Browsing by Author "Sahin, O."
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Item Open Access Analysis of tip-sample interaction in tapping-mode atomic force microscope using an electrical circuit simulator(AIP Publishing, 2001-05-07) Sahin, O.; Atalar, AbdullahWe present a mechanical model for the atomic force microscope tip tapping on a sample. The model treats the tip as a forced oscillator and the sample as an elasticmaterial with adhesiveproperties. It is possible to transform the model into an electrical circuit, which offers a way of simulating the problem with an electrical circuit simulator. Also, the model predicts the energy dissipation during the tip–sample interaction. We briefly discuss the model and give some simulation results to promote an understanding of energy dissipation in a tapping mode.Item Open Access Biomarker-guided sequential targeted therapies to overcome therapy resistance in rapidly evolving highly aggressive mammary tumors(Nature Publising Group, 2014) Sahin, O.; Wang, Q.; Brady, S. W.; Ellis, K.; Wang, H.; Chang, C. C.; Zhang, Q.; Priya, P.; Zhu, R.; Wong, S. T.; Landis, M. D.; Muller, W. J.; Esteva, F. J.; Chang, J.; Yu, D.Combinatorial targeted therapies are more effective in treating cancer by blocking by-pass mechanisms or inducing synthetic lethality. However, their clinical application is hampered by resistance and toxicity. To meet this important challenge, we developed and tested a novel concept of biomarker-guided sequential applications of various targeted therapies using ErbB2-overexpressing/PTEN-low, highly aggressive breast cancer as our model. Strikingly, sustained activation of ErbB2 and downstream pathways drives trastuzumab resistance in both PTEN-low/trastuzumab-resistant breast cancers from patients and mammary tumors with intratumoral heterogeneity from genetically-engineered mice. Although lapatinib initially inhibited trastuzumab-resistant mouse tumors, tumors by-passed the inhibition by activating the PI3K/mTOR signaling network as shown by the quantitative protein arrays. Interestingly, activation of the mTOR pathway was also observed in neoadjuvant lapatinib-treated patients manifesting lapatinib resistance. Trastuzumab + lapatinib resistance was effectively overcome by sequential application of a PI3K/mTOR dual kinase inhibitor (BEZ235) with no significant toxicity. However, our p-RTK array analysis demonstrated that BEZ235 treatment led to increased ErbB2 expression and phosphorylation in genetically-engineered mouse tumors and in 3-D, but not 2-D, culture, leading to BEZ235 resistance. Mechanistically, we identified ErbB2 protein stabilization and activation as a novel mechanism of BEZ235 resistance, which was reversed by subsequent treatment with lapatinib + BEZ235 combination. Remarkably, this sequential application of targeted therapies guided by biomarker changes in the tumors rapidly evolving resistance doubled the life-span of mice bearing exceedingly aggressive tumors. This fundamentally novel approach of using targeted therapies in a sequential order can effectively target and reprogram the signaling networks in cancers evolving resistance during treatment.Item Open Access Discovering lncRNA mediated sponge interactions in breast cancer molecular subtypes(BioMed Central, 2018) Olgun, G.; Sahin, O.; Tastan, O.Background: Long non-coding RNAs (lncRNAs) can indirectly regulate mRNAs expression levels by sequestering microRNAs (miRNAs), and act as competing endogenous RNAs (ceRNAs) or as sponges. Previous studies identified lncRNA-mediated sponge interactions in various cancers including the breast cancer. However, breast cancer subtypes are quite distinct in terms of their molecular profiles; therefore, ceRNAs are expected to be subtype-specific as well. Results: To find lncRNA-mediated ceRNA interactions in breast cancer subtypes, we develop an integrative approach. We conduct partial correlation analysis and kernel independence tests on patient gene expression profiles and further refine the candidate interactions with miRNA target information. We find that although there are sponges common to multiple subtypes, there are also distinct subtype-specific interactions. Functional enrichment of mRNAs that participate in these interactions highlights distinct biological processes for different subtypes. Interestingly, some of the ceRNAs also reside in close proximity in the genome; for example, those involving HOX genes, HOTAIR, miR-196a-1 and miR-196a-2. We also discover subtype-specific sponge interactions with high prognostic potential. We found that patients differ significantly in their survival distributions if they are group based on the expression patterns of specific ceRNA interactions. However, it is not the case if the expression of individual RNAs participating in ceRNA is used. Conclusion: These results can help shed light on subtype-specific mechanisms of breast cancer, and the methodology developed herein can help uncover sponges in other diseases.Item Open Access Estimation of hmF2 and foF2 communication parameters of ionosphere F2-layer üsing GPS data and IRI-plas model(IEEE, 2013-10) Sezen, U.; Sahin, O.; Arikan, F.; Arıkan, OrhanF2-layer is the most important and characteristic layer of the ionosphere in the propagation of high frequency (HF) waves due to the highest level of conductivity in the propagation path. In this study, the relation of Total Electron Content (TEC) with the maximum ionization height (hmF2) and the critical frequency (foF2) of F2 -layer are investigated within their defined parametric range using the IRI model extended towards the plasmasphere (IRI-Plas). These two parameters are optimized using daily observed GPS-TEC (IONOLAB-TEC) in an iterational loop through Non-Linear Least Squares (NLSQ) optimization while keeping the physical correlation between hmF2 and foF2 parameters. Optimization performance is examined for daily (24-hour) and hourly TEC optimizations separately. It is observed that hourly TEC optimization produces results with much smaller estimation errors. As a result of the hourly optimization, we obtain the hourly hmF2 and foF2 estimates as they are the optimization parameters. Obtained hmF2 and foF2 estimates are compared with the ionosonde estimates for various low, middle and high latitude locations for both quite and disturbed days of ionosphere. The results show that hmF2 and foF2 estimates obtained from IRI-Plas optimization (IRI-Plas-Opt) and ionosonde are very much in agreement with each other. These results also signify that IRI-Plas provides a reliable background model for ionosphere. With the proposed method, it is possible to build a virtual ionosonde via optimization of IRI-Plas model using the observed TEC values.Item Open Access High-resolution imaging of elastic properties using harmonic cantilevers(Elsevier, 2004) Sahin, O.; Yaralioglu, G.; Grow, R.; Zappe, S. F.; Atalar, Abdullah; Quate, C.; Solgaard, O.We present a micromachined scanning probe cantilever, in which a specific higher-order flexural mode is designed to be resonant at an exact integer multiple of the fundamental resonance frequency. We have fabricated such cantilevers by reducing the stiffness of the third order flexural mode relative to the fundamental mode, and we have demonstrated that these cantilevers enable sensing of non-linear mechanical interactions between the atomically sharp tip at the free end of the cantilever and a surface with unknown mechanical properties in tapping-mode atomic force microscopy. Images of surfaces with large topographical variations show that for such samples harmonic imaging has better resolution than standard tapping-mode imaging.Item Open Access MicroRNA-519a is a novel oncomir conferring tamoxifen resistance by targeting a network of tumour-suppressor genes in ER+ breast cancer(John Wiley and Sons Ltd, 2014) Ward, A.; Shukla, K.; Balwierz, A.; Soons, Z.; König, R.; Sahin, O.; Wiemann, S.Tamoxifen is an endocrine therapy which is administered to up to 70% of all breast cancer patients with oestrogen receptor alpha (ERα) expression. Despite the initial response, most patients eventually acquire resistance to the drug. MicroRNAs (miRNAs) are a class of small non-coding RNAs which have the ability to post-transcriptionally regulate genes. Although the role of a few miRNAs has been described in tamoxifen resistance at the single gene/target level, little is known about how concerted actions of miRNAs targeting biological networks contribute to resistance. Here we identified the miRNA cluster, C19MC, which harbours around 50 mature miRNAs, to be up-regulated in resistant cells, with miRNA-519a being the most highly up-regulated. We could demonstrate that miRNA-519a regulates tamoxifen resistance using gain- and loss-of-function testing. By combining functional enrichment analysis and prediction algorithms, we identified three central tumour-suppressor genes (TSGs) in PI3K signalling and the cell cycle network as direct target genes of miR-519a. Combined expression of these target genes correlated with disease-specific survival in a cohort of tamoxifen-treated patients. We identified miRNA-519a as a novel oncomir in ER+ breast cancer cells as it increased cell viability and cell cycle progression as well as resistance to tamoxifen-induced apoptosis. Finally, we could show that elevated miRNA-519a levels were inversely correlated with the target genes' expression and that higher expression of this miRNA correlated with poorer survival in ER+ breast cancer patients. Hence we have identified miRNA-519a as a novel oncomir, co-regulating a network of TSGs in breast cancer and conferring resistance to tamoxifen. Using inhibitors of such miRNAs may serve as a novel therapeutic approach to combat resistance to therapy as well as proliferation and evasion of apoptosis in breast cancer.Item Open Access Resonant harmonic response in tapping-mode atomic force microscopy(American Physical Society, 2004) Sahin, O.; Quate, C. F.; Solgaard, O.; Atalar, AbdullahHigher harmonics in tapping-mode atomic force microscopy offers the potential for imaging and sensing material properties at the nanoscale. The signal level at a given harmonic of the fundamental mode can be enhanced if the cantilever is designed in such a way that the frequency of one of the higher harmonics of the fundamental mode (designated as the resonant harmonic) matches the resonant frequency of a higher-order flexural mode. Here we present an analytical approach that relates the amplitude and phase of the cantilever vibration at the frequency of the resonant harmonic to the elastic modulus of the sample. The resonant harmonic response is optimized for different samples with a proper design of the cantilever. It is found that resonant harmonics are sensitive to the stiffness of the material under investigation.Item Open Access Simulation of higher harmonics generation in tapping-mode atomic force microscopy(American Institute of Physics, 2001) Sahin, O.; Atalar, AbdullahIn tapping-mode atomic force microscopy, nonlinear tip-sample interactions give rise to higher harmonics of the cantilever vibration. We present an electrical circuit to model the atomic force microscope cantilever with its first three flexural eigenmodes. An electrical circuit simulator is used to simulate the tapping-mode operation. Amplitude and phase responses of the third flexural eigenmode are obtained for different sample properties. It is found that amplitude and phase of higher harmonics depend highly on sample properties. © 2001 American Institute of Physics.Item Open Access Targeting HIF1-alpha/miR-326/ITGA5 axis potentiates chemotherapy response in triple-negative breast cancer(Springer New York LLC, 2022-03-25) Tokat, Unal Metin; Tarman, Ibrahim Oguzhan; Ersan, Pelin Gulizar; Raza, Umar; Saatci, O.; Sahin, O.; Ogul, H.; Riazalhosseini, Y.; Can, T.; Assidicky, RidhoPurpose Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer that is frequently treated with chemotherapy. However, many patients exhibit either de novo chemoresistance or ultimately develop resistance to chemotherapy, leading to significantly high mortality rates. Therefore, increasing the efficacy of chemotherapy has potential to improve patient outcomes. Methods Here, we performed whole transcriptome sequencing (both RNA and small RNA-sequencing), coupled with network simulations and patient survival data analyses to build a novel miRNA-mRNA interaction network governing chemoresistance in TNBC. We performed cell proliferation assay, Western blotting, RNAi/miRNA mimic experiments, FN coating, 3D cultures, and ChIP assays to validate the interactions in the network, and their functional roles in chemoresistance. We developed xenograft models to test the therapeutic potential of the identified key miRNA/proteins in potentiating chemoresponse in vivo. We also analyzed several patient datasets to evaluate the clinical relevance of our findings. Results We identified fibronectin (FN1) as a central chemoresistance driver gene. Overexpressing miR-326 reversed FN1-driven chemoresistance by targeting FN1 receptor, ITGA5. miR-326 was downregulated by increased hypoxia/HIF1A and ECM stiffness in chemoresistant tumors, leading to upregulation of ITGA5 and activation of the downstream FAK/Src signaling pathways. Overexpression of miR-326 or inhibition of ITGA5 overcame FN1-driven chemotherapy resistance in vitro by inhibiting FAK/Src pathway and potentiated the efficacy of chemotherapy in vivo. Importantly, lower expression of miR-326 or higher levels of predicted miR-326 target genes was significantly associated with worse overall survival in chemotherapy-treated TNBC patients. Conclusion FN1 is central in chemoresistance. In chemoresistant tumors, hypoxia and resulting ECM stiffness repress the expression of the tumor suppressor miRNA, miR-326. Hence, re-expression of miR-326 or inhibition of its target ITGA5 reverses FN1-driven chemoresistance making them attractive therapeutic approaches to enhance chemotherapy response in TNBCs.Item Open Access Upregulation of lactate dehydrogenase a by 14-3-3ζ leads to increased glycolysis critical for breast cancer initiation and progression(Impact Journals LLC, 2016-05) Chang, C.; Zhang, C.; Zhang, Q.; Sahin, O.; Wang, H.; Xu, J.; Xiao, Y.; Zhang, J.; Rehman, S. K.; Li, P.; Hung, M. C.; Behbod, F.; Yu, D.Metabolic reprogramming is a hallmark of cancer. Elevated glycolysis in cancer cells switches the cellular metabolic flux to produce more biological building blocks, thereby sustaining rapid proliferation. Recently, new evidence has emerged that metabolic dysregulation may occur at early-stages of neoplasia and critically contribute to cancer initiation. Here, our bioinformatics analysis of microarray data from early-stages breast neoplastic lesions revealed that 14-3-3ζ expression is strongly correlated with the expression of canonical glycolytic genes, particularly lactate dehydrogenase A (LDHA). Experimentally, increasing 14-3-3ζ expression in human mammary epithelial cells (hMECs) up-regulated LDHA expression, elevated glycolytic activity, and promoted early transformation. Knockdown of LDHA in the 14-3-3ζ-overexpressing hMECs significantly reduced glycolytic activity and inhibited transformation. Mechanistically, 14-3-3ζ overexpression activates the MEK-ERK-CREB axis, which subsequently up-regulates LDHA. In vivo, inhibiting the activated the MEK/ERK pathway in 14-3-3ζ-overexpressing hMEC-derived MCF10DCIS.COM lesions led to effective inhibition of tumor growth. Therefore, targeting the MEK/ERK pathway could be an effective strategy for intervention of 14-3-3ζ-overexpressing early breast lesions. Together, our data demonstrate that overexpression of 14-3-3ζ in early stage pre-cancerous breast epithelial cells may trigger an elevated glycolysis and transcriptionally up-regulating LDHA, thereby contributes to human breast cancer initiation.