Master Degree / Yüksek Lisans Tezleri
Permanent URI for this collectionhttps://hdl.handle.net/11147/3008
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Master Thesis Investigation of Malignant Melanoma Cancer and Cancer Stem Cells Using Optical Spectroscopy Techniques(01. Izmir Institute of Technology, 2024) Uslu, Bensu Rüya; Güler, GünnurKanser kök hücreleri, kök hücre ve progenitör hücrelerdeki akümüle mutasyonlardan kaynaklanan kanser hücrelerinin düşük bir yüzdesini oluşturmalarına rağmen kanserin tekrarından, tedaviye direnç göstermesinden ve metastazından büyük ölçüde sorumludurlar. Malign melanom yaygın bir kanserdir, ve insidansı, mortatalitesi ve morbitesi alarm verici seviyede artmaktadır. Bu çalışmanın amacı kanser kök hücrelerinin malign melanom modeli üzerinde titreşimsel spektroskopi ile incelenmesidir. Titreşimsel spektroskopi moleküllere dair hem nitel hem nicel bilgi verir. Yani hücrelerin biyokimyasal içeriği ve moleküllerin miktarı titreşimsel spektroskopi ile belirlenebilir. Dahası, deney grupları arasındaki ilişkiler ve spektral verinin istatistiksel önemi kaydedilen spektrumlara çok-değişkenli Analiz yöntemleri uygulanarak değerlendirilebilir. Titreşimsel spektroskopi, infrared ve Raman spektroskopileri, hücresel ve diğer biyolojik çalışmalarda yaygın olarak kullanılmaktadır ve başarılı sonuçlar elde edilmektedir. Bu çalışmada, kanser kök hücreleri, kök hücre olmayan kanser hücreleri ve bulk hücre popülasyonu hücreleri infrared ve Raman spektroskopileri ile incelenmiştir ve elde edilen veriler hücre döngüsünün 11, 24, 48 ve 72. saatlerinde çok-değişkenli yöntemlerle analiz edilmiştir. Sonuç olarak, üç grup arasındaki biyokimyasal ve biyofiziksel farklar farklı saatler için belirlenmiş ve hücrelerin hüçre döngüsüne ilişkin bilgiler elde edilmiştir. Bu çalışma titreşimsel spektroskopinin hücre karakterizasyonunda kullanılabileceğini ve çok-değişkenli analizlerle birleştirildiğinde spektrumlardan elde edilen bilginin ciddi ölçüde geliştirilebileceğini desteklemektedir.Master Thesis Synthesis of 1,5-Disubstituted 1,2,3-Triazole Modified Azacoumarins(01. Izmir Institute of Technology, 2022) Çetin, Başak; Çağır, AliCancer is a deadly disease that threatens human health and all life, and it is still a serious problem despite all scientific studies for more than half a century. Pharmacophores are a part of the structure of a drug (or drug candidate) responsible from the biological activity. This thesis is related with the synthesis of novel compounds having two well-known pharmacophore structures, 1,2,3-triazole and 1-azacoumarin. Both structures can be found in the structure of many biologically active molecules. Triazole modified coumarin derivatives are scarce in the literature. In this study, we aimed to improve the synthetic route toward the synthesis of 1- azacoumarin derivative modified by 1,2,3-triazole group at position 4-. Synthesis starts with the conversion of methyl 4-chloroanthranilate to the corresponding 4-OH azacoumarin. Then it is transferred into the 4-OTf group by simply addition of Tf group to OH under basic condition. After Sonogashira reaction and removal of TMS group 4- alkynyl-1-azacoumarin was produced. At this point, conversion of alkyne into 1,5- disubstituted 1,2,3-triazole was examined in the presence of Cp2Ni-Xantphos and RuCl(COD)Cp* catalytic systems but all of trials were failed probably due to the presence of ester group close to the reaction site. In further studies, design of the molecule will be reperformed and ester group will be moved over phenyl rings in order to test its biological activity over cancer cell lines.Master Thesis Quantitative Phase Analysis in Lensless Digital Inline Holographic Microscopy(01. Izmir Institute of Technology, 2021) Demir, Ali Aslan; Tekin, Hüseyin Cumhur; Varlıklı, CananComputational imaging modalities replace the bulky, complex, and expensive optical components of traditional imaging procedures with numerical reconstruction steps. Digital holographic microscopy is one of the most prominent ones with the possibility of obtaining quantitative phase information by measuring the phase shift change caused by the refractive index of objects. In the lensless digital holographic microscopy system, a pinhole and a light-emitting diode are sufficient to create a holographic pattern on the camera sensor. Here, the optimization of a digital lensless inline holographic microscopy setup was performed to obtain optimal phase value. Also, to retrieve the lost phase information during the recording step, the numerical solution was performed with the single and multi-shot phase retrieval methods. Then, human breast adenocarcinoma (MDA-MB-231) and human myeloid leukemia (U937) cells were analyzed to obtain phase shift, perimeter, and circularity values. These parameters were used to obtain a quantitative differentiation model to replace the traditional labeling or visual confirmation steps with a direct analysis manner. The analysis of respective cells with the classification, object detection, and conditional generative adversarial models can be used directly with pre-trained weights to lessen the computational workloads. With this study, the quantitative analysis with lensless holographic microscopy setup was shown to be a label-free differentiation mechanism to separate cancer cells from monocytes cells which could be used for the early diagnosis of cancer. Also, the proposed method has the potential to be used to identify other cells with links to the diagnosis of different diseases.Master Thesis Investigation of Anticancer Properties of Novel Mdm2 Inhibitors(Izmir Institute of Technology, 2021) Özdemir, Sefayi Merve; Çağır, AliCancer is one major disease causing death worldwide. Current cancer treatments are not %100 effective to cure for patients, yet. Thereby, the synthesis and discovery of new therapeutics have been important to improve the survival period of the cancer patients. There are many strategies for synthesis of cancer therapeutics. One of the most important strategy for cancer treatment is the reactivation of p53. MDM2 is a negative regulator of p53 in cell, because it causes the inactivation of p53. In this thesis, the anticancer and MDM2 inhibitory properties of ezetimibe, desfluoro ezetimibe and intermediates during ezetimibe synthesis (named as SM2-9) and a side product from the synthesis of benidipine (named as SM1) on prostate cancer (LnCAP, wild-type p53), breast cancer (MCF7, wild type p53) and uterus cancer (HeLa, wild type nonfunctional p53) cells were investigated. For this purpose, the cytotoxic, cytostatic and apoptotic properties of these compounds were determined. Compounds SM2, SM3, SM4 and SM6 demonstrated cytotoxic effects, whereas compounds SM5, SM8 and SM9 had cytostatic effects on three cells. Compound SM7 had no effect on these cells, up to 100 μM concentration. Compounds SM1 had cytostatic effect on MCF7 cells, but it showed no activity on other cells. Compounds SM8 and SM9 had strong cytostatic activity. Thus, the apoptotic properties of these compounds were examined by caspases 3/7 activation and Annexin-V FITC assays. Besides, MDM2 inhibitor profiles of these compounds were investigated by fluorescence polarization assay. This study provides novel and potential molecules for drug discovery in cancer treatmentMaster Thesis Studies Toward the Asymmetric Synthesis of Ester Functionalized Novel 1,4-Oxazepine Derivatives(01. Izmir Institute of Technology, 2021) Bozoğlu, Hülya; Çağır, AliThe MDM2/p53 is one of the most widely studied protein-protein interaction because of being a valuable target for the development of novel anticancer agents. MDM2 protein is the natural inhibitor of p53 protein which act as a tumor suppressor. When MDM2 is overexpressed, damaged DNA is allowed to replicate and therefore cancerous cells can be generated because p53 has lost of its activity. For this reason; maintaining the activity of wild-type p53 through inhibition of MDM2 can stop the proliferation of cancer cells. New drugs that inhibit this interaction are important for the treatment of cancer. The aim of the study is synthesize chiral 1,4-oxazepine-5-one derivatives. (R)-2-amino-2-(4-chlorophenyl)acetic acid was used as starting material for the synthesis. The first step was a trityl protection of amine with trityl chloride. Trityl protected amino acid was reduced to N-Trt amino alcohol with LiAlH4 then oxidized to aldehyde by using Dess-Martin periodinane. The resulting aldehyde was reacted with 3-chlorophenylmagnesium bromide. Up to this part of the synthesis, reactions were performed successfully. Then trityl group was removed by TFA and amino alcohol was obtained. Then addition of several α,β-unsaturated carbonyls to the deprotected amino alcohol was studied by coupling reagents such as HATU. Afterwards we performed some intramolecular cyclization attempts but all cyclization attempts were failed.Master Thesis In-Vitro Evaluation Cytotoxic Potential of Novel Isoindole Derivatives on Various Cancer Cell Lines(01. Izmir Institute of Technology, 2021) Yemeztaşlıca Yetişkin, Egehan; Gülşah Şanlı MohamedCancer, which is the disease of our age, arises because of a very complex set of mechanisms. Especially with the proliferation of cancer disease and the increase in cancer-related deaths, it has a great impact on the development of drug studies by improving existing treatments or researching new treatment methods. Cantharidine and its analogs are natural anhydrides with an inhibitory effect on protein phosphatases. However, they are not included in cancer therapies due to their toxicity. In recent studies, it has been found that derivatives of cantharidin as isoindole-1,3-dione and its derivatives have anticancer effects. The main purpose of this study to investigate the effects of four different drugs, which are newly synthesized isoindole derivatives for use in cancer treatment, on different cancer cells. The cytotoxic effects of drugs on A549 (human lung adenocarcinoma), HeLa (human cervical carcinoma), PC3 (human prostate carcinoma), MCF-7 (human breast carcinoma), and Caco-2 (human colorectal carcinoma) cell lines were investigated by the MTT assay method, and the optimum incubation time was determined, then IC50 values were calculated. Then, the IC50 concentrations of the drugs were applied at 48 hours, which is the optimum incubation period, and apoptotic stages and cell cycle stages were compared using flow cytometry to understand whether the drugs have a suppressive function in cancer development. Scratch assay was performed to investigate the migration effect of drugs on cells. The results showed that the drugs are suppressive to cancer cells and can be used for therapeutic purposes in the future.Master Thesis Time Dependent Expression and Localization of Connexin 32: Implication in Epithelial To Mesenchymal Transition of Mammary Epithelial Mcf10a and Triple Negative Breast Cancer Mda Mb 231 Cells(01. Izmir Institute of Technology, 2020) Ünal, Yağmur Ceren; Meşe Özçivici, GülistanBreast cancer is the most frequent and the second leading cause of cancer-related deaths among women worldwide. Epithelial to mesenchymal transition (EMT) is critical driving force in metastasis. Connexins as a basic subunit of gap junctions indicate critical roles in regulation of EMT. In addition to Cx26 and Cx43, Cx32 is associated with breast cancer and elevated levels of Cx32 has been reported in lymph node metastasis compared to primary breast cancer while the role of Cx32 in breast cancer is still elusive. Here we aimed to shed light on the effect of Cx32 on breast cancer. Our study suggested that Cx32 acquired mesenchymal morphology and decreased proliferation in MCF10A cells but not in MDA MB 231 cells. To further elucidate whether Cx32 indicate these changes through EMT, EMT markers were examined and subsequently it was revealed that Cx32 expression was strongly correlated with increased E-cadherin and Vimentin in MCF10A cells while decreased E-cadherin and Snail in MDA MB 231 cells. Importantly majority of Cx32 did not localize to the plasma membrane and indicated dynamic changes in a day dependent manner in both MCF10A and MDA MB 231 cells. Moreover, day dependent expression and localization of Cx32 revealed strong correlation with Zeb2 expression in MCF10A cells. In conclusion, Cx32 indicated differential effects in regulation of EMT between MCF10A and MDA MB 231 cells. It was the first time that the role of Cx32 on EMT was investigated in breast cancer and differential localization of Cx32 was identified.Master Thesis Investigating Oncogenic Role of Sema6d in Breast Cancer Cells(Izmir Institute of Technology, 2019) Günyüz, Zehra Elif; Yalçın Özuysal, ÖzdenBreast cancer, the most commonly diagnosed cancer type and the leading cause of cancer-associated deaths, is the major health issue among women worldwide. In many cancer types, the expression of the semaphorins and their receptors such as plexins and neuropilins are dysregulated. SEMA6D is a member of class-6 family transmembrane semaphorin proteins and acts through Plexin-A1 receptor. It was previously shown that overexpression of SEMA6D in breast cancer cell line MCF-7 leads to a reduction in proliferation and an increase in migration. On the other hand, in the MDA-MB-231 breast cancer cell line, overexpression of SEMA6D had no significant effect on proliferation but enhanced migration. In this study, we aimed to analyze the effects of SEMA6D overexpression in normal breast cell line MCF10A and investigate the invasive behavior and transformation capacity of SEMA6D overexpressing breast cancer cell lines. We demonstrated that overexpression of SEMA6D leads to elevated proliferation, viability and migration in MCF10A cells, whereas it did not trigger their anchorage-independent growth. On the other hand, MDA-MB-231 and MCF7 cells stably expressing SEMA6D showed reduced colony formation in the soft-agar assay. Furthermore, the invasiveness of MDA-MB-231 cells was elevated with SEMA6D overexpression, whereas SEMA6D overexpression did not stimulate the invasiveness of MCF-7 cells through matrigel microenvironment, whereas slightly trigger invasion through bone microenvironment. In conclusion, SEMA6D overexpression has cell-specific effects on breast cancer. The exact role of SEMA6D in breast cancer development remains undefined and must be further investigated.Master Thesis Determination of Therapeutic Potential of Luteolin for Acute Lymphoblastic Leukemia Cells(Izmir Institute of Technology, 2019) Gürler, Sevim Beyza; Baran, YusufAcute lymphoblastic leukemia (ALL) is a hematologic malignancy characterized by increased level of immature lymphoblasts in bone marrow and peripheral blood. The developments of lymphoblasts are genetically/epigenetically inhibited. One of the most common genetic abnormalities in ALL is BCR/ABL translocation which regulates the several pathways related to proliferation, anti-apoptotic and drug resistance through its aberrant tyrosine kinase activity. Although the current treatment strategies include targeting BCR/ABL via tyrosine kinase inhibitors; complete remission, overall survival and mortality of Ph+ ALL patients are still worse as compared to Ph- ALL patients. Therefore, new strategies combined with current treatments are needed for Ph+ ALL patients who are qualified as high risk group of ALL. Different studies showed thatluteolin has anti-cancer and anti-tumor effects on wide range cancer types including breast, colon, lung cancer except ALL in both in vitro and in vivo. In this study, the dose and time dependent cytotoxic, apoptotic and cytostatic effects of luteolin on Philadelphia chromosome +ALL cells were determined for the first time. Besides, the effect of luteolin on cell growth and proliferation of two different healthy cell lines was shown. Moreover, the effect of luteolin on bioactive sphingolipids genes which regulate the several pathways including cell proliferation, apoptosis, drug resistance and senescence in cell was determined in Ph positive ALL cells for the first time. As a consequence, luteolin has cytotoxic, apoptotic and cytostatic effects on Ph positive ALL cells and bioactive sphingolipids genes are regulated in this therapeutic potential by luteolin.Master Thesis Analysis of Tnfrsf10b-As Long-Noncoding Rna's Effects on Various Cancer Cell Properties(Izmir Institute of Technology, 2019) Alkan, Ayşe Hale; Akgül, BünyaminLong noncoding RNAs (lncRNAs) being longer than 200 nucleotides constitute a different class of RNA molecules. Several studies indicated that they have regulatory role in cellular processes including cancer development. Some of them have exclusively high expression in particular cancer types and regulate certain cancer cell properties. This renders them potential biomarker or therapeutic target in cancer. In this study, effects of a candidate lncRNA TNFRSF10B-AS and lncCAMTA1 on cancer cell properties were investigated. Candidate lncRNAs from Doxorubicin, Fas mAB, TNF-alpha and Cisplatin treated HeLa cell line were chosen and their expression level was measured in different cell lines including healthy (BEAS2B and MCF10A), metastatic (H1299 and MDA-MB- 231) and non-metastatic cell lines (A549 and MCF-7) by qPCR. From a few candidates lncCAMTA1 and TNFRSF10B-AS were selected for further analysis. qPCR results obtained from comparison of different cancer cell lines showed that their expression differs at least in one comparison of cell lines. TNFRSF10B-AS silencing decreased proliferation of HeLa cells. lncCAMTA1 was silenced or overexpressed in HeLa cells but phenotypic effect couldn’t be detected by apoptosis and cell proliferation assay. Additionally, phenotypic effect also couldn’t be observed in other cell lines when TNFRSF10B-AS was silenced.
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