bluuebunny/crossref_metadata_2025_split huggingface dataset:
Role of drug transporters and drug accumulation in the temporal acquisition of drug resistance
Authors: Hembruff Stacey L , Laberge Monique L , Villeneuve David J , Guo Baoqing , Veitch Zachary , Cecchetto Melanie , Parissenti Amadeo M 
Published: November 2008

Abstract

Background
Anthracyclines and taxanes are commonly used in the treatment of breast cancer. However, tumor resistance to these drugs often develops, possibly due to overexpression of drug transporters. It remains unclear whether drug resistance in vitro occurs at clinically relevant doses of chemotherapy drugs and whether both the onset and magnitude of drug resistance can be temporally and causally correlated with the enhanced expression and activity of specific drug transporters. To address these issues, MCF-7 cells were selected for survival in increasing concentrations of doxorubicin (MCF-7DOX-2), epirubicin (MCF-7EPI), paclitaxel (MCF-7TAX-2), or docetaxel (MCF-7TXT). During selection cells were assessed for drug sensitivity, drug uptake, and the expression of various drug transporters.

Results
In all cases, resistance was only achieved when selection reached a specific threshold dose, which was well within the clinical range. A reduction in drug uptake was temporally correlated with the acquisition of drug resistance for all cell lines, but further increases in drug resistance at doses above threshold were unrelated to changes in cellular drug uptake. Elevated expression of one or more drug transporters was seen at or above the threshold dose, but the identity, number, and temporal pattern of drug transporter induction varied with the drug used as selection agent. The pan drug transporter inhibitor cyclosporin A was able to partially or completely restore drug accumulation in the drug-resistant cell lines, but had only partial to no effect on drug sensitivity. The inability of cyclosporin A to restore drug sensitivity suggests the presence of additional mechanisms of drug resistance.

Conclusion
This study indicates that drug resistance is achieved in breast tumour cells only upon exposure to concentrations of drug at or above a specific selection dose. While changes in drug accumulation and the expression of drug transporters does occur at the threshold dose, the magnitude of resistance cannot be attributed solely to changes in drug accumulation or the activity of drug transporters. The identities of these additional drug-transporter-independent mechanisms are discussed, including their likely clinical relevance.
Spontaneous transformation of human granulosa cell tumours into an aggressive phenotype: a metastasis model cell line
Authors: Imai Misa , Muraki Miho , Takamatsu Kiyoshi , Saito Hidekazu , Seiki Motoharu , Takahashi Yuji 
Published: November 2008

Abstract

Background
Granulosa cell tumours (GCTs) are frequently seen in menopausal women and are relatively indolent. Although the physiological properties of normal granulosa cells have been studied extensively, little is known about the molecular mechanism of GCT progression. Here, we characterise the unique behavioural properties of a granulosa tumour cell line, KGN cells, for the molecular analysis of GCT progression.

Methods
Population doubling was carried out to examine the proliferation capacity of KGN cells. Moreover, the invasive capacity of these cells was determined using the in vitro invasion assay. The expression level of tumour markers in KGN cells at different passages was then determined by Western blot analysis. Finally, the growth and metastasis of KGN cells injected subcutaneously (s.c.) into nude mice was observed 3 months after injection.

Results
During in vitro culture, the advanced passage KGN cells grew 2-fold faster than the early passage cells, as determined by the population doubling assay. Moreover, we found that the advanced passage cells were 2-fold more invasive than the early passage cells. The expression pattern of tumour markers, such as p53, osteopontin, BAX and BAG-1, supported the notion that with passage, KGN cells became more aggressive. Strikingly, KGN cells at both early and advanced passages metastasized to the bowel when injected s.c. into nude mice. In addition, more tumour nodules were formed when the advanced passage cells were implanted.

Conclusion
KGN cells cultured in vitro acquire an aggressive phenotype, which was confirmed by the analysis of cellular activities and the expression of biomarkers. Interestingly, KGN cells injected s.c. are metastatic with nodule formation occurring mostly in the bowel. Thus, this cell line is a good model for analysing GCT progression and the mechanism of metastasis in vivo.
The association between C-reactive protein and the likelihood of progression to joint replacement in people with rheumatoid arthritis: a retrospective observational study
Authors: Poole Chris D , Conway Pete , Reynolds Alan , Currie Craig J 
Published: November 2008

Abstract

Background
This study sought to evaluate the association between systemic inflammation as measured by C-reactive protein and total joint replacement and the association between change in CRP status (low, ≤ 10 mg/L and high, >10 mg/L) measured over one year and total joint replacement in patients diagnosed with rheumatoid arthritis.

Methods
A cohort of patients was selected from The Health Improvement Network (THIN) dataset of anonymised patient-level data from UK general practice with a confirmed chronic rheumatic diagnosis. Surgery-free survival was evaluated using Cox proportional hazards regression models (CPHM).

Results
2,421 cases had at least one CRP measurement of which 125 cases (5.2%) had at least one major joint replacement. In CPHM, each additional unit increase in log mean CRP (range 1 to 6) was associated with a hazard ratio (HR) for major orthopaedic surgery of 1.36 (95% CI 1.10 to 1.67; p = 0.004), after controlling for age at first rheumatoid presentation and average body mass index over the same observation period. Repeated CRP observations around one year apart were recorded in 1,314 subjects. After controlling for confounding factors, in cases whose CRP remained high (>10 mg/L), the HR for joint replacement increased more than two-fold (p = 0.040) relative to cases whose CRP remained low. In patients whose CRP increased from low to high, the HR was 1.86 compared to those who remained in a low state (p = 0.217). By comparison, among those subjects whose CRP was reduced from a high to low state, the hazard ratio was more than halved (1.46) from to those who remained high (p = 0.441). Although underpowered, the trend evident from CRP change corroborates the association of TJR progression with mean CRP.

Conclusion
CRP level predicts progression to major joint replacement after standardisation for relevant risk factors as did change in CRP status between low and high states observed over one year.
Implications of computer tomography measurement in the management of renal tumours
Authors: Mistry Rahul , Manikandan Ramaswamy , Williams Penny , Philip Joe , Littler Peter , Foster Christopher S , Parsons Keith F 
Published: November 2008

Abstract

Background
To compare radiographic measurement and pathological measurement of renal tumours to see if there was a significant difference between the two as this may have implications in the management.

Methods
We retrospectively analyzed CT measurements of 106 consecutive patients who underwent either radical or nephron sparing surgery in our institution and compared this to the actual measurement of the surgical specimen. The largest axial measurement was compared as this is the primary consideration before offering either treatment modality.

Results
The mean age of the patients was 64 years (range 31–92). There were 76 males and 30 females. The median tumour size was 70 mm (range 16–175) on CT and 65 mm (range 15–90) on pathological measurement. 25 patients had a CT size ≤ 40 mm. CT tended to overestimate the size of tumours in 41 patients, underestimate in 45 and agree with surgical size in 20 patients. Statistically there was no significant difference between the two measurements (p = 0.7, Wilcoxon sign ranked test). When subdivided into tumours less than 40 mm (p = 0.7) and more than 40 mm (p = 0.09) again there was no statistically significant difference between the two measurements. However in 5(5%) patients who were not offered nephron sparing surgery based on CT findings (size > 40 mm) the pathological size was ≤ 40 mm (p = < 0.001, Fishers Exact test). Pathologically the tumours were classified as renal cell carcinoma (n = 98), angiomyolipoma (3), and oncocytoma (5).

Conclusion
CT measurement of renal tumour size correlates well with the actual size of the tumour. However CT does tend to overestimate the size in a small number of patients which may have a bearing on the modality of treatment offered.
Exposure to mobile telecommunication networks assessed using personal dosimetry and well-being in children and adolescents: the German MobilEe-study
Authors: Thomas Silke , Kühnlein Anja , Heinrich Sabine , Praml Georg , von Kries Rüdiger , Radon Katja 
Published: November 2008

Abstract

Background
Despite the increase of mobile phone use in the last decade and the growing concern whether mobile telecommunication networks adversely affect health and well-being, only few studies have been published that focussed on children and adolescents. Especially children and adolescents are important in the discussion of adverse health effects because of their possibly higher vulnerability to radio frequency electromagnetic fields.

Methods
We investigated a possible association between exposure to mobile telecommunication networks and well-being in children and adolescents using personal dosimetry. A population-based sample of 1.498 children and 1.524 adolescents was assembled for the study (response 52%). Participants were randomly selected from the population registries of four Bavarian (South of Germany) cities and towns with different population sizes. During a Computer Assisted Personal Interview data on participants' well-being, socio-demographic characteristics and potential confounder were collected. Acute symptoms were assessed three times during the study day (morning, noon, evening).
Using a dosimeter (ESM-140 Maschek Electronics), we obtained an exposure profile over 24 hours for three mobile phone frequency ranges (measurement interval 1 second, limit of determination 0.05 V/m) for each of the participants. Exposure levels over waking hours were summed up and expressed as mean percentage of the ICNIRP (International Commission on Non-Ionizing Radiation Protection) reference level.

Results
In comparison to non-participants, parents and adolescents with a higher level of education who possessed a mobile phone and were interested in the topic of possible adverse health effects caused by mobile telecommunication network frequencies were more willing to participate in the study. The median exposure to radio frequency electromagnetic fields of children and adolescents was 0.18% and 0.19% of the ICNIRP reference level respectively.

Conclusion
In comparison to previous studies this is one of the first to assess the individual level of exposure to mobile telecommunication networks using personal dosimetry, enabling objective assessment of exposure from all sources and longer measurement periods. In total, personal dosimetry was proofed to be a well accepted tool to study exposure to mobile phone frequencies in epidemiologic studies including health effects on children and adolescents.
Concentrations versus amounts of biomarkers in urine: a comparison of approaches to assess pyrethroid exposure
Authors: Fortin Marie-Chantale , Carrier Gaétan , Bouchard Michèle 
Published: November 2008

Abstract

Background
Assessment of human exposure to non-persistent pesticides such as pyrethroids is often based on urinary biomarker measurements. Urinary metabolite levels of these pesticides are usually reported in volume-weighted concentrations or creatinine-adjusted concentrations measured in spot urine samples. It is known that these units are subject to intra- and inter-individual variations. This research aimed at studying the impact of these variations on the assessment of pyrethroid absorbed doses at individual and population levels.

Methods
Using data obtained from various adult and infantile populations, the intra and inter-individual variability in the urinary flow rate and creatinine excretion rate was first estimated. Individual absorbed doses were then calculated using volume-weighted or creatinine-adjusted concentrations according to published approaches and compared to those estimated from the amounts of biomarkers excreted in 15- or 24-h urine collections, the latter serving as a benchmark unit. The effect of the units of measurements (volume-weighted or creatinine adjusted concentrations or 24-h amounts) on results of the comparison of pyrethroid biomarker levels between two populations was also evaluated.

Results
Estimation of daily absorbed doses of permethrin from volume-weighted or creatinine-adjusted concentrations of biomarkers was found to potentially lead to substantial under or overestimation when compared to doses reconstructed directly from amounts excreted in urine during a given period of time (-70 to +573% and -83 to +167%, respectively). It was also shown that the variability in creatinine excretion rate and urinary flow rate may introduce a bias in the case of between population comparisons.

Conclusion
The unit chosen to express biomonitoring data may influence the validity of estimated individual absorbed dose as well as the outcome of between population comparisons.
Spatial heterogeneity of malaria in Indian reserves of Southwestern Amazonia, Brazil
Authors: Souza-Santos Reinaldo , de Oliveira Maurício VG , Escobar Ana Lúcia , Santos Ricardo Ventura , Coimbra Carlos EA 
Published: November 2008

Abstract

Background
Malaria constitutes a major cause of morbidity in the Brazilian Amazon where an estimated 6 million people are considered at high risk of transmission. Indigenous peoples in the Amazon are particularly vulnerable to potentially epidemic disease such as malaria; notwithstanding, very little is known about the epidemiology of malaria in Indian reservations of the region. The aim of this paper is to present a spatial analysis of malaria cases over a four-year time period (2003–2006) among indigenous peoples of the Brazilian State of Rondônia, southwestern Amazon, by using passive morbidity data (results from Giemsa-stained thick blood smears) gathered from the National Malaria Epidemiologic Surveillance System databank.

Results
A total of 4,160 cases of malaria were recorded in 14 Indian reserves in the State of Rondônia between 2003 and 2006. In six reservations no cases of malaria were reported in the period. Overall, P. vivax accounted for 76.18 of malaria cases reported in the indigenous population of Rondônia. The P. vivax/P. falciparum ratio for the period was 3.78. Two reserves accounted for over half of the cases reported for the total indigenous population in the period – Roosevelt and Pacaas Novas – with a total of 1,646 (39.57%) and 1,145 (27.52%) cases, respectively. Kernel mapping of malaria mean Annual Parasite Index – API according to indigenous reserves and environmental zones revealed a heterogeneous pattern of disease distribution, with one clear area of high risk of transmission comprising reservations of west Rondônia along the Guaporé-Madeira River basins, and another high risk area to the east, on the Roosevelt reserve.

Conclusion
By means of kernel mapping, it was shown that malaria risk varies widely between Indian reserves and environmental zones defined on the basis of predominant ecologic characteristics and land use patterns observed in the southwestern Brazilian Amazon. The geographical approach in this paper helped to determine where the greatest needs lie for more intensively focused malaria control activities in Indian reserves in the region. It also provided a reference to assess the effectiveness of control measures that have been put in place by Brazilian public health authorities.
Bifidobacterium strains suppress in vitro the pro-inflammatory milieu triggered by the large intestinal microbiota of coeliac patients
Authors: Medina Marcela , De Palma Giada , Ribes-Koninckx Carmen , Calabuig Miguel , Sanz Yolanda 
Published: November 2008

AbstractBackgroundCoeliac disease (CD) is an enteropathy characterized by an aberrant immune response to cereal-gluten proteins. Although gluten peptides and microorganisms activate similar pro-inflammatory pathways, the role the intestinal microbiota may play in this disorder is unknown. The purpose of this study was to assess whether the faecal microbiota of coeliac patients could contribute to the pro-inflammatory milieu characteristic of CD and the possible benefits of bifidobacteria.MethodsThe effect of faeces of 26 CD patients with active disease (mean age 5.5 years, range 2.1–12.0 years), 18 symptom-free coeliac disease (SFCD) patients (mean age 5.5 years, range 1.0–12.3 years) on a gluten-free diet for 1–2 years; and 20 healthy children (mean age 5.3 years, range 1.8–10.8 years) on induction of cytokine production and surface antigen expression in peripheral blood mononuclear cells (PBMCs) were determined. The possible regulatory roles ofBifidobacterium longumES1 andB. bifidumES2 co-incubated with faecal samples were also assessedin vitro.ResultsFaeces of both active CD and SFCD patients, representing an imbalanced microbiota, significantly increased TNF-α production and CD86 expression in PBMCs, while decreased IL-10 cytokine production and CD4 expression compared with control samples. Active CD-patient samples also induced significantly higher IFN-γ production compared with controls. However,Bifidobacteriumstrains suppressed the pro-inflammatory cytokine pattern induced by the large intestinal content of CD patients and increased IL-10 production. Cytokine effects induced by faecal microbiota seemed to be mediated by the NFκB pathway.ConclusionThe intestinal microbiota of CD patients could contribute to the Th1 pro-inflammatory milieu characteristic of the disease, whileB. longumES1 andB. bifidumES2 could reverse these deleterious effects. These findings hold future perspectives of interest in CD therapy.
Three-dimensional growth as multicellular spheroid activates the proangiogenic phenotype of colorectal carcinoma cells via LFA-1-dependent VEGF: implications on hepatic micrometastasis
Authors: Valcárcel María , Arteta Beatriz , Jaureguibeitia Arrate , Lopategi Aritz , Martínez Iñigo , Mendoza Lorea , Muruzabal Francisco J , Salado Clarisa , Vidal-Vanaclocha Fernando 
Published: November 2008

AbstractBackgroundThe recruitment of vascular stromal and endothelial cells is an early event occurring during cancer cell growth at premetastatic niches, but how the microenvironment created by the initial three-dimensional (3D) growth of cancer cells affects their angiogenesis-stimulating potential is unclear.MethodsThe proangiogenic profile of CT26 murine colorectal carcinoma cells was studied in seven-day cultured 3D-spheroids of <300 μm in diameter, produced by the hanging-drop method to mimic the microenvironment of avascular micrometastases prior to hypoxia occurrence.ResultsSpheroid-derived CT26 cells increased vascular endothelial growth factor (VEGF) secretion by 70%, which in turn increased thein vitromigration of primary cultured hepatic sinusoidal endothelium (HSE) cells by 2-fold. More importantly, spheroid-derived CT26 cells increased lymphocyte function associated antigen (LFA)-1-expressing cell fraction by 3-fold; and soluble intercellular adhesion molecule (ICAM)-1, given to spheroid-cultured CT26 cells, further increased VEGF secretion by 90%, via cyclooxygenase (COX)-2-dependent mechanism. Consistent with these findings, CT26 cancer cells significantly increased LFA-1 expression in non-hypoxic avascular micrometastases at their earliest inception within hepatic lobulesin vivo; and angiogenesis also markedly increased in both subcutaneous tumors and hepatic metastases produced by spheroid-derived CT26 cells.Conclusion3D-growthper seenriched the proangiogenic phenotype of cancer cells growing as multicellular spheroids or as subclinical hepatic micrometastases. The contribution of integrin LFA-1 to VEGF secretion via COX-2 was a micro environmental-related mechanism leading to the pro-angiogenic activation of soluble ICAM-1-activated colorectal carcinoma cells. This mechanism may represent a new target for specific therapeutic strategies designed to block colorectal cancer cell growth at a subclinical micrometastatic stage within the liver.
Intragenic transcriptional cis-activation of the human immunodeficiency virus 1 does not result in allele-specific inhibition of the endogenous gene
Authors: De Marco Alex , Biancotto Chiara , Knezevich Anna , Maiuri Paolo , Vardabasso Chiara , Marcello Alessandro 
Published: November 2008

Abstract

Background
The human immunodeficiency virus type 1 (HIV-1) favors integration in active genes of host chromatin. It is believed that transcriptional interference of the viral promoter over the endogenous gene or vice versa might occur with implications in HIV-1 post-integrative transcriptional latency.

Results
In this work a cell line has been transduced with a HIV-based vector and selected for Tat-inducible expression. These cells were found to carry a single silent integration in sense orientation within the second intron of the HMBOX1 gene. The HIV-1 Tat transactivator induced the viral LTR and repressed HMBOX1 expression independently of vector integration. Instead, single-cell quantitative in situ hybridization revealed that allele-specific transcription of HMBOX1 carrying the integrated provirus was not affected by the transactivation of the viral LTR in cis.

Conclusion
A major observation of the work is that the HIV-1 genome has inserted in genes that are also repressed by Tat and this could be an advantage for the virus during transcriptional reactivation. In addition, it has also been observed that transcription of the provirus and of the endogenous gene in which it is integrated may coexist at the same time in the same genomic location.