3D culture reveals a signaling network

The behavior of a cell is significantly influenced by its context. Epithelial cells derived from glandular organs such as the breast recreate their glandular organization when grown under 3D culture conditions. While traditional monolayer cultures are powerful tools to understand how cells proliferate, grow and respond to stress, they do not recreate the 3D property observed in vivo. Multiple studies demonstrate that 3D organization can reveal novel and unexpected insights into the mechanisms by which normal and tumorderived epithelial cells function. In the present article we comment on a study that reports identification of a RasV12-induced IL-6 signaling network in mammary epithelial cells in 3D cultures

UGT1A and TYMS genetic variants predict toxicity and response of colorectal cancer patients treated with first-line irinotecan and fluorouracil combination therapy

BACKGROUND: The impact of thymidylate synthase (TYMS) and UDP-glucoronosyltransferase 1A (UGT1A) germline polymorphisms on the outcome of colorectal cancer (CRC) patients treated with irinotecan plus 5-fluorouracil (irinotecan/5FU) is still controversial. Our objective was to define a genetic-based algorithm to select patients to be treated with irinotecan/5FU. METHODS: Genotyping of TYMS (5'TRP and 3'UTR), UGT1A1*28, UGT1A9*22 and UGT1A7*3 was performed in 149 metastatic CRC patients treated with irinotecan/5FU as first-line chemotherapy enrolled in a randomised phase 3 study. Their association with response, toxicity and survival was investigated by univariate and multivariate statistical analysis. RESULTS: TYMS 3TRP/3TRP genotype was the only independent predictor of tumour response (OR=5.87, 95% confidence interval (CI)=1.68-20.45; P=0.005). UGT1A1*28/*28 was predictive for haematologic toxicity (OR=6.27, 95% CI=1.09-36.12; P=0.04), specifically for neutropenia alone (OR=6.40, 95% CI=1.11-37.03; P=0.038) or together with diarrhoea (OR=18.87, 95% CI=2.14-166.67; P=0.008). UGT1A9*1/*1 was associated with non-haematologic toxicity (OR=2.70, 95% CI=1.07-6.82; P=0.035). Haplotype VII (all non-favourable alleles) was associated with non-haematologic toxicity (OR=2.11, 95% CI-1.12-3.98; P-0.02). CONCLUSION: TYMS and UGT1A polymorphisms influence on tumour response and toxicities derived from irinotecan/5FU treatment in CRC patients. A genetic-based algorithm to optimise treatment individualisation is proposed. British Journal of Cancer (2010) 103, 581-589. doi:10.1038/sj.bjc.6605776 www.bjcancer.com Published online 13 July 2010 (C) 2010 Cancer Research U

The epidemiology of malaria in adults in a rural area of southern Mozambique

BACKGROUND: Epidemiological studies of malaria in adults who live in malaria endemic areas are scarce. More attention to the natural history of malaria affecting adults is needed to understand the dynamics of malaria infection and its interaction with the immune system. The present study was undertaken to investigate the clinical, parasitological and haematological status of adults exposed to malaria, and to characterize parasites in these individuals who progressively acquire protective immunity. METHODS: A cross-sectional survey of 249 adults was conducted in a malaria endemic area of Mozambique. Clinical, parasitological and haematological status of the study population was recorded. Sub-microscopic infections and multiplicity of infections were investigated using polymerase chain reaction (PCR) and restriction fragment length polymorphism of Plasmodium falciparum merozoite surface protein 2 (msp2). RESULTS: Prevalence of P. falciparum infection by microscopy (14%) and PCR (42%) decreased progressively during adulthood, in parallel with an increase in the prevalence of sub-microscopic infections. Anaemia was only related to parasitaemia as detected by PCR. Multiplicity of infection decreased with age and was higher in subjects with high P. falciparum densities, highlighting density-dependent constraints upon the PCR technique. CONCLUSION: Adults of Manhiça progressively develop non-sterile, protective immunity against P. falciparum malaria. The method of parasite detection has a significant effect on the observed natural history of malaria infections. A more sensitive definition of malaria in adults should be formulated, considering symptoms such as diarrhoea, shivering and headache, combined with the presence of parasitaemia

HIPPIE: Integrating Protein Interaction Networks with Experiment Based Quality Scores

Protein function is often modulated by protein-protein interactions (PPIs) and therefore defining the partners of a protein helps to understand its activity. PPIs can be detected through different experimental approaches and are collected in several expert curated databases. These databases are used by researchers interested in examining detailed information on particular proteins. In many analyses the reliability of the characterization of the interactions becomes important and it might be necessary to select sets of PPIs of different confidence levels. To this goal, we generated HIPPIE (Human Integrated Protein-Protein Interaction rEference), a human PPI dataset with a normalized scoring scheme that integrates multiple experimental PPI datasets. HIPPIE's scoring scheme has been optimized by human experts and a computer algorithm to reflect the amount and quality of evidence for a given PPI and we show that these scores correlate to the quality of the experimental characterization. The HIPPIE web tool (available at http://cbdm.mdc-berlin.de/tools/hippie) allows researchers to do network analyses focused on likely true PPI sets by generating subnetworks around proteins of interest at a specified confidence level

Contribution of Recipient-Derived Cells in Allograft Neointima Formation and the Response to Stent Implantation

Allograft coronary disease is the dominant cause of increased risk of death after cardiac transplantation. While the percutaneous insertion of stents is the most efficacious revascularization strategy for allograft coronary disease there is a high incidence of stent renarrowing. We developed a novel rabbit model of sex-mismatched allograft vascular disease as well as the response to stent implantation. In situ hybridization for the Y-chromosome was employed to detect male cells in the neointima of stented allograft, and the population of recipient derived neointimal cells was measured by quantitative polymerase chain reaction and characterized by immunohistochemistry. To demonstrate the participation of circulatory derived cells in stent neointima formation we infused ex vivo labeled peripheral blood mononuclear cells into native rabbit carotid arteries immediately after stenting. Fourteen days after stenting the neointima area was 58% greater in the stented vs. non-stented allograft segments (p = 0.02). Male cells were detected in the neointima of stented female-to-male allografts. Recipient-derived cells constituted 72.1±5.7% and 81.5±4.2% of neointimal cell population in the non-stented and stented segments, respectively and the corresponding proliferation rates were only 2.7±0.5% and 2.3±0.2%. Some of the recipient-derived neointimal cells were of endothelial lineage. The ex vivo tagged cells constituted 9.0±0.4% of the cells per high power field in the stent neointima 14 days after stenting. These experiments provide important quantitative data regarding the degree to which host-derived blood-borne cells contribute to neointima formation in allograft vasculopathy and the early response to stent implantation

Observation of associated near-side and away-side long-range correlations in √sNN=5.02 TeV proton-lead collisions with the ATLAS detector

Two-particle correlations in relative azimuthal angle (Δϕ) and pseudorapidity (Δη) are measured in √sNN=5.02  TeV p+Pb collisions using the ATLAS detector at the LHC. The measurements are performed using approximately 1  μb-1 of data as a function of transverse momentum (pT) and the transverse energy (ΣETPb) summed over 3.1<η<4.9 in the direction of the Pb beam. The correlation function, constructed from charged particles, exhibits a long-range (2<|Δη|<5) “near-side” (Δϕ∼0) correlation that grows rapidly with increasing ΣETPb. A long-range “away-side” (Δϕ∼π) correlation, obtained by subtracting the expected contributions from recoiling dijets and other sources estimated using events with small ΣETPb, is found to match the near-side correlation in magnitude, shape (in Δη and Δϕ) and ΣETPb dependence. The resultant Δϕ correlation is approximately symmetric about π/2, and is consistent with a dominant cos⁡2Δϕ modulation for all ΣETPb ranges and particle pT

Jet energy measurement with the ATLAS detector in proton-proton collisions at root s=7 TeV

The jet energy scale and its systematic uncertainty are determined for jets measured with the ATLAS detector at the LHC in proton-proton collision data at a centre-of-mass energy of √s = 7TeV corresponding to an integrated luminosity of 38 pb-1. Jets are reconstructed with the anti-kt algorithm with distance parameters R=0. 4 or R=0. 6. Jet energy and angle corrections are determined from Monte Carlo simulations to calibrate jets with transverse momenta pT≥20 GeV and pseudorapidities {pipe}η{pipe}<4. 5. The jet energy systematic uncertainty is estimated using the single isolated hadron response measured in situ and in test-beams, exploiting the transverse momentum balance between central and forward jets in events with dijet topologies and studying systematic variations in Monte Carlo simulations. The jet energy uncertainty is less than 2. 5 % in the central calorimeter region ({pipe}η{pipe}<0. 8) for jets with 60≤pT<800 GeV, and is maximally 14 % for pT<30 GeV in the most forward region 3. 2≤{pipe}η{pipe}<4. 5. The jet energy is validated for jet transverse momenta up to 1 TeV to the level of a few percent using several in situ techniques by comparing a well-known reference such as the recoiling photon pT, the sum of the transverse momenta of tracks associated to the jet, or a system of low-pT jets recoiling against a high-pT jet. More sophisticated jet calibration schemes are presented based on calorimeter cell energy density weighting or hadronic properties of jets, aiming for an improved jet energy resolution and a reduced flavour dependence of the jet response. The systematic uncertainty of the jet energy determined from a combination of in situ techniques is consistent with the one derived from single hadron response measurements over a wide kinematic range. The nominal corrections and uncertainties are derived for isolated jets in an inclusive sample of high-pT jets. Special cases such as event topologies with close-by jets, or selections of samples with an enhanced content of jets originating from light quarks, heavy quarks or gluons are also discussed and the corresponding uncertainties are determined. © 2013 CERN for the benefit of the ATLAS collaboration

Measurement of the inclusive and dijet cross-sections of b-jets in pp collisions at sqrt(s) = 7 TeV with the ATLAS detector

The inclusive and dijet production cross-sections have been measured for jets containing b-hadrons (b-jets) in proton-proton collisions at a centre-of-mass energy of sqrt(s) = 7 TeV, using the ATLAS detector at the LHC. The measurements use data corresponding to an integrated luminosity of 34 pb^-1. The b-jets are identified using either a lifetime-based method, where secondary decay vertices of b-hadrons in jets are reconstructed using information from the tracking detectors, or a muon-based method where the presence of a muon is used to identify semileptonic decays of b-hadrons inside jets. The inclusive b-jet cross-section is measured as a function of transverse momentum in the range 20 < pT < 400 GeV and rapidity in the range |y| < 2.1. The bbbar-dijet cross-section is measured as a function of the dijet invariant mass in the range 110 < m_jj < 760 GeV, the azimuthal angle difference between the two jets and the angular variable chi in two dijet mass regions. The results are compared with next-to-leading-order QCD predictions. Good agreement is observed between the measured cross-sections and the predictions obtained using POWHEG + Pythia. MC@NLO + Herwig shows good agreement with the measured bbbar-dijet cross-section. However, it does not reproduce the measured inclusive cross-section well, particularly for central b-jets with large transverse momenta.Comment: 10 pages plus author list (21 pages total), 8 figures, 1 table, final version published in European Physical Journal

The functional capacity and quality of life of women with advanced breast cancer

The rehabilitation needs of patients with metastatic breast cancer (MBC) are poorly studied. The primary aim of the study was to evaluate the functional capacity of women with MBC and quality of life (QoL). The present study is an open, non-randomized, prospective cross-sectional observation study. The functional capacity of 128 MBC patients with ongoing cancer treatments, were studied in Helsinki University Hospital (HUS): Peak expiratory flow (PEF), dynamic and static balance, 6 minute walking distance (6MWD), 10 meter walking, sit-to-stand test, repeated squat, grip strength, shoulder movement, pain, and QoL by Beck's depression scale (BDI), health assessment questionnaire (HAQ), RAND SF-36 and EORTC QLQ-30 items. The walking capacity was compromised in half and the strength of the lower extremities in one-third of the patients. PEF was below the normal reference in 55 %, static balance in 62 % and dynamic balance in 73 % (= 61 year olds). The grip power was lowered in 44/30 % of the patients (right/left) and the shoulder movement was restricted in 30 %. Some disability in physical functioning experienced 55 % (HAQ) and 37 % felt depressive (BDI). The QoL (RAND SF-36) was poor especially in the field of physical, role and social functioning and bodily pain (<0.001). Pain, depression, and a poor 6MWD results independently determined the physical component of QoL (p <0.001). The functional capacity of patients with MBC was significantly lowered. This, in association with distressing symptoms like pain and depression causes a vicious circle further leading to functional disabilities and impaired QoL.Peer reviewe

Measurement of the cross-section of high transverse momentum vector bosons reconstructed as single jets and studies of jet substructure in pp collisions at √s = 7 TeV with the ATLAS detector

This paper presents a measurement of the cross-section for high transverse momentum W and Z bosons produced in pp collisions and decaying to all-hadronic final states. The data used in the analysis were recorded by the ATLAS detector at the CERN Large Hadron Collider at a centre-of-mass energy of √s = 7 TeV;{\rm Te}{\rm V}$and correspond to an integrated luminosity of$4.6\;{\rm f}{{{\rm b}}^{-1}}$. The measurement is performed by reconstructing the boosted W or Z bosons in single jets. The reconstructed jet mass is used to identify the W and Z bosons, and a jet substructure method based on energy cluster information in the jet centre-of-mass frame is used to suppress the large multi-jet background. The cross-section for events with a hadronically decaying W or Z boson, with transverse momentum${{p}_{{\rm T}}}\gt 320\;{\rm Ge}{\rm V}$and pseudorapidity$|\eta |\lt 1.9$, is measured to be${{\sigma }_{W+Z}}=8.5\pm 1.7$ pb and is compared to next-to-leading-order calculations. The selected events are further used to study jet grooming techniques