The life history of 21 breast cancers.

Cancer evolves dynamically as clonal expansions supersede one another driven by shifting selective pressures, mutational processes, and disrupted cancer genes. These processes mark the genome, such that a cancer's life history is encrypted in the somatic mutations present. We developed algorithms to decipher this narrative and applied them to 21 breast cancers. Mutational processes evolve across a cancer's lifespan, with many emerging late but contributing extensive genetic variation. Subclonal diversification is prominent, and most mutations are found in just a fraction of tumor cells. Every tumor has a dominant subclonal lineage, representing more than 50% of tumor cells. Minimal expansion of these subclones occurs until many hundreds to thousands of mutations have accumulated, implying the existence of long-lived, quiescent cell lineages capable of substantial proliferation upon acquisition of enabling genomic changes. Expansion of the dominant subclone to an appreciable mass may therefore represent the final rate-limiting step in a breast cancer's development, triggering diagnosis

Properties and customization of sensor materials for biomedical applications.

Low-power chemo- and biosensing devices capable of monitoring clinically important parameters in real time represent a great challenge in the analytical field as the issue of sensor calibration pertaining to keeping the response within an accurate calibration domain is particularly significant (1–4). Diagnostics, personal health, and related costs will also benefit from the introduction of sensors technology (5–7). In addition, with the introduction of Registration, Evaluation, Authorization, and Restriction of Chemical Substances (REACH) regulation, unraveling the cause–effect relationships in epidemiology studies will be of outmost importance to help establish reliable environmental policies aimed at protecting the health of individuals and communities (8–10). For instance, the effect of low concentration of toxic elements is seldom investigated as physicians do not have means to access the data (11)

Mass transfer resistance in a liquid-phase microextraction employing a single hollow fiber under unsteady-state conditions

In this study, the mass transport resistance in liquid-phase microextraction (LPME) in a single hollow fiber was investigated. A mathematical model has been developed for the determination of the overall mass transfer coefficient based on the acceptor phase in an unsteady state. The overall mass transfer coefficient in LPME in a single hollow fiber has been estimated from time-dependent concentration of extracted analyte in the acceptor phase while maintaining a constant analyte concentration in the donor phase. It can be achieved either using a high volume of donor to acceptor phase ratio or tuning the extraction conditions to obtain a low-enrichment factor, so that the analyte concentration in the sample is not significantly influenced by the mass transfer. Two extraction systems have been used to test experimentally the developed model: the extraction of Lu(III) from a buffer solution and the extraction of three local anesthetics from a buffer or plasma solution. The mass transfer resistance, defined as a reciprocal values of the mass transfer coefficient, was found to be 1.2 x 103 cm-1 min for Lu(III) under optimal conditions and from 1.96 to 3.3 x 103 cm-1 min for the local anesthetics depending on the acceptor pH and the hydrophobicity of the drug

Tumor specific VEGF-A and VEGFR2/KDR protein are co-expressed in breast cancer

Angiogenesis is a prognostic indicator in primary breast cancer regulated by specific angiogenic factors and their receptors. Vascular endothelial growth factor-A (VEGF-A), so far considered the most important, acts through dimerization of the receptor VEGFR2/KDR within the receptor tyrosine kinase family of VEGF receptors. In order to study the interplay between VEGF-A and VEGFR2/KDR in breast cancer we evaluated their expression by immunohistochemistry in 102 breast cancers organized in a tumor tissue array system allowing semi-quantitative evaluation of cytoplasmatic staining intensity. In addition, VEGF-A(165) was analyzed by an enzyme immuno assay (ELISA) in protein extracts prepared from frozen tissue from 98 of 102 tumors included in the array. Cytoplasmatic staining of VEGF of varying intensity was observed in all samples and correlated with the ELISA results of VEGF content (p=0.007). Interestingly, VEGFR2/KDR expression correlated with VEGF expression using immunohistochemistry, indicating that VEGF and VEGFR2/KDR may be co-expressed in breast cancer. Furthermore, high levels of VEGF-A(165) in the protein extracts was associated with impaired short time survival but not long term survival whereas immunohistochemically assessed VEGF and VEGFR2/KDR were not significantly associated with survival. In summary, immunohistochemically based analysis of VEGF using a tumor tissue array system seems to be a useful method for VEGF quantification in breast cancer here validated using an ELISA based method. The tumor tissue array system enables opportunities of simultaneous analysis of markers engaged in angiogenesis justifying further studies using larger series of tumors

P27Kip1 is a predictive factor for tamoxifen treatment response but not a prognostic marker in premenopausal breast cancer patients

The cell cycle regulating protein p27(Kip1) (p27) has dual roles by acting as both a cdk-inhibitor and as an assembly factor for different cdk-complexes. Loss of p27 has been linked to malignant features in tumours, however the exact role of p27 deregulation in breast cancer regarding prognostic and treatment predictive information has not been fully clarified. We have evaluated p27 expression in 328 primary, stage II breast cancers from premenopausal patients who had been randomised to either tamoxifen treatment or no adjuvant treatment after surgery. p27 was associated with the oestrogen receptor (ER) and cyclin D1, and p27 downregulation was associated with high proliferation. There was no association between recurrence-free-survival (RFS) and p27 (HR=0.800, 95%CI 0.523-1.222, p=0.300), indicating that p27 is not a prognostic marker. The predictive value of p27 was analysed by comparing RFS in tamoxifen treated and untreated patients in subgroups of low and high p27 expression (HR=0.747, 95%CI 0.335-1.664, p=0.474 and HR=0.401, 95%CI 0.240-0.670, p<0.001, respectively). Only patients with p27 high tumours benefited from tamoxifen (multivariate interaction analysis p=0.034). Our study suggests that p27 downregulation is associated with tamoxifen resistance in premenopausal breast cancer but is not linked to impaired prognosis. (c) 2010 UICC

Voxel-wise body composition analysis using image registration of a three-slice CT imaging protocol : methodology and proof-of-concept studies

Background Computed tomography (CT) is an imaging modality commonly used for studies of internal body structures and very useful for detailed studies of body composition. The aim of this study was to develop and evaluate a fully automatic image registration framework for inter-subject CT slice registration. The aim was also to use the results, in a set of proof-of-concept studies, for voxel-wise statistical body composition analysis (Imiomics) of correlations between imaging and non-imaging data.Methods The current study utilized three single-slice CT images of the liver, abdomen, and thigh from two large cohort studies, SCAPIS and IGT. The image registration method developed and evaluated used both CT images together with image-derived tissue and organ segmentation masks. To evaluate the performance of the registration method, a set of baseline 3-single-slice CT images (from 2780 subjects including 8285 slices) from the SCAPIS and IGT cohorts were registered. Vector magnitude and intensity magnitude error indicating inverse consistency were used for evaluation. Image registration results were further used for voxel-wise analysis of associations between the CT images (as represented by tissue volume from Hounsfield unit and Jacobian determinant) and various explicit measurements of various tissues, fat depots, and organs collected in both cohort studies.Results Our findings demonstrated that the key organs and anatomical structures were registered appropriately. The evaluation parameters of inverse consistency, such as vector magnitude and intensity magnitude error, were on average less than 3 mm and 50 Hounsfield units. The registration followed by Imiomics analysis enabled the examination of associations between various explicit measurements (liver, spleen, abdominal muscle, visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT), thigh SAT, intermuscular adipose tissue (IMAT), and thigh muscle) and the voxel-wise image information.Conclusion The developed and evaluated framework allows accurate image registrations of the collected three single-slice CT images and enables detailed voxel-wise studies of associations between body composition and associated diseases and risk factors

The stem cell regulator PEDF is dispensable for maintenance and function of hematopoietic stem cells

Pigment epithelium derived factor (PEDF), a ubiquitously expressed 50 kDa secreted glycoprotein, was recently discovered to regulate self-renewal of neural stem cells and have a supportive effect on human embryonic stem cell growth. Here, we analyzed expression of PEDF in the murine hematopoietic stem cell (HSC) compartments and found that PEDF is highly expressed in primary long-term HSCs. Therefore, we characterized the hematopoietic system in a knockout mouse model for PEDF and using this model we surprisingly found that PEDF is dispensable for HSC regulation. PEDF knockout mice exhibit normal hematopoiesis in steady state conditions and the absence of PEDF lead to normal regeneration capacity in a serial competitive transplantation setting. Additionally, PEDF-deficient cells exhibit unaltered lineage distribution upon serial transplantations. When human cord blood stem and progenitor cells were cultured in media supplemented with recombinant PEDF they did not show changes in growth potential. Taken together, we report that PEDF is not a critical regulatory factor for HSC function during regeneration in vivo or growth of human stem/progenitor cells in vitro.Funding Agencies|Hemato-Linne grant (Swedish Research Council Linnaeus); STEMTHERAPY (Swedish Research Council); Swedish Cancer Society (Cancerfonden); Swedish Childhood Cancer Foundation; Swedish Research Council; Royal Swedish Academy of Sciences - Tobias Foundation; Lund University Hospital (ALF grant); Royal Physiographic Society in Lund (Kungliga Fysiograftska sallskapet); center of excellence grant in Life Sciences from the Swedish Foundation for Strategic Research</p

Long-term cost and effect on quality of life of osteoporosis-related fractures in Sweden

Background and purpose Few economic or quality-of-life studies have investigated the long-term consequences of fragility fractures. This prospective observational data collection study assessed the cost and quality of life related to hip, vertebral, and wrist fracture 13-18 months after the fracture, based on 684 patients surviving 18 months after fracture. Patients and methods Data regarding resource use and quality of life related to fractures was collected using questionnaires at 7 research centers in Sweden. Information was collected using patient records, register sources, and by asking the patient. Quality of life was estimated using the EQ-5D questionnaire. Direct and indirect costs were estimated from a societal standpoint. Results The mean fracture-related cost 13-18 months after a hip, vertebral, or wrist fracture were estimated to be (sic)2,422, (sic)3,628, and (sic)316, respectively. Between 12 and 18 months after hip, vertebral, and wrist fracture, utility increased by 0.03, 0.05, and 0.02, respectively. Compared to prefracture levels, the mean loss in quality of life between 13 and 18 months after fracture was estimated to be 0.05, 0.11, and 0.005 for hip, vertebral, and wrist fracture. Interpretation The sample of vertebral fracture patients was fairly small and included a high proportion of fractures leading to hospitalization, but the results indicate higher long-term costs and greater loss in quality of life related to vertebral fracture than previously believed