226 research outputs found
Transfer of assembled collagen fibrils to flexible substrates for mechanically tunable contact guidance cues
Contact guidance or bidirectional migration along aligned fibers modulates many physiological and pathological processes such as wound healing and cancer invasion. Aligned 2D collagen fibrils epitaxially grown on mica substrates replicate many features of contact guidance seen in aligned 3D collagen fiber networks. However, these 2D collagen self-assembled substrates are difficult to image through, do not have known or tunable mechanical properties and cells degrade and mechanically detach collagen fibrils from the surface, leading to an inability to assess contact guidance over long times. Here, we describe the transfer of aligned collagen fibrils from mica substrates to three different functionalized target substrates: glass, polydimethylsiloxane (PDMS) and polyacrylamide (PA). Aligned collagen fibrils can be efficiently transferred to all three substrates. This transfer resulted in substrates that were to varying degrees resistant to cell-mediated collagen fibril deformation that resulted in detachment of the collagen fibril field, allowing for contact guidance to be observed over longer time periods. On these transferred substrates, cell speed is lowest on softer contact guidance cues for both MDA-MB-231 and MTLn3 cells. Intermediate stiffness resulted in the fastest migration. MTLn3 cell directionality was low on soft contact guidance cues, whereas MDA-MB-231 cell directionality marginally increased. It appears that the stiffness of the contact guidance cue regulates contact guidance differently between cell types. The development of this collagen fibril transfer method allows for the attachment of aligned collagen fibrils on substrates, particularly flexible substrates, that do not normally promote aligned collagen fibril growth, increasing the utility of this collagen self-assembly system for the fundamental examination of mechanical regulation of contact guidance
Gemcitabine and carboplatin in intensively pretreated patients with metastatic breast cancer
Background: Patients with metastatic breast cancer (MBC) are increasingly exposed to anthracyclines and taxanes either during treatment of primary breast cancer or during initial therapy of metastatic disease. The combination of gemcitabine and carboplatin was therefore investigated as an anthracycline- and taxane-free treatment option. Patients and Methods: MBC patients previously treated with chemotherapy were enrolled in a multicenter phase II study. Treatment consisted of gemcitabine (1,000 mg/m(2) i.v. on days 1 and 8) and carboplatin (AUC 4 i.v. on day 1) applied every 3 weeks. Results: Thirty-nine patients were recruited, and a total of 207 treatment cycles were applied with a median of 5 cycles per patient. One complete response and 11 partial responses were observed for an overall response rate of 31% (95% CI: 17-48%). Twelve patients (31%) had stable disease. Median time to progression was 5.3 months (95% CI: 2.6-6.7 months) and median overall survival from start of treatment was 13.2 months (95% CI: 8.7-16.7 months). Grade 3/4 hematological toxicity included leukopenia (59%/5%), thrombo-cytopenia (26%/23%) and anemia (10%/0%). Nonhematological toxicity was rarely severe. Conclusion: Combination chemotherapy with gemcitabine and carboplatin is an effective and generally well-tolerated treatment option for intensively pretreated patients with MBC. Due to a considerable incidence of severe thrombocytopenia it would be reasonable to consider starting gemcitabine at the lower dose level of 800 mg/m(2). Copyright (c) 2008 S. Karger AG, Basel
Dosimetric verification of the anisotropic analytical algorithm for radiotherapy treatment planning
BACKGROUND AND PURPOSE:
To investigate the accuracy of photon dose calculations performed by the Anisotropic Analytical Algorithm, in homogeneous and inhomogeneous media and in simulated
treatment plans.
MATERIALS AND METHODS:
Predicted dose distributions were compared with ionisation chamber and film
measurements for a series of increasingly complex situations. Initially, simple and complex fields in a
homogeneous medium were studied. The effect of inhomogeneities was investigated using a range of
phantoms constructed of water, bone and lung substitute materials. Simulated treatment plans were
then produced using a semi-anthropomorphic phantom and the delivered doses compared to the doses predicted by the Anisotropic Analytical Algorithm.
RESULTS:
In a homogeneous medium, agreement was found to be within 2% dose or 2mm dta in most
instances. In the presence of heterogeneities, agreement was generally to within 2.5%. The simulated
treatment plan measurements agreed to within 2.5% or 2mm.
Conclusions: The accuracy of the algorithm was found to be satisfactory at 6MV and 10MV both in homogeneous and inhomogeneous situations and in the simulated treatment plans. The algorithm was more accurate than the Pencil Beam Convolution model, particularly in the presence of low density heterogeneities
Degradation and Remodeling of Epitaxially Grown Collagen Fibrils
Introduction: The extracellular matrix (ECM) in the tumor microenvironment contains high densities of collagen that are highly aligned, resulting in directional migration called contact guidance that facilitates efficient migration out of the tumor. Cancer cells can remodel the ECM through traction force controlled by myosin contractility or proteolytic activity controlled by matrix metalloproteinase (MMP) activity, leading to either enhanced or diminished contact guidance.
Methods: Recently, we have leveraged the ability of mica to epitaxially grow aligned collagen fibrils in order to assess contact guidance. In this article, we probe the mechanisms of remodeling of aligned collagen fibrils on mica by breast cancer cells.
Results: We show that cells that contact guide with high fidelity (MDA-MB-231 cells) exert more force on the underlying collagen fibrils than do cells that contact guide with low fidelity (MTLn3 cells). These high traction cells (MDA-MB-231 cells) remodel collagen fibrils over hours, pulling so hard that the collagen fibrils detach from the surface, effectively delaminating the entire contact guidance cue. Myosin or MMP inhibition decreases this effect. Interestingly, blocking MMP appears to increase the alignment of cells on these substrates, potentially allowing the alignment through myosin contractility to be uninhibited. Finally, amplification or dampening of contact guidance with respect to a particular collagen fibril organization is seen under different conditions.
Conclusions: Both myosin II contractility and MMP activity allow MDA-MB-231 cells to remodel and eventually destroy epitaxially grown aligned collagen fibrils
Long-term outcome prediction by clinicopathological risk classification algorithms in node-negative breast cancer—comparison between Adjuvant!, St Gallen, and a novel risk algorithm used in the prospective randomized Node-Negative-Breast Cancer-3 (NNBC-3) trial
Background: Defining risk categories in breast cancer is of considerable clinical significance. We have developed a novel risk classification algorithm and compared its prognostic utility to the Web-based tool Adjuvant! and to the St Gallen risk classification. Patients and methods: After a median follow-up of 10 years, we retrospectively analyzed 410 consecutive node-negative breast cancer patients who had not received adjuvant systemic therapy. High risk was defined by any of the following criteria: (i) age 2 cm. All patients were also characterized using Adjuvant! and the St Gallen 2007 risk categories. We analyzed disease-free survival (DFS) and overall survival (OS). Results: The Node-Negative-Breast Cancer-3 (NNBC-3) algorithm enlarged the low-risk group to 37% as compared with Adjuvant! (17%) and St Gallen (18%), respectively. In multivariate analysis, both Adjuvant! [P = 0.027, hazard ratio (HR) 3.81, 96% confidence interval (CI) 1.16-12.47] and the NNBC-3 risk classification (P = 0.049, HR 1.95, 95% CI 1.00-3.81) significantly predicted OS, but only the NNBC-3 algorithm retained its prognostic significance in multivariate analysis for DFS (P < 0.0005). Conclusion: The novel NNBC-3 risk algorithm is the only clinicopathological risk classification algorithm significantly predicting DFS as well as O
Long-term outcome prediction by clinicopathological risk classification algorithms in node-negative breast cancer--comparison between Adjuvant!, St Gallen, and a novel risk algorithm used in the prospective randomized Node-Negative-Breast Cancer-3 (NNBC-3) trial.
Defining risk categories in breast cancer is of considerable clinical significance. We have developed a novel risk classification algorithm and compared its prognostic utility to the Web-based tool Adjuvant! and to the St Gallen risk classification.
After a median follow-up of 10 years, we retrospectively analyzed 410 consecutive node-negative breast cancer patients who had not received adjuvant systemic therapy. High risk was defined by any of the following criteria: (i) age <35 years, (ii) grade 3, (iii) human epithelial growth factor receptor-2 positivity, (iv) vascular invasion, (v) progesterone receptor negativity, (vi) grade 2 tumors >2 cm. All patients were also characterized using Adjuvant! and the St Gallen 2007 risk categories. We analyzed disease-free survival (DFS) and overall survival (OS).
The Node-Negative-Breast Cancer-3 (NNBC-3) algorithm enlarged the low-risk group to 37% as compared with Adjuvant! (17%) and St Gallen (18%), respectively. In multivariate analysis, both Adjuvant! [P = 0.027, hazard ratio (HR) 3.81, 96% confidence interval (CI) 1.16-12.47] and the NNBC-3 risk classification (P = 0.049, HR 1.95, 95% CI 1.00-3.81) significantly predicted OS, but only the NNBC-3 algorithm retained its prognostic significance in multivariate analysis for DFS (P < 0.0005).
The novel NNBC-3 risk algorithm is the only clinicopathological risk classification algorithm significantly predicting DFS as well as OS
Measurement of the neutron capture cross section of the s-only isotope 204Pb from 1 eV to 440 keV
The neutron capture cross section of 204Pb has been measured at the CERN
n_TOF installation with high resolution in the energy range from 1 eV to 440
keV. An R-matrix analysis of the resolved resonance region, between 1 eV and
100 keV, was carried out using the SAMMY code. In the interval between 100 keV
and 440 keV we report the average capture cross section. The background in the
entire neutron energy range could be reliably determined from the measurement
of a 208Pb sample. Other systematic effects in this measurement could be
investigated and precisely corrected by means of detailed Monte Carlo
simulations. We obtain a Maxwellian average capture cross section for 204Pb at
kT=30 keV of 79(3) mb, in agreement with previous experiments. However our
cross section at kT=5 keV is about 35% larger than the values reported so far.
The implications of the new cross section for the s-process abundance
contributions in the Pb/Bi region are discussed.Comment: 8 pages, 3 figures, article submitted to Phys. Rev.
New measurement of neutron capture resonances of 209Bi
The neutron capture cross section of Bi209 has been measured at the CERN n
TOF facility by employing the pulse-height-weighting technique. Improvements
over previous measurements are mainly because of an optimized detection system,
which led to a practically negligible neutron sensitivity. Additional
experimental sources of systematic error, such as the electronic threshold in
the detectors, summing of gamma-rays, internal electron conversion, and the
isomeric state in bismuth, have been taken into account. Gamma-ray absorption
effects inside the sample have been corrected by employing a nonpolynomial
weighting function. Because Bi209 is the last stable isotope in the reaction
path of the stellar s-process, the Maxwellian averaged capture cross section is
important for the recycling of the reaction flow by alpha-decays. In the
relevant stellar range of thermal energies between kT=5 and 8 keV our new
capture rate is about 16% higher than the presently accepted value used for
nucleosynthesis calculations. At this low temperature an important part of the
heavy Pb-Bi isotopes are supposed to be synthesized by the s-process in the He
shells of low mass, thermally pulsing asymptotic giant branch stars. With the
improved set of cross sections we obtain an s-process fraction of 19(3)% of the
solar bismuth abundance, resulting in an r-process residual of 81(3)%. The
present (n,gamma) cross-section measurement is also of relevance for the design
of accelerator driven systems based on a liquid metal Pb/Bi spallation target.Comment: 10 pages, 5figures, recently published in Phys. Rev.
Measurement of the radiative neutron capture cross section of 206Pb and its astrophysical implications
The (n, gamma) cross section of 206Pb has been measured at the CERN n_TOF
facility with high resolution in the energy range from 1 eV to 600 keV by using
two optimized C6D6 detectors. In the investigated energy interval about 130
resonances could be observed, from which 61 had enough statistics to be
reliably analyzed via the R-matrix analysis code SAMMY. Experimental
uncertainties were minimized, in particular with respect to (i) angular
distribution effects of the prompt capture gamma-rays, and to (ii) the
TOF-dependent background due to sample-scattered neutrons. Other background
components were addressed by background measurements with an enriched 208Pb
sample. The effect of the lower energy cutoff in the pulse height spectra of
the C6D6 detectors was carefully corrected via Monte Carlo simulations.
Compared to previous 206Pb values, the Maxwellian averaged capture cross
sections derived from these data are about 20% and 9% lower at thermal energies
of 5 keV and 30 keV, respectively. These new results have a direct impact on
the s-process abundance of 206Pb, which represents an important test for the
interpretation of the cosmic clock based on the decay of 238U.Comment: 11 pages, 8 figures, paper to be submitted to Phys. Rev.
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