Cooperation of Notch and Ras/MAPK signaling pathways in human breast carcinogenesis

Background: Recent studies have implicated aberrant Notch signaling in breast cancers. Yet, relatively little is known about the pattern of expression of various components of the Notch pathway, or its mechanism of action. To better understand the role of the Notch pathway in breast cancer, we have undertaken a detailed expression analysis of various Notch receptors, their ligands, and downstream targets at different stages of breast cancer progression. Results: We report here that there is a general increase in the expression levels of Notch 1, 2, 4, Jagged1, Jagged2, and Delta-like 4 proteins in breast cancers, with simultaneous upregulation of multiple Notch receptors and ligands in a given cancer tissue. While Notch3 and Delta-like1 were undetectable in normal tissues, moderate to high expression was detected in several cancers. We detected the presence of active, cleaved Notch1, along with downstream targets of the Notch pathway, Hes1/Hes5, in similar to 75% of breast cancers, clearly indicating that in a large proportion of breast cancers Notch signaling is aberrantly activated. Furthermore, we detected cleaved Notch1 and Hes1/5 in early precursors of breast cancers - hyperplasia and ductal carcinoma in situ suggesting that aberrant Notch activation may be an early event in breast cancer progression. Mechanistically, while constitutively active Notch1 alone failed to transform immortalized breast cells, it synergized with the Ras/MAPK pathway to mediate transformation. This cooperation is reflected in vivo, as a subset of cleaved Notch positive tumors additionally expressed phopsho-Erk1/2 in the nuclei. Such cases exhibited high node positivity, suggesting that Notch-Ras cooperation may lead to poor prognosis. Conclusions: High level expression of Notch receptors and ligands, and its increased activation in several breast cancers and early precursors, places Notch signaling as a key player in breast cancer pathogenesis. Its cooperation with the Ras/MAPK pathway in transformation offers combined inhibition of the two pathways as a new modality for breast cancer treatment.

Hydrologic drought prediction under climate change: Uncertainty modeling with Dempster-Shafer and Bayesian approaches

Representation and quantification of uncertainty in climate change impact studies are a difficult task. Several sources of uncertainty arise in studies of hydrologic impacts of climate change, such as those due to choice of general circulation models (GCMs), scenarios and downscaling methods. Recently, much work has focused on uncertainty quantification and modeling in regional climate change impacts. In this paper, an uncertainty modeling framework is evaluated, which uses a generalized uncertainty measure to combine GCM, scenario and downscaling uncertainties. The Dempster-Shafer (D-S) evidence theory is used for representing and combining uncertainty from various sources. A significant advantage of the D-S framework over the traditional probabilistic approach is that it allows for the allocation of a probability mass to sets or intervals, and can hence handle both aleatory or stochastic uncertainty, and epistemic or subjective uncertainty. This paper shows how the D-S theory can be used to represent beliefs in some hypotheses such as hydrologic drought or wet conditions, describe uncertainty and ignorance in the system, and give a quantitative measurement of belief and plausibility in results. The D-S approach has been used in this work for information synthesis using various evidence combination rules having different conflict modeling approaches. A case study is presented for hydrologic drought prediction using downscaled streamflow in the Mahanadi River at Hirakud in Orissa, India. Projections of n most likely monsoon streamflow sequences are obtained from a conditional random field (CRF) downscaling model, using an ensemble of three GCMs for three scenarios, which are converted to monsoon standardized streamflow index (SSFI-4) series. This range is used to specify the basic probability assignment (bpa) for a Dempster-Shafer structure, which represents uncertainty associated with each of the SSFI-4 classifications. These uncertainties are then combined across GCMs and scenarios using various evidence combination rules given by the D-S theory. A Bayesian approach is also presented for this case study, which models the uncertainty in projected frequencies of SSFI-4 classifications by deriving a posterior distribution for the frequency of each classification, using an ensemble of GCMs and scenarios. Results from the D-S and Bayesian approaches are compared, and relative merits of each approach are discussed. Both approaches show an increasing probability of extreme, severe and moderate droughts and decreasing probability of normal and wet conditions in Orissa as a result of climate change. (C) 2010 Elsevier Ltd. All rights reserved.

Implementation of a phase array diffuse optical tomographic imager

Diffuse optical tomography (DOT) using near-infrared (NIR) light is a promising tool for noninvasive imaging of deep tissue. This technique is capable of quantitative reconstructions of absorption coefficient inhomogeneities of tissue. The motivation for reconstructing the optical property variation is that it, and, in particular, the absorption coefficient variation, can be used to diagnose different metabolic and disease states of tissue. In DOT, like any other medical imaging modality, the aim is to produce a reconstruction with good spatial resolution and accuracy from noisy measurements. We study the performance of a phase array system for detection of optical inhomogeneities in tissue. The light transport through a tissue is diffusive in nature and can be modeled using diffusion equation if the optical parameters of the inhomogeneity are close to the optical properties of the background. The amplitude cancellation method that uses dual out-of-phase sources (phase array) can detect and locate small objects in turbid medium. The inverse problem is solved using model based iterative image reconstruction. Diffusion equation is solved using finite element method for providing the forward model for photon transport. The solution of the forward problem is used for computing the Jacobian and the simultaneous equation is solved using conjugate gradient search. The simulation studies have been carried out and the results show that a phase array system can resolve inhomogeneities with sizes of 5 mm when the absorption coefficient of the inhomogeneity is twice that of the background tissue. To validate this result, a prototype model for performing a dual-source system has been developed. Experiments are carried out by inserting an inhomogeneity of high optical absorption coefficient in an otherwise homogeneous phantom while keeping the scattering coefficient same. The high frequency (100 MHz) modulated dual out-of-phase laser source light is propagated through the phantom. The interference of these sources creates an amplitude null and a phase shift of 180° along a plane between the two sources with a homogeneous object. A solid resin phantom with inhomogeneities simulating the tumor is used in our experiment. The amplitude and phase changes are found to be disturbed by the presence of the inhomogeneity in the object. The experimental data (amplitude and the phase measured at the detector) are used for reconstruction. The results show that the method is able to detect multiple inhomogeneities with sizes of 4 mm. The localization error for a 5 mm inhomogeneity is found to be approximately 1 mm.

Comprehensive Probabilistic Seismic Hazard Analysis of the Andaman-Nicobar Regions

An updated catalog of earthquakes has been prepared for the Andaman-Nicobar and adjoining regions. The catalog was homogenized to a unified magnitude scale, and declustering of the catalog was performed to remove aftershocks and foreshocks. Eleven regional source zones were identified in the study area to account for local variability in seismicity characteristics. The seismicity parameters were estimated for each of these source zones, and the seismic hazard evaluation of the Andaman-Nicobar region has been performed using different source models and attenuation relations. Probabilistic seismic hazard analysis has been performed with currently available data and their best possible scientific interpretation using an appropriate instrument such as the logic tree to explicitly account for epistemic uncertainty by considering alternative models (source models, maximum magnitude, and attenuation relationships). The hazard maps for different periods have been produced for horizontal ground motion on the bedrock level.

Deterministic seismic hazard macrozonation of India

Earthquakes are known to have occurred in Indian subcontinent from ancient times. This paper presents the results of seismic hazard analysis of India (6 degrees-38 degrees N and 68 degrees-98 degrees E) based on the deterministic approach using latest seismicity data (up to 2010). The hazard analysis was done using two different source models (linear sources and point sources) and 12 well recognized attenuation relations considering varied tectonic provinces in the region. The earthquake data obtained from different sources were homogenized and declustered and a total of 27,146 earthquakes of moment magnitude 4 and above were listed in the study area. The sesismotectonic map of the study area was prepared by considering the faults, lineaments and the shear zones which are associated with earthquakes of magnitude 4 and above. A new program was developed in MATLAB for smoothing of the point sources. For assessing the seismic hazard, the study area was divided into small grids of size 0.1 degrees x 0.1 degrees (approximately 10 x 10 km), and the hazard parameters were calculated at the center of each of these grid cells by considering all the seismic sources within a radius of 300 to 400 km. Rock level peak horizontal acceleration (PHA) and spectral accelerations for periods 0.1 and 1 s have been calculated for all the grid points with a deterministic approach using a code written in MATLAB. Epistemic uncertainty in hazard definition has been tackled within a logic-tree framework considering two types of sources and three attenuation models for each grid point. The hazard evaluation without logic tree approach also has been done for comparison of the results. The contour maps showing the spatial variation of hazard values are presented in the paper.

AN ITERATIVE ALGORITHM FOR PHASE RETRIEVAL WITH SPARSITY CONSTRAINTS: APPLICATION TO FREQUENCY DOMAIN OPTICAL COHERENCE TOMOGRAPHY

We address the problem of phase retrieval, which is frequently encountered in optical imaging. The measured quantity is the magnitude of the Fourier spectrum of a function (in optics, the function is also referred to as an object). The goal is to recover the object based on the magnitude measurements. In doing so, the standard assumptions are that the object is compactly supported and positive. In this paper, we consider objects that admit a sparse representation in some orthonormal basis. We develop a variant of the Fienup algorithm to incorporate the condition of sparsity and to successively estimate and refine the phase starting from the magnitude measurements. We show that the proposed iterative algorithm possesses Cauchy convergence properties. As far as the modality is concerned, we work with measurements obtained using a frequency-domain optical-coherence tomography experimental setup. The experimental results on real measured data show that the proposed technique exhibits good reconstruction performance even with fewer coefficients taken into account for reconstruction. It also suppresses the autocorrelation artifacts to a significant extent since it estimates the phase accurately.

Data-resolution based optimal choice of minimum required measurements for image-guided diffuse optical tomography

Image-guided diffuse optical tomography has the advantage of reducing the total number of optical parameters being reconstructed to the number of distinct tissue types identified by the traditional imaging modality, converting the optical image-reconstruction problem from underdetermined in nature to overdetermined. In such cases, the minimum required measurements might be far less compared to those of the traditional diffuse optical imaging. An approach to choose these optimally based on a data-resolution matrix is proposed, and it is shown that such a choice does not compromise the reconstruction performance. (C) 2013 Optical Society of America

Photocytotoxic lanthanide complexes

Lanthanide complexes have recently received considerable attention in the field of therapeutic and diagnostic medicines. Among many applications of lanthanides, gadolinium complexes are used as magnetic resonance imaging (MRI) contrast agents in clinical radiology and luminescent lanthanides for bioanalysis, imaging and sensing. The chemistry of photoactive lanthanide complexes showing biological applications is of recent origin. Photodynamic therapy (PDT) is a non-invasive treatment modality of cancer using a photosensitizer drug and light. This review primarily focuses on different aspects of the chemistry of lanthanide complexes showing photoactivated DNA cleavage activity and cytotoxicity in cancer cells. Macrocyclic texaphyrin-lanthanide complexes are known to show photocytotoxicity with the PDT effect in near-IR light. Very recently, non-macrocyclic lanthanide complexes are reported to show photocytotoxicity in cancer cells. Attempts have been made in this perspective article to review and highlight the photocytotoxic behaviour of various lanthanide complexes for their potential photochemotherapeutic applications.

Efficient gradient-free simplex method for estimation of optical properties in image-guided diffuse optical tomography

Typical image-guided diffuse optical tomographic image reconstruction procedures involve reduction of the number of optical parameters to be reconstructed equal to the number of distinct regions identified in the structural information provided by the traditional imaging modality. This makes the image reconstruction problem less ill-posed compared to traditional underdetermined cases. Still, the methods that are deployed in this case are same as those used for traditional diffuse optical image reconstruction, which involves a regularization term as well as computation of the Jacobian. A gradient-free Nelder-Mead simplex method is proposed here to perform the image reconstruction procedure and is shown to provide solutions that closely match ones obtained using established methods, even in highly noisy data. The proposed method also has the distinct advantage of being more efficient owing to being regularization free, involving only repeated forward calculations. (C) 2013 Society of Photo-Optical Instrumentation Engineers (SPIE)

Photoacoustic and thermoacoustic signal characteristics study

Photoacoustic/thermoacoustic imaging is an emerging hybrid imaging modality combining optical/microwave imaging with ultrasound imaging. The photoacoustic/thermoacoustic signal generated are affected by the nature of excitation pulse waveform, pulse width, target object size, transducer size etc. In this study k-wave was used to simulate various configurations of excitation pulse, transducer types, and target object sizes and to see their effect on the photoacoustic/thermoacoustic signals. Numerical blood vessel phantom was also used to see the effect of various pulse waveform and excitation pulse width on the reconstructed images. This study will help in optimizing transducer design and reconstruction methods to obtain the superior reconstructed image.

Deconvolution-based deblurring of reconstructed images in photoacoustic/thermoacoustic tomography

Photoacoustic/thermoacoustic tomography is an emerging hybrid imaging modality combining optical/microwave imaging with ultrasound imaging. Here, a k-wave MATLAB toolbox was used to simulate various configurations of excitation pulse shape, width, transducer types, and target object sizes to see their effect on the photoacoustic/thermoacoustic signals. A numerical blood vessel phantom was also used to demonstrate the effect of various excitation pulse waveforms and pulse widths on the reconstructed images. Reconstructed images were blurred due to the broadening of the pressure waves by the excitation pulse width as well as by the limited transducer bandwidth. The blurring increases with increase in pulse width. A deconvolution approach is presented here with Tikhonov regularization to correct the photoacoustic/thermoacoustic signals, which resulted in improved reconstructed images by reducing the blurring effect. It is observed that the reconstructed images remain unaffected by change in pulse widths or pulse shapes, as well as by the limited bandwidth of the ultrasound detectors after the use of the deconvolution technique. (C) 2013 Optical Society of America

Imaging Flow Cytometry With Femtosecond Laser-Micromachined Glass Microfluidic Channels

Microfluidic/optofluidic microscopy is a versatile modality for imaging and analyzing properties of cells/particles while they are in flow. In this paper, we demonstrate the integration of fused silica microfluidics fabricated using femtosecond laser machining into optofluidic imaging systems. By using glass for the sample stage of our microscope, we have exploited its superior optical quality for imaging and bio-compatibility. By integrating these glass microfluidic devices into a custom-built bright field microscope, we have been able to image red blood cells in flow with high-throughputs and good fidelity. In addition, we also demonstrate imaging as well as detection of fluorescent beads with these microfluidic devices.

DECT evaluation of noncalc fied coronary artery plaque

Purpose: Composition of the coronary artery plaque is known to have critical role in heart attack. While calcified plaque can easily be diagnosed by conventional CT, it fails to distinguish between fibrous and lipid rich plaques. In the present paper, the authors discuss the experimental techniques and obtain a numerical algorithm by which the electron density (rho(e)) and the effective atomic number (Z(eff)) can be obtained from the dual energy computed tomography (DECT) data. The idea is to use this inversion method to characterize and distinguish between the lipid and fibrous coronary artery plaques. Methods: For the purpose of calibration of the CT machine, the authors prepare aqueous samples whose calculated values of (rho(e), Z(eff)) lie in the range of (2.65 x 10(23) <= rho(e) <= 3.64 x 10(23)/cm(3)) and (6.80 <= Z(eff) <= 8.90). The authors fill the phantom with these known samples and experimentally determine HU(V-1) and HU(V-2), with V-1,V-2 = 100 and 140 kVp, for the same pixels and thus determine the coefficients of inversion that allow us to determine (rho(e), Z(eff)) from the DECT data. The HU(100) and HU(140) for the coronary artery plaque are obtained by filling the channel of the coronary artery with a viscous solution of methyl cellulose in water, containing 2% contrast. These (rho(e), Z(eff)) values of the coronary artery plaque are used for their characterization on the basis of theoretical models of atomic compositions of the plaque materials. These results are compared with histopathological report. Results: The authors find that the calibration gives Pc with an accuracy of 3.5% while Z(eff) is found within 1% of the actual value, the confidence being 95%. The HU(100) and HU(140) are found to be considerably different for the same plaque at the same position and there is a linear trend between these two HU values. It is noted that pure lipid type plaques are practically nonexistent, and microcalcification, as observed in histopathology, has to be taken into account to explain the nature of the observed (rho(e), Z(eff)) data. This also enables us to judge the composition of the plaque in terms of basic model which considers the plaque to be composed of fibres, lipids, and microcalcification. Conclusions: This simple and reliable method has the potential as an effective modality to investigate the composition of noncalcified coronary artery plaques and thus help in their characterization. In this inversion method, (rho(e), Z(eff)) of the scanned sample can be found by eliminating the effects of the CT machine and also by ensuring that the determination of the two unknowns (rho(e), Z(eff)) does not interfere with each other and the nature of the plaque can be identified in terms of a three component model. (C) 2015 American Association of Physicists in Medicine.