Development of Single and Multimodality Imaging Probes for PET, SPECT and Fluorescence Imaging

This dissertation is in an integrated format discussing three major projects centered around probe development. In the first project, novel metal-chelated and fluorinated GLP-1 derivatives were prepared all containing D-Ala-8, a modification known to improve resistance towards degradation by dipeptidyl-peptidase IV. The effect of increased distance between DOTA and the peptide chain was investigated using a spacer, in order to reduce steric effects imposed by DOTA. Placement of linker and DOTA moieties were varied within the GLP-1 sequence to test for optimal metal-complex location. Binding affinity of peptide derivatives was determined in vitro with CHO/GLP-1R cell line and shown to be in the nM range. In vivo imaging was carried out using C57BL/6 mice. Modifications made to the peptide backbone, based on charge distribution, were shown to improve pharmacokinetics. Our results suggest developed GLP-1 tracers to be potential candidates for the non-invasive imaging of pancreatic islets in vivo. In the second project, Gallium-chelated protoporphyrin IX (PPIX) derivatives containing the tripeptide RGD αvβ3-targeting moiety were prepared and evaluated. Reaction conditions for both naturally occurring 69/71Ga-labeling as well as 68Ga-radiolabeling were optimized using a microwave reactor. Optical properties were evaluated in order to study the effects of ligand conjugation and gallium chelation on absorption/emission properties of PPIX. Quantum yields pre- and post gallium chelation were comparable, indicating that the presence of gallium does not quench the inherent fluorescence of PPIX. The targeted compound was preferentially taken up by αvβ3 integrin-expressing cancer cells versus the non-targeted form, as assessed by fluorescence microscopy. Our results suggest that gallium-PPIX conjugates could be used as dual modality positron emission tomography/fluorescence microscopy probes and can assist in bridging imaging agent discovery from in vitro microscopy through to in vivo imaging. In the third and final project, a novel high-throughput cell-based technique was developed for screening one-bead-one-compound (OBOC) libraries. In order to validate this technique, a small library consisting of heptameric peptides, and the αvβ3 integrins targeting RGD sequence, was synthesized on Tentagel beads via a photo-labile linker. Compounds were screened against the αvβ3-expressing MD 435 cell line. After fluorescent-based sorting, peptides were photolytically cleaved off resin and analyzed using MALDI-TOF/TOF. Deconvolution of all peptide sequences was carried out successfully indicating this screening process to be a facile and efficient technique for discovery of novel targeting entities

Bladder Lymphangioma Treated by Holmium Laser: Extremely Rare Case Report

Introduction: Lymphangioma is a sporadic benign tumor of the bladder. It is a congenital disorder and based on the size of lymphatic spaces, it is divided into 3 types of capillary, cavernous, and cystic.Case Report: In this paper, we presented a 40-year-old woman with microscopic hematuria and a normal urinary ultrasound. Urethrocystoscopy showed a flat 4 mm highlighted strawberry-like lesion on the right lateral wall of the bladder. After a cold cup biopsy, the lesion was coagulated by the holmium: YAG (Ho: YAG) laser.Conclusion: In Bladder Lymphangioma Based on the size of the lesion, partial cystectomy or minimally invasive surgeries such as laser modality would be the principal treatment. 

Laplacian-Former: Overcoming the Limitations of Vision Transformers in Local Texture Detection

Vision Transformer (ViT) models have demonstrated a breakthrough in a wide range of computer vision tasks. However, compared to the Convolutional Neural Network (CNN) models, it has been observed that the ViT models struggle to capture high-frequency components of images, which can limit their ability to detect local textures and edge information. As abnormalities in human tissue, such as tumors and lesions, may greatly vary in structure, texture, and shape, high-frequency information such as texture is crucial for effective semantic segmentation tasks. To address this limitation in ViT models, we propose a new technique, Laplacian-Former, that enhances the self-attention map by adaptively re-calibrating the frequency information in a Laplacian pyramid. More specifically, our proposed method utilizes a dual attention mechanism via efficient attention and frequency attention while the efficient attention mechanism reduces the complexity of self-attention to linear while producing the same output, selectively intensifying the contribution of shape and texture features. Furthermore, we introduce a novel efficient enhancement multi-scale bridge that effectively transfers spatial information from the encoder to the decoder while preserving the fundamental features. We demonstrate the efficacy of Laplacian-former on multi-organ and skin lesion segmentation tasks with +1.87\% and +0.76\% dice scores compared to SOTA approaches, respectively. Our implementation is publically available at https://github.com/mindflow-institue/Laplacian-FormerComment: Accepted in the main conference MICCAI 202

Retrograde-assisted Percutaneous Cystolitholapaxy versus Transurethral Cystolithotripsy with Holmium-YAG Laser, A Retrospective Study

Introduction: The retrograde approach is a modification that makes the percutaneous cystolitholapaxy (PCCL) a more trendy method, especially in operating rooms with limited facilities. The transurethral approach for bladder calculi lithotripsy by a laser has become popular among urologists. In this study, we investigate the feasibility and safety of retrograde assisted access for PCCL in comparison with transurethral cystolithotripsy by the holmium-YAG laser (Ho:YAG).Methods: According to the type of intervention, the patients were stratified to two matched groups. In the retrograde-assisted percutaneous cystolitholapaxy (RPCCL) group, a Benique was conducted through the urethra into the bladder; palpating the suprapubic region, an about 1.5 cm incision was done over the tip, then an Amplatz sheath was placed over it, treading into the bladder; further cystolitholapaxy was done by a routine order. In transurethral Ho: YAG laser lithotripsy (TULL) via 200 μm fiber vaporize the stone.Results: A total of 124 male patients with the mean age of 50.33 ± 9.64 years and the average stone burden of 3.35 ± 1.07 cm were included in the study. The most common cause of vesical calculi was spinal cord injury. Statistically significant differences were found in terms of the mean operation time in favor of the RPCCL group (P ≤ 0.05) and the mean hospital stay in favor of the TULL group (P ≤ 0.05). The stone-free rate (SFR) was 100% in both methods after a one month follow-up. None of the interventions changed to open surgery. There were not any major complications in both methods.Conclusion: RPCCL is a safe and effective method in bladder stone treatment and is applicable inmedical centers without Ho: YAG equipment

Multiple Pulmonary Calssified Nodules and Cavitation Filled With the Dense Body on Chest X-Ray: A Case Report

Imaging in the clinical study has a significant value in medical diagnosing and the following diseases. The characteristic signs of imaging are a clue in approach to differential diagnosis. A conventional chest x-ray radiography is a more prevalent image used in the initial clinical assessment of pulmonary diseases. Iran is one of the 9 countries with a 95% burden of tuberculosis in the Eastern Mediterranian region. Chest radiography is the initial imaging for the evaluation of pulmonary tuberculosis

Web Runner 2049: Evaluating Third-Party Anti-bot Services

International audienceGiven the ever-increasing number of malicious bots scouring the web, many websites are turning to specialized services that advertise their ability to detect bots and block them. In this paper, we investigate the design and implementation details of commercial anti-bot services in an effort to understand how they operate and whether they can effectively identify and block malicious bots in practice. We analyze the JavaScript code which their clients need to include in their websites and perform a set of gray box and black box analyses of their proprietary back-end logic, by simulating bots utilizing well-known automation tools and popular browsers. On the positive side, our results show that by relying on browser fingerprinting, more than 75% of protected websites in our dataset, successfully defend against attacks by basic bots built with Python scripts or PhantomJS. At the same time, by using less popular browsers in terms of automation (e.g., Safari on Mac and Chrome on Android) attackers can successfully bypass the protection of up to 82% of protected websites. Our findings show that the majority of protected websites are prone to bot attacks and the existing anti-bot solutions cannot substantially limit the ability of determined attackers. We have responsibly disclosed our findings with the anti-bot service providers