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Publication Open Access DNA methylation profiling identifies novel markers of progression in hepatitis B-related chronic liver disease(BioMed Central, 2016) Vatansever, Sezgin; Hardy, Timothy; Sarı, Aysegül Akder; Çakalağaoğlu, Fulya; Avcı, Arzu; Zeybel, Gemma Louise; Bashton, Matthew; Mathers, John C.; Ünsal, Belkis; Mann, Jelena; N/A; Department of Molecular Biology and Genetics; Zeybel, Müjdat; Karahüseyinoğlu, Serçin; Faculty Member; Faculty Member; Department of Molecular Biology and Genetics; School of Medicine; 214694; 110772Background: Chronic hepatitis B infection is characterized by hepatic immune and inflammatory response with considerable variation in the rates of progression to cirrhosis. Genetic variants and environmental cues influence predisposition to the development of chronic liver disease; however, it remains unknown if aberrant DNA methylation is associated with fibrosis progression in chronic hepatitis B. Results: To identify epigenetic marks associated with inflammatory and fibrotic processes of the hepatitis B-induced chronic liver disease, we carried out hepatic genome-wide methylation profiling using Illumina Infinium beadarrays comparing mild and severe fibrotic disease in a discovery cohort of 29 patients. We obtained 310 differentially methylated regions and selected four loci comprising three genes from the top differentially methylated regions: hypermethylation of HOXA2 and HDAC4 along with hypomethylation of PPP1R18 were significantly linked to severe fibrosis. We replicated the prominent methylation marks in an independent cohort of 102 patients by bisulfite modification and pyrosequencing. The timing and causal relationship of epigenetic modifications with disease severity was further investigated using a cohort of patients with serial biopsies. Conclusions: Our findings suggest a linkage of widespread epigenetic dysregulation with disease progression in chronic hepatitis B infection. Cpg methylation at novel genes sheds light on new molecular pathways, which can be potentially exploited as a biomarker or targeted to attenuate inflammation and fibrosis.Publication Open Access Hybrid arc: combining forward IMRT and double arc VMAT in locally advanced rectum cancer(Akademi Doktorlar Yayınevi, 2019) Sağlam, Yücel; Alpan, Vildan; Bingölbali, Ayhan; N/A; Bölükbaşı, Yasemin; Sezen, Duygu; Selek, Uğur; Faculty Member; Faculty Member; Faculty Member; School of Medicine; 216814; N/A; 27211To investigate the potential of increasing target dose conformity and organ at risk (OAR) sparing of Hybrid Arc approach for patients with locally advanced rectum cancer (LARC) in comparison to VMAT and inverse IMRT. This study consisted of thirteen patients who had LARC, were treated with VMAT in 25Gy in 5 fractions. Two different new plans for each patient were generated on Pinnacle TPS by inverse IMRT (7 fields) and Hybrid Arc technique (combining forward IMRT (3 fields) with 20% weight and VMAT (double full arcs) with 80% weight). Treatment plans; Hybrid Arc, VMAT and inverse IMRT, were assessed using dose-volume histogram (DVH) parameters of OARs doses for bladder, small bowel, femur heads and penile bulb in male patients' cases. Ad-ditionally, monitor units (MU), conformity index (CI) and homogeneity index (HI) for clinical target volumes (CTV) were compared for all three techniques. Most DVH parameters pertaining to OARs significantly favored Hybrid Arc technique compared to VMAT and inverse IMRT. Hybrid Arc provided significantly improved Bladder DVH parameters in comparison to IMRT & VMAT. The Hybrid technique provided significantly lower small bowel doses in comparison to inverse IMRT and VMAT for all DVH pa-rameters. Mean MU of inverse IMRT was the highest one (MUIMRT= 1803, p= 0.001 vs VMAT; p= 0.023 vs Hybrid Arc). The target dose conformity and homogeneity of VMAT were better than the other two techniques. Hybrid technique combined the advantages of forward IMRT and VMAT for better OAR sparing in comparison to VMAT and inverse IMRT. / Lokal ileri rektum kanserli (LİRK) olgularda, Hibrit Ark yaklaşımının, VMAT ve IMRT ile karşılaştırılarak, hedef doz konformalitesini ve risk altındaki organ (OAR) korumasını arttırma potansiyelini araştırmaktır. Çalışmamıza, 5 fraksiyonda 25 Gy VMAT ile tedavi edilen 13 LİRK’li olgu dahil edilmiştir. Her hasta için, yeni IMRT ve Hibrit Ark tekniği (forward IMRT (3 alanlar: 275 °, 80 °, 180 °) %20 ağırlık ile ve VMAT (çift tam ark: 182°-178°) %80 ağırlık ile birleştiren) kullanılarak yapılan planlar, Pinnacle TPS’de oluşturuldu. Tedavi planları; Hibrit Ark, VMAT ve IMRT, mesane (V25Gy %, V20Gy %, V15Gy %, V10Gy % ve Dort), ince bağırsak (V25Gy cc, V15Gy cc, V10Gy cc, Dmaks and Dort), femur başları (V25Gy %, V15Gy %, Dmax and Dmean) ve erkek olgularda penis bulb (Dmax and Dmean) için OAR dozları doz hacim histogramı (DVH) parametreleri kullanılarak değerlendirildi. Ek olarak, klinik hedef hacimleri (CTV) için monitör birimleri (MU), konformalite indeksi (CI) ve homojenite indeksi (HI) her üç teknik için karşılaştırıldı. OAR’larla ilgili DVH parametrelerinin çoğu, VMAT ve IMRT’ye kıyasla önemli ölçüde Hibrit Ark tekniğinden yanaydı. Hibrit Ark yönteminin, IMRT ve VMAT karşılaştırıldığında, Mesane DVH parametrelerini (V25Gy cc, V15Gy cc, V10Gy cc, Dmax and Dmean) azalttığı gösterilmiştir. Hibrit planlama tekniği, ortalama doz dahil olmak üzere listelenen tüm ince bağırsak DVH parametreleri için, IMRT ve VMAT ile karşılaştırıldığında belirgin şekilde daha düşük dozlar sağlamıştır. Hibrit tekniği, VMAT’a kıyasla V20Gy%, V15Gy %’de daha düşük femur başı dozları olduğu saptanmıştır. Penis bulbusun, ortalama ve maksimum dozları her üç teknik için benzerdir. IMRT’nin ortalama MU değeri en yüksektir (MUIMRT= 1803, p= 0.001 vs VMAT; p= 0.023 vs Hybrid Arc). VMAT’ın hedef doz konformalitesi ve homojenitesi diğer iki teknikten daha iyiydi. (CIVMAT=1.16 vs CIHybrid=1.19, p= 0.003; vs CIIMRT= 1.22, p= 0.001 and HIVMAT= 0.33 vs HIHybrid= 0.36, p= 0.01; vs HIIMRT= 0.37, p= 0.012). Hibrit tekniğinin, VMAT ve IMRT’ye kıyasla, daha iyi OAR koruması için ileri IMRT ve VMAT’ın avantajlarını birleştirmektedir.Publication Open Access The present and future opportunities of the Rare Cancer network: an international consortium for advancement of oncologic care(PAGEpress, 2015) Sio, Terence T.; Mirimanoff, Rene-Olivier; Özyar, Enis; Belkacemi, Yazid; Miller, Robert C.; Villa, Salvador; Thariat, Juliette; Krengli, Marco; Scandolaro, Luciano; Atalar, Banu; Uğurluer, Gamze; Gutierrez Garcia, Beatriz; Ashman, Jonathan B.; Anacak, Yavuz; Onal, Cem; Arat, Mutlu; Sun, Xu Shan; Tesanovic, Dusanka; Lassen-Ramshad, Yasmin; Oksuz, Didem; Dinçbaş, Fazilet; Akyürek, Serap; Kütük, Tuğce; Bölükbaşı, Yasemin; Eren, Gülnihan; Paryani, Nitesh N.; Ahmed, Safia K.; Moretti, Luigi; Merrell, Kenneth W.; Chang, Kenneth; Mayeda, Mark; Arnett, Andrea L.; Habboush, Jacob Y.; Özşahin, Mahmut; N/A; Sezen, Duygu; Faculty Member; School of MedicineTo date, the Rare Cancer Network (RCN) has initiated more than 90 studies and 54 peer-reviewed publications were produced as a result. The Second International Symposium of the Rare Cancer Network recently took place in Istanbul, Turkey on April 17-18, 2015, and update was given on multiple currently ongoing projects, while also giving room for new proposals which will shape the direction of future studies for the group. This companion issue of the RCN Proceedings summarized the findings of this meeting, while also serving as a call for fresh projects and papers which will continue to energize the group and advance the oncologic science. A brief introduction to the principles, history, and vision of the RCN was also included. To review, the academic year of 2014-15 marked an enormous success for the international members of the RCN, with the generation of 8 fully published papers and more than 12 newly proposed topics. By the collective efforts of all RCN members, in the future, we look forward to the upcoming opportunities in continuing to advance the standard of chemo-and radiotherapeutic oncologic care for selected rare tumor topics. The studies of these rare cancers often do not allow the design and execution of prospectively enrolled trials; however, these uncommon malignancies do impact the humankind and add to its suffering globally in significant ways.Publication Open Access Adjuvant chemotherapy for gastric cancer in elderly patients has same benefits as in younger patients(Medknow Publications, 2018) Karaca, Mustafa; Tural, Deniz; Koçoğlu, Hakan; Bilgetekin, İrem; Özet, Ahmet; N/A; Selçukbiricik, Fatih; Faculty Member; School of MedicineObjective: The age-adjusted mortality rate due to gastric cancer was reported to increase with age. This study aims to investigate the results of adjuvant chemotherapy in patients aged 65 years or older comparing with younger patients and focusing on its impact on survival. Materials and Methods: A total of 406 patients with nonmetastatic gastric cancer that consisted of 283 patients younger than 65 years (range: 23-64 years) and 123 patients 65 years of age or older (range: 65-75 years) were retrospectively evaluated. Categorical and continuous variables were summarized using the descriptive statistics and compared with Chi-square and Mann-Whitney U-tests, respectively. Cancer-specific survival rates were estimated by the Kaplan-Meier method. Results: Median age at diagnosis was 58 years (range: 23-75 years). There was no significant difference in gender, tumor localization in the stomach (cardia/noncardia), tumor histology, perineural invasion, lymphovascular invasion, histopathological characteristics of the tumor, and tumor stage between groups. No significant difference was detected in survival between groups. The median survivals were 20.8 months (range: 17-24.6) in patients younger than 65 years and 19.5 months (range: 14.8-24.1) in patients 65 years of age or older (P = 0.9). Conclusions: We showed that adjuvant chemotherapy in elderly patients with gastric cancer has same effectiveness as nonelderly patients. However, further well-designated prospective studies are needed to confirm these findings.Publication Open Access Pancreas-specific activation of mTOR and loss of p53 induce tumors reminiscent of acinar cell carcinoma(BioMed Central, 2016) Kong, Bo; Cheng Tao; Qian, Chengjia; Wu, Weiwei; Steiger, Katja; Cao, Jing; Schlitter, Anna Melissa; Regel, Ivonne; Raulefs, Susanne; Friess, Helmut; Esposito, Irene; Kleeff, Joerg; Michalski, Christoph W.; N/A; Erkan, Murat Mert; Faculty Member; School of Medicine; 214689Background: Pancreatic acinar cell carcinoma (ACC) is a rare tumor entity with an unfavorable prognosis. Recent whole-exome sequencing identified p53 mutations in a subset of human ACC. Activation of the mammalian target of rapamycin (mTOR) pathway is associated with various pancreatic neoplasms. We thus aimed at analyzing whether activation of mTOR with a concomitant loss of p53 may initiate ACC. Methods: We generated transgenic mouse models in which mTOR was hyperactivated through pancreas-specific, homozygous tuberous sclerosis 1 (Tsc1) deficiency, with or without deletion of p53 (Tsc1(-/-) and Tsc1(-/-); p53(-/-)). Activity of mTOR signaling was investigated using mouse tissues and isolated murine cell lines. Human ACC specimens were used to corroborate the findings from the transgenic mouse models. Results: Hyperactive mTOR signaling in Tsc1(-/-) mice was not oncogenic but rather induced a near-complete loss of the pancreatic acinar compartment. Acinar cells were lost as a result of apoptosis which was associated with p53 activation. Concomitantly, ductal cells were enriched. Ablation of p53 in Tsc1-deficient mice prevented acinar cell death but promoted formation of acinar cells with severe nuclear abnormalities. One out of seven Tsc1(-/-); p53(-/-) animals developed pancreatic tumors showing a distinctive tumor morphology, reminiscent of human ACC. Hyperactive mTOR signaling was also detected in a subset of human ACC. Conclusion: Hyperactive mTOR signaling combined with loss of p53 in mice induces tumors similar to human ACC.Publication Open Access Activated leukocyte cell adhesion molecule regulates the interaction between pancreatic cancer cells and stellate cells(Spandidos Publications, 2016) Zhang, Wei-Wei; Zhan, Shu-Hui; Geng, Chang-Xin; Sun, Xin; Kleeff, Joerg; Xie, Xiang-Jun; N/A; Erkan, Murat Mert; Faculty Member; School of Medicine; 214689Activated leukocyte cell adhesion molecule (ALCAM/CD166) is a transmembrane glycoprotein that is involved in tumor progression and metastasis. In the present study, the expression and functional role of ALCAM in pancreatic cancer cells and pancreatic stellate cells (PSCs) was investigated. Tissue specimens were obtained from patients with pancreatic ductal adenocarcinoma (n=56) or chronic pancreatitis (CP; n=10), who underwent pancreatic resection, and from normal pancreatic tissue samples (n=10). Immunohistochemistry was used to analyze the localization and expression of ALCAM in pancreatic tissues. Subsequently, reverse transcription-quantitative polymerase chain reaction and immunoblotting were applied to assess the expression of ALCAM in pancreatic cancer Panc-1 and T3M4 cells, as well as in PSCs. An enzyme-linked immunosorbent assay was used to measure ALCAM levels in cell culture medium stimulated by hypoxia, tumor necrosis factor (TNF)- and transforming growth factor-. Silencing of ALCAM was performed using ALCAM small interfering (si)RNA and immunocytochemistry was used to analyze the inhibition efficiency. An invasion assay and a cell interaction assay were performed to assess the invasive ability and co-cultured adhesive potential of Panc-1 and T3M4 cells, as well as PSCs. Histologically, ALCAM expression was generally weak or absent in pancreatic cancer cells, but was markedly upregulated in PSCs in pancreatic cancer tissues. ALCAM was highly expressed in PSCs from CP tissues and PSCs surrounding pancreatic intraepithelial neoplasias, as well as in pancreatic cancer cells. ALCAM mRNA was highly expressed in PSCs, with a low to moderate expression in T3M4 and Panc-1 cells. Similar to the mRNA expression, immunoblotting demonstrated that ALCAM protein levels were high in PSCs and T3M4 cells, but low in Panc-1 cells. The expression of TNF- increased, while hypoxia decreased the secretion of ALCAM in pancreatic cancer Panc-1 and T3M4 cells, and also in PSCs. Silencing of ALCAM by siRNA revealed no significant alteration in the invasion of pancreatic cancer cells, however, it inhibited the invasive ability of PSCs, and decreased the interaction between Panc-1 cells and PSCs. In conclusion, ALCAM is upregulated in PSCs of pancreatic cancer tissues, suggesting a potential role of ALCAM in regulating pancreatic cancer cell-PSC interactions.Publication Open Access Determining the origin of synchronous multifocal bladder cancer by exome sequencing(BioMed Central, 2015) Özkurt, Ezgi; Demir, Gulfem; Alkan, Can; Somel, Mehmet; N/A; N/A; Esen, Tarık; Lack, Nathan Alan; Acar, Ömer; Saraç, Hilal; Faculty Member; Faculty Member; Faculty Member; PhD Student; School of Medicine; 50536; 120842; 237530; N/ABackground: Synchronous multifocal tumours are commonly observed in urothelial carcinomas of the bladder. The origin of these physically independent tumours has been proposed to occur by either intraluminal migration (clonal) or spontaneous transformation of multiple cells by carcinogens (field effect). It is unclear which model is correct, with several studies supporting both hypotheses. A potential cause of this uncertainty may be the small number of genetic mutations previously used to quantify the relationship between these tumours. Methods: To better understand the genetic lineage of these tumours we conducted exome sequencing of synchronous multifocal pta urothelial bladder cancers at a high depth, using multiple samples from three patients. Results: Phylogenetic analysis of high confidence single nucleotide variants (SNV) demonstrated that the sequenced multifocal bladder cancers arose from a clonal origin in all three patients (bootstrap value 100 %). Interestingly, in two patients the most common type of tumour-associated snvs were cytosine mutations of tpc* dinucleotides (Fisher's exact test p < 10-41), likely caused by APOBEC-mediated deamination. Incorporating these results into our clonal model, we found that tpc* type mutations occurred 2-5x more often among snvs on the ancestral branches than in the more recent private branches (p < 10-4) suggesting that tpc* mutations largely occurred early in the development of the tumour. Conclusions: These results demonstrate that synchronous multifocal bladder cancers frequently arise from a clonal origin. Our data also suggests that APOBEC-mediated mutations occur early in the development of the tumour and may be a driver of tumourigenesis in non-muscle invasive urothelial bladder cancer.Publication Open Access Expanding congenital abnormalities of the kidney and urinary tract (CAKUT) genetics: basonuclin 2 (BNC2) and lower urinary tract obstruction(AME Publishing Company, 2019) Fernandez-Prado, Raul; Ortiz, Alberto; Vanessa Perez-Gomez, Maria; N/A; Kanbay, Mehmet; Faculty Member; School of Medicine; 110580Publication Open Access Baseline hemoglobin <11.0 g/dL has stronger prognostic value than anemia status in nasopharynx cancers treated with chemoradiotherapy(Sage, 2019) Topkan, Erkan; Ekici, Nur Yücel; Özdemir, Yurday; Besen, Ali Ayberk; Yıldırım, Berna Akkuş; Mertsoylu, Hüseyin; N/A; Sezen, Duygu; Selek, Uğur; Faculty Member; Faculty Member; School of Medicine; N/A; 27211Background: to retrospectively investigate the influence of pretreatment anemia and hemoglobin levels on the survival of nasopharyngeal carcinoma patients treated with concurrent chemoradiotherapy (C-CRT). Methods: a total of 149 nasopharyngeal carcinoma patients who received C-CRT were included. All patients had received 70 Gy to the primary tumor plus the involved lymph nodes, and 59.4 Gy and 54 Gy to the intermediate- and low-risk neck regions concurrent with 1-3 cycles of cisplatin. Patients were dichotomized into non-anemic and anemic (hemoglobin <12 g/dL (women) or <13 g/dL (men)) groups according to their pre-treatment hemoglobin measures. Receiver operating characteristic (ROC) curve analysis was utilized for accessibility of a pre-treatment hemoglobin cut-off that impacts outcomes. Potential interactions between baseline anemia status and hemoglobin measures and overall survival, locoregional progression-free survival (LRPFS), and progression-free survival were assessed. Results: Anemia was evident in 36 patients (24.1%), which was related to significantly shorter overall survival (P=0.007), LRPFS (P<0.021), and progression-free survival (P=0.003) times; all three endpoints retained significance in multivariate analyses (P<0.05, for each). A baseline hemoglobin value of 11.0 g/dL exhibited significant association with outcomes in ROC curve analysis: hemoglobin <11.0 g/dL (N=26) was linked with shorter median overall survival (P<0.001), LRPFS (P=0.004), and progression-free survival (P<0.001) times, which also retained significance for all three endpoints in multivariate analyses and suggested a stronger prognostic worth for the hemoglobin Conclusion: pre-C-CRT hemoglobin <11.0 g/dL has a stronger prognostic worth than the anemia status with regard to LRPFS, progression-free survival, and overall survival for nasopharyngeal carcinoma patients.Publication Open Access beta III-Tubulin: a novel mediator of chemoresistance and metastases in pancreatic cancer(Impact Journals, 2015) McCarroll, Joshua A.; Sharbeen, George; Liu, Jie; Youkhana, Janet; Goldstein, David; McCarthy, Nigel; Limbri, Lydia F.; Dischl, Dominic; Ceyhan, Gueralp O.; Johns, Amber L.; Biankin, Andrew V.; Kavallaris, Maria; Phillips, Phoebe A.; N/A; Erkan, Murat Mert; Faculty Member; School of Medicine; 214689Pancreatic cancer is a leading cause of cancer-related deaths in Western societies. This poor prognosis is due to chemotherapeutic drug resistance and metastatic spread. Evidence suggests that microtubule proteins namely, beta-tubulins are dysregulated in tumor cells and are involved in regulating chemosensitivity. However, the role of beta-tubulins in pancreatic cancer are unknown. We measured the expression of different beta-tubulin isotypes in pancreatic adenocarcinoma tissue and pancreatic cancer cells. Next, we used RNAi to silence beta III-tubulin expression in pancreatic cancer cells, and measured cell growth in the absence and presence of chemotherapeutic drugs. Finally, we assessed the role of beta III-tubulin in regulating tumor growth and metastases using an orthotopic pancreatic cancer mouse model. We found that beta III-tubulin is highly expressed in pancreatic adenocarcinoma tissue and pancreatic cancer cells. Further, we demonstrated that silencing beta III-tubulin expression reduced pancreatic cancer cell growth and tumorigenic potential in the absence and presence of chemotherapeutic drugs. Finally, we demonstrated that suppression of beta III-tubulin reduced tumor growth and metastases in vivo. Our novel data demonstrate that beta III-tubulin is a key player in promoting pancreatic cancer growth and survival, and silencing its expression may be a potential therapeutic strategy to increase the long-term survival of pancreatic cancer patients.