merve aslan - Academia.edu (original) (raw)
Papers by merve aslan
Methods in molecular biology, 2022
Cell Reports Medicine
In brief Rice et al. identify SU086 as a therapeutic strategy for treatment of prostate cancer, a... more In brief Rice et al. identify SU086 as a therapeutic strategy for treatment of prostate cancer, as it impairs prostate cancer growth, inhibits HSP90, and impairs glycolysis and intratumoral metabolism. SU086 alone and in combination therapy strategies has strong therapeutic potential in pre-clinical models of prostate cancer.
Yol güvenliği, insan, araç ve çevre ile ilgili faktörler arasındaki etkileşimin bir sonucudur. Bu... more Yol güvenliği, insan, araç ve çevre ile ilgili faktörler arasındaki etkileşimin bir sonucudur. Bu çalışmada, yol güvenliğinde çevre ile ilgili bir faktör olarak yol aşinalığı araştırılmıştır. Bu çalışmanın temel amacı, sürücülerin aşina oldukları ve olmadıkları yollardaki öznel risk algılarının incelenmesidir. Çalışmaya 279 erkek ve 201 kadın olmak üzere toplam 480 sürücü katılmıştır. Katılımcılar demografik bilgi formunu ve Risk Algısı Envanteri’ni doldurmuştur. Sonuçlar, sürücülerin aşina olmadıkları yollarda araç kullanmayı aşina oldukları yollara göre daha riskli algıladıklarını göstermiştir. Ayrıca, kadın sürücüler hem aşina oldukları hem de aşina olmadıkları yollarda erkek sürücülere göre daha yüksek risk algısı raporlamışlardır. Sonuç olarak, yola aşinalık, sürücülerin risk değerlendirmesinde önemli bir faktör olarak değerlendirilmiştir. Sonuçlar, ilgili literatür ışığında karayolu güvenliği üzerindeki etkileri ile tartışılmıştır
Cancer Research, 2021
Introduction and Objectives: Breast cancer remains the second most lethal cancer among women in t... more Introduction and Objectives: Breast cancer remains the second most lethal cancer among women in the US, with triple negative breast cancer (TNBC) as the most aggressive subtype with limited treatment options. Trop2, a cell membrane glycoprotein, is overexpressed nearly all epithelial cancers including triple negative breast cancer. In this study, we demonstrate that loss of Trop2 derives downregulation of metabolic genes. Trop2 oncogene-driven metabolic gene signature is highly elevated in breast cancer patients and predicts poor outcome. Methods: Trop2 expression levels in two independent patient cohorts were analyzed with immunohistochemistry. Trop2 was knockdown in TNBC cell line HCC1806 with shRNA and knock-out in HCC1806 with CRISPR Cas9 system. Trop2 downregulation or gene deletion effect was tested in vitro with colony formation and 3D Matrigel invasion assays. The effect of Trop2 downregulation in tumorigenesis was evaluated in vivo by subcutaneous implantation of control an...
Iranian Journal of Fuzzy Systems, 2021
Fuzzy arithmetic performed with the product t-norm is the focus of this paper. The subject is han... more Fuzzy arithmetic performed with the product t-norm is the focus of this paper. The subject is handled from both practical and theoretical perspectives. Explicit formulas for product-sum and product-multiplication of triangular fuzzy numbers are obtained. These formulas can effectively replace the computational methods proposed so far. The issue that these operations are not shape preserving is solved by the presentation of appropriate approximations. Finally, the product arithmetic is compared in detail to the arithmetic performed with the boundary t-norms, namely the minimum and drastic sum.
Biology Methods and Protocols, 2021
Metastasis is the main cause of cancer-associated morbidity which will account for ∼ 600,000 deat... more Metastasis is the main cause of cancer-associated morbidity which will account for ∼ 600,000 deaths in the USA in 2021. Defining new mechanisms that drive cancer metastasis is vital for developing new therapeutic strategies and improving clinical outcomes for cancer patients. Herein, we describe a recently established 3D Matrigel drop invasion assay to measure cancer cell invasion and migration capability in vitro. This assay is a versatile and simple tool to test the ability of cells to invade and migrate, test the functional role of genes of interest in cell invasion and migration, analyze the localization of the target proteins at the cell invasion edge in situ, and screen drug effects on cancer cell invasion and migration.
SSRN Electronic Journal, 2021
Dunyamizda ve ulkemizde giderek artan cevre sorunlari, ekolojik degerlerin oneminin farkina varil... more Dunyamizda ve ulkemizde giderek artan cevre sorunlari, ekolojik degerlerin oneminin farkina varilmasina neden olmus, bu durum tasarim ve planlama sureclerine yansiyarak, ekolojik tasarim, ekolojik planlama, ekolojik mimarlik, ekolojik malzeme gibi kavramlar gundeme gelmistir. Ekolojik ve cevresel degerlerin on plana ciktigi, surdurulebilirligin insanoglunun gelecegi icin ciddi onem tasidigi bu kavramlar bircok alanda oldugu gibi kentsel alanda, kent mobilyalari tasariminda ve uretiminde onemli etkenler haline gelmistir. Calismada kent mobilyalari uretiminde ahsap malzeme kullanan ureticilerin ekolojik tasarim acisindan degerlendirilmesi esas teskil etmektedir. Bu amacla Turkiye genelinde kent mobilyalari uretimi yapan firmalara ulasilip bu konuya olan yaklasimlari degerlendirilmis ve ekolojik tasarim acisindan uretim surecleri anket yontemi ile incelenerek degerlendirme yapilmaya calisilmistir. Calismanin sonucunda, ekolojik tasarim bilinci acisindan, ureticilerde, yalnizca kullanil...
Road safety is the result of the interaction between human, vehicle, and environment-related fact... more Road safety is the result of the interaction between human, vehicle, and environment-related factors. Road familiarity, as a human-and environment-related factor in road safety, was investigated in the present study. More specifically, the main aim of the current study is to investigate the subjective risk evaluations of drivers on familiar and unfamiliar roads. A total sample of 479 drivers, 278 males and 201 females, participated in the present study, and filled out the demographic information questionnaire and Risk Perception Inventory. The results showed that drivers evaluated risk as higher when driving on an unfamiliar road as compared to driving in a familiar road. Moreover, females reported a higher risk perception level than males on both familiar and unfamiliar roads. As a result, familiarity with the road was evaluated as an essential factor in the risk evaluation of drivers. The results were discussed with regard to their implications for road safety in light of the relevant literature.
Scientific Reports, 2021
Prostate cancer remains the most common non-cutaneous malignancy among men in the United States. ... more Prostate cancer remains the most common non-cutaneous malignancy among men in the United States. To discover potential serum-based biomarkers for high-risk prostate cancer, we performed a high-multiplex immunoassay utilizing patient-matched pre-operative and post-operative serum samples from ten men with high-grade and high-volume prostate cancer. Our study identified six (CASP8, MSLN, FGFBP1, ICOSLG, TIE2 and S100A4) out of 174 proteins that were significantly decreased after radical prostatectomy. High levels of CASP8 were detected in pre-operative serum samples when compared to post-operative serum samples and serum samples from patients with benign prostate hyperplasia (BPH). By immunohistochemistry, CASP8 protein was expressed at higher levels in prostate cancer tissues compared to non-cancerous and BPH tissues. Likewise, CASP8 mRNA expression was significantly upregulated in prostate cancer when compared to benign prostate tissues in four independent clinical datasets. In addi...
npj Breast Cancer, 2021
Breast cancer remains the second most lethal cancer among women in the United States and triple-n... more Breast cancer remains the second most lethal cancer among women in the United States and triple-negative breast cancer is the most aggressive subtype with limited treatment options. Trop2, a cell membrane glycoprotein, is overexpressed in almost all epithelial cancers. In this study, we demonstrate that Trop2 is overexpressed in triple-negative breast cancer (TNBC), and downregulation of Trop2 delays TNBC cell and tumor growth supporting the oncogenic role of Trop2 in breast cancer. Through proteomic profiling, we discovered a metabolic signature comprised of TALDO1, GPI, LDHA, SHMT2, and ADK proteins that were downregulated in Trop2-depleted breast cancer tumors. The identified oncogene-mediated metabolic gene signature is significantly upregulated in TNBC patients across multiple RNA-expression clinical datasets. Our study further reveals that the metabolic gene signature reliably predicts poor survival of breast cancer patients with early stages of the disease. Taken together, ou...
Scientific Reports, 2021
Neuroendocrine prostate cancer (NEPC) is a lethal subtype of prostate cancer that rarely develops... more Neuroendocrine prostate cancer (NEPC) is a lethal subtype of prostate cancer that rarely develops de novo in primary tumors and is commonly acquired during the development of treatment resistance. NEPC is characterized by gain of neuroendocrine markers and loss of androgen receptor (AR), making it resistant to current therapeutic strategies targeting the AR signaling axis. Here, we report that MCM2, MCM3, MCM4, and MCM6 (MCM2/3/4/6) are elevated in human NEPC and high levels of MCM2/3/4/6 are associated with liver metastasis and poor survival in prostate cancer patients. MCM2/3/4/6 are four out of six proteins that form a core DNA helicase (MCM2-7) responsible for unwinding DNA forks during DNA replication. Inhibition of MCM2-7 by treatment with ciprofloxacin inhibits NEPC cell proliferation and migration in vitro, significantly delays NEPC tumor xenograft growth, and partially reverses the neuroendocrine phenotype in vivo. Our study reveals the clinical relevance of MCM2/3/4/6 prot...
Cancer Research, 2021
Background: The first line of treatment for men with advanced prostate cancer is androgen depriva... more Background: The first line of treatment for men with advanced prostate cancer is androgen deprivation therapy. Although initial responses are observed, prostate cancer commonly relapses in its lethal metastatic form referred to as castration resistant prostate cancer (CRPC) with 1-2 years mean survival time. Neuroendocrine prostate cancer (NEPC) is highly aggressive, AR independent subtype and usually emerges post castration resistance. We recently identified that the cell surface receptor, Trop2, is a new driver of NEPC. Moreover, we demonstrated that Trop2 regulates prostate cancer growth and metastasis. In this study, we set out to delineate the molecular mechanisms through which Trop2 regulates prostate cancer growth and metastasis. Methods: Proximity-dependent Biotin Identification (BioID) followed by mass spectrometry was performed to identify Trop2 interactome. Lentiviral infection was used to generate prostate cancer cell lines with over-expression of Trop2 and knock-down of...
Cancer Research, 2021
Ferroptosis is a type of programmed cell death induced by the accumulation of lipid peroxidation ... more Ferroptosis is a type of programmed cell death induced by the accumulation of lipid peroxidation and lipid reactive oxygen species in cells. It has been recently demonstrated that cancer cells are vulnerable to ferroptosis inducers (FIN). However, the therapeutic potential of FINs in prostate cancer in preclinical settings has not been explored. In this study, we demonstrate that mediators of ferroptosis, solute carrier family 7 member 11, SLC3A2, and glutathione peroxidase, are expressed in treatment-resistant prostate cancer. We further demonstrate that treatment-resistant prostate cancer cells are sensitive to two FINs, erastin and RSL3. Treatment with erastin and RSL3 led to a significant decrease in prostate cancer cell growth and migration in vitro and significantly delayed the tumor growth of treatment-resistant prostate cancer in vivo, with no measurable side effects. Combination of erastin or RSL3 with standard-of-care second-generation antiandrogens for advanced prostate c...
British Journal of Cancer, 2020
Distinguishing clinically significant from indolent prostate cancer (PC) is a major clinical chal... more Distinguishing clinically significant from indolent prostate cancer (PC) is a major clinical challenge. We utilised targeted protein biomarker discovery approach to identify biomarkers specific for pro-metastatic PC. Serum samples from the cancer-free group; Cambridge Prognostic Group 1 (CPG1, low risk); CPG5 (high risk) and metastatic disease were analysed using Olink Proteomics panels. Tissue validation was performed by immunohistochemistry in a radical prostatectomy cohort (n = 234). We discovered that nine proteins (pleiotrophin (PTN), MK, PVRL4, EPHA2, TFPI-2, hK11, SYND1, ANGPT2, and hK14) were elevated in metastatic PC patients when compared to other groups. PTN levels were increased in serum from men with CPG5 compared to benign and CPG1. High tissue PTN level was an independent predictor of biochemical recurrence and metastatic progression in low- and intermediate-grade disease. These findings suggest that PTN may represent a novel biomarker for the presence of poor prognos...
Proceedings of the National Academy of Sciences, 2020
Significance NEPC is a highly aggressive subtype of prostate cancer that is increasing in inciden... more Significance NEPC is a highly aggressive subtype of prostate cancer that is increasing in incidence, likely due to use of new secondary androgen deprivation therapies. Here, we demonstrate that Trop2 is significantly elevated in CRPC and NEPC and represents a driver of metastatic NEPC. Trop2 overexpression increases tumor growth, drives metastasis and neuroendocrine phenotype, and significantly increases PARP1 levels. Inhibition of PARP1 in Trop2-driven NEPC significantly decreases neuroendocrine features, tumor growth, and metastatic colonization in vivo, suggesting that PARP1 inhibitors may represent a promising therapeutic strategy for metastatic prostate cancer expressing high levels of Trop2.
Molecular Cancer Therapeutics, 2019
Prostate cancer remains among the leading causes of cancer-related deaths in men. Patients with a... more Prostate cancer remains among the leading causes of cancer-related deaths in men. Patients with aggressive disease typically undergo hormone deprivation therapy. Although treatment is initially very successful, these men commonly progress to lethal, castration-resistant prostate cancer (CRPC) in 2 to 3 years. Standard therapies for CRPC include second-generation antiandrogens, which prolong patient lifespan by only several months. It is imperative to advance our understanding of the mechanisms leading to resistance to identify new therapies for aggressive prostate cancer. This study identifies Notch1 as a therapeutic target in prostate cancer. Loss of NOTCH1 in aggressive prostate cancer cells decreases proliferation, invasion, and tumorsphere formation. Therapeutic inhibition of Notch1 activity with gamma secretase inhibitors RO4929097 or DAPT in prostate cancer cells further results in decreased proliferative abilities. Loss of NOTCH1 and treatment of immunocompromised mice bearin...
Advanced Materials Research, 2013
Novel proton conducting nanocomposite membranes included binary and ternary mixtures of acid modi... more Novel proton conducting nanocomposite membranes included binary and ternary mixtures of acid modified nanotitania particles particles with polymers such as poly (vinyl alcohol) (PVA),pol (vinyl phosphonic acid), sulfonated polysulfone (SPSU) and poly (1-vinyl 1,2,4-triazole) (PVTri) . The interaction of functional nanoparticles with the host matrix were searched by FT-IR spectroscopy. The homogeneous distribution of functional nanoparticles in the membranes was confirmed by SEM micrographs. The spectroscopic measurements and water/methanol uptake studies suggested a complexation between polymers and sulphonic acid that inhibited the leaching out of acidic units. The TGA results verified that the presence of modified nanoparticles in the composite membranes the thermel stability of the membranes enhanced up to above 200 °C.
Solid State Ionics, 2009
Proton-conducting properties of the graft copolymer electrolytes were examined throughout this wo... more Proton-conducting properties of the graft copolymer electrolytes were examined throughout this work. The homopolymers poly(glycidyl methacrylate), PGMA and poly(vinyl phosphonic acid), PVPA were synthesized by free-radical polymerizations of the monomers glycidyl methacrylate, GMA, and vinyl phosphonic acid, VPA, respectively. The graft copolymers were produced by grafting of PVPA onto PGMA via ring opening of ethylene oxide groups. To examine the influence of the concentration of VPA on the proton conductivity, several graft copolymers were produced at various stoichiometric ratios with respect to monomer repeat units. The materials were characterized by FT-IR and 1 H NMR spectroscopy and the thermal properties were studied by thermogravimetry (TG) and differential scanning calorimetry (DSC). The TGA results demonstrated that the samples are thermally stable up to at least 150°C. The proton conductivities of humidified and dry samples were studied via impedance spectroscopy. In the anhydrous state, the proton conductivity of P(GMA)-graft-P(VPA) 10 was 5 × 10 − 5 S/cm at 150°C. The proton conductivity of the same material increased with the humidity content and reached to 0.03 S/cm at 80°C under 50% of RH, which approached to that of Nafion ® at the same humidification level.
Journal of Applied Polymer Science, 2013
ABSTRACT Anhydrous polymer electrolytes based on azole functional methacrylates and methacrylamid... more ABSTRACT Anhydrous polymer electrolytes based on azole functional methacrylates and methacrylamides have been produced for use in proton exchange membrane fuel cells (PEMFCs). Poly(methacryloyl chloride) (PMAC) was prepared first by free-radical polymerization of methacryloyl chloride, followed by side chain functionalization with 5-aminotetrazole (ATet), 3-amino-1,2,4-triazole (ATri) and 1H-1,2,4-triazole (Tri). Finally, the obtained polymers were doped with triflic acid (TA) at stoichometric ratios of 1.0, 2.0 and 4.0 with respect to azole units, and the anhydrous polymer electrolytes were obtained. The membranes were characterized by FT-IR, 13C-NMR, and elemental analysis. Thermal behaviour of polymers was explored by TGA and DSC. The samples were thermally stable up to approximately 200 oC. Proton conductivity was measured by impedance spectroscopy. Trifilic acid doped poly(methacryloyl aminotetrazole) (PMAATet-(TA)4), poly(methacryloyl-3-amino-1,2,4-triazole) (PMA-Tri-(TA)4), and poly(methacryloyl-1,2,4-triazole) (PMA-ATri-(TA)4) showed maximum proton conductivities of 0.01 Scm−1, 0.02 Scm−1 and 8.7x10−4 Scm−1, respectively, at 150°C and anhydrous conditions. © 2013 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014, 131, 39915.
Methods in molecular biology, 2022
Cell Reports Medicine
In brief Rice et al. identify SU086 as a therapeutic strategy for treatment of prostate cancer, a... more In brief Rice et al. identify SU086 as a therapeutic strategy for treatment of prostate cancer, as it impairs prostate cancer growth, inhibits HSP90, and impairs glycolysis and intratumoral metabolism. SU086 alone and in combination therapy strategies has strong therapeutic potential in pre-clinical models of prostate cancer.
Yol güvenliği, insan, araç ve çevre ile ilgili faktörler arasındaki etkileşimin bir sonucudur. Bu... more Yol güvenliği, insan, araç ve çevre ile ilgili faktörler arasındaki etkileşimin bir sonucudur. Bu çalışmada, yol güvenliğinde çevre ile ilgili bir faktör olarak yol aşinalığı araştırılmıştır. Bu çalışmanın temel amacı, sürücülerin aşina oldukları ve olmadıkları yollardaki öznel risk algılarının incelenmesidir. Çalışmaya 279 erkek ve 201 kadın olmak üzere toplam 480 sürücü katılmıştır. Katılımcılar demografik bilgi formunu ve Risk Algısı Envanteri’ni doldurmuştur. Sonuçlar, sürücülerin aşina olmadıkları yollarda araç kullanmayı aşina oldukları yollara göre daha riskli algıladıklarını göstermiştir. Ayrıca, kadın sürücüler hem aşina oldukları hem de aşina olmadıkları yollarda erkek sürücülere göre daha yüksek risk algısı raporlamışlardır. Sonuç olarak, yola aşinalık, sürücülerin risk değerlendirmesinde önemli bir faktör olarak değerlendirilmiştir. Sonuçlar, ilgili literatür ışığında karayolu güvenliği üzerindeki etkileri ile tartışılmıştır
Cancer Research, 2021
Introduction and Objectives: Breast cancer remains the second most lethal cancer among women in t... more Introduction and Objectives: Breast cancer remains the second most lethal cancer among women in the US, with triple negative breast cancer (TNBC) as the most aggressive subtype with limited treatment options. Trop2, a cell membrane glycoprotein, is overexpressed nearly all epithelial cancers including triple negative breast cancer. In this study, we demonstrate that loss of Trop2 derives downregulation of metabolic genes. Trop2 oncogene-driven metabolic gene signature is highly elevated in breast cancer patients and predicts poor outcome. Methods: Trop2 expression levels in two independent patient cohorts were analyzed with immunohistochemistry. Trop2 was knockdown in TNBC cell line HCC1806 with shRNA and knock-out in HCC1806 with CRISPR Cas9 system. Trop2 downregulation or gene deletion effect was tested in vitro with colony formation and 3D Matrigel invasion assays. The effect of Trop2 downregulation in tumorigenesis was evaluated in vivo by subcutaneous implantation of control an...
Iranian Journal of Fuzzy Systems, 2021
Fuzzy arithmetic performed with the product t-norm is the focus of this paper. The subject is han... more Fuzzy arithmetic performed with the product t-norm is the focus of this paper. The subject is handled from both practical and theoretical perspectives. Explicit formulas for product-sum and product-multiplication of triangular fuzzy numbers are obtained. These formulas can effectively replace the computational methods proposed so far. The issue that these operations are not shape preserving is solved by the presentation of appropriate approximations. Finally, the product arithmetic is compared in detail to the arithmetic performed with the boundary t-norms, namely the minimum and drastic sum.
Biology Methods and Protocols, 2021
Metastasis is the main cause of cancer-associated morbidity which will account for ∼ 600,000 deat... more Metastasis is the main cause of cancer-associated morbidity which will account for ∼ 600,000 deaths in the USA in 2021. Defining new mechanisms that drive cancer metastasis is vital for developing new therapeutic strategies and improving clinical outcomes for cancer patients. Herein, we describe a recently established 3D Matrigel drop invasion assay to measure cancer cell invasion and migration capability in vitro. This assay is a versatile and simple tool to test the ability of cells to invade and migrate, test the functional role of genes of interest in cell invasion and migration, analyze the localization of the target proteins at the cell invasion edge in situ, and screen drug effects on cancer cell invasion and migration.
SSRN Electronic Journal, 2021
Dunyamizda ve ulkemizde giderek artan cevre sorunlari, ekolojik degerlerin oneminin farkina varil... more Dunyamizda ve ulkemizde giderek artan cevre sorunlari, ekolojik degerlerin oneminin farkina varilmasina neden olmus, bu durum tasarim ve planlama sureclerine yansiyarak, ekolojik tasarim, ekolojik planlama, ekolojik mimarlik, ekolojik malzeme gibi kavramlar gundeme gelmistir. Ekolojik ve cevresel degerlerin on plana ciktigi, surdurulebilirligin insanoglunun gelecegi icin ciddi onem tasidigi bu kavramlar bircok alanda oldugu gibi kentsel alanda, kent mobilyalari tasariminda ve uretiminde onemli etkenler haline gelmistir. Calismada kent mobilyalari uretiminde ahsap malzeme kullanan ureticilerin ekolojik tasarim acisindan degerlendirilmesi esas teskil etmektedir. Bu amacla Turkiye genelinde kent mobilyalari uretimi yapan firmalara ulasilip bu konuya olan yaklasimlari degerlendirilmis ve ekolojik tasarim acisindan uretim surecleri anket yontemi ile incelenerek degerlendirme yapilmaya calisilmistir. Calismanin sonucunda, ekolojik tasarim bilinci acisindan, ureticilerde, yalnizca kullanil...
Road safety is the result of the interaction between human, vehicle, and environment-related fact... more Road safety is the result of the interaction between human, vehicle, and environment-related factors. Road familiarity, as a human-and environment-related factor in road safety, was investigated in the present study. More specifically, the main aim of the current study is to investigate the subjective risk evaluations of drivers on familiar and unfamiliar roads. A total sample of 479 drivers, 278 males and 201 females, participated in the present study, and filled out the demographic information questionnaire and Risk Perception Inventory. The results showed that drivers evaluated risk as higher when driving on an unfamiliar road as compared to driving in a familiar road. Moreover, females reported a higher risk perception level than males on both familiar and unfamiliar roads. As a result, familiarity with the road was evaluated as an essential factor in the risk evaluation of drivers. The results were discussed with regard to their implications for road safety in light of the relevant literature.
Scientific Reports, 2021
Prostate cancer remains the most common non-cutaneous malignancy among men in the United States. ... more Prostate cancer remains the most common non-cutaneous malignancy among men in the United States. To discover potential serum-based biomarkers for high-risk prostate cancer, we performed a high-multiplex immunoassay utilizing patient-matched pre-operative and post-operative serum samples from ten men with high-grade and high-volume prostate cancer. Our study identified six (CASP8, MSLN, FGFBP1, ICOSLG, TIE2 and S100A4) out of 174 proteins that were significantly decreased after radical prostatectomy. High levels of CASP8 were detected in pre-operative serum samples when compared to post-operative serum samples and serum samples from patients with benign prostate hyperplasia (BPH). By immunohistochemistry, CASP8 protein was expressed at higher levels in prostate cancer tissues compared to non-cancerous and BPH tissues. Likewise, CASP8 mRNA expression was significantly upregulated in prostate cancer when compared to benign prostate tissues in four independent clinical datasets. In addi...
npj Breast Cancer, 2021
Breast cancer remains the second most lethal cancer among women in the United States and triple-n... more Breast cancer remains the second most lethal cancer among women in the United States and triple-negative breast cancer is the most aggressive subtype with limited treatment options. Trop2, a cell membrane glycoprotein, is overexpressed in almost all epithelial cancers. In this study, we demonstrate that Trop2 is overexpressed in triple-negative breast cancer (TNBC), and downregulation of Trop2 delays TNBC cell and tumor growth supporting the oncogenic role of Trop2 in breast cancer. Through proteomic profiling, we discovered a metabolic signature comprised of TALDO1, GPI, LDHA, SHMT2, and ADK proteins that were downregulated in Trop2-depleted breast cancer tumors. The identified oncogene-mediated metabolic gene signature is significantly upregulated in TNBC patients across multiple RNA-expression clinical datasets. Our study further reveals that the metabolic gene signature reliably predicts poor survival of breast cancer patients with early stages of the disease. Taken together, ou...
Scientific Reports, 2021
Neuroendocrine prostate cancer (NEPC) is a lethal subtype of prostate cancer that rarely develops... more Neuroendocrine prostate cancer (NEPC) is a lethal subtype of prostate cancer that rarely develops de novo in primary tumors and is commonly acquired during the development of treatment resistance. NEPC is characterized by gain of neuroendocrine markers and loss of androgen receptor (AR), making it resistant to current therapeutic strategies targeting the AR signaling axis. Here, we report that MCM2, MCM3, MCM4, and MCM6 (MCM2/3/4/6) are elevated in human NEPC and high levels of MCM2/3/4/6 are associated with liver metastasis and poor survival in prostate cancer patients. MCM2/3/4/6 are four out of six proteins that form a core DNA helicase (MCM2-7) responsible for unwinding DNA forks during DNA replication. Inhibition of MCM2-7 by treatment with ciprofloxacin inhibits NEPC cell proliferation and migration in vitro, significantly delays NEPC tumor xenograft growth, and partially reverses the neuroendocrine phenotype in vivo. Our study reveals the clinical relevance of MCM2/3/4/6 prot...
Cancer Research, 2021
Background: The first line of treatment for men with advanced prostate cancer is androgen depriva... more Background: The first line of treatment for men with advanced prostate cancer is androgen deprivation therapy. Although initial responses are observed, prostate cancer commonly relapses in its lethal metastatic form referred to as castration resistant prostate cancer (CRPC) with 1-2 years mean survival time. Neuroendocrine prostate cancer (NEPC) is highly aggressive, AR independent subtype and usually emerges post castration resistance. We recently identified that the cell surface receptor, Trop2, is a new driver of NEPC. Moreover, we demonstrated that Trop2 regulates prostate cancer growth and metastasis. In this study, we set out to delineate the molecular mechanisms through which Trop2 regulates prostate cancer growth and metastasis. Methods: Proximity-dependent Biotin Identification (BioID) followed by mass spectrometry was performed to identify Trop2 interactome. Lentiviral infection was used to generate prostate cancer cell lines with over-expression of Trop2 and knock-down of...
Cancer Research, 2021
Ferroptosis is a type of programmed cell death induced by the accumulation of lipid peroxidation ... more Ferroptosis is a type of programmed cell death induced by the accumulation of lipid peroxidation and lipid reactive oxygen species in cells. It has been recently demonstrated that cancer cells are vulnerable to ferroptosis inducers (FIN). However, the therapeutic potential of FINs in prostate cancer in preclinical settings has not been explored. In this study, we demonstrate that mediators of ferroptosis, solute carrier family 7 member 11, SLC3A2, and glutathione peroxidase, are expressed in treatment-resistant prostate cancer. We further demonstrate that treatment-resistant prostate cancer cells are sensitive to two FINs, erastin and RSL3. Treatment with erastin and RSL3 led to a significant decrease in prostate cancer cell growth and migration in vitro and significantly delayed the tumor growth of treatment-resistant prostate cancer in vivo, with no measurable side effects. Combination of erastin or RSL3 with standard-of-care second-generation antiandrogens for advanced prostate c...
British Journal of Cancer, 2020
Distinguishing clinically significant from indolent prostate cancer (PC) is a major clinical chal... more Distinguishing clinically significant from indolent prostate cancer (PC) is a major clinical challenge. We utilised targeted protein biomarker discovery approach to identify biomarkers specific for pro-metastatic PC. Serum samples from the cancer-free group; Cambridge Prognostic Group 1 (CPG1, low risk); CPG5 (high risk) and metastatic disease were analysed using Olink Proteomics panels. Tissue validation was performed by immunohistochemistry in a radical prostatectomy cohort (n = 234). We discovered that nine proteins (pleiotrophin (PTN), MK, PVRL4, EPHA2, TFPI-2, hK11, SYND1, ANGPT2, and hK14) were elevated in metastatic PC patients when compared to other groups. PTN levels were increased in serum from men with CPG5 compared to benign and CPG1. High tissue PTN level was an independent predictor of biochemical recurrence and metastatic progression in low- and intermediate-grade disease. These findings suggest that PTN may represent a novel biomarker for the presence of poor prognos...
Proceedings of the National Academy of Sciences, 2020
Significance NEPC is a highly aggressive subtype of prostate cancer that is increasing in inciden... more Significance NEPC is a highly aggressive subtype of prostate cancer that is increasing in incidence, likely due to use of new secondary androgen deprivation therapies. Here, we demonstrate that Trop2 is significantly elevated in CRPC and NEPC and represents a driver of metastatic NEPC. Trop2 overexpression increases tumor growth, drives metastasis and neuroendocrine phenotype, and significantly increases PARP1 levels. Inhibition of PARP1 in Trop2-driven NEPC significantly decreases neuroendocrine features, tumor growth, and metastatic colonization in vivo, suggesting that PARP1 inhibitors may represent a promising therapeutic strategy for metastatic prostate cancer expressing high levels of Trop2.
Molecular Cancer Therapeutics, 2019
Prostate cancer remains among the leading causes of cancer-related deaths in men. Patients with a... more Prostate cancer remains among the leading causes of cancer-related deaths in men. Patients with aggressive disease typically undergo hormone deprivation therapy. Although treatment is initially very successful, these men commonly progress to lethal, castration-resistant prostate cancer (CRPC) in 2 to 3 years. Standard therapies for CRPC include second-generation antiandrogens, which prolong patient lifespan by only several months. It is imperative to advance our understanding of the mechanisms leading to resistance to identify new therapies for aggressive prostate cancer. This study identifies Notch1 as a therapeutic target in prostate cancer. Loss of NOTCH1 in aggressive prostate cancer cells decreases proliferation, invasion, and tumorsphere formation. Therapeutic inhibition of Notch1 activity with gamma secretase inhibitors RO4929097 or DAPT in prostate cancer cells further results in decreased proliferative abilities. Loss of NOTCH1 and treatment of immunocompromised mice bearin...
Advanced Materials Research, 2013
Novel proton conducting nanocomposite membranes included binary and ternary mixtures of acid modi... more Novel proton conducting nanocomposite membranes included binary and ternary mixtures of acid modified nanotitania particles particles with polymers such as poly (vinyl alcohol) (PVA),pol (vinyl phosphonic acid), sulfonated polysulfone (SPSU) and poly (1-vinyl 1,2,4-triazole) (PVTri) . The interaction of functional nanoparticles with the host matrix were searched by FT-IR spectroscopy. The homogeneous distribution of functional nanoparticles in the membranes was confirmed by SEM micrographs. The spectroscopic measurements and water/methanol uptake studies suggested a complexation between polymers and sulphonic acid that inhibited the leaching out of acidic units. The TGA results verified that the presence of modified nanoparticles in the composite membranes the thermel stability of the membranes enhanced up to above 200 °C.
Solid State Ionics, 2009
Proton-conducting properties of the graft copolymer electrolytes were examined throughout this wo... more Proton-conducting properties of the graft copolymer electrolytes were examined throughout this work. The homopolymers poly(glycidyl methacrylate), PGMA and poly(vinyl phosphonic acid), PVPA were synthesized by free-radical polymerizations of the monomers glycidyl methacrylate, GMA, and vinyl phosphonic acid, VPA, respectively. The graft copolymers were produced by grafting of PVPA onto PGMA via ring opening of ethylene oxide groups. To examine the influence of the concentration of VPA on the proton conductivity, several graft copolymers were produced at various stoichiometric ratios with respect to monomer repeat units. The materials were characterized by FT-IR and 1 H NMR spectroscopy and the thermal properties were studied by thermogravimetry (TG) and differential scanning calorimetry (DSC). The TGA results demonstrated that the samples are thermally stable up to at least 150°C. The proton conductivities of humidified and dry samples were studied via impedance spectroscopy. In the anhydrous state, the proton conductivity of P(GMA)-graft-P(VPA) 10 was 5 × 10 − 5 S/cm at 150°C. The proton conductivity of the same material increased with the humidity content and reached to 0.03 S/cm at 80°C under 50% of RH, which approached to that of Nafion ® at the same humidification level.
Journal of Applied Polymer Science, 2013
ABSTRACT Anhydrous polymer electrolytes based on azole functional methacrylates and methacrylamid... more ABSTRACT Anhydrous polymer electrolytes based on azole functional methacrylates and methacrylamides have been produced for use in proton exchange membrane fuel cells (PEMFCs). Poly(methacryloyl chloride) (PMAC) was prepared first by free-radical polymerization of methacryloyl chloride, followed by side chain functionalization with 5-aminotetrazole (ATet), 3-amino-1,2,4-triazole (ATri) and 1H-1,2,4-triazole (Tri). Finally, the obtained polymers were doped with triflic acid (TA) at stoichometric ratios of 1.0, 2.0 and 4.0 with respect to azole units, and the anhydrous polymer electrolytes were obtained. The membranes were characterized by FT-IR, 13C-NMR, and elemental analysis. Thermal behaviour of polymers was explored by TGA and DSC. The samples were thermally stable up to approximately 200 oC. Proton conductivity was measured by impedance spectroscopy. Trifilic acid doped poly(methacryloyl aminotetrazole) (PMAATet-(TA)4), poly(methacryloyl-3-amino-1,2,4-triazole) (PMA-Tri-(TA)4), and poly(methacryloyl-1,2,4-triazole) (PMA-ATri-(TA)4) showed maximum proton conductivities of 0.01 Scm−1, 0.02 Scm−1 and 8.7x10−4 Scm−1, respectively, at 150°C and anhydrous conditions. © 2013 Wiley Periodicals, Inc. J. Appl. Polym. Sci. 2014, 131, 39915.