Spatial coherence of backscattered signals in multi-line transmit ultrasound imaging and its effect on short-lag Filtered-Delay Multiply and Sum beamforming

In Multi-Line Transmission (MLT), high frame-rate ultrasound imaging is achieved by the simultaneous transmission of multiple focused beams along different directions, which unfortunately generates unwanted artifacts in the image due to inter-beam crosstalk. The Filtered-Delay Multiply and Sum (F-DMAS) beamformer, a non-linear spatial-coherence (SC)-based algorithm, was demonstrated to successfully reduce such artifacts, improving the spatial resolution at the same time. In this paper, we aim to provide further insights on the working principle and performance of F-DMAS beamforming in MLT imaging. First, we carry out an analytical study to analyze the behavior and trend of backscattered signals SC in MLT images, when the number of simultaneously transmitted beams and/or their angular spacing change. We then reconsider the F-DMAS algorithm proposing the “short-lag F-DMAS” formulation, in order to limit the maximum lag of signals used for the SC computation on which the beamformer is based. Therefore, we investigate in simulations how the performance of short-lag F-DMAS varies along with the maximum lag in the different MLT configurations considered. Finally, we establish a relation between the obtained results and the signals SC trend

Triple blockade of EGFR, MEK and PD-L1 has antitumor activity in colorectal cancer models with constitutive activation of MAPK signaling and PD-L1 overexpression

Càncer colorectal; Resistència a inhibidors de MEK; Inhibidors de PD-L1Cáncer colorrectal; Resistencia a inhibidores de MEK; Inhibidores de PD-L1Colorectal cancer; MEK inhibitor resistance; PD-L1 inhibitorsBackground Molecular mechanisms driving acquired resistance to anti-EGFR therapies in metastatic colorectal cancer (mCRC) are complex but generally involve the activation of the downstream RAS-RAF-MEK-MAPK pathway. Nevertheless, even if inhibition of EGFR and MEK could be a strategy for overcoming anti-EGFR resistance, its use is limited by the development of MEK inhibitor (MEKi) resistance. Methods We have generated in vitro and in vivo different CRC models in order to underline the mechanisms of MEKi resistance. Results The three different in vitro MEKi resistant models, two generated by human CRC cells quadruple wild type for KRAS, NRAS, BRAF, PI3KCA genes (SW48-MR and LIM1215-MR) and one by human CRC cells harboring KRAS mutation (HCT116-MR) showed features related to the gene signature of colorectal cancer CMS4 with up-regulation of immune pathway as confirmed by microarray and western blot analysis. In particular, the MEKi phenotype was associated with the loss of epithelial features and acquisition of mesenchymal markers and morphology. The change in morphology was accompanied by up-regulation of PD-L1 expression and activation of EGFR and its downstream pathway, independently to RAS mutation status. To extend these in vitro findings, we have obtained mouse colon cancer MC38- and CT26-MEKi resistant syngeneic models (MC38-MR and CT26-MR). Combined treatment with MEKi, EGFR inhibitor (EGFRi) and PD-L1 inhibitor (PD-L1i) resulted in a marked inhibition of tumor growth in both models. Conclusions These results suggest a strategy to potentially improve the efficacy of MEK inhibition by co-treatment with EGFR and PD-L1 inhibitors via modulation of host immune responses.This research has been supported by a grant from Associazione Italiana per la Ricerca sul Cancro (AIRC) to FC (AIRC IG 18972) and and Regione Campania Cancer Research Campaign I-CURE grant to FC

A mm-Wave 2D Ultra-Wideband Imaging Radar for Breast Cancer Detection

This paper presents the preliminary design of a mm-wave ultra-wideband (UWB) radar for breast cancer detection. A mass screening of women for breast cancer is essential, as the early diagnosis of the tumour allows best treatment outcomes. A mm-wave UWB radar could be an innovative solution to achieve the high imaging resolution required without risks for the patient. The 20–40 GHz frequency band used in the system proposed in this work guarantees high cross/range resolution performances. The developed preliminary architecture employs two monomodal truncated double-ridge waveguides that act as antennas; these radiators are shifted by microstep actuators to form a synthetic linear aperture. The minimum antenna-to-antenna distance achievable, the width of the synthetic aperture, and the minimum frequency step determine the performance of the 2D imaging system. Measures are performed with a mm-wave vector network analyzer driven by an automatic routine, which controls also the antennas shifts. The scattering matrix is then calibrated and the delay-multiply-and-sum (DMAS) algorithm is applied to elaborate a high-resolution 2D image of the targets. Experimental results show that 3 mm cross and 8 mm range resolutions were achieved, which is in line with theoretical expectations and promising for future developments

Documenting cultural heritage in an INSPIRE-based 3D GIS for risk and vulnerability analysis

Purpose The study, within the Increasing Resilience of Cultural Heritage (ResCult) project, aims to support civil protection to prevent, lessen and mitigate disasters impacts on cultural heritage using a unique standardised-3D geographical information system (GIS), including both heritage and risk and hazard information. Design/methodology/approach A top-down approach, starting from existing standards (an INSPIRE extension integrated with other parts from the standardised and shared structure), was completed with a bottom-up integration according to current requirements for disaster prevention procedures and risk analyses. The results were validated and tested in case studies (differentiated concerning the hazard and type of protected heritage) and refined during user forums. Findings Besides the ensuing reusable database structure, the filling with case studies data underlined the tough challenges and allowed proposing a sample of workflows and possible guidelines. The interfaces are provided to use the obtained knowledge base. Originality/value The increasing number of natural disasters could severely damage the cultural heritage, causing permanent damage to movable and immovable assets and tangible and intangible heritage. The study provides an original tool properly relating the (spatial) information regarding cultural heritage and the risk factors in a unique archive as a standard-based European tool to cope with these frequent losses, preventing risk

Receptor tyrosine kinase-dependent PI3K activation is an escape mechanism to vertical suppression of the EGFR/RAS/MAPK pathway in KRAS-mutated human colorectal cancer cell lines

Abstract BACKGROUND: Previous studies showed that the combination of an anti-Epidermal growth factor (EGFR) and a MEK-inhibitor is able to prevent the onset of resistance to anti-EGFR monoclonal antibodies in KRAS-wild type colorectal cancer (CRC), while the same combination reverts anti-EGFR primary resistance in KRAS mutated CRC cell lines. However, rapid onset of resistance is a limit to combination therapies in KRAS mutated CRC. METHODS: We generated four different KRAS mutated CRC cell lines resistant to a combination of cetuximab (an anti-EGFR antibody) and refametinib (a selective MEK-inhibitor) after continuous exposure to increasing concentration of the drugs. We characterized these resistant cell lines by evaluating the expression and activation status of a panel of receptor tyrosine kinases (RTKs) and intracellular transducers by immunoblot and qRT-PCR. Oncomine comprehensive assay and microarray analysis were carried out to investigate new acquired mutations or transcriptomic adaptation, respectively, in the resistant cell lines. Immunofluorescence assay was used to show the localization of RTKs in resistant and parental clones. RESULTS: We found that PI3K-AKT pathway activation acts as an escape mechanism in cell lines with acquired resistance to combined inhibition of EGFR and MEK. AKT pathway activation is coupled to the activation of multiple RTKs such as HER2, HER3 and IGF1R, though its pharmacological inhibition is not sufficient to revert the resistant phenotype. PI3K pathway activation is mediated by autocrine loops and by heterodimerization of multiple receptors. CONCLUSIONS: PI3K activation plays a central role in the acquired resistance to the combination of anti-EGFR and MEK-inhibitor in KRAS mutated colorectal cancer cell lines. PI3K activation is cooperatively achieved through the activation of multiple RTKs such as HER2, HER3 and IGF1R

Dual inhibition of TGFβ and AXL as a novel therapy for human colorectal adenocarcinoma with mesenchymal phenotype

A subset of colorectal cancer (CRC) with a mesenchymal phenotype (CMS4) displays an aggressive disease, with an increased risk of recurrence after surgery, reduced survival, and resistance to standard treatments. It has been shown that the AXL and TGFβ signaling pathways are involved in epithelial-to-mesenchymal transition, migration, metastatic spread, and unresponsiveness to targeted therapies. However, the prognostic role of the combination of these biomarkers and the anti-tumor effect of AXL and TGFβ inhibition in CRC still has to be assessed. To evaluate the role of AXL and TGFβ as negative biomarker in CRC, we conducted an in-depth in silico analysis of CRC samples derived from the Gene Expression Omnibus. We found that AXL and TGFβ receptors are upregulated in CMS4 tumors and are correlated with an increased risk of recurrence after surgery in stage II/III CRC and a reduced overall survival. Moreover, we showed that AXL receptor is differently expressed in human CRC cell lines. Dual treatment with the TGFβ galunisertib and the AXL inhibitor, bemcentinib, significantly reduced colony formation and migration capabilities of tumor cells and displayed a strong anti-tumor activity in 3D spheroid cultures derived from patients with advanced CRC. Our work shows that AXL and TGFβ receptors identify a subgroup of CRC with a mesenchymal phenotype and correlate with poor prognosis. Dual inhibition of AXL and TGFβ could represent a novel therapeutic strategy for patients with this aggressive disease

Principal components analysis based control of a multi-dof underactuated prosthetic hand

<p>Abstract</p> <p>Background</p> <p>Functionality, controllability and cosmetics are the key issues to be addressed in order to accomplish a successful functional substitution of the human hand by means of a prosthesis. Not only the prosthesis should duplicate the human hand in shape, functionality, sensorization, perception and sense of body-belonging, but it should also be controlled as the natural one, in the most intuitive and undemanding way. At present, prosthetic hands are controlled by means of non-invasive interfaces based on electromyography (EMG). Driving a multi degrees of freedom (DoF) hand for achieving hand dexterity implies to selectively modulate many different EMG signals in order to make each joint move independently, and this could require significant cognitive effort to the user.</p> <p>Methods</p> <p>A Principal Components Analysis (PCA) based algorithm is used to drive a 16 DoFs underactuated prosthetic hand prototype (called CyberHand) with a two dimensional control input, in order to perform the three prehensile forms mostly used in Activities of Daily Living (ADLs). Such Principal Components set has been derived directly from the artificial hand by collecting its sensory data while performing 50 different grasps, and subsequently used for control.</p> <p>Results</p> <p>Trials have shown that two independent input signals can be successfully used to control the posture of a real robotic hand and that correct grasps (in terms of involved fingers, stability and posture) may be achieved.</p> <p>Conclusions</p> <p>This work demonstrates the effectiveness of a bio-inspired system successfully conjugating the advantages of an underactuated, anthropomorphic hand with a PCA-based control strategy, and opens up promising possibilities for the development of an intuitively controllable hand prosthesis.</p