bluuebunny/crossref_metadata_2025 huggingface dataset:
Integrated Profiling of Basal and Luminal Breast Cancers
Authors: Adélaïde José , Finetti Pascal , Bekhouche Ismahane , Repellini Laetitia , Geneix Jeannine , Sircoulomb Fabrice , Charafe-Jauffret Emmanuelle , Cervera Nathalie , Desplans Jérôme , Parzy Daniel , Schoenmakers Eric , Viens Patrice , Jacquemier Jocelyne , Birnbaum Daniel , Bertucci François , Chaffanet Max
Published: December 2007

Basal and luminal are two molecular subtypes of breast cancer with opposite histoclinical features. We report a combined, high-resolution analysis of genome copy number and gene expression in primary basal and luminal breast cancers. First, we identified and compared genomic alterations in 45 basal and 48 luminal tumors by using 244K oligonucleotide array comparative genomic hybridization (aCGH). We found various genome gains and losses and rare high-level gene amplifications that may provide therapeutic targets. We show that gain of 10p is a new alteration in basal breast cancer and that a subregion of the 8p12 amplification is specific of luminal tumors. Rare high-level amplifications contained BCL2L2, CCNE, EGFR, FGFR2, IGF1R, NOTCH2, and PIK3CA. Potential gene breaks involved ETV6 and FLT3. Second, we analyzed both aCGH and gene expression profiles for 42 basal and 32 luminal breast cancers. The results support the existence of specific oncogenic pathways in basal and luminal breast cancers, involving several potential oncogenes and tumor suppressor genes (TSG). In basal tumors, 73 candidate oncogenes were identified in chromosome regions 1q21-23, 10p14, and 12p13 and 28 candidate TSG in regions 4q32-34 and 5q11-23. In luminal breast cancers, 33 potential oncogenes were identified in 1q21-23, 8p12-q21, 11q13, and 16p12-13 and 61 candidate TSG in 16q12-13, 16q22-24, and 17p13. HORMAD1 (P = 6.5 × 10−5) and ZNF703 (P = 7 × 10−4) were the most significant basal and luminal potential oncogenes, respectively. Finally, among 10p candidate oncogenes associated with basal subtype, we validated CDC123/C10orf7 protein as a basal marker. [Cancer Res 2007;67(24):11565–75]
Ada3 Requirement for HAT Recruitment to Estrogen Receptors and Estrogen-Dependent Breast Cancer Cell Proliferation
Authors: Germaniuk-Kurowska Aleksandra , Nag Alo , Zhao Xiangshan , Dimri Manjari , Band Hamid , Band Vimla
Published: December 2007

We have previously shown that evolutionarily conserved alteration/deficiency in activation (Ada) protein associates with and promotes estrogen receptor (ER)–mediated target gene expression. Here, we examined the role of endogenous Ada3 to recruit histone acetyl transferases (HAT) to an ER-responsive promoter and its role in estrogen-dependent cell proliferation and malignant phenotype. Using a combination of glycerol gradient cosedimentation and immunoprecipitation analyses, we show that Ada3, ER, and three distinct HATs [p300, (p300/CBP-associated factor) PCAF, and general control nonrepressed 5 (Gcn5)] are present in a complex. Using chromatin immunoprecipitation analysis, we show that short hairpin RNA (shRNA)–mediated knockdown of Ada3 in ER-positive breast cancer cells significantly reduced the ligand-dependent recruitment of p300, PCAF, and Gcn5 to the ER-responsive pS2 promoter. Finally, we use shRNA knockdown to show that Ada3 is critical for estrogen-dependent proliferation of ER-positive breast cancer cell lines in two-dimensional, as well as three-dimensional, culture. Knockdown of Ada3 in ER-positive MCF-7 cells induced reversion of the transformed phenotype in three-dimensional culture. Thus, our results show an important role of Ada3 in HAT recruitment to estrogen-responsive target gene promoters and for estrogen-dependent proliferation of breast cancer cells. [Cancer Res 2007;67(24):11789–97]
MUC1 Oncoprotein Regulates Bcr-Abl Stability and Pathogenesis in Chronic Myelogenous Leukemia Cells
Authors: Kawano Takeshi , Ito Masaki , Raina Deepak , Wu Zekui , Rosenblatt Jacalyn , Avigan David , Stone Richard , Kufe Donald
Published: December 2007

Chronic myelogenous leukemia (CML) results from expression of the Bcr-Abl fusion protein in hematopoietic stem cells. The MUC1 heterodimeric protein is aberrantly overexpressed in diverse human carcinomas. The present studies show that MUC1 is expressed in the human K562 and KU812 CML cell lines. The results show that MUC1 associates with Bcr-Abl through a direct interaction between the Bcr N-terminal region and the MUC1 cytoplasmic domain. Stable silencing of MUC1 decreased cytoplasmic Bcr-Abl levels by promoting Bcr-Abl degradation. Silencing MUC1 was also associated with decreases in K562 and KU812 cell self-renewal capacity and with a more differentiated erythroid phenotype. The results further show that silencing MUC1 increases sensitivity of CML cells to imatinib-induced apoptosis. Analysis of primary CML blasts confirmed that, as found with the CML cell lines, MUC1 blocks differentiation and the apoptotic response to imatinib treatment. These findings indicate that MUC1 stabilizes Bcr-Abl and contributes to the pathogenesis of CML cells by promoting self renewal and inhibiting differentiation and apoptosis. [Cancer Res 2007;67(24):11576–84]
Inhibition of Membrane-Type 1 Matrix Metalloproteinase at Cell-Matrix Adhesions
Authors: Takino Takahisa , Saeki Hiromi , Miyamori Hisashi , Kudo Tomoya , Sato Hiroshi
Published: December 2007

Membrane-type 1 matrix metalloproteinase (MT1-MMP) has been implicated in tumor invasion and metastasis. We previously reported that extracellular matrix degradation by MT1-MMP regulates cell migration via modulating sustained integrin-mediated signals. In this study, MT1-MMP–expressing cells were plated onto fibronectin-coated plates and monitored for cell-matrix adhesion formation and fibronectin degradation. The fibronectin was degraded and removed in line with the cell migration track. The migrating cells showed a polarized morphology and were in contact with the edge of fibronectin through the leading edge, in which cell-matrix adhesions are concentrated. Expression of MT1-MMP targeted to cell-matrix adhesions by fusing with the focal adhesion targeting (FAT) domain of focal adhesion kinase (FAK) promoted the initial fibronectin lysis at the cell periphery immediately after adhesion. These results suggest that fibronectin is degraded by MT1-MMP located at cell-matrix adhesions, which are concentrated at the leading edge of the migrating cells. To inhibit MT1-MMP at cell-matrix adhesion, the dominant negative form of MT1-MMP (MT1-Pex) was targeted to the cell-matrix adhesion by fusing with the FAT domain (MT1-Pex-FAT). MT1-Pex-FAT accumulated at cell-matrix adhesions and inhibited fibronectin degradation as well as FAK phosphorylation more effectively than parental MT1-Pex. MT1-Pex-FAT was also shown to suppress the invasion of tumor cells into three-dimensional collagen gel more strongly than MT1-Pex. These results suggest that MT1-MMP–mediated extracellular matrix lysis at cell-matrix adhesions induces the establishment of cell polarity, which facilitates cell-matrix adhesion turnover and subsequent cell migration. This model highlights the role of MT1-MMP at the leading edge of migrating cells. [Cancer Res 2007;67(24):11621–9]
Caspase-8 Interacts with the p85 Subunit of Phosphatidylinositol 3-Kinase to Regulate Cell Adhesion and Motility
Authors: Senft Jamie , Helfer Brooke , Frisch Steven M.
Published: December 2007

Cell migration plays an important role in tumor cell invasion and metastasis. Previously, we reported that caspase-8 contributes to cell migration and adhesion, a novel nonapoptotic function of an established apoptotic factor. Herein, we report that pro-caspase-8 is capable of restoring cell migration/adhesion to caspase-8-null cells, establishing the first biological function of a pro-caspase. The catalytic activity of caspase-8 was not required for cell motility. Stimulation of motility with epidermal growth factor induced the phosphorylation of caspase-8 on tyrosine-380 and the interaction of caspase-8 with the p85α subunit of phosphatidylinositol 3-kinase. Tyrosine-380 was required for the restoration of cell motility and cell adhesion in caspase-8-null cells, demonstrating the importance of the caspase-8–p85 interaction for these nonapoptotic functions. These results suggest that caspase-8 phosphorylation converts it from a proapoptotic factor to a cell motility factor that, through tyrosine-380, interacts with p85, an established cell migration component. [Cancer Res 2007;67(24):11505–9]
Kallikrein-binding protein inhibits growth of gastric carcinoma by reducing vascular endothelial growth factor production and angiogenesis
Authors: Zhu Baohe , Lu Lei , Cai Weibin , Yang Xia , Li Chaoyang , Yang Zhonghan , Zhan Wenhua , Ma Jian-xing , Gao Guoquan
Published: December 2007

Kallikrein-binding protein (KBP) has been identified as an endogenous angiogenic inhibitor. We previously showed that KBP inhibited rat retinal neovascularization by down-regulation of vascular endothelial growth factor (VEGF) in endothelial cells. However, its antiangiogenic potential for inhibition of gastric carcinoma and the effect on VEGF in tumor cells have not been elucidated. The present study was designed to investigate the effect of KBP on growth of gastric carcinoma and the possible molecular mechanism. Recombinant KBP dose dependently inhibited proliferation and induced apoptosis of endothelial cells, but no effect on proliferation and apoptosis of SGC-7901 gastric carcinoma cells. I.p. injection of KBP resulted in growth inhibition of both heterotopic and orthotopic gastric carcinoma xenografts at 61.4% and 52.3%, respectively. Microvessel density in tumor tissues treated with KBP was significantly decreased, suggesting that KBP suppressed tumor growth by antiangiogenesis. The expression and release of VEGF, a major angiogenic stimulator, were down-regulated by KBP in SGC-7901 cells and gastric carcinoma xenografts. RNA levels of VEGF in SGC-7901 cells were also decreased by KBP, thus suggesting the regulation at the transcriptional level. Therefore, hypoxia-inducible factor 1α (HIF-1α), a crucial transcriptional factor for VEGF expression, was examined in SGC-7901 cells treated by KBP. KBP reduced HIF-1α protein level and nuclear translocation, which may be responsible for the down-regulation of VEGF transcription. Down-regulation of VEGF expression and release in tumor cells through inhibiting HIF-1α, thus attenuating the paracrine effect of VEGF on endothelial cell proliferation and vascular permeability in tumor tissues, may represent a novel mechanism for the antiangiogenic and antitumor activity of KBP. [Mol Cancer Ther 2007;6(12):3297–306]
Inactivation of glycogen synthase kinase-3β contributes to brain-derived neutrophic factor/TrkB-induced resistance to chemotherapy in neuroblastoma cells
Authors: Li Zhijie , Tan Fei , Thiele Carol J.
Published: December 2007

Elucidating signaling pathways that mediate cell survival or apoptosis will facilitate the development of targeted therapies in cancer. In neuroblastoma tumors, brain-derived neurotrophic factor (BDNF) and its receptor TrkB are associated with poor prognosis. Our previous studies have shown that BDNF activation of TrkB induces resistance to chemotherapy via activation of phosphoinositide-3-kinase (PI3K)/Akt pathway. To study targets of PI3K/Akt that mediate protection from chemotherapy, we focused on glycogen synthase kinase-3β (GSK-3β), which is a known modulator of apoptosis. We used pharmacologic and genetic methods to study the role of GSK-3β in the BDNF/TrkB/PI3K/Akt protection of neuroblastoma from chemotherapy. BDNF activation of TrkB induced the Akt-dependent phosphorylation of GSK-3β, resulting in its inactivation. Treatment of neuroblastoma cells with inhibitors of GSK-3β, LiCl, GSK-3β inhibitor VII, kenpaullone, or a GSK-3β–targeted small interfering RNA (siRNA) resulted in a 15% to 40% increase in neuroblastoma cell survival after cytotoxic treatment. Transfection of neuroblastoma cells with a constitutively active GSK-3β S9A9 caused a 10% to 15% decrease in cell survival. Using real-time, dynamic measurements of cell survival, we found that 6 to 8 h after etoposide treatment was the period during which critical events regulating the induction of cell death or BDNF/TrkB-induced protection occurred. During this period, etoposide treatment was associated with the dephosphorylation and activation of GSK-3β in the mitochondria that was blocked by BDNF activation of TrkB. These data indicate that the inactivation of GSK-3β contributes to the BDNF/TrkB/PI3K/Akt protection of neuroblastoma cells from chemotherapy. [Mol Cancer Ther 2007;6(12):3113–21]
In vitro transport of gimatecan (7-t-butoxyiminomethylcamptothecin) by breast cancer resistance protein, P-glycoprotein, and multidrug resistance protein 2
Authors: Marchetti Serena , Oostendorp Roos L. , Pluim Dick , van Eijndhoven Monique , van Tellingen Olaf , Schinkel Alfred H. , Versace Richard , Beijnen Jos H. , Mazzanti Roberto , Schellens Jan H.
Published: December 2007

Lipophilic camptothecin derivatives are considered to have negligible affinity for breast cancer resistance protein (BCRP; ABCG2). Gimatecan, a new orally available 7-t-butoxyiminomethyl–substituted lipophilic camptothecin derivative, has been previously reported to be not a substrate for BCRP. Using a panel of in vitro models, we tested whether gimatecan is a substrate for BCRP as well as for P-glycoprotein (MDR1) or multidrug resistance protein 2 (MRP2; ABCC2), ATP-binding cassette drug efflux transporters involved in anticancer drug resistance, and able to affect the pharmacokinetics of substrate drugs. Cell survival, drug transport, accumulation, and efflux were studied in IGROV1 and (human BCRP overexpressing) T8 cells, Madin-Darby canine kidney II (MDCKII-WT, MDCKII-Bcrp1, MDCKII-MDR1, and MDCKII-MRP2), and LLCPK (LLCPK-WT and LLCPK-MDR1) cells. Competition with methotrexate uptake was studied in Sf9-BCRP membrane vesicles. In vitro, expression of BCRP resulted in 8- to 10-fold resistance to gimatecan. In Transwell experiments, gimatecan was transported by Bcrp1 and transport was inhibited by the BCRP/P-glycoprotein inhibitors elacridar and pantoprazole. Efflux of gimatecan from MDCKII-Bcrp1 cells was faster than in WT cells. In Sf9-BCRP membrane vesicles, gimatecan significantly inhibited BCRP-mediated transport of methotrexate. In contrast, gimatecan was not transported by MDR1 or MRP2. Gimatecan is transported by BCRP/Bcrp1 in vitro, although to a lesser extent than the camptothecin analogue topotecan. Implications of BCRP expression in the gut for the oral development of gimatecan and the interaction between gimatecan and other BCRP substrate drugs and/or inhibitors warrant further clinical investigation. [Mol Cancer Ther 2007;6(12):3307–13]
Initial Aspirin Dose and Outcome Among ST-Elevation Myocardial Infarction Patients Treated With Fibrinolytic Therapy
Authors: Berger Jeffrey S. , Stebbins Amanda , Granger Christopher B. , Ohman Eric M. , Armstrong Paul W. , Van de Werf Frans , White Harvey D. , Simes R. John , Harrington Robert A. , Califf Robert M. , Peterson Eric D.
Published: December 2007

Background—

Although treatment with immediate aspirin reduces morbidity and mortality in ST-elevation myocardial infarction, the optimal dose is unclear. We therefore compared the acute mortality and bleeding risks associated with the initial use of 162 versus 325 mg aspirin in fibrinolytic-treated ST-elevation myocardial infarction patients.

Methods and Results—

Using combined data from the Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO I) and Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO III) trials (n=48 422 ST-elevation myocardial infarction patients), we compared the association between initial aspirin dose of 162 versus 325 mg and 24-hour and 7-day mortality, as well as rates of in-hospital moderate/severe bleeding. Results were adjusted for previously identified mortality and bleeding risk factors. Overall, 24.4% of patients (n=11 828) received an initial aspirin dose of 325 mg, and 75.6% (n=36 594) received 162 mg. The 24-hour mortality rates were 2.9% versus 2.8% (
P
=0.894) for those receiving an initial aspirin dose of 325 versus 162 mg. Mortality rates at 7 and 30 days were 5.2% versus 4.9% (
P
=0.118) and 7.1% versus 6.5% (
P
=0.017) among patients receiving the 325 versus 162 mg aspirin. After adjustment, aspirin dose was not associated with 24-hour (odds ratio [OR], 1.01; 95% CI, 0.82 to 1.25), 7-day (OR, 1.00; 95% CI, 0.87 to 1.17), or 30-day (OR, 0.99; 95% CI, 0.87 to 1.12) mortality rates. No significant difference was noted for myocardial infarction or the composite of death or myocardial infarction between groups. In-hospital moderate/severe bleeding occurred in 9.3% of those treated with 325 mg versus 12.2% among those receiving 162 mg (
P
<0.001). After adjustment, 325 mg was associated with a significant increase in moderate/severe bleeding (OR, 1.14; 95% CI, 1.05 to 1.24;
P
=0.003).

Conclusion—

These data suggest that an initial dose of 162 mg aspirin may be as effective as and perhaps safer than 325 mg for the acute treatment of ST-elevation myocardial infarction.
Suppression of Cardiomyocyte Hypertrophy by Inhibition of the Ubiquitin-Proteasome System
Authors: Meiners Silke , Dreger Henryk , Fechner Mandy , Bieler Sven , Rother Wim , Günther Christoph , Baumann Gert , Stangl Verena , Stangl Karl
Published: December 2007

Inhibitors of the proteasome interfere with transcriptional regulation of growth signaling pathways and block cell cycle progression of mitotic cells. As growth signaling pathways are highly conserved between mitotic and postmitotic cells, we hypothesized that proteasome inhibition might also be a valuable approach to interfere with hypertrophic growth of postmitotic cardiomyocytes. To test this hypothesis, we analyzed the effects of proteasome inhibition on hypertrophic growth of neonatal rat cardiomyocytes. Partial inhibition of the proteasome effectively suppressed cardiomyocyte hypertrophy as determined by reduced cell size, inhibition of hypertrophy-mediated induction of RNA and protein synthesis, reduced expression of several hypertrophic marker genes, and diminished transcriptional activation of the BNP promotor. Importantly, suppression of hypertrophic growth was independent of the hypertrophic agonist used. Expressional profiling and subsequent Western blot and kinase assays revealed that proteasome inhibition induced a cellular stress response with reduced expression of conserved growth signaling mediators and impaired G1/S phase transition of cardiomyocytes. In hypertensive Dahl-salt sensitive rats, inhibition of the proteasome with low doses of the FDA approved proteasome inhibitor
Velcade
significantly reduced hypertrophic heart growth. Our data provide important insight into the suppressive effects of proteasome inhibitors on hypertrophic growth of cardiomyocytes and establish low-dose proteasome inhibition as a new and broad-spectrum approach to interfere with cardiac hypertrophy.
Lifestyle variables and the risk of myocardial infarction in the General Practice Research Database
Authors: Delaney Joseph AC , Daskalopoulou Stella S , Brophy James M , Steele Russell J , Opatrny Lucie , Suissa Samy
Published: December 2007

Background

The primary objective of this study is to estimate the association between body mass index (BMI) and the risk of first acute myocardial infarction (AMI). As a secondary objective, we considered the association between other lifestyle variables, smoking and heavy alcohol use, and AMI risk.

Methods

This study was conducted in the general practice research database (GPRD) which is a database based on general practitioner records and is a representative sample of the United Kingdom population. We matched cases of first AMI as identified by diagnostic codes with up to 10 controls between January 1st, 2001 and December 31st, 2005 using incidence density sampling. We used multiple imputation to account for missing data.

Results

We identified 19,353 cases of first AMI which were matched on index date, GPRD practice and age to 192,821 controls. There was a modest amount of missing data in the database, and the patients with missing data had different risks than those with recorded values. We adjusted our analysis for each lifestyle variable jointly and also for age, sex, and number of hospitalizations in the past year. Although a record of underweight (BMI <18.0 kg/m2) did not alter the risk for AMI (adjusted odds ratio (OR): 1.00; 95% confidence interval (CI): 0.87–1.11) when compared with normal BMI (18.0–24.9 kg/m2), obesity (BMI ≥30 kg/m2) predicted an increased risk (adjusted OR: 1.41; 95% CI: 1.35–1.47). A history of smoking also predicted an increased risk of AMI (adjusted OR: 1.81; 95% CI: 1.75–1.87) as did heavy alcohol use (adjusted OR: 1.15; 95% CI: 1.06–1.26).

Conclusion

This study illustrates that obesity, smoking and heavy alcohol use, as recorded during routine care by a general practitioner, are important predictors of an increased risk of a first AMI. In contrast, low BMI does not increase the risk of a first AMI.
Sphingomyelin phosphodiesterase-1 (SMPD1) coding variants do not contribute to low levels of high-density lipoprotein cholesterol
Authors: Dastani Zari , Ruel Isabelle L , Engert James C , Genest Jacques , Marcil Michel
Published: December 2007

Background

Niemann-Pick disease type A and B is caused by a deficiency of acid sphingomyelinase due to mutations in the sphingomyelin phosphodiesterase-1 (SMPD1) gene. In Niemann-Pick patients, SMPD1 gene defects are reported to be associated with a severe reduction in plasma high-density lipoprotein (HDL) cholesterol.

Methods

Two common coding polymorphisms in the SMPD1 gene, the G1522A (G508R) and a hexanucleotide repeat sequence within the signal peptide region, were investigated in 118 unrelated subjects of French Canadian descent with low plasma levels of HDL-cholesterol (< 5th percentile for age and gender-matched subjects). Control subjects (n = 230) had an HDL-cholesterol level > the 25th percentile.

Results

For G1522A the frequency of the G and A alleles were 75.2% and 24.8% respectively in controls, compared to 78.6% and 21.4% in subjects with low HDL-cholesterol (p = 0.317). The frequency of 6 and 7 hexanucleotide repeats was 46.2% and 46.6% respectively in controls, compared to 45.6% and 49.1% in subjects with low HDL-cholesterol (p = 0.619). Ten different haplotypes were observed in cases and controls. Overall haplotype frequencies in cases and controls were not significantly different.

Conclusion

These results suggest that the two common coding variants at the SMPD1 gene locus are not associated with low HDL-cholesterol levels in the French Canadian population.
Use of comparative data for integrated cancer services
Authors: Wilkinson Dawn L , McCarthy Mark
Published: December 2007

Background

Comparative data are an important resource for management of integrated care. In 2001, the English Department of Health created 34 cancer networks, broadly serving populations of half to three million people, to coordinate cancer services across providers. We have investigated how national and regional routine data are used by the cancer network management teams.

Methods

Telephone interviews using a standardised semi-structured questionnaire were conducted with 68 participants in 29 cancer network teams. Replies were analysed both quantitatively and qualitatively.

Results

While most network teams had a formal information strategy, data were used ad hoc more than regularly, and were not thought to be as influential in network decision making as other sources of information. Data collection was more prominent in information strategies than data use. Perceptions of data usefulness were mixed and there were worries over data quality, relevance, and potential misuse. Participants were receptive to the idea of a new limited dataset collating comparative data from currently available routine data sources. Few network structural factors were associated with data use, perceptions of current data, or receptivity to a new dataset.

Conclusion

Comparative data are underused for managing integrated cancer services in England. Managers would welcome more comparative data, but also desired data to be relevant, quality assured and contextualised, and for the teams to be better resourced for data use.
'I believe that the staff have reduced their closeness to patients': an exploratory study on the impact of HIV/AIDS on staff in four rural hospitals in Uganda
Authors: Dieleman Marjolein , Bwete Vincent , Maniple Everd , Bakker Mirjam , Namaganda Grace , Odaga John , van der Wilt Gert Jan
Published: December 2007

Background

Staff shortages could harm the provision and quality of health care in Uganda, so staff retention and motivation are crucial. Understanding the impact of HIV/AIDS on staff contributes to designing appropriate retention and motivation strategies. This research aimed 'to identify the influence of HIV/AIDS on staff working in general hospitals at district level in rural areas and to explore support required and offered to deal with HIV/AIDS in the workplace'. Its results were to inform strategies to mitigate the impact of HIV/AIDS on hospital staff.

Methods

A cross-sectional study with qualitative and quantitative components was implemented during two weeks in September 2005. Data were collected in two government and two faith-based private not-for-profit hospitals purposively selected in rural districts in Uganda's Central Region. Researchers interviewed 237 people using a structured questionnaire and held four focus group discussions and 44 in-depth interviews.

Results

HIV/AIDS places both physical and, to some extent, emotional demands on health workers. Eighty-six per cent of respondents reported an increased workload, with 48 per cent regularly working overtime, while 83 per cent feared infection at work, and 36 per cent reported suffering an injury in the previous year. HIV-positive staff remained in hiding, and most staff did not want to get tested as they feared stigmatization. Organizational responses were implemented haphazardly and were limited to providing protective materials and the HIV/AIDS-related services offered to patients. Although most staff felt motivated to work, not being motivated was associated with a lack of daily supervision, a lack of awareness on the availability of HIV/AIDS counselling, using antiretrovirals and working overtime. The specific hospital context influenced staff perceptions and experiences.

Conclusion

HIV/AIDS is a crucially important contextual factor, impacting on working conditions in various ways. Therefore, organizational responses should be integrated into responses to other problematic working conditions and adapted to the local context. Opportunities already exist, such as better use of supervision, educational sessions and staff meetings. However, exchanges on interventions to improve staff motivation and address HIV/AIDS in the health sector are urgently required, including information on results and details of the context and implementation process.
Complement activation in Ghanaian children with severe Plasmodium falciparum malaria
Authors: Helegbe Gideon K , Goka Bamenla Q , Kurtzhals Joergen AL , Addae Michael M , Ollaga Edwin , Tetteh John KA , Dodoo Daniel , Ofori Michael F , Obeng-Adjei George , Hirayama Kenji , Awandare Gordon A , Akanmori Bartholomew D
Published: December 2007

Background

Severe anaemia (SA), intravascular haemolysis (IVH) and respiratory distress (RD) are severe forms of Plasmodium falciparum malaria, with RD reported to be of prognostic importance in African children with malarial anaemia. Complement factors have been implicated in the mechanism leading to excess anaemia in acute P. falciparum infection.

Methods

The direct Coombs test (DCT) and flow cytometry were used to investigate the mean levels of RBC-bound complement fragments (C3d and C3bαβ) and the regulatory proteins [complement receptor 1 (CD35) and decay accelerating factor (CD55)] in children with discrete clinical forms of P. falciparum malaria. The relationship between the findings and clinical parameters including coma, haemoglobin (Hb) levels and RD were investigated.

Results

Of the 484 samples tested, 131(27%) were positive in DCT, out of which 115/131 (87.8%) were positive for C3d alone while 16/131 (12.2%) were positive for either IgG alone or both. 67.4% of the study population were below 5 years of age and DCT positivity was more common in this age group relative to children who were 5 years or older (Odds ratio, OR = 3.8; 95%CI, 2.2–6.7, p < 0.001). DCT correlated significantly with RD (β = -304, p = 0.006), but multiple regression analysis revealed that, Hb (β = -0.341, p = 0.012) and coma (β = -0.256, p = 0.034) were stronger predictors of RD than DCT (β = 0.228, p = 0.061). DCT was also not associated with IVH, p = 0.19, while spleen size was inversely correlated with Hb (r = -402, p = 0.001). Flow cytometry showed similar mean fluorescent intensity (MFI) values of CD35, CD55 and C3bαβ levels on the surfaces of RBC in patients and asymptomatic controls (AC). However, binding of C3bαβ correlated significantly with CD35 or CD55 (p < 0.001).

Conclusion

These results suggest that complement activation contributed to anaemia in acute childhood P. falciparum malaria, possibly through induction of erythrophagocytosis and haemolysis. In contrast to other studies, this study did not find association between levels of the complement regulatory proteins, CD35 and CD55 and malarial anaemia. These findings suggest that complement activation could also be involved in the pathogenesis of RD but larger studies are needed to confirm this finding.
Species-Specific Pharmacology of Trichloro(Sulfanyl)ethyl Benzamides as Transient Receptor Potential Ankyrin 1 (TRPA1) Antagonists
Authors: Klionsky Lana , Tamir Rami , Gao BaoXi , Wang Weiya , Immke David C , Nishimura Nobuko , Gavva Narender R
Published: December 2007

Agonists of TRPA1 such as mustard oil and its key component AITC cause pain and neurogenic inflammation in humans and pain behavior in rodents. TRPA1 is activated by numerous reactive compounds making it a sensor for reactive compounds in the body. Failure of AITC, formalin and other reactive compounds to trigger pain behavior in TRPA1 knockout mice, as well as the ability of TRPA1 antisense to alleviate cold hyperalgesia after spinal nerve ligation, suggest that TRPA1 is a potential target for novel analgesic agents. Here, we have characterized CHO cells expressing human and rat TRPA1 driven by an inducible promoter. As reported previously, both human and rat TRPA1 are activated by AITC and inhibited by ruthenium red. We have also characterized noxious cold response of these cell lines and show that noxious cold activates both human and rat TRPA1. Further, we have used CHO cells expressing human TRPA1 to screen a small molecule compound library and discovered that ‘trichloro(sulfanyl)ethyl benzamides’ (AMG2504, AMG5445, AMG7160 and AMG9090) act as potent antagonists of human TRPA1 activated by AITC and noxious cold. However, trichloro(sulfanyl)ethyl benzamides' (TCEB compounds) displayed differential pharmacology at rat TRPA1. AMG2504 and AMG7160 marginally inhibited rat TRPA1 activation by AITC, whereas AMG5445 and AMG9090 acted as partial agonists. In summary, we conclude that both human and rat TRPA1 channels show similar AITC and noxious cold activation profiles, but TCEB compounds display species-specific differential pharmacology at TRPA1.
A prospective pilot clinical trial evaluating the utility of a dynamic near-infrared imaging device for characterizing suspicious breast lesions
Authors: Xu Ronald X , Young Donn C , Mao Jimmy J , Povoski Stephen P
Published: December 2007

Introduction

Characterizing and differentiating between malignant tumors, benign tumors, and normal breast tissue is increasingly important in the patient presenting with breast problems. Near-infrared diffuse optical imaging and spectroscopy is capable of measuring multiple physiologic parameters of biological tissue systems and may have clinical applications for assessing the development and progression of neoplastic processes, including breast cancer. The currently available application of near-infrared imaging technology for the breast, however, is compromised by low spatial resolution, tissue heterogeneity, and interpatient variation.

Materials and methods

We tested a dynamic near-infrared imaging schema for the characterization of suspicious breast lesions identified on diagnostic clinical ultrasound. A portable handheld near-infrared tissue imaging device (P-Scan; ViOptix Inc., Fremont, CA, USA) was utilized. An external mechanical compression force was applied to breast tissue. The tissue oxygen saturation and hemoglobin concentration were recorded simultaneously by the handheld near-infrared imaging device. Twelve categories of dynamic tissue parameters were derived based on real-time measurements of the tissue hemoglobin concentration and the oxygen saturation.

Results

Fifty suspicious breast lesions were evaluated in 48 patients. Statistical analyses were carried out on 36 out of 50 datasets that satisfied our inclusion criteria. Suspicious breast lesions identified on diagnostic clinical ultrasound had lower oxygenation and higher hemoglobin concentration than the surrounding normal breast tissue. Furthermore, histopathologic-proven malignant breast tumors had a lower differential hemoglobin contrast (that is, the difference of hemoglobin concentration variability between the suspicious breast lesion and the normal breast parenchyma located remotely elsewhere within the ipsilateral breast) as compared with histopathologic-proven benign breast lesions.

Conclusion

The proposed dynamic near-infrared imaging schema has the potential to differentiate benign processes from those of malignant breast tumors. Further development and refinement of the dynamic imaging device and additional subsequent clinical testing are necessary for optimizing the accuracy of detection.
Survival After a Psychoeducational Intervention for Patients With Cutaneous Malignant Melanoma: A Replication Study
Authors: Boesen Ellen H. , Boesen Sidsel H. , Frederiksen Kirsten , Ross Lone , Dahlstrøm Karin , Schmidt Grethe , Næsted Jesper , Krag Christen , Johansen Christoffer
Published: December 2007

Purpose

The results of a randomized, intervention study done in 1993 of psychoeducation for patients with early-stage malignant melanoma showed a beneficial effect on recurrence and survival 6 years after the intervention. In the present study, we replicated the study with 258 Danish patients with malignant melanoma. We also compared recurrence and survival among the participants in the randomized study with 137 patients who refused to participate.

Patients and Methods

We randomly assigned 262 patients with primary malignant melanoma to a control or an intervention group. Patients in the intervention group were offered six weekly 2-hour sessions of psychoeducation. Participants and nonparticipants were followed up for vital status and recurrence 4 to 6 years after surgical treatment. Prognostic factors (thickness of the tumor and lymph node status), sex, and age were adjusted for in a Cox regression model (proportional hazards regression) to derive an adjusted survival rate ratio and an adjusted relapse-free survival rate ratio, with 95% CIs.

Results

The hazard ratio was 1.30 (95% CI, 0.5 to 3.5) for survival and 0.73 (95% CI, 0.3 to 1.9) for recurrence. Being a nonparticipant increased the risk for death by more than two-fold (hazard ratio, 2.26; 95% CI, 1.0 to 5.2) over that of participants.

Conclusion

Psychoeducation did not increase survival or the recurrence-free interval among patients with malignant melanoma; however, nonparticipants had a statistically significantly greater risk for death than participants.
Sustained Remissions of High-Risk Acute Myeloid Leukemia and Myelodysplastic Syndrome After Reduced-Intensity Conditioning Allogeneic Hematopoietic Transplantation: Chronic Graft-Versus-Host Disease Is the Strongest Factor Improving Survival
Authors: Valcárcel David , Martino Rodrigo , Caballero Dolores , Martin Jesus , Ferra Christelle , Nieto Jose B. , Sampol Antonia , Bernal M. Teresa , Piñana Jose L. , Vazquez Lourdes , Ribera Jose M. , Besalduch Joan , Moraleda Jose M. , Carrera Dolores , Brunet M. Salut , Perez-Simón Jose A. , Sierra Jorge
Published: December 2007

Purpose

Reduced-intensity conditioning (RIC) for allogeneic stem-cell transplantation (allo-SCT) reduces nonrelapse mortality (NRM). This reduction makes it possible for patients who are ineligible for high-dose myeloablative conditioning allo-SCT to benefit from graft-versus-leukemia reaction. In this multicenter, prospective study of patients with acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS), we investigated the efficacy of RIC allo-SCT from a human leukocyte antigen–identical sibling by using a regimen that uses fludarabine and busulfan.

Patients and Methods

Ninety-three patients with AML (n = 59) and MDS (n = 34) were included, and the median age was of 53 years. Follow-up for survivors was 43 months (range, 3 to 89 months). The conditioning regimen consisted of fludarabine (150 mg/m2) and oral busulfan (8 to 10 mg/kg). All except one patient received mobilized peripheral blood stem cells. Graft-versus-host disease (GVHD) prophylaxis consisted of cyslosporine and methotrexate or mycophenolate mofetil.

Results

The 100-day, 1-year, and 4-year incidences of NRM were 8, 16%, and 21%, respectively. The 1- and 4-year relapse cumulative incidences were 23% and 37%, respectively, and leukemia recurrence was the main cause of death. The 4-year disease-free survival (DFS) and overall survival (OS) rates were 43% and 45%, respectively. The 4-year cumulative incidence of chronic GVHD was 53% (45% extensive), and its development was the major factor associated with lower relapse incidence and improved DFS and OS.

Conclusion

Our results confirm the capacity of this RIC regimen to obtain long-term remissions in patients ineligible for a conventional allo-SCT. The results suggest an important role of the development of chronic GVHD in reducing relapse and improving DFS and OS.
Survival After Adjuvant Oophorectomy and Tamoxifen in Operable Breast Cancer in Premenopausal Women
Authors: Love Richard R. , Van Dinh Nguyen , Quy Tran Tu , Linh Nguyen Dieu , Tung Nguyen Dinh , Shen Tien-zhen , Hade Erinn M. , Young Gregory S. , Jarjoura David
Published: December 2007

Purpose

Worldwide, approximately 750,000 new cases of breast cancer are diagnosed annually in premenopausal women with limited economic resources. Longer-term survival benefits from adjuvant therapies in such women with operable breast cancer are unknown.

Patients and Methods

From 1993 to 1999, we recruited 709 premenopausal women with operable breast cancer to a multisite randomized clinical trial of adjuvant oophorectomy and tamoxifen for 5 years or observation and this combined hormonal therapy on recurrence.

Results

With a median follow-up of 7.0 years, disease-free and overall survival were significantly improved with the adjuvant treatment (log-rank P = .0003 and .0002, respectively). Five year disease-free survival (DFS) probabilities of 74% and 61% (95% CI for difference, 7% to 21%) and overall survival (OS) rates of 78% and 71% (95% CI for difference, 1% to 21%) were observed in the adjuvant and observation groups. Ten-year DFS probabilities of 62% and 51% (95% CI for difference, 4% to 22%) and OS probabilities of 70% and 52% (95% CI for difference, 6% to 34%) between adjuvant and observation groups, respectively, were observed. In the subset of estrogen receptor–positive patients, 5-year DFS probabilities were 83% and 61%, and 10-year DFS probabilities were 66% and 47%, while 5-year OS probabilities were 88% and 74%, and 10-year OS probabilities were 82% and 49% in the adjuvant and observation groups, respectively.

Conclusion

In premenopausal women with operable breast cancer not selected for estrogen receptor status or with estrogen receptor–positive tumors, 5- and 10-year DFS and OS rates are significantly improved following adjuvant oophorectomy and tamoxifen.
Symptoms and Patient-Reported Well-Being: Do They Predict Survival in Malignant Pleural Mesothelioma? A Prognostic Factor Analysis of EORTC-NCIC 08983: Randomized Phase III Study of Cisplatin With or Without Raltitrexed in Patients With Malignant Pleural Mesothelioma
Authors: Bottomley Andrew , Coens Corneel , Efficace Fabio , Gaafar Rabab , Manegold Christian , Burgers Sjaak , Vincent Mark , Legrand Catherine , van Meerbeeck Jan P.
Published: December 2007

Purpose

Malignant pleural mesothelioma (MPM) is a rare disease. Unlike other advanced cancer types, little is known about patient-reported symptoms or health-related quality of life (HRQOL) and their possible prognostic value. This study reports an evaluation of the prognostic value of these factors using data gathered from a recent randomized controlled trial.

Patients and Methods

Patients were entered onto this trial if they had a histologically proven unresectable MPM, not pretreated with chemotherapy, WHO performance status ≤ 2, and adequate hematologic, renal, and hepatic function. Patients were randomly assigned to receive cisplatin 80 mg/m2 intravenously on day 1, without or with preceding infusion of raltitrexed 3 mg/m2. HRQOL was assessed using the European Organisation for Research and Treatment of Cancer (EORTC) QLQ-C30/Lung Cancer 13 tool. The Cox proportional hazards regression model was used for the univariate and multivariate analyses of survival, along with a bootstrap validation technique. Included were the EORTC prognostic index (PI) composed of stage of disease, histology type, time since diagnosis, and WBC, and, in addition, 10 selected key symptoms and HRQOL scales.

Results

Two hundred fifty patients were randomly assigned (80% male; median age, 58 years; WHO performance status 0, 1, 2 in 25%, 62%, and 13% of cases, respectively). Two hundred twenty-nine patients (91.6%) had a valid HRQOL assessment. The final multivariate model retained the PI, pain (P < .0001), and appetite loss (P = .0100) as independent prognostic indicators of survival.

Conclusion

Results suggest that the PI, pain, and appetite loss may be independent prognostic factors in patients with advanced MPM.
Randomized Phase II Study of Gemcitabine Plus Cisplatin or Carboplatin, With or Without Cetuximab, As First-Line Therapy for Patients With Advanced or Metastatic Non–Small-Cell Lung Cancer
Authors: Butts Charles A. , Bodkin David , Middleman Edward L. , Englund Craig W. , Ellison David , Alam Yasmin , Kreisman Harvey , Graze Peter , Maher James , Ross Helen J. , Ellis Peter M. , McNulty William , Kaplan Edward , Pautret Virginie , Weber Martin R. , Shepherd Frances A.
Published: December 2007

Purpose

To evaluate the efficacy of cetuximab added to first-line gemcitabine/platinum in chemotherapy-naïve patients with advanced non–small-cell lung cancer (NSCLC).

Patients and Methods

In this noncomparative, randomized trial, chemotherapy-naïve patients with recurrent/metastatic NSCLC (stage IV or stage IIIB with malignant pleural effusion) were eligible. Patients received cisplatin (75 mg/m2 IV, every 3 weeks) or carboplatin (area under the concentration-versus-time curve of 5 intravenously [IV], every 3 weeks), and gemcitabine (1,250 or 1,000 mg/m2 IV, days 1 and 8) plus cetuximab (400 mg/m2 IV day 1, followed by 250 mg/m2 weekly), in arm A, or chemotherapy alone, in arm B. Response rate was the primary end point; safety, progression-free survival, and overall survival were secondary end points.

Results

Sixty-five patients were randomly assigned to arm A and 66 to arm B. Partial responses were observed in 18 patients (27.7%; 95% CI, 17.3 to 40.2) in arm A and 12 (18.2%; 95% CI, 9.8 to 29.6) in arm B. Median progression-free survival was 5.09 months for arm A (95% CI, 4.17 to 5.98) and 4.21 months (95% CI, 3.81 to 5.49) in arm B. Median overall survival was 11.99 months (95% CI, 8.80 to 15.18) and 9.26 months (95% CI, 7.43 to 11.79) in arms A and B, respectively. Overall toxicity was acceptable and consistent with the profiles of the individual agents.

Conclusion

First-line treatment with cetuximab plus gemcitabine/platinum is well tolerated and can be administered safely in patients with advanced NSCLC. Differences in response rate, progression-free survival, and overall survival suggest that the addition of cetuximab to platinum/gemcitabine may improve clinical outcomes. Larger studies are in progress to address this hypothesis.
Involvement of Family Physicians in the Care of Cancer Patients Seen in the Palliative Rapid Response Radiotherapy Program
Authors: Barnes Elizabeth A. , Fan Grace , Harris Kristin , Doyle Meagan , Librach Lawrence S. , Chow Edward , Barbera Lisa , Tsao May , Lam Kelvin , Danjoux Cyril
Published: December 2007

Purpose

It is important for cancer patients to maintain continuity of care with their family physician (FP) while being followed at the cancer center. The primary objective of this study was to determine the perception of patients seen in the palliative Rapid Response Radiotherapy Program (RRRP) on FP involvement in their cancer care. Secondary objectives were to identify factors predicting for perceived FP involvement in patient cancer care.

Patients and Methods

Consecutive patients were approached for study enrollment at the time of RRRP visit and asked to complete a 15-item survey.

Results

Three hundred sixty-five patients were accrued over 15 months. Ninety-eight percent had an FP, and 43% felt their FP was involved in their cancer care. Eighty percent of patients were satisfied with the overall medical care provided by their FP, and 71% had been with their FP for ≥ 5 years. The most common reason patients gave for perceiving limited FP involvement was the medical oncologist looking after all of their cancer needs. Multivariate analysis found that satisfaction with overall medical care provided by the FP, shorter time since last FP visit, seeing the FP since cancer diagnosis, and FP providing on-call service for after-hour emergencies all significantly predicted for patients perceiving FP involvement in their cancer care.

Conclusion

Less than half of patients surveyed perceived their FP as involved in their cancer care. Encouraging continuity of care between patients and FPs may allow for easier transition of care back to the FP once palliative treatment at the cancer center has finished and help facilitate end-of-life planning.