bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4342: The allosteric Akt inhibitor MK-2206 inhibits neuroblastoma tumor cell growth in vitro and in vivo
Authors: Li Zhijie , Ramalingam Sridevi , Yan Shuang , Thiele Carol J. 
Published: June 2012

Abstract
Background: Activated Akt in tumor tissue of NB patients is a marker of decreased event-free as well as overall survival. Our studies indicate activated Akt induces chemoresistance in NB cells and chemoresistance is a major problem in the treatment of Neuroblastoma (NB). The allosteric Akt inhibitor, MK-2206 inhibits the activation of the 3 Akt isoforms with IC50-Akt1 = 5.3nM, -Akt2 = 12nM and -Akt3 = 65nM. In this study we tested the effects of MK-2206 in vitro and in vivo pre-clinical models of NB.
Methods: NB cell lines (NGP, SY5Y, KCNR, BE2, SKNFI, and AS) were treated with increasing concentrations of MK-2206 for 48 hours. MK-2206-induced cell death was evaluated by MTS assay. Phosphorylated Akt and its downstream target S6 were determined by Western Blot analysis. The effect of MK-2206 (100 or 200mg/kg/3 days/wk) on NB tumor growth was evaluated in a xenograft nude mouse model.
Results: NB cell lines express all 3 Akt isoforms to varying levels. In in vitro studies, MK-2206 inhibited cell growth in all NB cell lines although with different sensitivities. The growth of NGP, SY5Y, KCNR and BE2 cells were more sensitive to MK-2206, with IC50&lt;4μM; while the growth of AS and SKNFI were less sensitive, with IC50&gt;11μM. MK-2206 treatment decreased phosphorylated-Akt and its target phosphorylated-S6 in NB cells to a comparable level in all tested cell lines regardless of biologic sensitivity to MK-2206. In in vivo studies, mice bearing the sensitive BE2 NB tumors were treated with MK-2206 (100 or 200mg/kg) while mice bearing the less sensitive AS tumors received MK-2206 (200mg/kg). There was an approx. 30% inhibition of tumor growth in each tumor model only in mice treated with 200mg/kg MK-2206 (P&lt;0.01). MK-2206 (200mg/kg) treatment led to a comparable increase in survival in both models (P&lt;0.01).
Conclusion: This study indicates that despite differences in in vitro growth sensitivities, the Akt inhibitor, MK-2206 has a comparable anti-tumor cell growth inhibiting activity in vivo. This study supports the future evaluation of the combination of MK-2206 with chemotherapeutic drugs to improve the treatment efficacy in NB.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4342. doi:10.1158/1538-7445.AM2011-4342
Abstract 4347: Anaplastic lymphoma kinase (ALK) expression is an independent prognostic factor in neuroblastoma patients and correlates well with ALK inhibitor response in vitro
Authors: Duijkers Floor A.M. , Gaal Jose , Meijerink Jules P.P. , Admiraal Pieter , Pieters Rob , de Krijger Ronald R. , van Noesel Max M. 
Published: June 2012

Abstract
Introduction: ALK mutations are one of the most common genetic aberrations occurring in 3-11% of the neuroblastoma (NBL) patients and are considered oncogenic. We determined the role of ALK protein levels on survival of NBL patients. Secondly, we tested in vitro responsiveness to ALK inhibitors in NBL cell lines with and without ALK mutation.
Results: Formalin-Fixed, Paraffin-Embedded material of 71 NBL, 12 ganglioneuroblastoma (GNBL) and 20 ganglioneuroma (GN) patients was stained for total ALK protein by immunohistochemistry (IHC). The percentage of ALK positive cells in IHC was stratified in 4 Ccategories; Category 1 (n=40): &lt; 20% ALK-positive cells, category 2 (n=25): 20-50% ALK positive cells, category 3 (n=25): 50-75% ALK positive cells, and category 4 (n=13): 75-100% ALK positive cells. These categories correlate significantly with overall survival in the spectrum of NBL, GNBL and GN (p=0.002, Logrank test). ALK mutations were identified in 2/63 NBL (3.2%) and 2/11 GNBL (18.2%) patients by sequencing. Importantly, in NBL and GNBL patients, ALK protein expression remains a significant factor in a multivariate model (Cox Proportional Hazard model) including the COG risk stratification (p&lt;0.000), which encompasses stage and NMYC status (see table).
Further, we studied the role of ALK levels in the response to ALK inhibitors in vitro in NBL cell lines. ALK inhibitor response (TAE684) correlates well with ALK protein levels (r=−0.813, p=0.001). ALK point mutated cell lines show higher ALK levels and a better ALK inhibitor response (LC50 values 14.9 fold lower, p=0.004) than WT and amplified cell lines.
In conclusion: ALK protein expression is an independent predictor of overall survival in NBL patients and ALK inhibitor response in vitro. ICH staining with ALK antibody is reliable and correlates well with prognosis.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4347. doi:10.1158/1538-7445.AM2011-4347
Abstract 4349: The tumor suppressor WTX is inactivated in a subset of pediatric tumors
Authors: Akhavanfard Sara , Rivera Miguel N. , Dias-Santagata Dora C. , Vargas Sara O. , Pomeroy Scott , Haber Daniel A. , Iafrate A. John 
Published: June 2012

Abstract
WTX is a recently identified tumor suppressor gene that is expressed during embryonic kidney development and that is inactivated by deletions and truncations in approximately 30% of Wilms tumors, the most common pediatric kidney cancer. Initial functional studies point to a role for this gene in Wnt signaling and WT1 mediated transcription. Given that WTX is also present in a variety of other tissues during development, we tested for potential involvement of WTX in other pediatric tumors. 25 hepatoblastomas, 87 rhabdomyosarcomas, 11 adrenocortical carcinomas, 15 pleuropulmonary blastomas, 30 neuroblastomas and 30 medulloblastomas were tested by 3 color- fluorescence in situ hybridization (FISH) with probes corresponding to WTX (Xq11.1) and two flanking control sites. Discrete WTX deletions were identified in two cases, one hepatoblastoma and one rhabdomyosarcoma, and not in matched control tissues. Direct sequencing of the full WTX open reading frame in 24 hepatoblastomas, 27 rhabdomyosarcomas and 11 adrenocortical carcinomas did not reveal point mutations in these tumor types. CTNNB1 exon 3 mutations, which are present in Wilms tumor but generally do not overlap with WTX inactivation, were detected in 8 of 25 hepatoblastomas but not in the tumor with a WTX deletion. Our results indicate that WTX inactivation is a genetic event that occurs in other pediatric malignancies, albeit at a lower frequency than in Wilms tumors. Notably, tumors with evidence of WTX inactivation, Wilms tumor, hepatoblastoma and rhabdomyosarcoma, constitute a subset of pediatric tumors that are linked to abnormalities of the IGF2 locus on 11p15 in the Beckwith-Wiedemann overgrowth syndrome. Finally, the high frequency of WTX inactivation in Wilms tumors compared to other pediatric malignancies, points to the specificity of the connection between WTX and the kidney developmental pathways that are dysregulated in this disease.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4349. doi:10.1158/1538-7445.AM2011-4349
Abstract 4353: Primary sarcoma of the liver and biliary tract in children: Results for the International Society of Paediatric Oncology (SIOP) studies MMT 84, MMT89 and MMT95
Authors: van Noesel Max M. , Mulder Willemijn , Rey Annie , Kelsey Anna , Stevens Michael C.G. , Martelli Hélène , Oberlin Odile 
Published: June 2012

Abstract
Purpose: Sarcomas of the liver (SL) are mostly Undifferentiated Embryonal Sarcoma of the Liver (UESL), or RMS. Sarcoma of the biliary tract (SBT) are usually botryoid or embryonal RMS. The prognosis is not well known. The value of common prognostic factors, (histology, tumor size, age, IRS grouping, chemotherapy) have only been described in case reports or very limited series.
Patients and Methods: Here, we analyzed outcome and modality of relapse for patients under 18 years of age with nonmetastatic SL and SBT of the prospective SIOP Malignant Mesenchymal Tumors studies (MMT 84, 89 and 95). MMT studies are based on IVA (Ifosfamide, vincristine, actinomycin-D) and local surgery and/or radiotherapy.
Results: The MMT studies (1984-2003) included 1554 sarcoma patients, of which 39 SL (11 RMS and 28 UESL) and 8 SBT, total 47 (3%). The median age was 6.3 years, M:F=39:10. The 5 years OS and EFS were 80%, not significantly different in RMS vs. UESL, or liver vs. biliary tract. Pre-surgical T1 vs. T2 tumors were significantly different in prognosis (5-yrs EFS 85 % vs. 62 %, resp.; p=0.03), but this was non-significantly different in the post surgical IRS staging (group I, II vs. III; p=0.08). Age at diagnosis, tumor size or histology, and treatment protocol were none significantly related to outcome. Complete remission (CR) was achieved in 45/47of the patients (96%), 7/47 (15%) after primary surgery, 3/47 after chemotherapy, 31/45 after surgery and chemo, 4/47 after chemo, radiotherapy and surgery, In 22 second, delayed surgery was performed, 21/22 achieved CR. Relapsed patients (11/47; 23%) did not survive. The effect of chemotherapy was no different between studies (MMT 84, 89, 95).
Conclusion: In the SIOP MMT studies, an IVA based chemotherapy combined with local treatment resulted in a favorable outcome for sarcomas of the liver and bile duct.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4353. doi:10.1158/1538-7445.AM2011-4353
Abstract 4354: Mesenchymal stem cells loaded with paclitaxel inhibit tumor growth and angiogenesis
Authors: Alessandri Giulio , Bonomi Arianna , Coccè Valentina , Cavicchini Loredana , Invernici Gloria , Cristini Silvia , Sisto Francesca , Ferrari Maura , Ciusani Emilio , Cappelletti Graziella , Cartelli Daniele , Parati Eugenio , Pessina Augusto 
Published: June 2012

Abstract
Background: Mesenchymal stem cells (MSCs) may represent an ideal candidate to deliver anti-cancer drugs. In a previous study, we demonstrated that simple exposure of bone marrow (BM) derived MSCs to high doses of Doxorubicin, led them to acquire anti-proliferative potential towards co-cultured haematopoitic stem cells (HSCs). We thus hypothesized whether MSCs, once primed in vitro with anti-cancer drugs and then localized near cancer cells, can inhibit proliferation. Methods: Paclitaxel (PTX) was used to prime culture of mouse and human MSCs. Incorporation of PTX into MSCs (MSCsPTX) was studied by using FICT-labelled-PTX and analyzed by FACS and confocal microscopy. Release of PTX in culture medium by MSCsPTX was investigated by HPLC. Culture of Endothelial cells (ECs) and aorta ring assay were used to test the anti-angiogenic activity of MSCsPTX, while anti-tumor activity was tested in vitro on the proliferation of different tumor cell lines and in vivo by co-transplanting MSCsPTX with cancer cells in mice.
Results: MSCs were able to rapidly incorporate PTX and could slowly release PTX in the culture medium in a time dependent manner. Primed MSCsPTX acquired a potent anti-tumor and anti-angiogenic activity in vitro that was dose dependent, and demonstrable by using their conditioned medium or by co-culture assay. Finally, MSCsPTX co-injected in immunodeficient mice with DU145 and B16 cancer cells, significantly delayed tumor takes and reduced tumor growth.
Conclusions: These data demonstrate that, without any genetic manipulation, MSCs can uptake and subsequently slowly release PTX, becoming a potential new tool for cancer therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4354. doi:10.1158/1538-7445.AM2011-4354
Abstract 4355: Metformin potentiates the efficacy of radiotherapy of tumors by eliminating cancer stem cells
Authors: Choi Bo-Hwa , Lee Hyemi , Park Moon-Taek , Oh Eun-Taex , Song Min-Jeong , Song Chang Won , Park Heon Joo 
Published: June 2012

Abstract
Metformin, a widely used drug for type II diabetes, possess significant anti-cancer property. In a recent study, metformin was able to selectively kill chemoresistant cancer stem cells (CSCs). It has been known that CSCs are resistant to irradiation and, thus, they are responsible for the recurrence of cancer after radiotherapy. The purpose of the present study was to investigate whether metformin enhances the response of tumors to radiotherapy by eradicating radioresistant CSCs. An incubation with metformin at 0.1 mM – 10 mM for 72 hours caused clonogenic cell death in a dose-dependent manner in MCF-7 human breast cancer cells, MIA PaCa-2 human pancreatic cancer cells, and FSaII mouse fibrosarcoma cells. In addition, the clonogenic cell death was enhanced by using the combination of metformin and irradiation. We then investigated the effect of metformin on CSCs of the three cell lines, which were identified by ALDH-1 activity, CD24low/CD44+ expression, and SP method. Metformin was preferentially cytotoxic to CSCs in all these cell lines. The formation of mammospheres from MCF-7 cells was also markedly inhibited by metformin. Both metformin and irradiation activated AMPK and suppressed the mTOR-S6K signaling pathway. Combined treatment of cells with metformin and irradiation was far more effective in activating AMPK and suppressing the mTOR-S6K pathway. The combined effects of metformin and X-irradiation on the growth of FSaII tumors induced in the hind legs of C3H mice were studied. Metformin treatment at 50 – 100 mg/kg/day, i.p., slightly suppressed the tumor growth, but it strikely potentiated the response of tumors to 20 Gy X-irradiation in a single exposure. It was likely that metformin treatment depleted the radioresistant CSCs in the tumors, thereby markedly enhancing the response of tumors to irradiation. However, in addition to killing CSCs, the possibility that metformin radiosensitized CSCs as well as non-CSCs could not be excluded. Our results demonstrated for the first time that metformin is potentially useful for enhancing the efficacy of radiotherapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4355. doi:10.1158/1538-7445.AM2011-4355
Abstract 4356: Combination use of anti-CD133 antibody and SSA lectin can effectively enrich cells with high tumorigenicity
Authors: Okudo Kumiko , Moriwaki Kenta , Haraguchi Naotsugu , Takeishi Shunsaku , Tanemura Masahiro , Mori Masaki , Miyoshi Eiji 
Published: June 2012

Abstract
A growing body of evidence has suggested that tumors are frequently composed of heterogeneous cell types, and that tumor initiation and growth are driven by a small subset of cells, termed cancer stem cells (CSCs) or tumor-initiating cells. CSCs can self-renew and also give rise to more differentiated progeny that comprise the bulk of a tumor. Glycans exhibit characteristic changes in their structures during development and thus have been used as markers for stem/progenitor cells. However, the glycan structures unique to CSCs have remained unknown. In this study, we examined glycan structures in CD133+CD13+ CSCs, which were recently found to have a high CSC ability, by means of lectin microarray. Seven sialylated glycan-recognizing lectins, MAL-I, SNA, SSA, TJA-I, ACG, ABA, and MAH, showed higher affinity to CD133+CD13+ CSCs than CD133+ cells with a lower CSC ability. In addition, we demonstrated that CD133+SSA+ cells isolated from Huh7 cells had a significantly higher ability to form tumors in NOD/SCID mice and spheres under serum-free conditions than CD133+SSA- cells. These results suggest that hepatic CSCs highly express sialylated glycans and that SSA lectin can be used as a tool for isolating CSCs. This study is the first report to demonstrate the characteristic glycan structures in CSCs and to indicate a new methodology involving lectins for isolating CSCs.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4356. doi:10.1158/1538-7445.AM2011-4356
Abstract 4360: Distinct energy metabolism in human pluripotent stem cells and differentiated cells regulated by UCP2
Authors: Zhang JIin , Khvorostov Ivan , Hong Jason , Oktay Yavuz , Vergnes Laurent , Nuebel Esther , Do Anna , Jung Hea-Jin , McCaffery Michael , Reue Karen , Koehler Carla , Teitell Michael 
Published: June 2012

Abstract
It has been assumed, based largely on morphologic evidence, that human pluripotent stem cells (hPSCs) contain underdeveloped, bioenergetically inactive mitochondria. In contrast, differentiated cells harbor a fused, branching mitochondrial network, with oxidative phosphorylation (OXPHOS) as the main energy source. A role for mitochondria in hPSC bioenergetics therefore remains uncertain. Here we show that hPSCs have functional respiratory complexes that consume O2 at maximal capacity. Despite this, ATP generation in hPSCs is mainly by glycolysis. To help maintain hPSC mitochondrial membrane potential, cell proliferation, and viability, glycolytic ATP is hydrolyzed by the mitochondrial F1F0ATP synthase. Uncoupling protein 2 (UCP2) regulates this unique pattern of hPSC energy metabolism while suppressing reactive oxygen species. Upon differentiation, UCP2 is repressed and cells shift from glycolysis and fatty acid oxidation to glucose oxidation dependency. Ectopic UCP2 expression during differentiation blocks this metabolic transition and blocks proper embryoid body formation. Combined, our data show that hPSC have distinct bioenergetics regulated by UCP2 and repression of UCP2 is required for metabolic reprogramming along differentiation
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4360. doi:10.1158/1538-7445.AM2011-4360
Abstract 4361: The enzymatic activity of aldehyde dehydrogenases 1A2 and 2 (ALDH1A2 and ALDH2) is detected by aldefluor, inhibited by diethylaminobenzaldehyde and has significant effects on cell proliferation and drug resistance
Authors: Moreb Jan S. , Ucar Deniz , Han Shuhong , Ostmark Blanca , Chang Lung-Ji 
Published: June 2012

Abstract
With the cancer stem cell theory, there has been an invigorated new interest in using ALDH activity as one marker for stem cells and such use became popular since a flow cytometry based assay, aldeflour staining, has become available. Diethylaminobenzaldehyde (DEAB), used in the aldeflour assay, has been published many years ago as a specific inhibitor for ALDH1 isoform. In this study, we explore the effects of specific ALDH isozymes, ALDH1A2 and ALDH2, and the specificity of DEAB as an inhibitor of their activity. We prepared lentiviral vectors containing the full length of either ALDH2 or ALDH1A2 cDNA and used them to over express the enzymes in K562 leukemia and H1299 lung cancer cell lines. Successful expression was measured by spectrophotometric ALDH activity assay, Western blot analysis, RT-PCR, as well as aldeflour staining assay. In addition, gene expression profiles were assessed by quantitative real-time RT-PCR using micro fluidic cards (Taqman Low Density Arrays, TLDA, Applied Biosystem), covering 19 ALDH and three housekeeping genes. The expression levels were compared between sorted K562 with high versus low ALDH activity. The results show that we created 4 cell lines with successful high expression of each of the two enzymes and high ALDH activity which was detected by aldefluor assay. Both cell lines, with either ALDH1A2 or ALDH2, exhibited higher cell proliferation rates, higher clonal efficiency, and increased drug resistance to 4-HC and doxorubicin. In order to study the specificity of two known ALDH activity inhibitors, DEAB and tetraethylthiuram disulfide (disulfiram), we incubated each cell line with either inhibitor at 25 μM for 48 hr and then measured the remaining ALDH enzymatic activity. Our results show that both inhibitors reduced ALDH activity of both overexpressed isozymes, ALDH2 and ALDH1A2, by 70-80%. TLDA analysis revealed that K562 cells express high levels of isozymes in the ALDH1, ALDH3, ALDH7 and ALDH8 families. We conclude that DEAB is not a specific inhibitor for ALDH1A1 and that aldefluor assay is not specific assay for ALDH1A1 either. In addition, other ALDH isozymes seem to play a major role in the biology and drug resistance of various malignant cells.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4361. doi:10.1158/1538-7445.AM2011-4361