Noninvasive pressure difference mapping derived from 4D flow MRI in patients with unrepaired and repaired aortic coarctation.

PURPOSE To develop a method for computing and visualizing pressure differences derived from time-resolved velocity-encoded three-dimensional phase-contrast magnetic resonance imaging (4D flow MRI) and to compare pressure difference maps of patients with unrepaired and repaired aortic coarctation to young healthy volunteers. METHODS 4D flow MRI data of four patients with aortic coarctation either before or after repair (mean age 17 years, age range 3-28, one female, three males) and four young healthy volunteers without history of cardiovascular disease (mean age 24 years, age range 20-27, one female, three males) was acquired using a 1.5-T clinical MR scanner. Image analysis was performed with in-house developed image processing software. Relative pressures were computed based on the Navier-Stokes equation. RESULTS A standardized method for intuitive visualization of pressure difference maps was developed and successfully applied to all included patients and volunteers. Young healthy volunteers exhibited smooth and regular distribution of relative pressures in the thoracic aorta at mid systole with very similar distribution in all analyzed volunteers. Patients demonstrated disturbed pressures compared to volunteers. Changes included a pressure drop at the aortic isthmus in all patients, increased relative pressures in the aortic arch in patients with residual narrowing after repair, and increased relative pressures in the descending aorta in a patient after patch aortoplasty. CONCLUSIONS Pressure difference maps derived from 4D flow MRI can depict alterations of spatial pressure distribution in patients with repaired and unrepaired aortic coarctation. The technique might allow identifying pathophysiological conditions underlying complications after aortic coarctation repair.

K-t GRAPPA-accelerated 4D flow MRI of liver hemodynamics: influence of different acceleration factors on qualitative and quantitative assessment of blood flow.

OBJECTIVE We sought to evaluate the feasibility of k-t parallel imaging for accelerated 4D flow MRI in the hepatic vascular system by investigating the impact of different acceleration factors. MATERIALS AND METHODS k-t GRAPPA accelerated 4D flow MRI of the liver vasculature was evaluated in 16 healthy volunteers at 3T with acceleration factors R = 3, R = 5, and R = 8 (2.0 × 2.5 × 2.4 mm(3), TR = 82 ms), and R = 5 (TR = 41 ms); GRAPPA R = 2 was used as the reference standard. Qualitative flow analysis included grading of 3D streamlines and time-resolved particle traces. Quantitative evaluation assessed velocities, net flow, and wall shear stress (WSS). RESULTS Significant scan time savings were realized for all acceleration factors compared to standard GRAPPA R = 2 (21-71 %) (p < 0.001). Quantification of velocities and net flow offered similar results between k-t GRAPPA R = 3 and R = 5 compared to standard GRAPPA R = 2. Significantly increased leakage artifacts and noise were seen between standard GRAPPA R = 2 and k-t GRAPPA R = 8 (p < 0.001) with significant underestimation of peak velocities and WSS of up to 31 % in the hepatic arterial system (p <0.05). WSS was significantly underestimated up to 13 % in all vessels of the portal venous system for k-t GRAPPA R = 5, while significantly higher values were observed for the same acceleration with higher temporal resolution in two veins (p < 0.05). CONCLUSION k-t acceleration of 4D flow MRI is feasible for liver hemodynamic assessment with acceleration factors R = 3 and R = 5 resulting in a scan time reduction of at least 40 % with similar quantitation of liver hemodynamics compared with GRAPPA R = 2.

MorphoGraphX: A platform for quantifying morphogenesis in 4D

Morphogenesis emerges from complex multiscale interactions between genetic and mechanical processes. To understand these processes, the evolution of cell shape, proliferation and gene expression must be quantified. This quantification is usually performed either in full 3D, which is computationally expensive and technically challenging, or on 2D planar projections, which introduces geometrical artifacts on highly curved organs. Here we present MorphoGraphX (www.MorphoGraphX.org), a software that bridges this gap by working directly with curved surface images extracted from 3D data. In addition to traditional 3D image analysis, we have developed algorithms to operate on curved surfaces, such as cell segmentation, lineage tracking and fluorescence signal quantification. The software’s modular design makes it easy to include existing libraries, or to implement new algorithms. Cell geometries extracted with MorphoGraphX can be exported and used as templates for simulation models, providing a powerful platform to investigate the interactions between shape, genes and growth.DOI: http://dx.doi.org/10.7554/eLife.05864.001Author keywordsResearch organism

Thiazolides promote apoptosis in colorectal tumor cells via MAP kinase-induced Bim and Puma activation

While many anticancer therapies aim to target the death of tumor cells, sophisticated resistance mechanisms in the tumor cells prevent cell death induction. In particular enzymes of the glutathion-S-transferase (GST) family represent a well-known detoxification mechanism, which limit the effect of chemotherapeutic drugs in tumor cells. Specifically, GST of the class P1 (GSTP1-1) is overexpressed in colorectal tumor cells and renders them resistant to various drugs. Thus, GSTP1-1 has become an important therapeutic target. We have recently shown that thiazolides, a novel class of anti-infectious drugs, induce apoptosis in colorectal tumor cells in a GSTP1-1-dependent manner, thereby bypassing this GSTP1-1-mediated drug resistance. In this study we investigated in detail the underlying mechanism of thiazolide-induced apoptosis induction in colorectal tumor cells. Thiazolides induce the activation of p38 and Jun kinase, which is required for thiazolide-induced cell death. Activation of these MAP kinases results in increased expression of the pro-apoptotic Bcl-2 homologs Bim and Puma, which inducibly bind and sequester Mcl-1 and Bcl-xL leading to the induction of the mitochondrial apoptosis pathway. Of interest, while an increase in intracellular glutathione levels resulted in increased resistance to cisplatin, it sensitized colorectal tumor cells to thiazolide-induced apoptosis by promoting increased Jun kinase activation and Bim induction. Thus, thiazolides may represent an interesting novel class of anti-tumor agents by specifically targeting tumor resistance mechanisms, such as GSTP1-1.

F. Bimḳo : der Dramaturg un Reʾalisṭ

Aharon Beḳerman

4D/3D reduction of dualities: mirrors on the circle

We engineer a brane picture for the reduction of Seiberg dualities from 4D to 3D, valid also in the presence of orientifold planes. We obtain effective 3D dualities on the circle by T-duality, geometrizing the non-perturbative superpotential which is an affine Toda potential. When reducing to pure 3D, we define a double-scaling limit which creates a sector of interacting singlets, giving a unified mechanism for the brane reduction of dualities.

Noninvasive 4D pressure difference mapping derived from 4D flow MRI in patients with repaired aortic coarctation: comparison with young healthy volunteers

To assess spatial and temporal pressure characteristics in patients with repaired aortic coarctation compared to young healthy volunteers using time-resolved velocity-encoded three-dimensional phase-contrast magnetic resonance imaging (4D flow MRI) and derived 4D pressure difference maps. After in vitro validation against invasive catheterization as gold standard, 4D flow MRI of the thoracic aorta was performed at 1.5T in 13 consecutive patients after aortic coarctation repair without recoarctation and 13 healthy volunteers. Using in-house developed processing software, 4D pressure difference maps were computed based on the Navier-Stokes equation. Pressure difference amplitudes, maximum slope of pressure amplitudes and spatial pressure range at mid systole were retrospectively measured by three readers, and twice by one reader to assess inter- and intraobserver agreement. In vitro, pressure differences derived from 4D flow MRI showed excellent agreement to invasive catheter measurements. In vivo, pressure difference amplitudes, maximum slope of pressure difference amplitudes and spatial pressure range at mid systole were significantly increased in patients compared to volunteers in the aortic arch, the proximal descending and the distal descending thoracic aorta (p < 0.05). Greatest differences occurred in the proximal descending aorta with values of the three parameters for patients versus volunteers being 19.7 ± 7.5 versus 10.0 ± 2.0 (p < 0.001), 10.9 ± 10.4 versus 1.9 ± 0.4 (p = 0.002), and 8.7 ± 6.3 versus 1.6 ± 0.9 (p < 0.001). Inter- and intraobserver agreements were excellent (p < 0.001). Noninvasive 4D pressure difference mapping derived from 4D flow MRI enables detection of altered intraluminal aortic pressures and showed significant spatial and temporal changes in patients with repaired aortic coarctation.

Improving 4D plan quality for PBS-based liver tumour treatments by combining online image guided beam gating with rescanning.

Pencil beam scanned (PBS) proton therapy has many advantages over conventional radiotherapy, but its effectiveness for treating mobile tumours remains questionable. Gating dose delivery to the breathing pattern is a well-developed method in conventional radiotherapy for mitigating tumour-motion, but its clinical efficiency for PBS proton therapy is not yet well documented. In this study, the dosimetric benefits and the treatment efficiency of beam gating for PBS proton therapy has been comprehensively evaluated. A series of dedicated 4D dose calculations (4DDC) have been performed on 9 different 4DCT(MRI) liver data sets, which give realistic 4DCT extracting motion information from 4DMRI. The value of 4DCT(MRI) is its capability of providing not only patient geometries and deformable breathing characteristics, but also includes variations in the breathing patterns between breathing cycles. In order to monitor target motion and derive a gating signal, we simulate time-resolved beams' eye view (BEV) x-ray images as an online motion surrogate. 4DDCs have been performed using three amplitude-based gating window sizes (10/5/3 mm) with motion surrogates derived from either pre-implanted fiducial markers or the diaphragm. In addition, gating has also been simulated in combination with up to 19 times rescanning using either volumetric or layered approaches. The quality of the resulting 4DDC plans has been quantified in terms of the plan homogeneity index (HI), total treatment time and duty cycle. Results show that neither beam gating nor rescanning alone can fully retrieve the plan homogeneity of the static reference plan. Especially for variable breathing patterns, reductions of the effective duty cycle to as low as 10% have been observed with the smallest gating rescanning window (3 mm), implying that gating on its own for such cases would result in much longer treatment times. In addition, when rescanning is applied on its own, large differences between volumetric and layered rescanning have been observed as a function of increasing number of re-scans. However, once gating and rescanning is combined, HI to within 2% of the static plan could be achieved in the clinical target volume, with only moderately prolonged treatment times, irrespective of the rescanning strategy used. Moreover, these results are independent of the motion surrogate used. In conclusion, our results suggest image guided beam gating, combined with rescanning, is a feasible, effective and efficient motion mitigation approach for PBS-based liver tumour treatments.

Temporally Coherent Disparity Maps Using CRFs with Fast 4D Filtering

State of the art methods for disparity estimation achieve good results for single stereo frames, but temporal coherence in stereo videos is often neglected. In this paper we present a method to compute temporally coherent disparity maps. We define an energy over whole stereo sequences and optimize their Conditional Random Field (CRF) distributions using mean-field approximation. We introduce novel terms for smoothness and consistency between the left and right views, and perform CRF optimization by fast, iterative spatio-temporal filtering with linear complexity in the total number of pixels. Our results rank among the state of the art while having significantly less flickering artifacts in stereo sequences.

BIM MEDIATES IMATINIB-INDUCED APOPTOSIS OF GASTROINTESTINAL STROMAL TUMORS: TRANSLATIONAL IMPLICATIONS

Gastrointestinal stromal tumors (GISTs) are oncogene-addicted cancers driven by activating mutations in the genes encoding receptor tyrosine kinases KIT and PDGFR-α. Imatinib mesylate, a specific inhibitor of KIT and PDGFR-α signaling, delays progression of GIST, but is incapable of achieving cure. Thus, most patients who initially respond to imatinib therapy eventually experience tumor progression, and have limited therapeutic options thereafter. To address imatinib-resistance and tumor progression, these studies sought to understand the molecular mechanisms that regulate apoptosis in GIST, and evaluate combination therapies that kill GISTs cells via complementary, but independent, mechanisms. BIM (Bcl-2 interacting mediator of apoptosis), a pro-apoptotic member of the Bcl-2 family, effects apoptosis in oncogene-addicted malignancies treated with targeted therapies, and was recently shown to mediate imatinib-induced apoptosis in GIST. This dissertation examined the molecular mechanism of BIM upregulation and its cytotoxic effect in GIST cells harboring clinically-representative KIT mutations. Additionally, imatinib-induced alterations in BIM and pro-survival Bcl-2 proteins were studied in specimens from patients with GIST, and correlated to apoptosis, FDG-PET response, and survival. Further, the intrinsic pathway of apoptosis was targeted therapeutically in GIST cells with the Bcl-2 inhibitor ABT-737. These studies show that BIM is upregulated in GIST cells and patient tumors after imatinib exposure, and correlates with induction of apoptosis, response by FDG-PET, and disease-free survival. These studies contribute to the mechanistic understanding of imatinib-induced apoptosis in clinically-relevant models of GIST, and may facilitate prediction of resistance and disease progression in patients. Further, combining inhibition of KIT and Bcl-2 induces apoptosis synergistically and overcomes imatinib-resistance in GIST cells. Given that imatinib-resistance and GIST progression may reflect inadequate BIM-mediated inhibition of pro-survival Bcl-2 proteins, the preclinical evidence presented here suggests that direct engagement of apoptosis may be an effective approach to enhance the cytotoxicity of imatinib and overcome resistance.

La problemática del chagas en 4d : Representaciones de docentes de nivel inicial y primario de La Plata

Se presenta el análisis de las representaciones sociales de docentes de nivel primario e inicial de la región de La Plata que asistieron a dos cursos de formación continua en el contexto de la realización de "La Semana del Chagas en el Museo de La Plata" en 2011. La propuesta implementada, destinada a difundir y visibilizar al tema como problemática compleja, incluyó un abordaje integral e interdisciplinario a partir de múltiples miradas, involucrando diferentes recursos y actores, planteando la problemática desde cuatro grandes dimensiones (biomédica, epidemiológica, sociocultural-económica y política). Las representaciones, identificadas a partir de textos producidos en respuesta a la pregunta ¿De qué hablamos cuando hablamos de Chagas?, reflejan fuertemente el discurso biomédico hegemónico, pero dando también lugar a la posibilidad de ver al tema como un problema más complejo, en el que lo social y lo político -y dentro de éste, lo educativo y el propio rol como docentes- están presentes