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The development of novel topoisomerase I (TOP1) inhibitors is crucial for overcoming the drawbacks and limitations of current TOP1 poisons. Here, we identified two potential TOP1 inhibitors, namely, FTY720 (a sphingosine 1-phosphate antagonist) and COH29 (a ribonucleotide reductase inhibitor), through experimental screening of known active compounds. Biological experiments verified that FTY720 and COH29 were nonintercalative TOP1 catalytic inhibitors that did not induce the formation of DNA-TOP1 covalent complexes. Molecular docking revealed that FTY720 and COH29 interacted favorably with TOP1. Molecular dynamics simulations revealed that FTY720 and COH29 could affect the catalytic domain of TOP1, thus resulting in altered DNA-binding cavity size. The alanine scanning and interaction entropy identified Arg536 as a hotspot residue. In addition, the bioinformatics analysis predicted that FTY720 and COH29 could be effective in treating malignant breast tumors. Biological experiments verified their antitumor activities using MCF-7 breast cancer cells. Their combinatory effects with TOP1 poisons were also investigated. Further, FTY720 and COH29 were found to cause less DNA damage compared with TOP1 poisons. The findings provide reliable lead compounds for the development of novel TOP1 catalytic inhibitors and offer new insights into the potential clinical applications of FTY720 and COH29 in targeting TOP1.

OBJECTIVES: To assess DWI for tumor visibility and breast cancer detection by the addition of different synthetic b-values. METHODS: Eighty-four consecutive women who underwent a breast-multiparametric-MRI (mpMRI) with enhancing lesions on DCE-MRI (BI-RADS 2-5) were included in this IRB-approved retrospective study from September 2018 to March 2019. Three readers evaluated DW acquired b-800 and synthetic b-1000, b-1200, b-1500, and b-1800 s/mm2 images for lesion visibility and preferred b-value based on lesion conspicuity. Image quality (1-3 scores) and breast composition (BI-RADS) were also recorded. Diagnostic parameters for DWI were determined using a 1-5 malignancy score based on qualitative imaging parameters (acquired + preferred synthetic b-values) and ADC values. BI-RADS classification was used for DCE-MRI and quantitative ADC values + BI-RADS were used for mpMRI. RESULTS: Sixty-four malignant (average = 23 mm) and 39 benign (average = 8 mm) lesions were found in 80 women. Although b-800 achieved the best image quality score, synthetic b-values 1200-1500 s/mm2 were preferred for lesion conspicuity, especially in dense breast. b-800 and synthetic b-1000/b-1200 s/mm2 values allowed the visualization of 84-90% of cancers visible with DCE-MRI performing better than b-1500/b-1800 s/mm2. DWI was more specific (86.3% vs 65.7%, p < 0.001) but less sensitive (62.8% vs 90%, p < 0.001) and accurate (71% vs 80.7%, p = 0.003) than DCE-MRI for breast cancer detection, where mpMRI was the most accurate modality accounting for less false positive cases. CONCLUSION: The addition of synthetic b-values enhances tumor conspicuity and could potentially improve tumor visualization particularly in dense breast. However, its supportive role for DWI breast cancer detection is still not definite. KEY POINTS: • The addition of synthetic b-values (1200-1500 s/mm2) to acquired DWI afforded a better lesion conspicuity without increasing acquisition time and was particularly useful

Diplomová práce pojednává o problematice nádorů prsu a jejich léčbě. Zaměřuje se na moderní trendy v managementu léčby těchto onemocnění. Práce se skládá ze dvou částí - teoretické a praktické. V teoretické části je popisována problematika onemocnění prsu, epidemiologické údaje, diagnostika, možnosti léčby a prognóza. Praktická část obsahuje informace o výsledcích výzkumu provedeném mezi pacientkami, které podstoupily operační léčbu na chirurgickém oddělení., This essay deals with breast tumors problems and focuses on the modern treatment methods. It consists of two parts- theoretical and research part. The are mentioned the epidemiology, diagnostics, treatment methods and prognosis in the theoretical part. Practical part includes information about results of research taken in the groups of women, who have passed the surgical treatement of breast tumor., Katedra ošetřovatelství, Hodnocení vedoucího: výborně mínus Hodnocení oponenta: velmi dobře Doplňující otázky k obhajobě: 1. Definujte sentinelovou uzlinu. 2. Používá se detekce sentinelové uzliny také v léčbě dalších nádorů? 3. Domníváte se, že užívání hormonální antikoncepce od časného věku (16,17 let) může mít vliv na vznik karcinomu prsu? 2 Obhajoba diplomové práce s prezentací velmi dobrá.

The goal of our project was to develop methods to image the processes that occur during tumor growth and metastatic spread or regression including the fate of minimal residual disease. The key to this was through the development of a dual modality imaging system capable of performing both optical and SPECT imaging in mice. To do so it is necessary to test the limits of sensitivity of newly developed techniques: our technical goal is to develop integrated light emission and single photon emission tomography. We have made substantial progress in our techniques for the detection of metastases. We have demonstrated our capability to detect millimeter or sub-millimeter metastases in mice by light emission. To this end we have used Light Emission Tomography (LET) a technique based on bioluminescence of cancer cells transfected with lucifernse to detect metastases in the lung bones and head. We have begun assessment of perfusion using fluorescence imaging. In addibon our technological focus is on the simultaneous use of Single-photon Emission Computed Tomography (SPECT) and to this end we have developed a new form of micro-SPECT based on cooled electron-multiplied Charge-Coupled Devices (EMCCDs)., The original document contains color images.

Magnetic Resonance Imaging is an emerging diagnostic tool for breast cancer that provides high-resolution three-dimensional images of tissues. A significant increase of specificity of detection of cancerous lesions could be achieved by use of tumor specific contrast agents (CA). Currently, tumor-specific targeting of CA is achieved by antibodies (Ab) or fragments thereof. The major disadvantages of Ab are their large size and ability to induce immune response. We proposed to use DNA aptamers for tumor-specific targeting of CA because short DNA molecules are smaller than Ab, have better tissue penetration and are non-toxic and non-immunogenic. During the study, PSI developed an experimental system and generated essential reagents for selection of DNA aptamers. Expression constructs encoding human EGF receptor (EGF-R) fusion protein were produced and used for generation of stable cell lines expressing this protein at suitable levels. EGF-R was used for isolation of DNA aptamers from combinatorial synthetic library. A group of structurally related aptamers was identified. In the course of the program a variety of technical challenges were identified and alternative approaches were undertaken. Full characterization and validation of the isolated EGF-R-specific aptamers was not completed. PSI research effort generated valuable reagents and technical knowledge for further development of the proposed technology., The original document contains color images.

Surgery for breast cancer includes removal of the breast tumor along with the axillary lymph nodes. The status of these nodes helps clinicians determine prognosis and guides treatment decisions. Unfortunately, a relatively common side effect following axillary lymph node dissection is upper-extremity lymphedema. The purpose of this study is to identify risk factors for lymphedema among women who have had axillary surgery for breast cancer. Specific aims include identifying risk factors for lymphedema and comparing quality of life (QOL) ratings for women who have and do not have lymphedema. A case-control study will be conducted with enrollment of 200 participants. Cases will be identified at their lymphedema consult in the physical therapy centers. Using the oncology registry, controls will include patients who have had breast cancer surgery and have not developed lymphedema. The severity of lymphedema and interference with daily life will be assessed with the Measure of Arm Symptom Survey (MASS), a patient-completed survey, and QOL will be collected with the SF-36. Treatment risk factors including previous surgery, radiotherapy and chemotherapy will be obtained from oncology registry data. This study will determine which factors play a role in lymphedema development.