bluuebunny/crossref_metadata_2025 huggingface dataset:
Geomorphic controls and transition zones in the lower Sabine River
Authors: Phillips Jonathan D.
Published: December 2007

Instream flow science and management requires identification of characteristic hydrological, ecological, and geomorphological attributes of stream reaches. This study approaches this problem by identifying geomorphic transition zones along the lower Sabine River, Texas and Louisiana. Boundaries were delineated along the lower Sabine River valley based on surficial geology, valley width, valley confinement, network characteristics (divergent versus convergent), sinuousity, slope, paleomeanders, and point bars. The coincidence of multiple boundaries reveals five key transition zones separating six reaches of distinct hydrological and geomorphological characteristics. Geologic controls and gross valley morphology play a major role as geomorphic controls, as does an upstream‐to‐downstream gradient in the importance of pulsed dam releases, and a down‐to‐upstream gradient in coastal backwater effects. Geomorphic history, both in the sense of the legacy of Quaternary sea level changes, and the effects of specific events such as avulsions and captures, are also critical. The transition zones delineate reaches with distinct hydrological characteristics in terms of the relative importance of dam releases and coastal backwater effects, single versus multi‐channel flow patterns, frequency of overbank flow, and channel‐floodplain connectivity. The transitional areas also represent sensitive zones which can be expected to be bellwethers in terms of responses to future environmental changes. Copyright © 2007 John Wiley & Sons, Ltd.
Optimising drug treatments in rehabilitation practice
Authors: Mortimer Ann M
Published: December 2007

In this article, Professor Mortimer discusses the results of two workshops held at the Royal College of Psychiatrists Facility of Social and Rehabilitation Psychiatry to investigate rehabilitation psychiatrist's views and experiences regarding drug management in rehabilitation practice. Copyright © 2007 Wiley Interface Ltd
EUFAMI congress
Authors: Gillam Tony
Published: December 2007

Delegates at a meeting in the home town of astronomer and mathematician, Nicolaus Copernicus, heard about the importance of family and the wider community to the recovery of people with severe mental illness.Tony Gillam, a mental health nurse specialist, reports on sessions he attended at ‘Touching the star’s the 4th EUFAMI congress, held in September in Torun, Poland. Copyright © 2007 Wiley Interface Ltd
Prophylaxis against respiratory syncytial virus in young children with cystic fibrosis
Authors: Giebels Karin , Marcotte Jacques‐Edouard , Podoba John , Rousseau Céline , Denis Marie‐Hélène , Fauvel Véronique , Laberge Sophie
Published: December 2007

Introduction

In cystic fibrosis (CF) patients, respiratory syncytial virus (RSV) infection is associated with significant morbidity. Although passive prophylaxis with palivizumab lowers hospitalization rate for RSV infection in populations at risk of severe infection, its use is not recommended in infants with CF disease.

Objective

To determine the effect of palivizumab prophylaxis on hospitalization for acute respiratory illness in young children with CF during the first RSV season following the diagnosis of CF.

Methods

In this retrospective study, medical records of patients diagnosed with CF between the years 1997 and 2005 inclusively and on whom the diagnosis was made before 18 months of age were reviewed. Collected data included age at diagnosis, palivizumab prophylaxis, occurrence of hospitalization for acute respiratory tract illness during the RSV season and identification of RSV infection.

Results

A diagnosis of CF was made in 76 young children and data collected from 75 children. Of those, 40 did not receive RSV prophylaxis while 35 received palivizumab injection monthly during the RSV season. Among non‐recipient children, 7 out of 40 were hospitalized for acute respiratory illness during the RSV season. Of these seven patients, RSV detection was positive in nasopharyngeal secretions in three patients, negative in one patient and not requested in the others. Among palivizumab recipients, 3 out of 35 children were hospitalized for acute respiratory illness (P > 0.05 compared to non‐recipients group). In these three palivizumab recipients, RSV detection was negative in nasopharyngeal secretions. Palivizumab recipients experienced fewer hospital days per patient for acute respiratory illness (mean ± SD: 0.8 ± 3.07 days) as compared to non‐recipients (mean ± SD: 1.73 ± 4.27 days) but this difference did not reach statistical significance.

Conclusion

CF infants may benefit from RSV immunoprophylaxis with palivizumab. Pediatr Pulmonol. 2008; 43:169–174. © 2007 Wiley‐Liss, Inc.
Childhood asthma epidemiology: Insights from comparative studies of rural and urban populations
Authors: Wong Gary W.K. , Chow Chung M.
Published: December 2007

Asthma is one of the most common chronic respiratory disorders. Many epidemiology studies have suggested an increasing trend of asthma in many different regions of the world but the exact reasons explaining such trend remain unclear. Nevertheless, changing environmental factors are most likely important in explaining the trend of asthma. Studies in the past decade have clearly shown a mark difference in the prevalence between urban and rural regions. The consistent findings of a markedly lower prevalence of asthma in children and adults who have been brought up in a farming environment clearly indicate the importance of environmental influence of asthma development. Although the exact protective environmental factors in the rural region remain to be defined, there have been many studies suggesting that early exposure to microbes or microbial products may play a role in modulating the immune system so as to reduce the future risk of asthma and allergies. Advances in the understanding of the genetic predisposition and how these genetic factors may interact with specific environment factors are of paramount importance for the future development of primary preventive strategies for asthma. Pediatr Pulmonol. 2008; 43:107–116. © 2007 Wiley‐Liss, Inc.
Checklist – Setting up a Library and Information Service
Authors: Oberwarth Michael
Published: December 2007

In this very practical checklist Michael Oberwarth identifies the key tasks to be undertaken when starting a law firm library from scratch. He then suggests strategies for setting up an information service which will add value to the fee earners.
Air‐sea interaction associated with a Greenland reverse tip jet
Authors: Martin Rebekah , Moore G. W. K.
Published: December 2007

Greenland lies in close proximity to the North Atlantic storm track, and as such can be a point of strong orographic interaction with atmospheric flow. For several years now, it has been known that the interaction of synoptic scale cyclones with Greenland's orography can spawn localized high wind speed events, known as tip jets off its southernmost point. Climatologies of these events have shown that tip jets can have either a westerly (normal) or easterly (reverse) sense. In this paper, we present the first simulation of a reverse tip jet presenting an examination of the air‐sea interaction that occurs during this event. The strength of this interaction demonstrates the potential influence that these events can have on the region's surface and abyssal oceanic circulation.
Rebate Contracts: Risks and Chances in the German Generic Market
Authors: Natz Alexander
Published: December 2007

This paper provides an overview on the current developments in the German healthcare market. Rebate contracts between pharmaceutical companies and statutory health insurers (SHIs) have proven to be an effective cost containment measure. Increased price pressure in the generic market has led to significant changes in market shares within months. While international companies with broad product portfolios successfully used this instrument to enter the German market, small- and medium-sized enterprises with a narrow product spectrum often saw a decrease in market share. Moreover, the instrument of rebate contracts replaces early entry strategies and might increase profits via portfolio contracts. An overview is given on the new legislation with respect to prescribers and pharmacists together with a look at the framework of public procurement law. Strategic options for generic companies are presented in the context of this legal framework. In addition, considerations that pharmaceutical companies should take into account before negotiating rebate contracts with SHIs are highlighted.
Issues in the Measurement of Localization
Authors: Fratesi Ugo
Published: December 2007

The degree of localization of manufacturing, defined as the excess geographic concentration remaining after correcting for both sectoral concentration and the agglomeration of overall economic activity, has recently gained new techniques of measurement in the form of indexes and numerical methods. These techniques are illustrated, compared, and theoretically discussed to show that they are consistent advancements, but none is yet able to satisfy all desirable properties. The measurement of localization would be more interesting if it could be related to economic processes and not limited to simple observational aspects. In achieving this, there are a number of complications, which are reviewed in the paper. Among these, the choice of the right sectoral scale at which these measures have to be applied is normally given too little importance. The second part of this paper advocates that this is a complex issue, since no digit level is appropriate for all industries. Moreover, different aggregations of narrowly defined subsectors may be more suitable than the standard industrial classifications. This is supported by an exploratory analysis, in two British sectors, based on the investigation of possible localization reasons identified in recent taxonomies. As the many localization measurement techniques have become available, it is recommended that they be applied to sector studies, and not confined to countrywide extensive explorations of all sectors.
Taxonomic revision of Jacksonia (Leguminosae: Mirbelieae)
Authors: Chappill Jennifer A. , Wilkins Carolyn F. , Crisp Michael D.
Published: December 2007

A taxonomic revision is presented of the Australian papilionoid legume genus Jacksonia R.Br. ex Sm. The group includes 74 species, the following 37 of them newly described here: Jacksonia acicularis Chappill, J. anthoclada Chappill, J. arenicola Chappill, J. arida Chappill, J. arnhemica Chappill, J. calcicola Chappill, J. chappilliae C.F. Wilkins, J. debilis Chappill, J. dendrospinosa Chappill, J. divisa Chappill, J. effusa Chappill, J. elongata Chappill, J. epiphyllum Chappill, J. flexuosa Chappill, J. gracillima Chappill, J. humilis Chappill, J. intricata Chappill, J. jackson Chappill, J. lanicarpa Chappill, J. lateritica Chappill, J. nutans Chappill, J. pendens Chappill, J. pungens Chappill, J. quairading Chappill, J. quinkanensis Chappill, J. ramulosa Chappill, J. reclinata Chappill, J. remota Chappill, J. rigida Chappill, J. rubra Chappill, J. rupestris Chappill, J. spicata Chappill, J. stellaris Chappill, J. tarinensis Chappill, J. velveta Chappill, J. venosa Chappill and J. viscosa Chappill.
Structural basis for the high
all-trans
-retinaldehyde reductase activity of the tumor marker AKR1B10
Authors: Gallego Oriol , Ruiz F. Xavier , Ardèvol Albert , Domínguez Marta , Alvarez Rosana , de Lera Angel R. , Rovira Carme , Farrés Jaume , Fita Ignacio , Parés Xavier
Published: December 2007

AKR1B10 is a human aldo-keto reductase (AKR) found to be elevated in several cancer types and in precancerous lesions.
In vitro
, AKR1B10 exhibits a much higher retinaldehyde reductase activity than any other human AKR, including AKR1B1 (aldose reductase). We here demonstrate that AKR1B10 also acts as a retinaldehyde reductase
in vivo
. This activity may be relevant in controlling the first step of retinoic acid synthesis. Up-regulation of AKR1B10, resulting in retinoic acid depletion, may lead to cellular proliferation. Both
in vitro
and
in vivo
activities of AKR1B10 were inhibited by tolrestat, an AKR1B1 inhibitor developed for diabetes treatment. The crystal structure of the ternary complex AKR1B10–NADP
+
–tolrestat was determined at 1.25-Å resolution. Molecular dynamics models of AKR1B10 and AKR1B1 with retinaldehyde isomers and site-directed mutagenesis show that subtle differences at the entrance of the retinoid-binding site, especially at position 125, are determinant for the
all-trans
-retinaldehyde specificity of AKR1B10. Substitutions in the retinaldehyde cyclohexene ring also influence the specificity. These structural features should facilitate the design of specific inhibitors, with potential use in cancer and diabetes treatments.
Definition of global and transcript-specific mRNA export pathways in metazoans
Authors: Farny Natalie G. , Hurt Jessica A. , Silver Pamela A.
Published: December 2007

Eukaryotic gene expression requires export of messenger RNAs (mRNAs) from their site of transcription in the nucleus to the cytoplasm where they are translated. While mRNA export has been studied in yeast, the complexity of gene structure and cellular function in metazoan cells has likely led to increased diversification of these organisms’ export pathways. Here we report the results of a genome-wide RNAi screen in which we identify 72 factors required for polyadenylated [poly-(A+)] mRNA export from the nucleus in Drosophila cells. Using structural and functional conservation analysis of yeast and Drosophila mRNA export factors, we expose the evolutionary divergence of eukaryotic mRNA export pathways. Additionally, we demonstrate the differential export requirements of two endogenous heat-inducible transcripts—intronless heat-shock protein 70 (HSP70) and intron-containing HSP83—and identify novel export factors that participate in HSP83 mRNA splicing. We characterize several novel factors and demonstrate their participation in interactions with known components of the Drosophila export machinery. One of these factors, Drosophila melanogaster PCI domain-containing protein 2 (dmPCID2), associates with polysomes and may bridge the transition between exported messenger ribonucleoprotein particles (mRNPs) and polysomes. Our results define the global network of factors involved in Drosophila mRNA export, reveal specificity in the export requirements of different transcripts, and expose new avenues for future work in mRNA export.
Predictors of Carbapenem-Resistant
Klebsiella pneumoniae
Acquisition among Hospitalized Adults and Effect of Acquisition on Mortality
Authors: Schwaber Mitchell J. , Klarfeld-Lidji Shiri , Navon-Venezia Shiri , Schwartz David , Leavitt Azita , Carmeli Yehuda
Published: December 2007

Carbapenem-resistant
Klebsiella pneumoniae
(CRKP) is an emerging nosocomial pathogen. Little is known about its risk factors or mortality. We performed a case-case-control study to assess the risks for CRKP isolation and a retrospective cohort study to assess mortality in three groups of hospitalized adults: (i) patients from whom CRKP was isolated, (ii) patients from whom carbapenem-susceptible
Klebsiella
spp. (CSKS) were isolated, and (iii) controls from whom no
Klebsiella
spp. were isolated. After adjustment for length of stay (LOS), the demographics, comorbidities, and exposures of each case group were compared with those of the controls. Significant covariates were incorporated into LOS-adjusted multivariable models. In the mortality study, we evaluated the effect of CRKP on in-hospital death. There were 48 patients with CRKP isolation (21 died [44%]), 56 patients with CSKS isolation (7 died [12.5%]), and 59 controls (1 died [2%]). Independent risk factors for CRKP isolation were poor functional status (odds ratio [OR], 15.4; 95% confidence interval [CI], 4.0 to 58.6;
P
< 0.001); intensive care unit (ICU) stay (OR, 17.4; 95% CI, 1.5 to 201.9;
P
= 0.02); and receipt of antibiotics (OR, 4.4; 95% CI, 1.0 to 19.2;
P
= 0.05), particularly fluoroquinolones (OR, 7.2; 95% CI, 1.1 to 49.4;
P
= 0.04). CRKP was independently associated with death when patients with CRKP were compared with patients with CSKS (OR, 5.4; 95% CI, 1.7 to 17.1;
P
= 0.005) and with controls (OR, 6.7; 95% CI, 2.4 to 18.8;
P
< 0.001). After adjustment for the severity of illness, CRKP isolation remained predictive of death, albeit with a lower OR (for the CRKP group versus the CSKS group, OR, 3.9; 95% CI, 1.1 to 13.6; and
P
= 0.03; for the CRKP group versus the controls, OR, 5.0; 95% CI, 1.7 to 14.8; and
P
= 0.004). CRKP affects patients with poor functional status, an ICU stay, and antibiotic exposure and is an independent predictor of death.
Emergence of Antibiotic Resistance during Therapy for Infections Caused by
Enterobacteriaceae
Producing AmpC β-Lactamase: Implications for Antibiotic Use
Authors: Choi Sang-Ho , Lee Jung Eun , Park Su Jin , Choi Seong-Ho , Lee Sang-Oh , Jeong Jin-Yong , Kim Mi-Na , Woo Jun Hee , Kim Yang Soo
Published: December 2007

Enterobacter
spp.,
Serratia marcescens
,
Citrobacter freundii
, and
Morganella morganii
are characterized by chromosomally encoded AmpC β-lactamases and possess the ability to develop resistance upon exposure to broad-spectrum cephalosporins. To determine the incidences of the emergence of resistance during antimicrobial therapy for infections caused by these organisms and the effect of the emergence of resistance on patient outcomes, all patients who were admitted to the Asan Medical Center (Seoul, Republic of Korea) from January 2005 to June 2006 and whose clinical specimens yielded
Enterobacter
spp.,
S. marcescens
,
C. freundii
, or
M. morganii
were monitored prospectively. The main end point was the emergence of resistance during antimicrobial therapy. A total of 732 patients with infections were included for analysis. The overall incidence of the emergence of antimicrobial resistance during antimicrobial therapy was 1.9% (14/732). Resistance to broad-spectrum cephalosporins, cefepime, extended-spectrum penicillin, carbapenem, fluoroquinolones, and aminoglycosides emerged during treatment in 5.0% (11/218), 0% (0/20), 2.0% (2/100), 0% (0/226), 0% (0/153), and 1.1% (1/89) of patients, respectively. The emergence of resistance to broad-spectrum cephalosporins occurred more often in
Enterobacter
spp. (8.3%, 10/121) than in
C. freundii
(2.6%, 1/39),
S. marcescens
(0%, 0/37), or
M. morganii
(0%, 0/21). Biliary tract infection associated with malignant bile duct invasion was significantly associated with the emergence of resistance to broad-spectrum cephalosporins (
P
= 0.024 at a significance level of 0.042, by use of the Bonferroni correction). Only 1 of the 14 patients whose isolates developed resistance during antimicrobial therapy died. The emergence of resistance was more frequently associated with broad-spectrum cephalosporins than with the other antimicrobial agents tested, especially in
Enterobacter
spp. However, the emergence of resistance was associated with a low risk of mortality.
A NONFINITELY BASED FINITE SEMIRING
Authors: DOLINKA IGOR
Published: December 2007

We present a semiring formed by seven binary relations on a two-element set (or, equivalently, by seven Boolean 2 × 2 matrices) that does not have a finite basis for its identities. Some related open problems are also discussed.
THE QUIVER OF THE SEMIGROUP ALGEBRA OF A LEFT REGULAR BAND
Authors: SALIOLA FRANCO V.
Published: December 2007

Recently it has been noticed that many interesting combinatorial objects belong to a class of semigroups called left regular bands, and that random walks on these semigroups encode several well-known random walks. For example, the set of faces of a hyperplane arrangement is endowed with a left regular band structure. This paper studies the module structure of the semigroup algebra of an arbitrary left regular band, extending results for the semigroup algebra of the faces of a hyperplane arrangement. In particular, a description of the quiver of the semigroup algebra is given and the Cartan invariants are computed. These are used to compute the quiver of the face semigroup algebra of a hyperplane arrangement and to show that the semigroup algebra of the free left regular band is isomorphic to the path algebra of its quiver.
GIS-based landslide hazard mapping in the Scotland District, Barbados
Authors: Hearn G. J. , Hodgson I. , Woddy S.
Published: December 2007

Rationale

The Scotland District occupies an area of approximately 60 km
2
forming the northeast coastline of Barbados (Fig. 1). The district is geologically and topographically distinct from the rest of Barbados in that the coral limestone cap that covers the remainder of Barbados is absent. The underlying Tertiary rocks exposed in the Scotland District are soft and erodible, and are themselves prone to landsliding and erosion. Land use in the district comprises forest, sugar cane, fruit and vegetable growing and pasture, and the district has high landscape value and eco-tourism potential. Low rise, low density housing has developed over the decades, predominantly along cart tracks and roads with alignments that tend to follow ridge and spur lines in an attempt to avoid potentially unstable side-long ground. However, there are numerous locations where erosion and ground movements have caused significant distress to road pavements, and where foundations to residential buildings have been undermined to the extent that some areas have been abandoned altogether.

The Soil Conservation Unit (Ministry of Agriculture and Rural Development) has been tackling slope instability and erosion problems in the district for over half a century. A number of useful projects have been commissioned to examine and remediate areas of known ground instability, and several schemes involving drainage and earthworks have proved successful. However, realizing that there were several geological, topographical, drainage and land use factors distributed throughout the district that had a role to play in the pattern of ground instability and erosion.
Terminations of large strike-slip faults: an alternative model from New Zealand
Authors: Mouslopoulou V. , Nicol A. , Little T. A. , Walsh J. J.
Published: December 2007

The 500-km-long strike-slip North Island Fault System (NIFS) intersects and terminates against the Taupo Rift. Both fault systems are active, with strike-slip displacement transferred into the rift without displacing normal faults along the rift margin. Data from displaced landforms, fault-trenching, gravity and seismic-reflection profiles, and aerial photograph analysis suggest that within 150 km of the northern termination of the NIFS, the main faults in the strike-slip fault system bend through 25°, splay into five principal strands and decrease their mean dip. These changes in fault geometry are accompanied by a gradual steepening of the pitch of the slip vectors, and by an anticlockwise swing (up to 50°) in the azimuth of slip on the faults in the NIFS. As a consequence of the bending of the strike-slip faults and the changes in their slip vectors, near their intersection, the slip vectors on the two component fault systems become subparallel to each other and to their mutual line of intersection. This subparallelism facilitates the transfer of displacement from one fault system to the other, accounting for a significant amount of the NE increase of extension along the rift, whilst maintaining the overall coherence of the strike-slip termination. Changes in the slip vectors of the strike-slip faults arise from the superimposition of rift-orthogonal differential extension outside the rift margin, resulting in differential motion of the footwall and hanging-wall blocks of each fault in the NIFS. The combination of rift-orthogonal heterogeneous extension (dip-slip) and strike-slip, results in a steepening of the pitch of the slip vectors on the terminating fault system. Slip vectors on each splay close to their terminations are, therefore, the sum of strike-slip and dip-slip components, with the total angle through which the pitch of the slip vectors steepens being dependent on the relative values of both these two component vectors. In circumstances where interaction of the velocity fields for the intersecting fault systems cannot resolve to a slip vector that is boundary-coherent, either rotation about vertical axes of the terminating fault relative to the through-going fault system may take place to accommodate the termination of the strike-slip fault system, or the rift may be offset by the strike-slip fault system rather than terminating into it. At the termination of the NIFS, an earlier phase of such rotations may have produced the 25° anticlockwise bend in fault strike and contributed up to about one-third of the anticlockwise deflection in slip azimuth. On the terminating strike-slip NIFS, therefore, rotational and non-rotational termination mechanisms have both played a role, but at different times in its evolution, as the thermal structure, the rheology and the thickness of the crust in the rift intersection region have changed.
PF00299804, an Irreversible Pan-ERBB Inhibitor, Is Effective in Lung Cancer Models withEGFRandERBB2Mutations that Are Resistant to Gefitinib
Authors: Engelman Jeffrey A. , Zejnullahu Kreshnik , Gale Christopher-Michael , Lifshits Eugene , Gonzales Andrea J. , Shimamura Takeshi , Zhao Feng , Vincent Patrick W. , Naumov George N. , Bradner James E. , Althaus Irene W. , Gandhi Leena , Shapiro Geoffrey I. , Nelson James M. , Heymach John V. , Meyerson Matthew , Wong Kwok-Kin , Jänne Pasi A.
Published: December 2007

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors gefitinib and erlotinib are effective treatments for a subset of non–small cell lung cancers. In particular, cancers with specific EGFR-activating mutations seem to be the most sensitive to these agents. However, despite their initial response, such cancers almost invariably develop resistance. In 50% of such cancers, a secondary EGFR mutation, T790M, has been identified that renders gefitinib and erlotinib ineffective inhibitors of EGFR kinase activity. Thus, there is a clinical need to develop novel EGFR inhibitors that can effectively inactivate T790M-containing EGFR proteins. In this study, we evaluate the effectiveness of a novel compound, PF00299804, an irreversible pan-ERBB inhibitor. The results from these studies show that PF00299804 is a potent inhibitor of EGFR-activating mutations as well as the EGFR T790M resistance mutation both in vitro and in vivo. Additionally, PF00299804 is a highly effective inhibitor of both the wild-type ERBB2 and the gefitinib-resistant oncogenic ERBB2 mutation identified in lung cancers. These preclinical evaluations support further clinical development of PF00299804 for cancers with mutations and/or amplifications of ERBB family members. [Cancer Res 2007;67(24):11924–32]
ARMS Depletion Facilitates UV Irradiation–Induced Apoptotic Cell Death in Melanoma
Authors: Liao Yi-Hua , Hsu Su-Ming , Huang Pei-Hsin
Published: December 2007

Tumor cells often aberrantly reexpress molecules that mediate proper embryonic development for advantageous growth or survival. Here, we report that ankyrin repeat-rich membrane spanning (ARMS), a transmembrane protein abundant in the developing and adult neural tissues, is overexpressed in melanoma, a tumor ontogenetically originating from neural crest. Immunohistochemical study of 79 melanocytic lesions showed significantly increased expression of ARMS in primary malignant melanomas (92.9%) and metastatic melanoma (60.0%) in comparison with benign nevocellular nevi (26.7%). To investigate the role of ARMS in melanoma formation, murine B16F0 melanoma cells with stable knockdown of ARMS were established by RNA interference. Down-regulation of ARMS resulted in significant inhibition of anchorage-independent growth in soft agar and restrictive growth of melanoma in severe combined immunodeficient mice. Importantly, depletion of ARMS facilitated UVB-induced apoptosis in melanoma cells through inactivation of mitogen-activated protein kinase/extracellular signal–regulated kinase (ERK) kinase (MEK)/ERK. Addition of MEK inhibitor PD98059 further sensitized ARMS-depleted melanoma cells to UVB-induced apoptosis, whereas constitutively active MEK rescued ARMS-depleted cells from apoptosis. We further showed that BRAF, a downstream signaling molecule of ARMS in ERK pathway, is not mutated as a constitutively active form in acral lentiginous melanoma; in contrast, BRAFT1799A mutation, which leads to constitutive activation of ERK signaling, was detected in 57.1% of superficial spreading melanoma. Our study suggests that overexpression of ARMS per se serves as one mechanism to promote melanoma formation by preventing stress-induced apoptotic death mediated by the MEK/ERK signaling pathway, especially in acral lentiginous melanoma, most of which does not harbor BRAF mutation. [Cancer Res 2007;67(24):11547–56]
Elements Related to Heterogeneity of Antibody-Dependent Cell Cytotoxicity in Patients Under Trastuzumab Therapy for Primary Operable Breast Cancer Overexpressing Her2
Authors: Varchetta Stefania , Gibelli Nadia , Oliviero Barbara , Nardini Elena , Gennari Roberto , Gatti Giovanna , Silva Luzemira Santos , Villani Laura , Tagliabue Elda , Ménard Sylvie , Costa Alberto , Fagnoni Francesco F.
Published: December 2007

Preliminary results from a pilot trial on trastuzumab's mechanism of action against operable breast tumors overexpressing Her2 suggested a role for antibody-dependent cell cytotoxicity (ADCC). To examine factors affecting ADCC intensity and variability, we extended this study to the phenotypic and functional analysis of circulating mononuclear cells in 18 patients. ADCC was induced by trastuzumab therapy in 15 of 18 patients (83%). Inability to develop ADCC in three patients did not depend on inadequate levels of trastuzumab because further increase in its concentration in vitro was ineffective. Rather, susceptibility to develop ADCC was fairly predicted by test with trastuzumab before therapy and was correlated to the number of lymphocytes coexpressing CD16 and CD56. Phenotypic analysis at the end of ADCC evaluating down-regulation of CD16, and up-regulation of CD69 and CD107a, confirmed that natural killer (NK) cells and CD56+ T cells were involved in productive engagement of trastuzumab. Also, the killing efficiency of CD16+ lymphocytes was influenced by 158 V/F polymorphism of FcγRIII (CD16), whereas variations of CD247 on NK cells were consistent with trends between ADCC before and after therapy. Complete pathologic response was observed in one patient showing ADCC of outstanding intensity, whereas four cases of partial response showed intermediate ADCC; none of the three patients unable to mount ADCC had significant tumor regression. These data indicate that quantity and lytic efficiency of CD16+ lymphocytes are major factors for ADCC induction by trastuzumab, and confirm that breast cancer responses to short-term trastuzumab monotherapy may depend on involvement of the ADCC mechanism. [Cancer Res 2007;67(24):11991–9]
Oncogenic BARD1 Isoforms Expressed in Gynecological Cancers
Authors: Li Lin , Ryser Stephan , Dizin Eva , Pils Dietmar , Krainer Michael , Jefford Charles Edward , Bertoni Francesco , Zeillinger Robert , Irminger-Finger Irmgard
Published: December 2007

BARD1 is required for protein stability and tumor suppressor functions of BRCA1, which depend on the ubiquitin ligase activity of the BRCA1-BARD1 heterodimer. The NH2-terminal RING domains of both proteins act as interaction modules and form a ubiquitin ligase, which has functions in DNA repair, cell cycle checkpoint regulation, and mitosis. Interestingly, up-regulated expression of truncated BARD1 isoforms was found to be associated with poor prognosis in breast and ovarian cancers and, in a hormonally regulated fashion, in the human cytotrophoblast, a cell type with properties reminiscent of cancer cells. We therefore performed reverse transcription-PCR to determine the structure of BARD1 isoforms in cell lines derived from hormone-dependent and hormone-independent cancers. We found a specific combination of isoforms, generated by differential splicing and alternative transcription initiation, mostly lacking the BRCA1 interaction domain, in gynecologic but not hematologic cancer cell lines. To investigate the prevalence of BARD1 isoforms in tumors, we applied immunohistochemistry to ovarian cancers, using antibodies distinguishing full-length BARD1 and isoforms. Expression of NH2 terminally truncated BARD1 was correlated with advanced stage of cancer, and expression of spliced isoforms was typical for clear cell carcinoma, the ovarian cancer with worst prognosis, suggesting a role of BARD1 isoforms in cancer progression. To challenge this hypothesis, we silenced BARD1 isoforms in ovarian cancer cells that lacked wild-type BARD1 by siRNA interference, which led to a complete proliferation arrest. Thus, BARD1 isoform expression is required for cancer cell proliferation, which is compatible with the notion that BARD1 isoforms act as cancer maintenance genes. [Cancer Res 2007;67(24):11876–85]
Effects of Dietary Energy Restriction on Gene Regulation in Mammary Epithelial Cells
Authors: Zhu Zongjian , Jiang Weiqin , McGinley John N. , Price Jennifer M. , Gao Bifeng , Thompson Henry J.
Published: December 2007

The objective of this study was to determine whether dietary energy restriction (DER) affects the pattern of gene expression in three interrelated energy metabolism pathways: glycolysis, gluconeogenesis, and the citric acid cycle. Mammary carcinogenesis was initiated by the i.p. injection of female Sprague-Dawley rats with 50 mg of 1-methyl-1-nitrosourea per kilogram of body weight. Five days following 1-methyl-1-nitrosourea administration, animals were fed ad libitum or 80% or 60% of the ad libitum intake. Epithelial cells were harvested from histologically confirmed adenocarcinomas (adenocarcinoma epithelial cell; ACEC) and uninvolved mammary gland (mammary gland epithelial cells; MGEC) via laser capture microdissection, whereas isolated RNA was arrayed on Affymetrix R230 2.0 genome chips. Principal components analysis revealed complete separation of the patterns of gene expression between ACEC versus MGEC. Further examination of the data set revealed an up-regulated pattern of expression in the ACEC of genes involved in glycolysis, whereas gluconeogenesis was suppressed. In general, genes involved in the citric acid cycle were not differentially expressed; however, pyruvate dehydrogenase expression was down-regulated and lactate dehydrogenase expression was increased in ACEC versus MGEC. Collectively, the observed patterns of expression were consistent with the Warburg effect. DER exerted no effect on the Warburg pattern of gene expression or on other aspects of these energy metabolism pathways. These findings imply that efforts to target the Warburg effect for cancer prevention are mechanistically distinct from those modulated by DER and provide a rationale for the combination of approaches that target basic defects in energy metabolism and energy-sensing pathways for the prevention of breast cancer. [Cancer Res 2007;67(24):12018–25]
Human Cancer Cells Commonly Acquire DNA Damage during Mitotic Arrest
Authors: Dalton W. Brian , Nandan Mandayam O. , Moore Ryan T. , Yang Vincent W.
Published: December 2007

The mitotic checkpoint is a mechanism that arrests the progression to anaphase until all chromosomes have achieved proper attachment to mitotic spindles. In cancer cells, satisfaction of this checkpoint is frequently delayed or prevented by various defects, some of which have been causally implicated in tumorigenesis. At the same time, deliberate induction of mitotic arrest has proved clinically useful, as antimitotic drugs that interfere with proper chromosome-spindle interactions are effective anticancer agents. However, how mitotic arrest contributes to tumorigenesis or antimitotic drug toxicity is not well defined. Here, we report that mitotic chromosomes can acquire DNA breaks during both pharmacologic and genetic induction of mitotic arrest in human cancer cells. These breaks activate a DNA damage response, occur independently of cell death, and subsequently manifest as karyotype alterations. Such breaks can also occur spontaneously, particularly in cancer cells containing mitotic spindle abnormalities. Moreover, we observed evidence of some breakage in primary human cells. Our findings thus describe a novel source of DNA damage in human cells. They also suggest that mitotic arrest may promote tumorigenesis and antimitotic toxicity by provoking DNA damage. [Cancer Res 2007;67(24):11487–92]
Efficacy and tissue distribution of DHP107, an oral paclitaxel formulation
Authors: Hong Jung Wan , Lee In-Hyun , Kwak Young Hak , Park Young Taek , Sung Ha Chin , Kwon Ick Chan , Chung Hesson
Published: December 2007

Paclitaxel is indispensable in treating human cancers. Due to poor drug solubility and efflux systems in the gastrointestinal tract, peroral delivery of paclitaxel has been a significant challenge. We developed a mucoadhesive oral formulation (DHP107) that can directly and effectively deliver paclitaxel to intestinal endothelial cells without concomitant use of P-glycoprotein inhibitors. Here, we evaluated the tissue distribution of paclitaxel, the antitumor efficacy and the absorption mechanism of DHP107. DHP107, which contains 10 mg/mL of paclitaxel in a mixture of monoolein, tricarprylin, and Tween 80 was administered p.o. to female BALB/c mice at a 50 mg/kg dose. Diluted Taxol was administered via bolus tail-vein injection at 10 mg/kg as a control. Blood and tissue samples were harvested at various time points and analyzed by high-performance liquid chromatography. Tissue sections were observed using light microscopy after immunohistochemical and Oil Red O staining. By day 27, tumor volume after DHP107 and Taxol treatments was one-third of that in the untreated group. After p.o. administration, paclitaxel was widely distributed in various organs (Tmax = 2 h), especially liver, spleen, and lung. DHP107 was effectively absorbed through the intestinal lipid transport system. DHP107 changed spontaneously into <100-μm droplets and micelles in the intestine, which in turn adhered to mucoepithelial cells, were absorbed via lipid uptake mechanism, and formed lipid bodies in the epithelium. Paclitaxel in DHP107 was effectively absorbed through the gastrointestinal tract via lipid uptake mechanism and was distributed in various tissues. The detailed uptake mechanism is currently under investigation. [Mol Cancer Ther 2007;6(12):3239–47]
Cytoreductive antitumor activity of PF-2341066, a novel inhibitor of anaplastic lymphoma kinase and c-Met, in experimental models of anaplastic large-cell lymphoma
Authors: Christensen James G. , Zou Helen Y. , Arango Maria E. , Li Qiuhua , Lee Joseph H. , McDonnell Scott R. , Yamazaki Shinji , Alton Gordon R. , Mroczkowski Barbara , Los Gerrit
Published: December 2007

A t(2;5) chromosomal translocation resulting in expression of an oncogenic kinase fusion protein known as nucleophosmin-anaplastic lymphoma kinase (NPM-ALK) has been implicated in the pathogenesis of anaplastic large-cell lymphoma (ALCL). PF-2341066 was recently identified as a p.o. bioavailable, small-molecule inhibitor of the catalytic activity of c-Met kinase and the NPM-ALK fusion protein. PF-2341066 also potently inhibited NPM-ALK phosphorylation in Karpas299 or SU-DHL-1 ALCL cells (mean IC50 value, 24 nmol/L). In biochemical and cellular screens, PF-2341066 was shown to be selective for c-Met and ALK at pharmacologically relevant concentrations across a panel of >120 diverse kinases. PF-2341066 potently inhibited cell proliferation, which was associated with G1-S–phase cell cycle arrest and induction of apoptosis in ALK-positive ALCL cells (IC50 values, ∼30 nmol/L) but not ALK-negative lymphoma cells. The induction of apoptosis was confirmed using terminal deoxyribonucleotide transferase–mediated nick-end labeling and Annexin V staining (IC50 values, 25–50 nmol/L). P.o. administration of PF-2341066 to severe combined immunodeficient-Beige mice bearing Karpas299 ALCL tumor xenografts resulted in dose-dependent antitumor efficacy with complete regression of all tumors at the 100 mg/kg/d dose within 15 days of initial compound administration. A strong correlation was observed between antitumor response and inhibition of NPM-ALK phosphorylation and induction of apoptosis in tumor tissue. In addition, inhibition of key NPM-ALK signaling mediators, including phospholipase C-γ, signal transducers and activators of transcription 3, extracellular signal-regulated kinases, and Akt by PF-2341066 were observed at concentrations or dose levels, which correlated with inhibition of NPM-ALK phosphorylation and function. Collectively, these data illustrate the potential clinical utility of inhibitors of NPM-ALK in treatment of patients with ALK-positive ALCL. [Mol Cancer Ther 2007;6(12):3314–22]
Zoledronic acid inhibits osteosarcoma growth in an orthotopic model
Authors: Dass Crispin R. , Choong Peter F.M.
Published: December 2007

Zoledronic acid (ZOL) has been shown to reduce osteolysis in bone metastasis. Its efficacy in osteosarcoma has not been convincingly proved in a clinically relevant model for the disease. In vitro, ZOL decreased osteosarcoma cell proliferation, mainly due to an increase in apoptosis in a dose-dependent fashion. There was a decrease in cell migration at ≥10 μmol/L concentrations, but invasion was inhibited at a much lower dose of 0.1 μmol/L. Reverse transcription-PCR showed that ZOL overall caused an increased expression of osteocalcin and decreased expression of alkaline phosphatase, osteopontin, osteonectin, and vascular endothelial growth factor, with no change in expression of osteoprotegerin. ZOL administration s.c. twice weekly at 0.12 mg/kg to SaOS-2 tumor–bearing mice resulted in primary tumor growth inhibition, reduction in lung metastases, and dramatic decrease in osteolysis. Furthermore, in the ZOL cohort, there was a clear reduction in the number of osteoclasts in bone exposed to tumor and a lower tumor vessel density. These data point to the adjuvant potential of ZOL in the management of osteosarcoma not only for its antiosteolytic properties but also for its ability to directly halt tumor cell growth and metastasis via its effects on viability, invasion, differentiation, and angiogenesis. [Mol Cancer Ther 2007;6(12):3263–70]
Lack of Association Between the
MEF2A
Gene and Myocardial Infarction
Authors: Lieb Wolfgang , Mayer Björn , König Inke R. , Borwitzky Iris , Götz Anika , Kain Silke , Hengstenberg Christian , Linsel-Nitschke Patrick , Fischer Marcus , Döring Angela , Wichmann H. -Erich , Meitinger Thomas , Kreutz Reinhold , Ziegler Andreas , Schunkert Heribert , Erdmann Jeanette
Published: December 2007

Background—

Coronary artery disease (CAD) and myocardial infarction (MI) are caused in part by genetic factors. Recently, the
MEF2A
gene was linked to MI/CAD in a single pedigree with autosomal-dominant pattern of inheritance. In addition, genetic variants within the gene have been associated with MI in case-control settings, producing inconsistent results.

Methods and Results—

The
MEF2A
gene was sequenced in MI patients from 23 MI families (≥5 affected members per family), but no mutation was identified in any of these extended families. Moreover, the Pro279Leu variant in exon 7 was analyzed in 1181 unrelated MI patients with a positive family history for MI/CAD, in 533 patients with sporadic MI, and in 2 control populations (n=1021 and n=1055), showing no evidence for association with MI/CAD. In addition, a (CAG)n repeat in exon 11 was genotyped in 543 sporadic MI patients and in 1190 controls without evidence for association with MI. Finally, analyzing 11 single-nucleotide polymorphisms from the GeneChip Mapping 500K Array, genotyped in 1644 controls and 753 cases, failed to provide evidence for association (region-wide
P
=0.23).

Conclusions—

Studying independent samples of >1700 MI patients, 2 large control populations, and multiple families with apparently mendelian inheritance of the disease, we found no evidence for any linkage or association signal in the
MEF2A
gene.
Mineralocorticoid Signaling in Transition to Heart Failure With Normal Ejection Fraction
Authors: Shapiro Brian P. , Owan Theophilus E. , Mohammed Selma , Kruger Martina , Linke Wolfgang A. , Burnett John C. , Redfield Margaret M.
Published: December 2007

Heart failure with normal ejection fraction occurs in elderly patients with hypertensive heart disease. We hypothesized that, in such patients, mineralocorticoid receptor activation accelerates the types of ventricular and vascular remodeling and dysfunction believed important in the transition to heart failure. We tested this hypothesis by administering deoxycorticosterone acetate (DOCA) without salt loading or nephrectomy to elderly dogs with experimental hypertension. Elderly dogs were made hypertensive by renal wrapping. After 5 weeks, dogs were randomly assigned to DOCA (1 mg/kg per day IM; old hypertensive [OH]+DOCA; n=11) or not (OH; n=11) for 3 weeks. At week 8, conscious echocardiography and hemodynamic assessment under anesthesia were performed. DOCA resulted in further increases in conscious blood pressure (
P
<0.05) without increases in cardiac output or diastolic volume. In the conscious state, effective arterial elastance (
P
<0.05) and systemic vascular resistance (
P
=0.06) were increased, and systemic arterial compliance (
P
<0.05) was decreased in OH+DOCA animals. After anesthesia, instrumentation, and autonomic blockade, blood pressure was lower, whereas left ventricular (LV) systolic elastance, LV diastolic stiffness, and ex vivo myofiber diastolic stiffness were increased in OH+DOCA animals. LV collagen was increased in OH+DOCA animals (
P
<0.05 for all), but LV mass, LV brain natriuretic peptide, and titin isoform profiles were not. Neither aortic stiffness nor aortic structure was altered in OH+DOCA animals. These findings suggest that age and hypertensive heart disease enhance sensitivity to exogenous mineralocorticoid administration and that mineralocorticoid receptor activation could contribute to the transition to heart failure in elderly persons by promoting increases in LV diastolic and systolic stiffness.
Marriage Patterns and Social Stratification in Present Hadrami Arab Societies in Central and Eastern Indonesia
Authors: Jacobsen Frode
Published: December 2007

While Hadrami Arabs in Indonesia still maintain some unique Hadrami customs and identify themselves as Hadrami (albeit not exclusively), the degree to which they have become assimilated into the general Muslim population is a question open for debate. Although the findings presented in this article does not provide any evidence for the strength of the present processes of assimilation (or indigenization), it presents some clear recent trends in marriage patterns of relevance to the debate, among Hadramis in some central and eastern Indonesian towns.
Internet-Mediated Experiences of Underdevelopment: A Four-Country Survey of Academia
Authors: ThOmpson Eric
Published: December 2007

Professional academics in Indonesia, Malaysia, Singapore and the United States have significantly different subjective experiences of Internet use. This difference appears not only in substantial inequalities of access, but also in a higher level of expectation and value placed on the Internet among Indonesians and secondarily Malaysians. These results, from a survey and interviews of teachers and researchers in the social sciences and humanities, are analyzed in the context of dependency theory within knowledge economies. While inadequate and unequal access to information and communication technology is a substantial problem, the article argues that emphasizing access, resource and skills development alone will not solve academic and other more general dependencies within knowledge economies. Rather, a simultaneous — if sometimes conflicting — emphasis on both infrastructural development and de-centered production of knowledge is called for.