Publications by authors named "Sami Znati"

6 Publications

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Radiosensitisation of Hepatocellular Carcinoma Cells by Vandetanib.

Cancers (Basel) 2020 Jul 13;12(7). Epub 2020 Jul 13.

University College London Cancer Institute, University College London, London WC1E 6BT, UK.

Hepatocellular Carcinoma (HCC) is increasing in incidence worldwide and requires new approaches to therapy. The combination of anti-angiogenic drug therapy and radiotherapy is one promising new approach. The anti-angiogenic drug vandetanib is a tyrosine kinase inhibitor of vascular endothelial growth factor receptor-2 (VEGFR-2) and RET proto-oncogene with radio-enhancement potential. To explore the benefit of combined vandetanib and radiotherapy treatment for HCC, we studied outcomes following combined treatment in pre-clinical models.

Methods: Vandetanib and radiation treatment were combined in HCC cell lines grown and . In addition to 2D migration and clonogenic assays, the combination was studied in 3D spheroids and a syngeneic mouse model of HCC.

Results: Vandetanib IC 50 s were measured in 20 cell lines and the drug was found to significantly enhance radiation cell kill and to inhibit both cell migration and invasion . , combination therapy significantly reduced cancer growth and improved overall survival, an effect that persisted for the duration of vandetanib treatment.

Conclusion: In 2D and 3D studies and in a syngeneic model , the combination of vandetanib plus radiotherapy was more efficacious than either treatment alone. This new combination therapy for HCC merits evaluation in clinical trials.
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http://dx.doi.org/10.3390/cancers12071878DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7408860PMC
July 2020

VEROnA Protocol: A Pilot, Open-Label, Single-Arm, Phase 0, Window-of-Opportunity Study of Vandetanib-Eluting Radiopaque Embolic Beads (BTG-002814) in Patients With Resectable Liver Malignancies.

JMIR Res Protoc 2019 Oct 2;8(10):e13696. Epub 2019 Oct 2.

National Institute for Health Research University College London Hospitals Biomedical Centre, University College London Cancer Institute, London, United Kingdom.

Background: Transarterial chemoembolization (TACE) is the current standard of care for patients with intermediate-stage hepatocellular carcinoma (HCC) and is also a treatment option for patients with liver metastases from colorectal cancer. However, TACE is not a curative treatment, and tumor progression occurs in more than half of the patients treated. Despite advances and technical refinements of TACE, including the introduction of drug-eluting beads-TACE, the clinical efficacy of TACE has not been optimized, and improved arterial therapies are required.

Objective: The primary objectives of the VEROnA study are to evaluate the safety and tolerability of vandetanib-eluting radiopaque embolic beads (BTG-002814) in patients with resectable liver malignancies and to determine concentrations of vandetanib and the N-desmethyl metabolite in plasma and resected liver following treatment with BTG-002814.

Methods: The VEROnA study is a first-in-human, open-label, single-arm, phase 0, window-of-opportunity study of BTG-002814 (containing 100 mg vandetanib) delivered transarterially, 7 to 21 days before surgery in patients with resectable liver malignancies. Eligible patients have a diagnosis of colorectal liver metastases, or HCC (Childs Pugh A), diagnosed histologically or radiologically, and are candidates for liver surgery. All patients are followed up for 28 days following surgery. Secondary objectives of this study are to evaluate the anatomical distribution of BTG-002814 on noncontrast-enhanced imaging, to evaluate histopathological features in the surgical specimen, and to assess changes in blood flow on dynamic contrast-enhanced magnetic resonance imaging following treatment with BTG-002814. Exploratory objectives of this study are to study blood biomarkers with the potential to identify patients likely to respond to treatment and to correlate the distribution of BTG-002814 on imaging with pathology by 3-dimensional modeling.

Results: Enrollment for the study was completed in February 2019. Results of a planned interim analysis were reviewed by a safety committee after the first 3 patients completed follow-up. The recommendation of the committee was to continue the study without any changes to the dose or trial design, as there were no significant unexpected toxicities related to BTG-002814.

Conclusions: The VEROnA study is studying the feasibility of administering BTG-002814 to optimize the use of this novel technology as liver-directed therapy for patients with primary and secondary liver cancer.

Trial Registration: ClinicalTrial.gov NCT03291379; https://clinicaltrials.gov/ct2/show/NCT03291379.

International Registered Report Identifier (irrid): DERR1-10.2196/13696.
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http://dx.doi.org/10.2196/13696DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6777276PMC
October 2019

Morphometric analysis of astrocytes in brainstem respiratory regions.

J Comp Neurol 2018 09 22;526(13):2032-2047. Epub 2018 Aug 22.

Cellular and Systems Neurobiology Section, National Institute of Neurological Disorders and Stroke (NINDS) National Institutes of Health (NIH), Bethesda, Maryland.

Astrocytes, the most abundant and structurally complex glial cells of the central nervous system, are proposed to play an important role in modulating the activities of neuronal networks, including respiratory rhythm-generating circuits of the preBötzinger complex (preBötC) located in the ventrolateral medulla of the brainstem. However, structural properties of astrocytes residing within different brainstem regions are unknown. In this study astrocytes in the preBötC, an intermediate reticular formation (IRF) region with respiratory-related function, and a region of the nucleus tractus solitarius (NTS) in adult rats were reconstructed and their morphological features were compared. Detailed morphological analysis revealed that preBötC astrocytes are structurally more complex than those residing within the functionally distinct neighboring IRF region, or the NTS, located at the dorsal aspect of the medulla oblongata. Structural analyses of the brainstem microvasculature indicated no significant regional differences in vascular properties. We hypothesize that high morphological complexity of preBötC astrocytes reflects their functional role in providing structural/metabolic support and modulation of the key neuronal circuits essential for breathing, as well as constraints imposed by arrangements of associated neurons and/or other local structural features of the brainstem parenchyma.
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http://dx.doi.org/10.1002/cne.24472DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6158060PMC
September 2018

A Universal Moiré Effect and Application in X-Ray Phase-Contrast Imaging.

Nat Phys 2016 25;12:830-834. Epub 2016 Apr 25.

Biophysics and Biochemistry Center, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, Maryland, USA.

A moiré pattern is created by superimposing two black-and-white or gray-scale patterns of regular geometry, such as two sets of evenly spaced lines. We observed an analogous effect between two transparent phase masks in a light beam which occurs at a distance. This phase moiré effect and the classic moiré effect are shown to be the two ends of a continuous spectrum. The phase moiré effect allows the detection of sub-resolution intensity or phase patterns with a transparent screen. When applied to x-ray imaging, it enables a polychromatic far-field interferometer (PFI) without absorption gratings. X-ray interferometry can non-invasively detect refractive index variations inside an object. Current bench-top interferometers operate in the near field with limitations in sensitivity and x-ray dose efficiency. The universal moiré effect helps overcome these limitations and obviates the need to make hard x-ray absorption gratings of sub-micron periods.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5063246PMC
http://dx.doi.org/10.1038/nphys3734DOI Listing
April 2016

Electrodeposition of Gold to Conformally Fill High Aspect Ratio Nanometric Silicon Grating Trenches: A Comparison of Pulsed and Direct Current Protocols.

J Surf Eng Mater Adv Technol 2015 Oct 16;5(4):207-213. Epub 2015 Oct 16.

Imaging Physics Laboratory, Biochemistry and Biophysics Center, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892.

Filling high-aspect-ratio trenches with gold is a frequent requirement in the fabrication of x-ray optics as well as micro-electronic components and other fabrication processes. Conformal electrodeposition of gold in sub-micron-width silicon trenches with an aspect ratio greater than 35 over a grating area of several square centimeters is challenging and has not been described in the literature previously. A comparison of pulsed plating and constant current plating led to a gold electroplating protocol that reliably filled trenches for such structures.
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http://dx.doi.org/10.4236/jsemat.2015.54022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4812826PMC
October 2015

Enhancing Tabletop X-Ray Phase Contrast Imaging with Nano-Fabrication.

Sci Rep 2015 Aug 28;5:13581. Epub 2015 Aug 28.

Imaging Physics Laboratory, Biochemistry and Biophysics Center, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892.

X-ray phase-contrast imaging is a promising approach for improving soft-tissue contrast and lowering radiation dose in biomedical applications. While current tabletop imaging systems adapt to common x-ray tubes and large-area detectors by employing absorptive elements such as absorption gratings or monolithic crystals to filter the beam, we developed nanometric phase gratings which enable tabletop x-ray far-field interferometry with only phase-shifting elements, leading to a substantial enhancement in the performance of phase contrast imaging. In a general sense the method transfers the demands on the spatial coherence of the x-ray source and the detector resolution to the feature size of x-ray phase masks. We demonstrate its capabilities in hard x-ray imaging experiments at a fraction of clinical dose levels and present comparisons with the existing Talbot-Lau interferometer and with conventional digital radiography.
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http://dx.doi.org/10.1038/srep13581DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4551996PMC
August 2015