide valuable information to the growing biological database for extant mammals. Left undisturbed, Asian Elephas maximus and African Loxodonta Africana elephants reproduce well in the wild. It is ironic then that most captive populations face possible‘extinction'because of historically poor reproductive performance. Some of the problems with breeding elephants in captivity are logistical but others, like ovarian and uterine pathologies and bull infertility, have management‐related aetiology. Through advances in endocrine monitoring and ultrasound imaging techniques, we are beginning to understand some of the complex mechanisms controlling reproductive function in elephants. Several reproductive characteristics appear to be unique to the taxon, such as luteal steroidogenic function, follicular development patterns, pituitary gonadotrophin secretion, a 22 month‐long gestation and musth (in ♂♂). One example is the‘double LH surge'occurring 3 weeks apart during the follicular or non‐luteal phase of the cycle, with only the second surge inducing ovulation. These qualities have at times both enhanced and hampered efforts to understand and control reproduction. We have learned that techniques developed for domestic or laboratory species are not always directly applicable to elephants. However, the recent success of artificial insemination based on new ultrasound and endocrine methodology offers hope that establishing selfsustaining populations is possible. This paper reviews our current knowledge of elephant reproduction and how it is being used to aid species conservation for maximal reproductive efficiency and enhancement of genetic management.
Population management of zoo elephants
Authors: WIESE R. J. , WILLIS K.
Published: July 2006

In Europe and North America the majority of Asian elephantElephas maximuspopulations are not self‐sustaining nor is the African elephantLoxodonta africanapopulation in North America. About 75% of Asian elephants in North America are wild‐caught or from semi‐wild logging camps and are presumed to be unrelated to the other Asian elephants in captivity. The genetic potential of these populations is healthy and will remain so if the demographic constraints impinging on them can be resolved. In order to become self‐sustaining the primary goal is to increase birth rates in the population, with a secondary goal of reducing infant‐mortality rates. As populations of elephants in zoos metamorphose from those maintained by importation to self‐sustaining groups maintained by captive breeding, there will be an increase in the number of bull elephants to be managed. This will require a significant change in elephant‐management practices.
An integrated management strategy for the conservation of Eastern black rhinocerosDiceros bicornis michaeliin Kenya
Authors: AMIN R. , OKITA‐OUMA B. , ADCOCK K. , EMSLIE R. H. , MULAMA M. , PEARCE‐KELLY P.
Published: July 2006

At time of writing Kenya holdsc.84% of the remainingin situpopulation of Critically Endangered Eastern black rhinocerosDiceros bicornis michaeli.The Kenyan 5 year Black Rhino Conservation and Management Strategy has given highest priority to the biological management of the subspecies in order to help achieve and maintain rapid metapopulation growth to increase rhinoceros numbers. Specific training and capacity building in monitoring of rhinoceros, from collection of field data to status reporting, have been implemented. Procedures to assess ecological carrying capacity for Eastern black rhinoceros habitat have been developed to help establish new viable populations and to optimize the management of existing sanctuaries, some of which face loss of suitable habitat owing to competition for resources between rhinoceros and other browsers. The management objective is to maintain rhinoceros populations below the ecological carrying capacity of a reserve in order to increase reproduction in‘donor'populations as well as the trans‐location of animals to create new populations with the potential for rapid growth. The conservation value of establishing site‐level support relationships is also discussed. Kenya, for the first time since the 1970s, achieved a growth rate of >5% over the period 2004 and 2005 (the national goal is to increase numbers by at least 5%).
Rhinoceros behaviour: implications for captive management and conservation
Authors: HUTCHINS M. , KREGER M. D.
Published: July 2006

All species of rhinoceros are, to varying degrees, threatened with extinction because of poaching, habitat loss, human‐rhinoceros conflict, hunting and civil unrest. Clearly the threats facing the five remaining species (Black rhinocerosDiceros bicornis, White rhinocerosCeratotherium simum, Greater one‐horned rhinocerosRhinoceros unicornis, Javan rhinocerosRhinoceros sondaicusand Sumatran rhinocerosDicerorhinus sumatrensis)are anthropogenic. Although many disciplines are important for conservation, understanding the behaviour characteristics of a species should be considered a key component when developing wildlife‐management and conservation strategies. A general overview of the behaviour of rhinoceros is presented, addressing ecology and social organization, activity and habitat use, feeding strategies, courtship and reproduction, and anti‐predator behaviour. The implications of behavioural studies for successful management and husbandry of rhinoceros in captivity are discussed in sections on group size and composition, enclosure design and enrichment programmes, activity patterns, introductions, reproduction, hand‐rearing, and health and stress. Finally, there is some discussion about the implications of this knowledge forin situconservation in relation to designing protected areas, further aspects of animal health and stress, and reintroduction and translocation. A detailed understanding of rhinoceros behaviour is important for survival both in range‐country protected areas and captivity, and such knowledge should be used to provide the most appropriate animal care and environments for these species.
Captive‐breeding programme for the Kihansi spray toad Nectophrynoides asperginis at the Wildlife Conservation Society, Bronx, New York
Authors: LEE S. , ZIPPEL K. , RAMOS L. , SEARLE J.
Published: July 2006

The Kihansi spray toad Nectophrynoides asperginis is a diminutive, ovoviviparous Bufonidae endemic to the Kihansi River Gorge in Tanzania. This region is part of the Udzungwa escarpment of the Eastern Arc Mountains. The species occurs within a c. 2 ha area, one of the smallest geographic ranges of any terrestrial vertebrate. The taxon is listed on Appendix I of CITES (Convention on International Trade of Endangered Species of Wild Fauna and Flora) and as Critically Endangered by IUCN (International Union for Conservation of Nature and Natural Resources). The Kihansi spray toad is particularly vulnerable to habitat alteration, disease and introduction of competitors or predators, any of which may cause extinction. The biology of this toad and its restricted range also make it especially susceptible to disturbance by humans. This paper discusses the efforts of the Wildlife Conservation Society (WCS) and the National Amphibian Conservation Center (NACC) to breed these toads in captivity as an integral part of the Kihansi Gorge conservation plan.
Chimpanzee Forest exhibit at Chester Zoo
Authors: WEHNELT S. , BIRD S. , LENIHAN A.
Published: July 2006

In 2000 an exhibit was altered substantially for ChimpanzeesPan troglodytesat Chester Zoo. A flat grass‐covered island was initially planted with over 300 plants of 31 species and a complex climbing structure, made from poles, hammocks, tyres and cargo nets, was erected in the centre of the enclosure. In this article the new Chimpanzee Forest exhibit is described and details of the plantings are given. The ways in which the structure and vegetation have improved the environment and how the Chimpanzees use the redesigned space are also reported.
Analysis of factors that affect maternal behaviour and breeding success in great apes in captivity
Authors: ABELLO M. T. , COLELL M.
Published: July 2006

In this paper the relationship between maternal behaviour and breeding success (or failure) in great apes is described. Data were gathered from a questionnaire survey returned by 48 zoos and from available studbook data, giving a total sample size of 687 individuals [GorillasGorilla gorilla (n= 277), BonobosPan paniscus (n= 37), ChimpanzeesPan troglodytes (n= 216) and OrangutansPongo pygmaeus (n= 157)] born between 1990 and 2000 at 86 institutions. The factors influencing maternal behaviour are discussed. Particular attention is paid to the importance of learning and experience for the development of good maternal skills. The rearing background and social‐group circumstances of the breeding ♀ were analysed, including her rearing situation (own mother, conspecific surrogate or hand‐reared), opportunity (or not) to observe maternal behaviour in conspecifics during development and previous breeding experience. The effects of maternal training are also analysed. The results show that for a ♀ great ape to demonstrate good maternal skills, the most effective experience is to have been reared by her own mother and to have observed maternal behaviour in a social group comprising mature individuals and infants. This gives ♀♀ the opportunity to observe and learn how to care adequately for their own offspring.
Influence of nutrition on the quality of semen in Jaguars Panthera onca in Brazilian zoos
Authors: PAZ R. C. RODRIGUES DA , GONÇALVES R. MORATO , CARCIOFI A. C. , GUIMARÃES M. A. B. V. , PESSUTI C. , SANTOS E. FERRAZ , FERREIRA F. , BARNABE R. C.
Published: July 2006

In Brazilian zoos wild felids in captivity are generally fed meat. However, considering the basic nutritional needs of the domestic cat Felis catus, beef may be deficient in calcium, phosphorus, copper, manganese, vitamins A, D and E, thiamin, folic acid and biotin. The aim of this study was to determine the influence of vitamin (A, D, E, B1, B2, folic acid and biotin) and mineral (calcium, phosphorus, iron, copper, iodine and manganese) supplementation on the quality of semen in Jaguars Panthera onca. Between August 1998 and August 1999 eight adult ♂ Jaguars were offered red meat (beef) and bovine heart once a day. The vitamin/mineral supplementation used was based on the National Research Council recommendations for the domestic cat F. catus. Semen was collected by electroejaculation at the beginning of the trial and every 2 months thereafter for 1 year (n= 7 collection dates). Statistical analyses were performed using the Wilcoxon test (for motility, vigour and sperm concentration), the Friedman test (for sperm and testicular volume) and analysis of variance (for sperm morphology). There were no significant differences between collections for semen volume, concentration, motility and vigour (P>0·05) during the trial period. There was also no difference in morphology between samples with respect to secondary defects but the percentage of primary defects decreased (P<0·05) between the means of the third and the seventh collection series. The conclusion is that dietary supplementation with vitamins and minerals appears to decrease sperm abnormalities, improving seminal characteristics in the animals studied.
Reproduction, behaviour and biology of the Giant river otter Pteronura brasiliensis at Cali Zoo
Authors: LONDOÑO G. CORREDOR , MUÑOZ N. TIGREROS
Published: July 2006

The Giant river otter Pteronura brasiliensis is endemic to South America and is Endangered. Breeding in captivity is one of the strategies for conservation of the species, despite the fact that historically this has not been successful. Between 1999 and 2004 a study into the behaviour and reproductive biology of a pair of Giant river otters was carried out at Cali Zoo. The ♀ gave birth to nine litters, with 14.6.1 pups born, 6.4 (48%) of which survived to > 1 year old. Two litters were reared with older siblings in the family group. Evidence of delayed implantation and pseudopregnancy were observed. The roles of the ♀, ♂ and juveniles in pup rearing are described. Significant features of infant development were recorded and a growth curve was established for P. brasiliensis up to 2 months old.
The Camera Never Lies?
Authors: Mehos Donna C.
Published: July 2006

Nature Exposed
. Photography as Eyewitness in Victorian Science.
By Jennifer Tucker
. Johns Hopkins University Press, Baltimore, MD, 2005. 306 pp. $55, £36.50. ISBN 0-8018-7991-4.

Ranging across scientific fields from microbiology to astronomy, Tucker explores the paths that led to the photograph being accepted as an accurate representation of nature.
Crystal Structure of a Divalent Metal Ion Transporter CorA at 2.9 Angstrom Resolution
Authors: Eshaghi Said , Niegowski Damian , Kohl Andreas , Molina Daniel Martinez , Lesley Scott A. , Nordlund Pär
Published: July 2006

CorA family members are ubiquitously distributed transporters of divalent metal cations and are considered to be the primary Mg
2+
transporter of Bacteria and Archaea. We have determined a 2.9 angstrom resolution structure of CorA from
Thermotoga maritima
that reveals a pentameric cone–shaped protein. Two potential regulatory metal binding sites are found in the N-terminal domain that bind both Mg
2+
and Co
2+
. The structure of CorA supports an efflux system involving dehydration and rehydration of divalent metal ions potentially mediated by a ring of conserved aspartate residues at the cytoplasmic entrance and a carbonyl funnel at the periplasmic side of the pore.
Previous injury as a risk factor for injury in elite football: a prospective study over two consecutive seasons
Authors: Hägglund M , Waldén M , Ekstrand J
Published: July 2006

Background:Previous injury is often proposed to be a risk factor for football injury, but most studies rely on players reporting their own medical history and are thus potentially subject to recall bias. Little is known about the natural variation in injury pattern between seasons.

Objectives:To study whether prospectively recorded injuries during one season are associated with injuries sustained during the following season, and to compare injury risk and injury pattern between consecutive seasons.

Methods:The medical staffs of 12 elite Swedish male football teams prospectively recorded individual exposure and time loss injuries over two full consecutive seasons (2001 and 2002). A multivariate model was used to determine the relation between previous injury, anthropometric data, and the risk of injury.

Results:The training and match injury incidences were similar between seasons (5.1v5.3 injuries/1000 training hours and 25.9v22.7/1000 match hours), but analysis of injury severity and injury patterns showed variations between seasons. Players who were injured in the 2001 season were at greater risk of any injury in the following season compared with non-injured players (hazard ratio 2.7; 95% confidence interval 1.7 to 4.3, p<0.0001). Players with a previous hamstring injury, groin injury, and knee joint trauma were two to three times more likely to suffer an identical injury in the following season, whereas no such relation was found for ankle sprain. Age was not associated with an increased injury risk.

Conclusions:This study confirmed previous results showing that previous injury is an important risk factor for football injury. Overall injury incidences were similar between consecutive seasons, indicating that an injury surveillance study covering one full season can provide a reasonable overview of the injury problem among elite football players in a specific environment. However, a prolonged study period is recommended for analyses of specific injury patterns.
HARDNESS AND APPROXIMATION OF GATHERING IN STATIC RADIO NETWORKS
Authors: BERMOND JEAN-CLAUDE , GALTIER JEROME , KLASING RALF , MORALES NELSON , PERENNES STEPHANE
Published: July 2006

In this paper, we address the problem of gathering information in a specific node (or sink) of a radio network, where interference constraints are present. We take into account the fact that, when a node transmits, it produces interference in an area bigger than the area in which its message can actually be received. The network is modeled by a graph; a node is able to transmit one unit of information to the set of vertices at distance at most dT in the graph, but when doing so it generates interference that does not allow nodes at distance up to dI (dI ≥ dT) to listen to other transmissions. Time is synchronous and divided into time-steps in each of which a round (set of non-interfering radio transmissions) is performed. We give general lower bounds on the number of rounds required to gather into a sink of a general graph, and present an algorithm working on any graph, with an approximation factor of 4. We also show that the problem of finding an optimal strategy for gathering is NP-HARD, for any values of dI and dT. If dI > dT, we show that the problem remains hard when restricted to the uniform case where each vertex in the network has exactly one piece of information to communicate to the sink.
A TIME-FREE ASSUMPTION TO IMPLEMENT EVENTUAL LEADERSHIP
Authors: MOSTEFAOUI ACHOUR , MOURGAYA ERIC , RAYNAL MICHEL , TRAVERS CORENTIN
Published: July 2006

Leader-based protocols rest on a primitive able to provide the processes with the same unique leader. Such protocols are very common in distributed computing to solve synchronization or coordination problems. Unfortunately, providing such a primitive is far from being trivial in asynchronous distributed systems prone to process crashes. (It is even impossible in fault-prone purely asynchronous systems.) To circumvent this difficulty, several protocols have been proposed that build a leader facility on top of an asynchronous distributed system enriched with synchrony assumptions. This paper introduces a novel approach to implement an eventual leader protocol, namely a time-free behavioral assumption on the flow of messages that are exchanged. It presents a very simple leader protocol based on this assumption. It then presents a second leader protocol combining this timeless assumption with eventually timely channels. As it considers several assumptions, the resulting hybrid protocol has the noteworthy feature to provide an increased overall assumption coverage. A probabilistic analysis shows that the time-free assumption is practically always satisfied.
Activation of a novel long-chain free fatty acid generation and export system in mitochondria of diabetic rat hearts
Authors: Gerber Lamar K. , Aronow Bruce J. , Matlib Mohammed A.
Published: July 2006

A number of reports indicate that a long-chain free fatty acid export system may be operating in mitochondria. In this study, we sought evidence of its existence in rat heart mitochondria. To determine its potential role, we also sought evidence of its activation or inhibition in streptozotocin (STZ)-induced diabetic rat heart mitochondria. If confirmed, it could be a novel mechanism for regulation of long-chain fatty acid oxidation (FAO) in mitochondria. To obtain evidence of its existence, we tested whether heart mitochondria presented with palmitoyl-carnitine can generate and export palmitate. We found that intact mitochondria indeed generate and export palmitate. We have also found that the rates of these processes are markedly higher in STZ-diabetic rat heart mitochondria, in which palmitoyl-carnitine oxidation is also increased. Since mitochondrial thioesterase-1 (MTE-1) hydrolyzes acyl-CoA to CoA-SH + free fatty acid, and uncoupling protein-3 (UCP-3), reconstituted in liposomes, transports free fatty acids, we examined whether these proteins are also increased in STZ-diabetic rat heart mitochondria. We found that both of these proteins are indeed increased. Gene expression profile analysis revealed striking expression of mitochondrial long-chain fatty acid transport and oxidation genes, accompanying overexpression of MTE-1 and UCP-3 in STZ-diabetic rat hearts. Our findings provide the first direct evidence for the existence of a long-chain free fatty acid generation and export system in mitochondria and its activation in STZ-diabetic rat hearts in which FAO is enhanced. We suggest that its activation may facilitate, and inhibition may limit, enhancement of FAO.
Dendritic Calcium Plateau Potentials Modulate Input–Output Properties of Juxtaglomerular Cells in the Rat Olfactory Bulb
Authors: Zhou Zhishang , Xiong Wenhui , Masurkar Arjun V. , Chen Wei R. , Shepherd Gordon M.
Published: July 2006

Understanding the intrinsic membrane properties of juxtaglomerular (JG) cells is a necessary step toward understanding the neural basis of olfactory signal processing within the glomeruli. We used patch-clamp recordings and two-photon Ca2+imaging in rat olfactory bulb slices to analyze a long-lasting plateau potential generated in JG cells and characterize its functional input–output roles in the glomerular network. The plateau potentials were initially generated by dendritic calcium channels. Bath application of Ni2+(250 μM to 1 mM) totally blocked the plateau potential. A local puff of Ni2+on JG cell dendrites, but not on the soma, blocked the plateau potentials, indicating the critical contribution of dendritic Ca2+channels. Imaging studies with two-photon microscopy showed that a dendritic Ca2+increase was always correlated with a dendritic but not a somatic plateau potential. The dendritic Ca2+conductance contributed to boosting the initial excitatory postsynaptic potentials (EPSPs) to produce the plateau potential that shunted and reduced the amplitudes of the following EPSPs. This enables the JG cells to act as low-pass filters to convert high-frequency inputs to low-frequency outputs. The low frequency (2.6 ± 0.8 Hz) of rhythmic plateau potentials appeared to be determined by the intrinsic membrane properties of the JG cell. These properties of the plateau potential may enable JG cells to serve as pacemaker neurons in the synchronization and oscillation of the glomerular network.
Peroxisome Proliferator-Activated Receptor γ and Growth Inhibition by Its Ligands in Uterine Endometrial Carcinoma
Authors: Ota Kyoko , Ito Kiyoshi , Suzuki Takashi , Saito Sumika , Tamura Mitsutoshi , Hayashi Shin-ichi , Okamura Kunihiro , Sasano Hironobu , Yaegashi Nobuo
Published: July 2006

Purpose: In this study, we evaluated the correlation between endometrial carcinoma and peroxisome proliferator-activated receptor γ (PPARγ) expression and assessed whether PPARγ ligands influence carcinoma growth.

Experimental Design: We examined the presence and cellular distribution of PPARγ protein in 42 normal endometria, 32 endometria with hyperplasia, and 103 endometria with endometrial carcinoma by immunohistochemistry. We then compared PPARγ mRNA expression in endometrial carcinoma with that in normal endometria using real-time reverse transcription-PCR. We subsequently confirmed expression of PPARγ mRNA by real-time reverse transcription-PCR and PPARγ protein by immunoblotting in endometrial carcinoma cell lines (Ishikawa, Sawano, and RL95-2 cells). We further examined the effects of PPARγ agonist 15-deoxy-Δ12,14-prostaglandin J2 (15d-PGJ2), a naturally occurring PPARγ ligand, to these endometrial carcinoma cell lines. We also examined the status of apoptosis and p21 mRNA expression of these endometrial carcinoma cell lines following addition of 15d-PGJ2.

Results: PPARγ immunoreactivity was detected in 11 of 23 (48%) of proliferative-phase endometrium, 14 of 19 (74%) of secretory-phase endometrium, 27 of 32 (84%) of endometrial hyperplasia, and 67 of 103 (65%) of carcinoma cases. PPARγ immunoreactivity was significantly lower in endometrial carcinoma than in secretory-phase endometrium (P = 0.012) and endometrial hyperplasia (P = 0.006). There was a significant positive association between the status of PPARγ and p21 expression in endometrial carcinoma (P < 0.0001). There was a significant negative association between the body mass index and PPARγ labeling index of carcinoma tissue in the patients with endometrial carcinoma (P < 0.0001). PPARγ mRNA was expressed abundantly in normal endometria but not in endometrial carcinoma. We showed that PPARγ agonist 15d-PGJ2 inhibited cell proliferation and induced p21 mRNA of endometrial carcinoma cell lines.

Conclusion: We showed the expression of PPARγ in human endometrial carcinoma and the effects of PPARγ ligand in endometrial carcinoma cells. These findings suggest that a PPARγ ligand, 15d-PGJ2, has antiproliferative activity against endometrial carcinoma.
A Phase I Clinical and Pharmacokinetic Study of Oral CI-1033 in Combination with Docetaxel in Patients with Advanced Solid Tumors
Authors: Garland Linda L. , Hidalgo Manuel , Mendelson David S. , Ryan David P. , Arun Banu K. , Lovalvo Jennifer L. , Eiseman Irene A. , Olson Stephen C. , Lenehan Peter F. , Eder Joseph P.
Published: July 2006

Purpose: CI-1033 is an orally available 4-anilinoquinazolone irreversible tyrosine kinase inhibitor of erbB-1, erbB-2, and erbB-4. We conducted a dose escalation study of CI-1033 with docetaxel to assess the safety profile and pharmacokinetics of the combination and to establish the maximum tolerated dose.

Experimental Design: Twenty-six patients with advanced solid tumors were treated on four dosing cohorts starting at CI-1033 (50 mg/d) + docetaxel (75 mg/m2). An intermittent dosing schedule avoided concurrent drug dosing.

Results: CI-1033 alone was escalated from 50 to 75 mg/d (dose level 2), where diarrhea was dose limiting; a 38% incidence of cycle 1 febrile neutropenia prompted dose de-escalation of both CI-1033 and docetaxel for dose level 3, where dose-limiting toxicities prompted further de-escalation of CI-1033 to 45 mg/d. Given equivalent safety profiles for dose level 1 [CI-1033 (50 mg/d) + docetaxel (75 mg/m2)] and dose level 4 [CI-1033 (45 mg/d) + docetaxel (60 mg/m2)], the former was determined to be the recommended phase II dose, given greater dose intensity of both drugs. Antitumor activity was noted in three patients, including a complete response in a patient with cervix uteri cancer. Pharmacokinetic analysis showed a possible effect of docetaxel on CI-1033 pharmacokinetics.

Conclusions: It is feasible to combine the irreversible pan-erbB tyrosine kinase inhibitor CI-1033 with docetaxel on an intermittent dosing schedule in advanced cancer patients. We established the maximum tolerated dose and recommended phase II dose for the combination. Further investigation of this combination should include a rigorous analysis of the effect of docetaxel on CI-1033 pharmacokinetics.
Xenografts of Human Hepatocellular Carcinoma: A Useful Model for Testing Drugs
Authors: Huynh Hung , Soo Khee Chee , Chow Pierce K.H. , Panasci Lawrence , Tran Evelyn
Published: July 2006

Purpose: Our aims were to establish and characterize primary human hepatocellular carcinoma xenografts. They were used to screen new drugs and improve our current treatment regimens used in hepatocellular carcinoma.

Experimental Design: Primary hepatocellular carcinomas were used to create the xenografts. Western blotting was used to determine the changes in proteins in these xenografts before and after therapies. Apoptotic and cell proliferation were analyzed by immunohistochemistry.

Results: Seven lines of xenografts were established from primary human hepatocellular carcinomas. Lines 4-1318, 2-1318, 2006, and 26-1004 grew rapidly in severe combined immunodeficient (SCID) mice and doubled its volume every 48 to 72 hours. Series 5-1318 (5-1318, 30-1004, and 29-1104) grew relatively slowly in SCID mice and required ∼6 to 10 days to double its tumor volume. Western blot analysis revealed that the growth rate of these xenografts was associated with abnormal expression of proteins associated with the cell cycle, signaling pathways, and tumor suppressor genes. Although hepatocellular carcinoma xenografts expressed the receptors for androgens, estrogens, and progesterone, their growth rate was not affected by either castration or sex steroid hormone supplementation. Cisplatin, oxaliplatin, vitamin D analogue EB1089, and Iressa had no effects on the growth rate in SCID mice. Although 5-fluorouracil exerted mild growth inhibition of these xenografts, i.p. delivery of 2-chloroethyl-3-sarcosinamide-1-nitrosourea (SarCNU) or doxorubicin resulted in a significant growth inhibition. Doxorubicin-induced growth suppression was associated with elevation of p53 and p21Cip1/Waf1. In addition to up-regulation of p53 and p21Cip1/Waf1, SarCNU also increased the levels of phosphorylated cdc-2 at Tyr15.

Conclusion: Hepatocellular carcinoma xenografts are powerful tools for screening drugs and SarCNU may be useful in the treatment of this fatal disease.
PC Cell–Derived Growth Factor Stimulates Proliferation and Confers Trastuzumab Resistance to Her-2-Overexpressing Breast Cancer Cells
Authors: Kim Wes E. , Serrero Ginette
Published: July 2006

Purpose: Trastuzumab is only effective in 25% to 30% of the administered breast cancer patients who overexpress the erbB2/Her-2 oncoprotein. PC cell–derived growth factor (PCDGF/GP88) is an 88-kDa glycoprotein growth factor overexpressed in 80% invasive ductal carcinomas. Our objective was to determine whether the increased levels of PCDGF/GP88 confers Trastuzumab resistance in erbB2-overexpressing breast cancer cells.

Experimental Design: The ability of PCDGF to induce erbB2 phosphorylation and to confer Trastuzumab resistance was studied in erbB2-overexpressing MCF-7 and SKBR3 breast cancer cell lines.

Results: PCDGF/GP88 added exogenously induced the phosphorylation of erbB2 in a dose-dependent and time-dependent manner in erbB2-overexpressing breast cancer cells. In addition, the overexpression of PCDGF/GP88 conferred Trastuzumab resistance in erbB2-overexpressing cells. Furthermore, overexpression of PCDGF/GP88 in erbB2-overexpressing cells provided a growth advantage over erbB2-overexpressing cells that do not have increased levels of PCDGF/GP88. Lastly, PCDGF/GP88 induced the phosphorylation of mitogen-activated protein kinase in a time-dependent manner in erbB2-overexpressing cells, and pretreatment with Trastuzumab was not able to attenuate the phosphorylation levels of mitogen-activated protein kinase induced by PCDGF/GP88.

Conclusion: These data suggest that PCDGF/GP88 confers Trastuzumab resistance in erbB2-overexpressing cells. Thus, the increase in PCDGF/GP88 levels may indicate Trastuzumab unresponsiveness in breast cancer patients.
High Fluorodeoxyglucose Uptake on Positron Emission Tomography in Patients with Advanced Non–Small Cell Lung Cancer on Platinum-Based Combination Chemotherapy
Authors: Lee Kyung-Hun , Lee Se-Hoon , Kim Dong-Wan , Kang Won Jun , Chung June-Key , Im Seock-Ah , Kim Tae-You , Kim Young Whan , Bang Yung-Jue , Heo Dae Seog
Published: July 2006

Purpose: To evaluate response and survival for platinum-based combination chemotherapy in chemonaive patients with non–small cell lung cancer (NSCLC) according to pretreatment standardized uptake values (SUV) by fluorodeoxyglucose positron emission tomography.

Experimental Design: Patients with advanced NSCLC who had not previously received chemotherapy were eligible. Response rates and survivals were analyzed according to maximal SUVs [low (≤7.5) versus high (>7.5), where 7.5 was the median value] before the first cycle of chemotherapy.

Results: Eighty-five consecutive patients were included in the retrospective study. Patients with high SUV tumors exhibited significantly higher response rates (34.1% for low SUVs versus 61.0% for high SUVs; P = 0.013). Other factors, including sex, age, histology, performance status, number of involved organs, regimens used, and disease stage, did not affect response. However, high SUVs were related with a shorter response duration (279 days for low SUVs versus 141 days for high SUVs; P = 0.003) and time to progression (282 days for low SUVs versus 169 days for high SUVs; P = 0.015). Overall survival was unaffected by maximal SUVs (623 days for low SUVs versus 464 days for high SUVs; P = 0.431).

Conclusions: Patients having NSCLC with high maximal SUVs showed a better response to platinum-based combination chemotherapy but had a shorter time to progression. Tumor glucose metabolism, as determined by SUVs on fluorodeoxyglucose positron emission tomography, was found to discriminate NSCLC subsets with different clinical and biological features.
Epidermal Growth Factor ReceptorMutation Testing in the Care of Lung Cancer Patients
Authors: Sequist Lecia V. , Joshi Victoria A. , Jänne Pasi A. , Bell Daphne W. , Fidias Panos , Lindeman Neal I. , Louis David N. , Lee Jeffrey C. , Mark Eugene J. , Longtine Janina , Verlander Peter , Kucherlapati Raju , Meyerson Matthew , Haber Daniel A. , Johnson Bruce E. , Lynch Thomas J.
Published: July 2006

As the literature about epidermal growth factor receptor (EGFR) mutations grows and screening for mutations becomes increasingly integrated into clinical care, it is important to examine how best to do somatic mutational analyses and how best to use the test results in clinical decision making. We began offering mutation screening by comprehensive direct sequence analysis of exons 18 to 24 of the tyrosine kinase domain of EGFR in August 2004 as part of clinical cancer care and protocol therapy at our institutions. All identified potential mutations are confirmed with three to five independent PCRs of the original genomic DNA sample and, if not previously noted in the literature, are compared with the patient's germ-line DNA to ensure the finding is somatic. We formally analyzed the first 100 patients to undergo EGFR sequence analysis and found that testing was feasible and significantly affected the treatment of patients with non–small cell lung cancer (NSCLC). Patients harboring EGFR mutations were significantly more likely to receive recommendations for therapy with EGFR tyrosine kinase inhibitors (i.e., gefitinib or erlotinib) than patients without mutations. However, negative EGFR test results did not prevent physicians from administering these agents to selected patients. Ideally, a standardized technique for mutation testing could be developed, with demonstrated reproducibility and validity. Clinical trials incorporating molecular diagnostics are ongoing to assess the efficacy of EGFR tyrosine kinase inhibitors as first-line therapy for metastatic NSCLC and as adjuvant therapy for early-stage resected NSCLC. It is likely that mutation testing and other molecular analyses will be most useful in these two clinical situations.
Clinical and Biological Effects of Recombinant Human Interleukin-18 Administered by Intravenous Infusion to Patients with Advanced Cancer
Authors: Robertson Michael J. , Mier James W. , Logan Theodore , Atkins Michael , Koon Henry , Koch Kevin M. , Kathman Steven , Pandite Lini N. , Oei Coreen , Kirby Lyndon C. , Jewell Roxanne C. , Bell William N. , Thurmond Linda M. , Weisenbach Jill , Roberts Suzanne , Dar Mohammed M.
Published: July 2006

Purpose: Interleukin-18 (IL-18) is an immunostimulatory cytokine with antitumor activity in preclinical animal models. A phase I study of recombinant human IL-18 (rhIL-18) was done to determine the toxicity, pharmacokinetics, and biological activities of rhIL-18 in patients with advanced cancer.

Experimental Design: Cohorts of patients were given escalating doses of rhIL-18, each administered as a 2-hour i.v. infusion on 5 consecutive days. Toxicities were graded using standard criteria. Serial blood samples were obtained for pharmacokinetic and pharmacodynamic measurements.

Results: Twenty-eight patients (21 with renal cell cancer, 6 with melanoma, and 1 with Hodgkin's lymphoma) were given rhIL-18 in doses ranging from 3 to 1,000 μg/kg. Common side effects included chills, fever, nausea, headache, and hypotension. Common laboratory abnormalities included transient, asymptomatic grade 1 to 2 neutropenia, thrombocytopenia, anemia, hypoalbuminemia, hyponatremia, and elevations in liver transaminases. One patient in the 100 μg/kg cohort experienced transient grade 3 hypotension and grade 2 bradycardia during the first infusion of rhIL-18. No other dose-limiting toxicities were observed. Plasma concentrations of rhIL-18 increased with increasing dose, and 2.5-fold accumulation was observed with repeated dosing. Biological effects of rhIL-18 included transient lymphopenia and increased expression of activation antigens on lymphocytes and monocytes. Increases in serum concentrations of IFN-γ, granulocyte macrophage colony-stimulating factor, IL-18 binding protein, and soluble Fas ligand were observed. Two patients experienced unconfirmed partial responses after rhIL-18 treatment.

Conclusions: rhIL-18 can be safely given in biologically active doses to patients with advanced cancer. A maximum tolerated dose of rhIL-18 was not determined. Further clinical studies of rhIL-18 are warranted.
Megakaryocyte Potentiation Factor Cleaved from Mesothelin Precursor Is a Useful Tumor Marker in the Serum of Patients with Mesothelioma
Authors: Onda Masanori , Nagata Satoshi , Ho Mitchell , Bera Tapan K. , Hassan Raffit , Alexander Richard H. , Pastan Ira
Published: July 2006

Purpose: To establish monoclonal antibodies (mAb) against megakaryocyte potentiation factor (MPF) and detect MPF in the blood of patients with mesothelioma.

Experimental Design: Mice were immunized with a purified recombinant human MPF-rabbit-Fc fusion protein and with MPF. Several hybridomas producing mAbs to MPF were established. A double-determinant (sandwich) ELISA was constructed using mAbs to two different epitopes and used to determine if MPF is present in the serum of patients with mesothelioma.

Results: We established seven anti-MPF mAbs whose topographical epitopes were classified into three nonoverlapping groups. All the mAbs reacted with recombinant MPF protein by ELISA. One of the mAbs detected MPF and the mesothelin precursor protein containing MPF in cell lysates on Western blotting. A sandwich ELISA using mAbs to two different epitopes was constructed and used to measure the presence of MPF in the media of various mesothelin-expressing cancer cell lines and in human serum. The ELISA showed that MPF levels were elevated in 91% (51 of 56) of patients with mesothelioma compared with healthy controls. Furthermore, serum MPF fell to normal levels in two patients after surgery for their peritoneal mesothelioma.

Conclusions: Using new mAbs to MPF, we showed that MPF is secreted by several mesothelioma cell lines and is frequently elevated in the blood of patients with mesothelioma. Measurement of MPF may be useful in following the response of mesothelioma to treatment.
Combining Targeted Agents: Blocking the Epidermal Growth Factor and Vascular Endothelial Growth Factor Pathways
Authors: Sandler Alan , Herbst Roy
Published: July 2006

Bevacizumab is a recombinant, humanized monoclonal antibody against vascular endothelial growth factor. Erlotinib HCl is a reversible, highly selective epidermal growth factor receptor tyrosine kinase inhibitor. Additionally, both agents have shown benefit in patients with previously treated non–small cell lung cancer (NSCLC). Preclinical data in xenograft models produced greater growth inhibition with the combination than with either agent alone. A phase I/II study in two centers examined combined erlotinib and bevacizumab treatment in patients with nonsquamous stage IIIB/IV NSCLC with one or more prior chemotherapy. In phase I, 150 mg/d erlotinib orally plus 15 mg/kg bevacizumab i.v. every 21 days was established as the phase II dose. A total of 40 patients were enrolled and treated in this study (34 patients at phase II dose): 21 were female, 30 had adenocarcinoma histology, 9 were never smokers, and 22 had two or more prior regimens. The most common adverse events were mild to moderate rash, diarrhea, and proteinuria. Preliminary data showed no pharmacokinetic interaction between erlotinib and bevacizumab. Eight patients (20.0%) had partial responses and 26 (65.0%) had stable disease as their best response. The median overall survival for the 34 patients treated at the phase II dose was 12.6 months, with progression-free survival of 6.2 months. Encouraging antitumor activity and safety of erlotinib plus bevacizumab support further development of this combination for patients with advanced NSCLC. A randomized phase II trial has been completed, and a phase III trial is ongoing.
Transient Receptor Potential Channels in Cardiovascular Function and Disease
Authors: Inoue Ryuji , Jensen Lars Jørn , Shi Juan , Morita Hiromitsu , Nishida Motohiro , Honda Akira , Ito Yushi
Published: July 2006

Sustained elevation in the intracellular Ca
2+
concentration via Ca
2+
influx, which is activated by a variety of mechanisms, plays a central regulatory role for cardiovascular functions. Recent molecular biological research has disclosed an unexpectedly diverse array of Ca
2+
-entry channel molecules involved in this Ca
2+
influx. These include more than ten transient receptor potential (TRP) superfamily members such as TRPC1, TRPC3–6, TRPV1, TRPV2, TRPV4, TRPM4, TRPM7, and polycystin (TRPP2). Most of them appear to be multimodally activated or modulated and show relevant features to both acute hemodynamic control and long-term remodeling of the cardiovascular system, and many of them have been found to respond not only to receptor stimulation but also to various forms of stimuli. There is good evidence to implicate TRPC1 in neointimal hyperplasia after vascular injury via store-depletion–operated Ca
2+
entry. TRPC6 likely contributes to receptor-operated and mechanosensitive Ca
2+
mobilizations, being involved in vasoconstrictor and myogenic responses and pulmonary arterial proliferation and its associated disease (idiopathic pulmonary arterial hypertension). Considerable evidence has also been accumulated for unique involvement of TRPV1 in blood flow/pressure regulation via sensory vasoactive neuropeptide release. New lines of evidence suggest that TRPV2 may act as a Ca
2+
-overloading pathway associated with dystrophic cardiomyopathy, TRPV4 as a mediator of endothelium-dependent hyperpolarization, TRPM7 as a proproliferative vascular Mg
2+
entry channel, and TRPP2 as a Ca
2+
-entry channel requisite for vascular integrity. This review attempts to provide an overview of the current knowledge on TRP proteins and discuss their possible roles in cardiovascular functions and diseases.
Leadership Revisited
Authors: Skodvin Tora , Andresen Steinar
Published: July 2006

In the late 1980s/early 1990s the concept of leadership was introduced in the study of international regimes to describe the role negotiating parties some-times would take on to craft agreement. The concept seemed to grasp an essential feature of multilateral cooperative efforts: that parties can be differentiated by the extent to which they are capable of, and willing to, take on a particular responsibility of guiding other parties in directions that could lead to joint solutions. The concept of leadership has only to a small extent been subjected to critical analytical and conceptual discussion. In this article we revisit the concept by asking: What are the characteristic features of leadership in international negotiations? Our analysis shows that current conceptualizations of leadership are associated with significant ambiguities that make it hard to distinguish leadership behavior from other types of bargaining behavior and that these problems are reproduced in empirical identifications of this mode of bargaining behavior.
Imperfect Science
Authors: Malnes Raino
Published: July 2006

On a crucial issue, the first report of the IPCC speaks with two tongues. It expresses confidence in the greenhouse theory and, at the same time, says that evidence for the theory is indeterminate and inconclusive. This article addresses it-self to two candidates for an explanation. The first hypothesis builds on the straightforward observation that people do not always speak their mind. But there is little reason to believe that contradictions in text can be traced to scientists' concern about boosting the credentials of the greenhouse theory. The second candidate for an explanation, which is the main contribution of the article, says that scientists may be diverted from the concern about truth because they take on tasks that are extraneous to the role of scientist. Thus, members of the IPCC are charged with providing premises for climate policy, and this may have affected both their research and the presentation of its results.