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Origanum sipyleum is used in folk medicine due to its anti-inflammatory, antimicrobial, and antioxidant properties. Ponatinib, an effective tyrosine kinase inhibitor in the treatment of chronic myeloid leukemia (CML), has severe side effects. Thus, we aimed to determine a novel herbal combination therapy that might not only increase the anti-leukemic efficacy but also reduce the dose of ponatinib in targeting CML cells. Origanum sipyleum was extracted with methanol (OSM), and secondary metabolites were determined by phytochemical screening tests. The cytotoxic effects of OSM on K562 cells were measured by WST-1 assay. Median-effect equation was used to analyze the combination of ponatinib and OSM (p-OSM). Apoptosis, proliferation, and cell-cycle were investigated by flow-cytometry. Cell-cycle-related gene expressions were evaluated by qRT-PCR. OSM that contains terpenoids, flavonoids, tannins, and anthracenes exhibited cytotoxic effects on K562 cells. The median-effect of p-OSM was found as synergistic; OSM reduced the ponatinib dose similar to 5-fold. p-OSM elevated the apoptotic and anti-proliferative activity of ponatinib. Consistently, p-OSM blocked cell-cycle progression in G(0)/G(1), S phases accompanied by regulations in TGFB2, ATR, PP2A, p18, CCND1, CCND2, and CCNA1 expressions. OSM enhanced the anti-leukemic activity of ponatinib synergistically via inducing apoptosis, suppressing proliferation, and cell-cycle. As a result, OSM might offer a potential strategy for treating patients with CML., 110S289, The Origanum sipyleum L. methanol extract was obtained from TuBTAK project no 110S289. We thank Ege University School of Foreign Languages and Lecturer Dr. Atiyye Hilal SENGENC for providing professional English editing for this manuscript.

In this study, a group of 4-substituted benzoyltaurinamide derivatives were designed, synthesized, and investigated for their anticancer activity against three cancer cell lines and one nontumorigenic cell line by MTT assay. Among the final compounds, methoxyphenyl derivatives 14, 15, 16 were found to be effective against all the tested cancerous cell lines with promising selectivity. The most active compounds were further evaluated to determine the molecular mechanism of their anticancer activity by using western blot assay and the Annexin V-FITC/PI test. Compound 14 (in SH-SY5Y and MDA-MB-231 cell lines) and 15 (in SH-SY5Y cell line) were found to induce intrinsic apoptotic pathway by upregulating BAX, caspase-3, and caspase-9, while downregulating Bcl-2 and Bcl-xL expression levels. According to mechanistic studies, compounds displayed their anticancer activity via three different mechanisms: a. caspase-dependent, b. caspase-independent, and c. caspase-dependent pathway that excluded caspase-9 activation. As a result, this study provides interesting data which can be used to design new taurine-based anticancer derivatives., Scientific and Technological Research Council of Turkey [TUBITAK]Turkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK) [SBAG-118S667], This study was supported by research grants from The Scientific and Technological Research Council of Turkey [TUBITAK; Project number: SBAG-118S667].

BACKGROUND/AIMS the purpose of this study was to research the effects of genistein on telomerase activity and apoptosis in an acute promyelocytic leukemia cell line (HL-60). MATERIAL and METHODS in HL-60 cells, the cytotoxic effect of commercially available genistein was evaluated by the XTT method. the XTT method is a Cell Proliferation Assay. the Annexin V-EGFP method was used to determine apoptosis. the human telomerase reverse transcriptase (hTERT) is a marker of telomerase activity. hTERT gene expression analysis was performed by LightCycler real-time RT-PCR. RESULTS in HL-60 cells, the IC50 of genistein was found to be 50 mu M at 72 hours. It was observed that the induction of apoptosis was 4.25-fold higher compared to the genistein untreated cells used as the control group. Compared to the control group, hTERT activity was found to decrease by 5.16, 3.81 and 5.04-fold at 24, 48 and 72 hours, respectively. CONCLUSION Induced apoptosis of HL-60 cells by the reduction of human telomerase reverse transcriptase activity may be a beneficial parameter in leukemia patients.

ASP was used to synthesize FeNPA. They were characterized by UV-vis spectroscopy, FT-IR, TEM, SEM, XRD and ZP. The aim of this study was to evaluate in vitro cytotoxic activity and antioxidant acitivities of FeNPA and ASP. The antioxidant properties were evaluated using DPPH, ABTS+ and H2O2 assays. FeNPA had higher antioxidant activity comparing to ASP according to DPPH (IC50: 3.48 ?g/mL) and ABTS+ (60.52%) assays. Anti-cancer activities of FeNPA and ASP were investigated in breast cancer, melanoma and control cell lines. FeNPA was more cytotoxic than ASP in MCF-7, MeWo, CHL-1, and HEL 299 cells. FeNPA had shown that mitochondria induce apoptosis through stress in MDA-MB-231, and cells MeWo. ASP also induced apoptosis 2.23-fold in MCF-7 cells. Progesterone receptor gene expression showed a 10-fold increase in a hormone-dependent MCF-7 cell line in ASP, and FeNPA treatment. Expressions of BCL6, CXCL12, DNAJC15, RB1 and TPM1 in melanoma cancer cell lines were significantly increased in ASP and FeNPA administration. It had been shown that FeNPA regulates gene expressions that may be considered important in terms of prognosis in breast cancer and melanoma cell lines and it is suggested that gene expressions regulated by FeNPA are also evaluated in animal models in vivo. © 2020 Tuzun et al., published by De Gruyter 2020., SBAG-114S730, This research was supported by TUBITAK (project number SBAG-114S730). We are thankful to FABAL (Ege University, Faculty of Pharmacy Pharmaceutical Sciences Research Centre) and Izmir Institute of Technology, Center for Materials Research.

LncRNAs are associated with malignancies with their tumor suppressor/oncogenic properties. Although many studies are conducted related to the mechanism of action for dasatinib and ponatinib in chronic myeloid leukemia (CML), their comparative effects on lncRNA expressions are largely unknown. Hence, we aimed to define the lncRNAs involved in the treatment of CML with dasatinib and ponatinib. We measured the cytotoxicities of dasatinib/ponatinib with CCK-8 assay and identified differentially expressed lncRNAs (DEL) by qRT-PCR. We determined the principal functions of DELs by Ingenuity Pathway Analysis (IPA) and performed gene ontology (GO) analysis for apoptosis and anti-proliferation-related lncRNAs. Apoptotic and anti-proliferative activities of dasatinib/ponatinib were confirmed by flow-cytometry. In K562 cells, dasatinib/ponatinib re-regulated lncRNAs which were dysregulated in leukemia. DELs after treatment (forty with dasatinib, thirty-seven with ponatinib) were related to increased cell death; decreased cell viability, proliferation, tumor growth, invasion, migration. Dasatinib-mediated network was related to cancer, hematological disease while ponatinib-mediated network was associated with cancer, cell death/survival, cell-to-cell signaling/interaction. Both treatments predicted activation of IFN gamma, IL1 beta, TNF as upstream regulators, specially this effect was higher in dasatinib. Comparison analysis showed that ponatinib was predicted more effective in cell death of tumor cell line than dasatinib. We confirmed that ponatinib was more potent than dasatinib to induce apoptosis and inhibit proliferation of CML cells, in consensus with IPA and GO analysis results. LncRNAs are specifically involved in anti-leukemic activities of dasatinib and ponatinib. Our findings will contribute to understanding signalization occurring in CML cells after standard treatments.

Bu çalışma, 30 Ağustos - 4 Eylül 2014 tarihleri arasında Paris[Fransa]'de düzenlenen 39th Congress of the Federation of European Biochemical Societies (FEBS) EMBO 2014 Conference'de ve 28-31 Ekim 2021 tarihlerinde düzenlenen XVII. Tıbbi Biyoloji ve Genetik Kongresi’nde bildiri olarak sunulmuştur. Meme kanseri kadınlarda en yaygın gözlenen kanser türüdür. Mevcut tedavilerin düşük seçicilik ya da zamanla oluşan ilaç direnci gibi eksiklerini giderebilecek yeni stratejilerin belirlenmesine ihtiyaç vardır. Çalışmamızda, çoklu hedefli bir tirozin kinaz inhibitörü olan ponatinibin meme kanseri hücreleri üzerindeki anti-kanser etkisini değerlendirmeyi ve ponatinib yanıtında yer alan miRNA'ların biyoinformatik yaklaşım ile sinyal yolaklarındaki potansiyel işlevini tanımlamayı hedefledik. Bu amaçla, MCF-7 hücrelerinde ponatinibin sitotoksik etkileri xCELLigence ile gerçek-zamanlı olarak belirlendi. Ponatinib uygulaması sonrasında apoptoz, proliferasyon hızı, hücre döngüsündeki değişimler akım sitometriyle, miRNA'ların ifadelerindeki düzenlenmeler qRT-PCR ile değerlendirildi. İfadelerinde anlamlı değişim belirlenen miRNA’ların ilişkili olduğu olası mRNA’lar ve sinyal yolakları KEGG yolak analizi ile tanımlandı. Ponatinibin MCF-7 hücreleri üzerinde sitotoksik etkiye sahip olduğu (IC50: 4,59 μM) belirlendi. Ponatinib uygulaması ile MCF-7 hücrelerinde anlamlı olarak apoptozun indüklen- diği, proliferasyonun baskılandığı ve hücre döngüsünün G0 /G1, S evrelerinde durakladığı belirlendi. Ayrıca, let-7a-5p, miR-29a-3p, miR-7-5p, miR-125b-5p, miR-212-3p ifadelerinde artış (p

Ponatinib is used for advanced treatment of chronic myeloid leukemia (CML), although low doses to prevent side effects do not suppress survival pathways and eradicate leukemia stem cells (LSCs). We evaluated the potential of ponatinib and PI3K/mTOR dual-inhibitor VS-5584 combination (PoVS) therapy to increase the anti-leukemic effects of ponatinib and investigated the underlying mechanisms at the molecular level. We measured the cytotoxicities of ponatinib, VS-5584, and PoVS (CCK-8 assay), and used the median-effect equation for combination analyses. We investigated the effects of inhibitory concentrations on apoptosis, cell viability and cell-cycle regulation (flow cytometry), protein levels (ELISA, Western blot), transcriptional activities (dual-luciferase reporter assay), gene expressions (qRT-PCR). VS-5584 exerted selective cytotoxic effects against CML and LSC cell lines. VS-5584 inhibited the PI3K/Akt/mTOR pathway, resulting in reduced cell viability, slightly induced caspase-independent apoptosis, prominent G0/G1 cell-cycle blockade that is not a consequence of quiescence. Normal hematopoietic stem cell line was the least affected. Moreover, ponatinib and VS-5584 mediated synergistic anti-leukemic effects on leukemic cells. VS-5584 reduced the ponatinib dose required to target leukemic cells. PoVS treatment inhibited PI3K/Akt/mTOR pathway more consistently than either of the two agents alone through reducing p-Akt, p-mTOR, p-S6K, p-PRAS40, p-S6. The subsequent downstream effects were an increase in C/EBP transcriptional activity and decreases in activities of E2F/DP1, Myc/Max, CREB, STAT3, NF kappa B, AP-1, Elk-1/SRF. Transcriptional regulation resulted in alterations in the expression levels of target mRNAs. Our results highlight PoVS can be a promising treatment strategy for eliminating CML cells and LSCs selectively, with the reduced ponatinib doses., Ege University Scientific Research Projects (BAP) Department [15-TIP-019, 2015-TIP-063], This work was supported by Ege University Scientific Research Projects (BAP) Department (Grand no. 15-TIP-019, 2015-TIP-063).

Background: Dysregulation of the cell cycle is one of the main causes of melanomagenesis. Genomewide studies showed that the expression of Aurora -A and -B significantly has been upregulated in melanoma. However, there is no FDA approved drug targeting aurora kinases in the treatment of melanoma. In addition, the development of resistance to chemotherapeutic agents in the treatment of melanoma and, as a result, the relapse due to heterogeneous cell groups in patients is a second phenomenon that causes treatment failure. Therefore, there is an urgent need for therapeutic alternatives targeting both melanoma and Melanoma Cancer Stem Cells (MCSCs) in treatments. At this stage, cell cycle regulators become promising targets. Objective: In this study, we aimed to identify the effects of Aurora kinase inhibitor CCT137690 on the cytotoxicity, apoptosis, cell cycle, migration, and colony formation and expression changes of genes related to proliferation, cell death and cell cycle in melanoma and melanoma cancer stem cell. In addition, we investigated the apoptotic and cytostatic effects of CCT137690 in normal fibroblast cells. Methods: We evaluated the cytotoxic effect of CCT137690 in MCSCs, NM2C5 referring as melanoma model cells and WI-38 cells by using the WST-1 test. The effect of CCT137690 on apoptosis was detected via Annexin V and JC-1 method; on cell cycle progression by cell cycle test; on gene expression by using RT-PCR, on migration activity by wound healing assay and clonal growth by clonogenic assay in NM2C5 cells and MCSCs. The effects of CCT137690 in WI-38, referring as healthy fibroblast cell, were assessed through Annexin V and cell cycle method. Results: CCT137690 was determined to have a cytotoxic and apoptotic effect in MCSCs and melanoma. It caused polyploidy and cell cycle arrest at the G2/M phase in MCSCs and melanoma cells. The significant decrease in the expression of MMP2, MMP7, MMP10, CCNB1, IRAK1, PLK2 genes, and the increase in the expression of PTEN, CASP7, p53 genes were detected. Conclusion: Aurora kinases inhibitor CCT137690 displays promising anticancer activity in melanoma and especially melanoma cancer stem cells. The effect of CCT137690 on melanoma and MCSC may provide a new approach to treatment protocols.

The effect of Wnt pathway in head and neck cancer could not be elucidated, even though the aberrant Wnt signaling plays a key role in the development of many types of cancer. The inhibitor of β-catenin responsive transcription (ICRT-3) blocks the Wnt signaling pathway by binding to β-catenin, which is a coactivator of the Wnt signaling pathway and a promising agent for inhibiting aberrant signaling. In our study, we aimed to evaluate the effect of ICRT-3 on the cytotoxicity, apoptosis, cell cycle progression, migration, and gene expressions in head and neck cancer stem cell (HNCSC) and hypopharynx cancer. The effect of this compound on cytotoxicity and cell viability in FaDu and HNCSC line was assessed by using the water-soluble tetrazolium salt-1 method. The effect of ICRT-3 on apoptosis was detected by using Annexin V and caspase-3, caspase-9 kit, on cell cycle progression by cycle test plus DNA reagent kit, on gene expression by dual luciferase reporter assay, and on migration activity by wound healing assay in both cell lines. ICRT-3 was determined to have cytotoxic and apoptotic effect in both cell lines. In addition, it was also found that the administration of ICRT-3 caused cell cycle arrest and significant decrease in gene expression level and migration ability of the cells.

WOS: 000425576500027, PubMed ID: 29309887, Acute promyelocytic leukemia (APL) is a subtype of AML that is a mixture of hematological malignancy, characterized by a specific translocation t(15;17). The using of all-trans retinoic acid (ATRA) with arsenic trioxide (ATO) or chemotherapeutic agents or both of these agents, composes main treatment strategy of APL. While it is possible to achieve success in treatment of low-risk APL with current treatment regimens, such success is not mentioned in high-risk APL. So, it may develop new approaches for treatment regimens for high-risk APL. In the present study, we aimed to investigate the effects of combinational of a classic anticancer agent paclitaxel and antidiabetic agent metformin on HL-60 APL cell line. The combination dose of paclitaxel and metformin was determined by WST-1 analysis. The effect of combinational dose on apoptosis was assessed in fluorescence microscope after using AnnexinV-EGFP Apoptosis and JC-1 Assay Kit. The effect of combinational dose on cell cycle, apoptosis and differentiation, and signaling pathways were determined investigating gene expression changes by using real time qRT-PCR. The combinational dose of paclitaxel and metformin was determined as 4.8 mu M and 398.7 mu M for 72 h, respectively. The combination dose significantly increased apoptosis for 48 h. In expression changes of genes associated cell cycle, apoptosis, cytokines, co-stimulator molecules, NF-kappa B and MAP/MAPK pathways, TLRs (Toll-like receptors) were found to be decreased or increased to provide apoptosis or differentiation. Consequently, we suggest that the combination of paclitaxel and metformin can be used as an option assessable for development of new treatment strategies for APL.

Long non-coding RNAs (lncRNAs) are involved in a range of biological processes, such as cellular differentiation, migration, apoptosis, invasion, proliferation, and transcriptional regulation. The aberrant expression of lncRNAs plays a significant role in several cancer types. Aurora kinases are increasingly expressed in various malignancies; accordingly, the inhibition of these enzymes may represent a novel approach for the treatment of various cancers. CCT137690, an Aurora kinase inhibitor, displays an anti-proliferative activity in human cancer cell lines. The aim of the present study was to investigate the anti-proliferative and cytotoxic effects of CCT137690 on estrogen receptor (ER)-positive human breast cancer cell line (MCF-7) and ER-negative human breast cancer cell line (MDA-MB-231). In addition, this study was targeted toward determining the changes induced in lncRNA expression levels following the initiation of Aurora kinase inhibitor treatment. The cytotoxic effects of CCT137690 were determined by means of the xCELLigence system. Furthermore, the anti-proliferative role of CCT137690 in breast cancer was investigated by checking the changes in lncRNA expression profiles using quantitative reverse-transcription polymerase chain reaction (qRT-PCR). The half-maximal inhibitory concentrations (IC50) of CCT137690 were determined as 4.5 μM (MCF-7) and 7.27 μM (MDA-MB-231). Several oncogenic lncRNAs (e.g., PRINS, HOXA1AS, and NCRMS) were downregulated in both ER-negative and ER-positive cell lines. On the other hand, tumor suppressor lncRNAs (e.g., DGCR5 and IGF2AS) were upregulated in the ER-positive cell line. After CCT137690 treatment, HOXA11AS and PCAT-14 lncRNAs were downregulated in the ER-positive cell lines. In addition, MER11C, SCA8, BC200, HOTAIR, PCAT-1, UCA1, SOX2OT, and HULC lncRNAs were downregulated in the ER-negative cell lines. The results of the present study indicated that Aurora kinase inhibitor CCT137690 could be a potential anti-cancer agent for breast cancer treatment.

Amac : Bu calismada akut lenfoblastik losemi (ALL) on tanili olgularda t(12;21) translokasyonu gercek zamanli kantitatif revers transkriptaz polimeraz zincir reaksiyonu (qRT-PZR) yontemi kullanilarak kantite edildi. Hastalar ve yontemler : Ocak 2009 - Aralik 2013 tarihleri arasinda Ege Universitesi Tip Fakultesi Tibbi Biyoloji Anabilim Dali’na basvuran 175 pediatrik ve 138 eriskin olmak uzere toplam 313 olguya ait kan ve kemik iligi orneklerinde t(12;22) (p13;q22) translokasyonu RNA sonuclari kantitatif olarak degerlendirildi. Olgulara ait 75 kan ve 484 kemik iligi orneklerinden total RNA veya haberci RNA izole edildi. RNA izolasyonlarinin ardindan tamamlayici DNA sentezi gerceklestirildi. t(12;21) (p13;q22) translokasyon calismasi LightCycler t(12;21) Kit’i ile fuzyon transkripte ozgul bicimde tasarlanmis primer ve problarla (Way2Gene) uygun olacak sekilde gerceklestirildi. Son adim olarak, t(12;21) translokasyon sonuclarinin kantitatif olarak degerlendirilmesi gercek zamanli qRT-PZR yontemi kullanilarak LightCycler2 ile gerceklestirildi. Bulgular : Otuz dort pediatrik olgu orneginde (%19) ve 17 eriskin olgunun orneginde (%12) TEL-AML-1 (ETV6-RUNX1) pozitif bulundu. TEL-AML1 (ETV6-RUNX1) kantitasyon degeri ortalamasi pediatrik olgularda 0.90±3.21, eriskin olgularda ise 0.34±1.20 olarak belirlendi. Sonuc : Elde ettigimiz veriler, gercek zamanli qRT-PZR yontemi ile ALL hastalarinda yeni tani doneminde ve tedavi surecinde t(12;21) translokasyonunun kantitatif tayininin hem taninin kesinlestirilmesinde hem de molekuler remisyon saglanmasina yonelik tedaviyi yonlendirmesinde degerli bir yontem oldugunu desteklemektedir.

Photodynamic therapy (PDT) is a medical treatment for the removal of target tissues involving the delivery of a photosensitizer agent followed by irradiation with visible light. In the present study, symmetric Zn(II) Pc 1 and asymmetrically substituted Zn(II) Pc 2 were synthesized and examined multifunctional agents for tumor nuclear imaging and PDT potential. The Zn(II) Pc 1 and Zn(II) Pc 2 were radiolabeled with 131 I with high efficiency (93.4 ± 1.6% and 91.4 ± 1.6%, respectively). The results of the biodistribution study showed that radiolabeled Zn(II) Pc 1 had high uptake on lung, large intestine, ovary and pancreas. However, the uptake of radiolabeled Zn(II) Pc 2 was statically significant in pancreas and intestine. In PDT studies, EMT6/P (mouse mammary cell) and HeLa (cervical adenocarcinoma cell) with Zn(II) Pc 1 and Zn(II) Pc 2 were exposed to red light at the doses of 10–30 J/cm 2 . Although PDT activity of Zn(II) Pc 2 in HeLa cell line was determined, Zn(II) Pc 1 showed no phototoxic effect in both cell lines. In conclusion, radiolabeled Zn(II) Pc 1 might be a promising imaging agent for the lung, the ovary pancreas, and the colon tumors. However, radiolabeled Zn(II) Pc 2 might be a promising nuclear imaging agent for the colon and the pancreas tumors and promising PDT agent for cervical tumors.

WOS: 000485707300011, BACKGROUND/AIMS Breast cancer is the most common type of cancer in women and is among the leading causes of cancer-related deaths. Long non-coding RNAs (lncRNAs) play significant roles in cell proliferation, transcriptional regulation, cell cycle progression, apoptosis, carcinogenesis, and metastasis. Studies have shown that ponatinib has an antiproliferative effect in some types of cancer. The aim of the present study was to evaluate the effect of ponatinib on cytotoxicity and to determine changes in lncRNA expression levels with the use of ponatinib treatment in estrogen receptor (ER)-independent MDA-MB-231 and ER-dependent MCF-7 breast cancer cells. MATERIAL and METHODS The cytotoxic effects of ponatinib were determined by using the xCELLigence system. Changes in lncRNA expression profiles were determined using quantitative reverse transcription polymerase chain reaction to investigate the antiproliferative roles of ponatinib in breast cancer. RESULTS In human breast adenocarcinoma cell lines (MCF-7 and MDA-MB-231), the IC50 doses of ponatinib were determined to be 4.59 mu M (72 h) and 1.41 mu M (48 h), respectively. After ponatinib treatment, we observed changes in lncRNA expression profiles in ER-independent MDA-MB- 231 and ER-dependent MCF-7 breast cancer cells compared with the control group. CONCLUSION The changes in the lncRNA expression profiles and the anti-cancer agent of ponatinib play roles in the definition of therapeutic target for new approach in breast cancer.

Paclitaxel, which isolated from Taxus brevifolia, is recently started to be used against prostate cancer treatment and it is a very effective compound against cancer. In this study, we aimed to test the synergistic effect of two plant active compounds (sulphoraphane (SFN) and silymarin (SILY)) and several endemic plant species from Turkey (such as Phlomis leucophracta, Rubia davisiana, Alkanna tinctoria), which are known to have anticarcinogenic effect on androgen-independent PC3 and DU145, and androgen-dependent VCaP prostate cancer cell lines, with paclitaxel on the expression of cell cycle signaling and apoptosis regulator genes. Herbal substances and endemic herbal extracts were combined with Paclitaxel drug. IC50 doses were identified as real-time online. The most effective synergistic doses were determined according to isobologram analysis. The apoptotic effects of effective combined doses were evaluated by TUNEL, Annexin V, and JC-1 methods. Apoptotic and/or cell cycle arrest effects of confirmed combined doses on the expression of genes in these pathways were assessed by real-time online. Endemic plant extracts (Alkanna tinctoria, Phlomis leucophracta and Rubia davisiana, IC50 < 220 μg/ml) and herbal substances (SILY, and SFN IC50 < 130 μM) indicated antiproliferative and apoptotic effects in prostate cancer cell lines. They testified to the synergistic effect of paclitaxel with endemic plant extracts (Combination Index CI, ED50 < 0.41). The combinations, which indicate the synergistic effect was increased to the Bax/Bcl‑2 ratio by suppressing Bcl‑2 gene expression into the prostate cancer cell lines. Besides, they increased the expression of TNFRSF10A, TNFRSF1A, CHEK1, CDKN1A, CDKN2B, CDK8, CDKN3 and CASP14 and decreased BAD, CDK5RAP1, CDC20, cyclin H, CDK5RAP1, CDC20. The effective doses of paclitaxel were reduced and G2/M arrest was induced by the endemic plant extracts and herbal substances that indicate a synergistic effect with paclitaxel. By using different combination of herbal extracts or active substances with paclitaxel, more economical and efficient treatment strategies can be developed. © 2018 Elsevier B.V.

Novel octylthio-containing asymmetrically substituted Zn(II) phthalocyanine (Zn(II)Pc1) and a symmetric derivative (Zn(II)Pc2) have been prepared to investigate the biological potential and ability to photosensitize singlet oxygen for photodynamic therapy applications. In this study, the singlet oxygen generation potential and in vitro photodynamic activities of these compounds have been tested. Both ZnPcs reveal to be very efficient singlet oxygen generators and promising PSs for PDT applications. In vitro PDT activities of the compounds were evaluated in EMT-6 murine mammary carcinoma and HeLa human cervix carcinoma cell lines. Moreover, Zn(II)Pc1 displayed the phototoxic effects in the mammary cancer cell line (6.25 μm concentration at 30 J/cm(2) light dose and 12.5 μm concentration at 20 J/cm(2) light dose), while Zn(II)Pc2 did not show any phototoxic effects both in two cell lines. Zn(II)Pcs were radiolabeled with (131) I in high yields. Biodistribution studies revealed that the radiolabeled Zn(II)Pc1 showed significant uptake in l. intestine, pancreas, brain, and ovary, while Zn(II)Pc2 has significant uptake in ovary and pancreas in normal rats. Hence, these Pcs derivatives could be promising candidate for tumor nuclear imaging.

Amaç: t(4;11), MLL-AF4 translokasyonu sonucu oluşan, 4q21 kromozomal bandına yerleşim gösteren AF4 geninin 11q23 kromozomal bandına yerleşim gösteren MLL genine füzyonu sonucu gelişen kromozomal bir anomalidir. Bu çalışmada, retrospektif olarak 2009-2013 yılları arasındaki akut lenfoblastik lösemi (ALL) hastalarındaki t(4;11) MLL- AF4 translokasyonunun analiz sonuçlarının incelenmesi amaçlandı. Gereç ve Yöntem: Ege Üniversitesi Tıp Fakültesi Tıbbi Biyoloji Anabilim Dalı’na 2009-2013 yılları arasında akut lösemi ön tanısıyla 176 çocuk (70 kız, 106 erkek) ve 144 yetişkin (60 kadın, 84 erkek) olgunun kan veya kemik iliği örnekleri incelendi. Bu olgulara ait 71 kan ve 473 kemik iliği örneğinin t(4;11) translokasyon RNA sonuçları, gerçek zamanlı RT-PCR yöntemi ile kantitatif olarak değerlendirildi. İlk aşamada, kan ve kemik iliği örneklerinden izole edilen total RNA veya mRNA’dan konvansiyonel bir PCR cihazı ile komplementer DNA sentezlendi. İkinci aşamada, gerçek zamanlı PCR cihazı ile t(4;11) kantitasyonu gerçekleştirildi. Olguların kantitatif olarak değerlendirilmesi, pozitif kontrol ve negatif kontrolün karşılaştırılması ile örneklerin negatif yada pozitif (pozitif olgu kopya sayısının referans kopya sayısına oranı) olması şeklinde yapıldı. Bulgular: Çalışmamızda 98’i takip hastası olmak üzere toplam 320 hasta t(4;11) MLL-AF4 translokasyonu için değerlendirildi. Çalışmaların sonucunda toplam 34 olgu (24 çocuk, 10 yetişkin) pozitif ve diğer örnekler negatif olarak bulundu. Sonuç: Bu değerlendirmenin sonuçları, RT-PCR yöntemi ile ALL hastalarında yeni tanı döneminde ve tedavi sürecinde t(4;11) MLL-AF4 translokasyonunun kantitatif tayini, hem tanının kesinleştirilmesinde hem de moleküler remisyon sağlanmasına yönelik tedaviyi yönlendirmesinde değerli bir yöntem olduğunu desteklemektedir., Aim: t(4,11) is a chromosomal abnormality formed by the translocation MLL-AF4, which is the result of the fusion of the AF4 gene, localized on 4q21 chromosomal band, to the MLL gene, localized on 11q23 chromosomal band. The aim of this study is to examine the results of the analysis of t (4;11) MLL-AF4 translocation in acute lymphoblastic leukemia (ALL) patients retrospectively. Materials and Methods: Peripheral blood or bone marrow samples of 176 children (70 girls, 106 boys) and 144 adults (60 women, 84 men) with a preliminary diagnosis of acute leukemia between 2009-2013 were analyzed in the Medical Biology Department of Ege University Faculty of Medicine. The translocation RNA results of 71 peripheral blood and 473 bone marrow samples of these patients were evaluated quantitatively for t(4;11) with real-time RT- PCR. t(4;11) quantitation was performed by real-time qRT-PCR instrument after the synthesis of complementary DNA with conventional PCR from total RNA or mRNA isolated from blood and bone marrow. Quantitative analysis of the patients was performed by comparing positive and negative controls and samples classified as positive or negative (the ratio of the number of positive copies to the number of reference copies). Results: A total of 320 patients, with 98 having also follow-ups, were evaluated for t(4;11) translocation. Totally 34 patients (24 children and 10 adults) were found positive and the other samples were negative. Conclusion: The assessment of these results supports that, quantitative determination of t(4;11) with RT-PCR method among newly diagnosed ALL patients and ALL patients undergoing treatment, is a valuable method for both confirming the diagnosis and guiding the treatment intended to achieve molecular remission.

In this study, the biological potential of a nickel chlorophyll derivative (Ni-PH-A) as a multimodal agent for tumor imaging and photodynamic therapy (PDT) was investigated. Optimum conditions of labeling with I-131 were investigated and determined as pH 10 and 1 mg amount of iodogen. Biodistribution results of I-131 labeled Ni-PH-A in female rats indicated that radiolabeled Ni-PH-A maximum uptake in the liver, spleen and ovary was observed at 30 min. Intercellular uptake and PDT efficacy of Ni-PH-A were better in MDAH-2774 (human ovarian endometrioid adenocarcinoma) than in MCF-7 (human breast adenocarcinoma) cells. Ni-PH-A might be a promising multimodal agent for lung, ovary and liver tumor imaging and PDT.

Amac: Bu calismada, Ege Universitesi Tip Fakultesi Tibbi Biyoloji Anabilim Dali'na 2009-2013 yillari arasinda akut myeloid losemi (AML) on tanisi ile basvuran 402 olgunun (322 yetiskin, 80 cocuk) kan veya kemik iligi orneklerinin inv16 kantitasyon analizlerinin RT-PCR yontemi ile degerlendirilmesi amaclandi. Gerec ve Yontem: Hastalardan alinan kan ve kemik iligi orneklerinden total RNA/mRNA izolasyonunu takiben cDNA'lari elde edilerek revers-transkriptaz-polimeraz zincir reaksiyonu (RT-PCR) yontemiyle inv16 kantitasyonu LightCycler2 cihazinda gerceklestirildi. Bulgular: Dort yuz iki olgu, inv(16) CBFBETA-MYH11 inversiyonu acisindan degerlendirildi. Yapilan analiz sonucunda 12 (% 4) eriskin ve 7 (% 9) cocuk olmak uzere toplam 19 olguda inv16 pozitifligi saptandi. Sonuc: Inv16 kantitatif analizi, AML hastalarinin klinik degerlendirilmesinde, hastaligin seyri ve remisyon saglanmasina yonelik tedavi protokollerinin uygulanmasinda etkili bir yontem oldugunu desteklemektedir. AML hasta grubunu iceren daha genis kapsamli calismalar yapilarak elde edilen sonuclar desteklenmelidir.

Acute myeloid leukemia (AML) is a heterogeneous group of hematopoietic malignancies. Magnet assisted transfection (MATRA) is one of the most effective non-viral transfection methods. We aimed to evaluate the apoptotic effect of resveratrol (RES), MDM2, RUNX3, RB gene expression exchanges and MicroRNA- 150 (miR-150) transfected with MATRA to HL-60 cells. MATRA was used as non-viral vector carrier for miR-150 transfection. IC50 dose of RES was determineted by Fahri et al. Resveratrol and miR-150 transfected cells were performed apoptosis and MDM2, RUNX3, RB gene expression assays in Human promyelocytic leukemia (HL-60) cells. IC50 dose of RES was used as 5 ?M. in HL-60 cells, it was found that miR-150, miR150-Resveratrol combination, resveratrol alone induces apoptosis by 6.48, 6.93 and 4.54 fold, respectively, compared to the control cells. Compared to control cells, MDM2, RUNX3, RB, gene expressions decreased (miR-150) 1.7, 1.3 and 1.4 fold, (miR-150-resveratrol) MDM2 expression increased 2.73 fold, RUNX3 and RB expression decreased 6.1, 1.07 fold, respectively. Combination with resveratrol, MDM2, RB decreased 2.9 and 1.4 fold, respectively. Non-viral miR-150 transfection may be effective in leukemia cells, induction of apoptotic effects and gene expression changes, following treatment with resveratrol and miR-150-resveratrol combinations., Akut myeloid lösemi (AML), hematopoetik malignitelerin heterojen bir grubudur. “Magnet assisted transfection” (MATRA), non-viral transfeksiyon metodlarında oldukça etkilidir. Çalışmamızda; İnsan promiyelositik lösemi (HL-60) hücrelerine MATRA ile MicroRNA150 (miR-150) transfekte edilip; MDM2,RUNX3,RB gen ekspresyon değişimleri ve resveratrolün apoptotik etkisini değerlendirmeyi amaçladık. MATRA, miR-150 transfeksiyonu için non-viral taşıyıcı olarak kullanılmıştır. Hl-60 hücrelerinde Resveratrolün IC50 dozu, Fahri et al tarafından saptanmıştır. Resveratrol ve miR-150 ile transfekte edilmiş HL-60 hücrelerinde apoptoz ve MDM2, RUNX3, RB gen ekspresyon analizleri yapıldı. HL-60 hücrelerinde Resveratrolün IC50 dozu, 5 µM olarak saptandı. kontrol hücreleriyle karşılaştırıldığında; HL-60 hücrelerinde sırasıyla; miR-150, miR150-Resveratrol kombinasyonu, resveratrolün tek başına apoptozu 6.48, 6.93 ve 4.54 kat indüklediği tespit edilmiştir. Kontrol hücrelerine göre miR-150 tranfeksiyonu yapılanlarda MDM2, RUNX3, RB gen expresyonlarının sırasıyla 1.7, 1.3 ve 1.4 kat azaldığı; miR-150-resveratrol kombinasyonlarında ise MDM2 ekspresyonu 2.73 kat artmış; RUNX3 ve RB ekspresyonları sırasıyla; 6.1, 1.07 kat azalmıştır. Resveratrol ile kombinasyonda MDM2, RB sırasıyla 2.9 ve 1.4 kat azalmıştır. miR-150- resveratrol ve resveratrol kombinasyonları ile tedaviyi takiben gen ekspresyon değişimleri ve apoptotik etkiyi indüklemeleri; non-viral miR-150 transfeksiyonunun lösemi hücrelerinde etkili olabileceğini göstermektedir.

WOS: 000414115100021, PubMed ID: 28942039, BCR-ABL tyrosine kinase inhibitors (TKIs) are selective therapies for the patients with Chronic Myeloid Leukemia (CML). Imatinib and ponatinib have remarkable long-term efficacy on a major molecular response. Although TKI related induction of cytotoxicity and apoptosis have been clearly investigated in molecular levels, their comparative effect on autophagy and miRNome are largely unknown. This study aimed to investigate the involvement of alterations of miRNA expressions in CML progression, and how imatinib and ponatinib affect this process, by comparing CML, imatinib-resistant CML and leukemia stem cells (LSC). Cytotoxicity analysis was conducted by WST-1, apoptosis was evaluated by AnnexinV, autophagy was analyzed by Tb/GFP TR-FRET LC3B assay and changes in miRNomes were evaluated with microarray method. Ponatinib showed higher cytotoxicity and apoptosis at far fewer concentrations than imatinib. Both imatinib and ponatinib was able to trigger autophagy in imatinib-resistant K562ima3 cell line but not in LSC. We pointed that imatinib and ponatinib caused significant miRNA profile alterations, especially in the expressions of miR-214-pre, miR-218, miR-19a-5p, miR-19b-1-5p, miR-27b-pre, miR-23b-pre, miR-320e, miR-200a-pre, miR-508-3p, miR-33-pre and miR-766. This study is the first comparative miRNome analysis of CML, resistant CML and LSCs following the imatinib or ponatinib treatment and may guide to identify new markers for diagnosis, follow-up of the disease and to develop novel therapeutic strategies if supported by preclinical studies., Ege University Research Projects (APAK)Ege University [APAK 12-TIP-017], This study is supported by Ege University Research Projects (APAK) within the scope of the project numbered APAK 12-TIP-017.

Breast cancer is one of the most common malignancies in women and metastasis is the cause of morbidity and mortality in patients. In the development of metastasis, the matrix metalloproteinase (MMP) family has a very important role in tumor development. MMP-2 and MMP-9 work together for extracellular matrix (ECM) cleavage to increase migration. Tomatine is a secondary metabolite that has a natural defense role against plants, fungi, viruses and bacteria that are synthesized from tomato. In addition, tomatine is also known that it breaks down the cell membrane and is a strong inhibitor in human cancer cells. In this study, it was aimed to evaluate the effect of tomatine on cytotoxicity, apoptosis and matrix metalloproteinase inhibition in MCF-7 cell lines. Human breast cancer cell line (MCF-7) was used as a cell line. In MCF-7 cells, the IC50 dose of tomatine was determined to be 7.07μM. According to the control cells, apoptosis increased 3.4 fold in 48thh. Activation of MMP-2, MMP-9 and MMP-9\NGAL has been shown to decrease significantly in cells treated with tomatine by gelatin zymography compared to the control. As a result, matrix metalloproteinase activity and cell proliferation were suppressed by tomatine and this may provide support in treatment methods.

Long non coding RNAs (lncRNAs) are associated with various biological roles such as embryogenesis, stem cell biology, cellular development and present specific tissue expression profiles. Aberrant expression of lncRNAs are thought to play a critical role in the progression and development of various cancer types, including gliomas. Glioblastomas (GBM) are common and malignant primary brain tumours. Brain cancer stem cells (BCSC) are isolated from both low and high-grade tumours in adults and children, by cell fraction which express neuronal stem cell surface marker CD133. The purpose of this study was to investigate the expression profiles of lncRNAs in brain tumour cells and determine its potential biological function. For this purpose, U118MG-U87MG; GBM stem cell series were used. Human parental brain cancer cells were included as the control group; the expressions of disease related human lncRNA profiles were studied by LightCycler 480 real-time PCR. Expression profiles of 83 lncRNA genes were analyzed for a significant dysregulation, compared to the control cells. Among lncRNAs, 51 lncRNA genes down-regulated, while 8 lncRNA genes were up-regulated. PCAT-1 (-2.36), MEG3 (-5.34), HOTAIR (-2.48) lncRNAs showed low expression in glioblastoma compared to the human (parental) brain cancer stem cells, indicating their role as tumour suppressor genes on gliomas. As a result, significant changes for anti-cancer gene expressions were detected with disease-related human lncRNA array plates. Identification of novel target genes may lead to promising developments in human brain cancer treatment.

Background and Objective: Pancreatic cancer is very common and difficult to diagnose in early stage. Imaging systems for diagnosing cancer have many disadvantages. However, combining different imaging modalities offers synergistic advantages. Optical imaging is the most multidirectional and widely used imaging modality in both clinical practice and research. Methods: In present study, Zinc(II) phthalocyanine [Zn(II)Pc] was synthesized, labeled with iodine- 131 and in vitro study was carried out. The intracellular uptake studies of radiolabeled Zn(II)Pc were performed in WI-38 [ATCC CCL-75™, tissue: human fibroblast lung] and MIA PaCa-2 [ATCC CRL-1420™, tissue: human epithelial pancreas carcinoma] cell lines. Results: The intracellular uptake efficiency of radiolabeled Zn(II)Pc in MIA PaCa-2 cells was determined two times higher than WI-38 cells. Also, fluorescence imaging (FI) efficiency of synthesized Zn(II)Pc was investigated in MIA PaCa-2 cells and significant uptake was observed. Conclusion: Zn(II)Pc might be used as a new agent for dual fluorescence/nuclear imaging for pancreatic cancer.

In recent years, the photodynamic therapy studies have gained considerable attention as an alternative method to surgery, chemotherapy and radiotherapy which is commonly used to fight cancer. In this study, biological potentials of a benzyloxy bearing zinc(II) pheophorbide-a (Zn-PH-A) were investigated via in vivo and in vitro experiments. Zn-PH-A was labeled with (131)I with high efficiency (95.3 ± 2.7%) and its biodistribution studies were investigated on female Albino Wistar rats. The radiolabeled photosensitizer had been intravenously injected into the tail vein, and then the animals were sacrificed at 30, 60 and 120 min post injection. The percent of radioactivity per gram of organs (%ID/g) was determined. The radiolabeled Zn-PH-A showed high uptake in ovary. In addition, photodynamic therapy studies of the photosensitizer were conducted in EMT6, murine mammary carcinoma and HeLa, human cervix carcinoma cell lines. For the photodynamic therapy studies, the cells with Zn-PH-A were exposed to red light (650 nm) at the doses of 10-30 J/cm(2). The results showed that Zn-PH-A has stronger PDT effect in EMT6 than HeLa cell. Our present work demonstrates (131)I-labeled photosensitizer as a bifunctional agent (PDT and nuclear imaging) which could be improved in future by using EMT6 growing tumor in nude mice.

Ponatinib (P) has been used for the treatment of chronic myeloid leukemia (CML) and it is known that inhibition of BCR-ABL fusion protein by ponatinib induces apoptosis of CML cells. Epigallocatechin-3-gallate (EGCG), which is a polyphenol in green tea, induces apoptosis in different types of cancer cells. The purpose of this study was to determine the cytotoxic and apoptotic effects of ponatinib and EGCG combination in K562 CML cell line. This study also aimed to detect alterations of the expression levels of cell cycle-regulation related genes after ponatinib and EGCG combination in K562 CML cell line.The cytotoxic effects of the compounds on K562 cells were determined in a time-and dose-dependent manner by using WST-1 analysis. The combination index (CI) isobologram was used to analyze the data. Apoptotic effects of P-EGCG were defined by flow cytometry and gene expressions were detected by RT-qPCR.IC50values of ponatinib and EGCG were 87.13 nM and 50μM, respectively. CI value of the P-EGCG was 0.658 and the combination showed synergistic effect (ED90 value: 28.39 nM ponatinib, 117.12 μg/ml EGCG). Ponatinib, EGCG and P-EGCG induced apoptosis compared to control cells. CyclinD1 and CDC25A were downregulated by P-EGCG by 2.49 and 2.63-fold, respectively. TGF-β2 was upregulated by 4.57-fold.EGCG possesses cytotoxic and apoptotic properties and may cooperate with the growth inhibiting activity of ponatinib synergistically against CML cells. P-EGCG mediated apoptosis might be associated with upregulation of TGF-β2 gene and downregulation of cyclinD1 and CDC25A genes.

The biological potential of a synthetic copper chlorophyll derivative was investigated via in vivo and in vitro experiments. The Cu-chlorophyll derivative photosensitizer (Cu-PH-A) was labeled with 131I with high efficiency (92.9 ± 4.2%) using the iodogen method. Cell culture studies were performed with the MCF-7 and MDAH-2774 cell lines after radiolabeling. The photosensitizing activity of Cu-PH-A was more effective in MDAH-2774 cells than in MCF-7 cells at a concentration of 50 μM. When the biodistribution in female Albino Wistar rats was examined, uptake of the radiolabeled photosensitizer was maximal in the liver and ovaries after 60 min. It is concluded that radiolabeled Cu-chlorophyll derivative photosensitizer has high uptake in ovaries in normal rats. In addition, the intercellular uptake and PDT efficacy of the Cu-PH-A in MDAH-2774 were good compared with MCF-7 cells. This photosensitizer could be useful for both ovary tumour imaging and PDT.

Amaç: Akut promyelösitik lösemi (APL), akut myeloid löseminin (AML) iyi tanımlanmış alt tipidir ve spesifik olarak t(15;17)(q22;q12) translokasyonu ile karakterizedir. t(15;17), 15. kromozom üzerinde bulunan promyelösitik lösemi (PML) ve 17. kromozomda lokalize retinoik asit reseptör alfa (RARA) genlerinin füzyonu sonucu oluşur. Translokasyon varlığı, konvansiyonel sitogenetik, floresan in situ hibridizasyon analizi (FISH) ve sıklıkla gerçek zamanlı kantitatif revers transkriptaz polimeraz zincir reaksiyonu (qRT-PCR) yöntemiyle saptanır. Bu çalışmada, anabilim dalımıza başvuran APL ön tanılı olgulara ait kan ya da kemik iliği materyallerinden t(15;17) translokasyonunun gerçek zamanlı qRT-PCR ile kantitasyonu amaçlanmıştır. Gereç ve Yöntem: Çalışmaya 2009-2013 yılları arasında başvuran 79 çocuk (7.28±5.20 yaş; 45 E, 34 K) ve 359 yetişkin (47.71±15.57 yaş; 193 E, 166 K) olgu dahil edilmiştir. Olguların kan ya da kemik iliği materyallerinden total RNA izolasyonunu takiben cDNA sentezi gerçekleştirilmiştir. Sonrasında, qRT-PCR ile t(15;17) translokasyonu çalışılıp, kantite edilmiştir. Bulgular: Çocuk olgulardan 2'si (%3), toplamda 6 test (%5) t(15;17) için pozitif olarak belirlenmiştir. Bu olgulara ait t(15;17) kantitasyon değeri ortalaması, 0.0002±0.0003’tür. Yetişkin olguların 26'sı (%7), toplamda 30 test (%8) t(15;17) için pozitif olarak belirlenmiştir. Bu olgulara ait t(15;17) kantitasyon değeri ortalaması, 0.067±0,144’tür. Sonuç: qRT-PCR’ın konvensiyonel sitogenetik çalışmalara göre üstünlüğü, tüm çalışma basamaklarının test esnasında eş zamanlı olarak izlenebilmesi ve oluşan amplikonların kantitasyonunun yapılabilmesidir. t(15;17) kalitatif tayininin klinikteki önemi, tanının kesinleştirilmesinde, tüm trans-retinoik asit ve trioksid arsenik tedavisine yanıtın öngörülmesi ve tedavinin yararlılığının bilinmesinde, minimal rezidüel hastalığın (MRH) takibi ve relapsın erken evrede belirlenebilmesidir., Aim: Acute promyelocytic leukemia (APL) is a well-defined subtype of acute myeloid leukemia (AML) specifically characterized by the t(15;17)(q22;q12) translocation. t(15;17) results in the fusion of the genes, promyelocytic leukemia (PML) on chromosome 15 and retinoic acid receptor alpha (RARA) located on 17th chromosome. Translocation is detected by conventional cytogenetic, fluorescence in situ hybridization analyses (FISH) and often a real time quantitative reverse transcriptase polymerase chain reaction (qRT-PCR) method. In this study, quantification of t(15; 17) translocation via real time qRT-PCR was aimed in blood or bone marrow materials belonging to APL pre-diagnosed cases that appealed our department. Materials and Methods: Seventy nine children (7.28 ± 5.20 years; 45 M, 34 F) and 359 adults (47.71 ± 15.57 years; 193 M, 166 F) were included in the study between the years 2009-2013. Following total RNA isolation from blood or bone marrow materials of the cases, cDNA synthesis was carried out. Then, t(15; 17) translocation was studied by qRT-PCR and quantitated. Results: Two cases from children (3%), and in total 6 tests (5%) were detected positive for t(15;17). The average t(15;17) quantification value was 0.0002 ± 0.0003. Twenty six cases of the adults (7%), in total 30 tests (8%) were determined as t(15;17) positive. Average t(15;17) quantification value of these cases was 0.067 ± 0.144. Conclusion: The superiority of qRT-PCR compared to conventional cytogenetic studies can be found in the fact that all working steps can be monitored simultaneously during the test and the resulting amplicons can be quantitated. The clinical significance of t(15;17) qualitative determination is, confirmation of the diagnosis, all trans-retinoic acid and trioxide arsenic treatment response prediction and treatment efficacy knowledge in addition to minimal residual disease (MRD) monitoring and ability to identify relapse at early ages.

54th Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) -- DEC 08-11, 2012 -- Atlanta, GA, WOS: 000314049604329, Amer Soc Hematol (ASH)

54th Annual Meeting and Exposition of the American-Society-of-Hematology (ASH) -- DEC 08-11, 2012 -- Atlanta, GA, WOS: 000314049606110, Amer Soc Hematol (ASH)

WOS: 000370676300102