bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 5452: Cancer-associated metabolite 2-hydroxyglutarate accumulates in AML with IDH1/2 mutations
Authors: Fantin Valeria R. , Gross Stefan , Cairns Rob A. , Minden Mark D. , Driggers Edward M. , Jang Hyun Gyung , Sasaki Masato , Jin Shengfang , Schenkein David P. , Su Shinsan M. , Dang Lenny , Mak Tak W. 
Published: February 2011

Abstract
Mutations in isocitrate dehydrogenase 1 and 2 (IDH1/2), are present in most gliomas and secondary glioblastomas, but are rare in other neoplasms. IDH1/2 mutations are heterozygous, and affect a single arginine residue. Recently, IDH1 mutations were identified in 8% of acute myelogenous leukemia (AML) patients. Our previous study revealed that IDH1 mutations cause a gain of function, resulting in the production and accumulation of 2-hydroxyglutarate (2-HG). Genotyping of 145 AML biopsies identified 11 IDH1 R132 mutant samples. Liquid chromatography-mass spectrometry metabolite screening revealed increased 2-HG levels in IDH1 R132 mutant cells and sera, and uncovered two IDH2 R172K mutations. IDH1/2 mutations were associated with normal karyotypes. Recombinant IDH1 R132C and IDH2 R172K proteins catalyze the novel NADPH -dependent reduction of alpha-ketoglutarate (a-KG) to 2-HG. The IDH1 R132C mutation commonly found in AML reduces the affinity for isocitrate, and increases the affinity for NADPH and a-KG. This prevents the oxidative decarboxylation of isocitrate to a-KG, and facilitates the conversion of a-KG to 2-HG. IDH1/2 mutations confer an enzymatic gain of function that dramatically increases 2-HG in AML. This provides an explanation for the heterozygous acquisition of these mutations during tumorigenesis. 2-HG is a tractable metabolic biomarker of mutant IDH1/2 enzyme activity.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5452.
Abstract 5466: nNOS, a novel target for melanoma prevention and therapy
Authors: Yang Sun , Yang Zhen , Meyskens Frank L. 
Published: February 2011

Abstract
It is well recognized that nitric oxide (NO) is involved in tumor progression, including human melanoma. Our data showed that NO stress by NO donor DETA treatment remarkably stimulated the proliferation of normal primary melanocytes with foci formed in culture and the metastatic capacity of human melanoma cells detected by matrigel invasion assays was also significantly induced with DETA incubation. Our previous mechanistic studies have revealed that NO-induced melanoma progression is mediated by Apurinic/apyrimidinic endonuclease-1/redox factor-1 (APE/Ref-1), which plays an important role in melanomagenesis and development, in a feed-forward loop manner. Both our in vitro cell culture (Immunoblotting) and in vivo human biopsy (Immunohistochemistry) studies have demonstrated the predominant elevations of nNOS expression levels in melanoma cells. Notably, induction of nNOS was evident with UVB radiation and growth factor bFGF treatments. Knockdown of nNOS with siRNA efficiently reduced the DETA-induced melanoma proliferation and invasion potential, and was associated with reductions of many genes that related to proliferation, anti-apoptosis and invasion, such as c-Jun, Bcl-2, and MMP-1. A novel synthesized nNOS inhibitor JI-11 was utilized to inhibit nNOS activity and our data showed that co-treatment of JI-11 at 1uM concentration significantly attenuated the alterations induced by UVB radiation and DETA treatments. MTS analysis also revealed that pretreatment of JI-11 sensitized melanoma cells to chemo-drug Cisplatin. We hypothesize that targeting nNOS/NO to prevent and treat melanoma is innovative and potentially of great benefit.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5466.
Abstract 5467: Breflate upregulates TRAIL gene transcription in Bax-null cells and induces TRAIL-mediated apoptosis independently of p53 in TRAIL-sensitive tumor lines
Authors: Allen Joshua E. , Patel Luv , Krigsfeld Gabriel , Mayes Patrick A. , Wu Gen Sheng , El-Deiry Wafik S. 
Published: February 2011

Abstract
TNF-related apoptosis-inducing ligand (TRAIL) has been hailed as a promising cancer drug target due to its apoptosis-inducing capabilities which are aimed selectively at cancer cells. Methods of inducing endogenous TRAIL as well as introducing exogenous recombinant human TRAIL (rhTRAIL) are being explored in preclinical studies and in the case of the latter, clinical trials. While the gene encoding for DR5, a TRAIL death receptor, has been known to be regulated by p53, we have recently shown that TRAIL is regulated by p53 at base pairs 504-1102 of its promoter (Kuribayashi et al., Cancer Biology and Therapy. 7:2034-2038, 2008). p53 is mutated in over half of all cancers; therefore, a method of upregulating endogenous TRAIL via a mechanism independent of p53 holds great potential therapeutic value for cancer. We searched for small molecule p53-independent upregulators of TRAIL using a luciferase reporter assay which utilized a plasmid with the gene encoding for firefly luciferase under the transcriptional control of the first 504 base pairs of the human TRAIL promoter. Screening with the NCI Diversity Set II library yielded several hits with &gt;2-fold TRAIL induction which were repeated and further analyzed for use as a drug and to gain mechanistic insight. Interestingly, one hit from this screen was breflate, the prodrug of Brefeldin A (BFA). BFA inhibits retrograde protein transport from the Golgi apparatus to the endoplasmic reticulum and is currently being investigated as a cancer therapeutic. Shao et al. (Exp. Cell Res. 227:190-196, 1996) have previously reported that BFA is a potent inducer of apoptosis in some cancer cell lines independently of p53, though the mechanistic relationship was not clear. Breflate clearly increased intracellular levels of TRAIL in HCT116 Bax−/− cells as determined by Western blot analysis, and in addition to the original reporter assay this is being corroborated by reverse transcriptase polymerase chain reaction (RT-PCR). Moreover, sub-G1 analysis found that breflate induced levels of apoptosis &gt;2-fold relative to control levels at 10μM after 24 hours in HCT116 p53−/− cells. Further mechanistic and ongoing in vivo studies are being conducted with breflate alone and in combination with chemotherapy or targeted cancer therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5467.
Abstract 5473: Antiproliferative and antimetastasic activity of a novel vasopressin V2 receptor peptide agonist in a breast cancer model
Authors: Ripoll Giselle V. , Garona Juan , Iannucci Nancy , Orlando Ulises , Cascone Osvaldo , Podestá Ernesto , Gomez Daniel E. , Alonso Daniel F. 
Published: February 2011

Abstract
Desmopressin (1-deamino-8-D-arginine vasopressin) is a synthetic analog of vasopressin with antimetastatic properties. The molecule is a well known and safe hemostatic compound that acts as a selective agonist for the vasopressin V2 membrane receptor, which is expressed in endothelium and also in some tumor cells. Previous data revealed that perioperative administration of desmopressin can minimize the spread and survival of residual cancer cells. This cyclic nonapeptide was substituted in positions 4 and 5 searching for compounds with improved biological activity and half life. Such positions belong to the disulphide loop (between positions 1-6), which have a major interaction with its receptor. In this work, we evaluated the in vitro biological activity of a novel analog designated VQ (1-deamino-4-valine-5-glutamine-8-D-arginine vasopressin) in MCF7 human mammary carcinoma cells, as well as its in vivo antitumor action in combination with chemotherapy using the syngeneic F3II mammary carcinoma model in Balb/c mice. Because V2 receptor signaling has been associated with cytostatic effects, we have examined peptide ability to modify in vitro cell proliferation of MCF7 cells expressing V2 receptor. Incubation with VQ analog (100-1500 nM) during 72 h significantly reduced cell proliferation (p&lt;0.001) showing a better performance than desmopressin at higher doses of 500-1500 nM (p&lt;0.05). Inhibition of cell proliferation was associated with an increase of intracellular cAMP levels and this was correlated with PKA activation in MCF7 cells. A similar antiproliferative profile was obtained with loop tetrapeptides (aminoacid positions 2-5) at low doses (&lt;500 nM), although cytostatic activity of tetrapeptides was lost at high concentrations. Three weekly i.v. doses of VQ (0.3 µg/kg/dose) reduced by 40% the subcutaneous tumor volume in mice implanted with F3II mammary carcinoma cells, while VQ treatment plus weekly i.p. cycles of carmustine (20 mg/kg/cycle) was even more effective (p&lt;0.001). Furthermore, VQ treatment, either in combination or not with carmustine cycles, prevented lung metastatic progression in tumor-bearing mice. VQ also inhibited F3II lung colonization in the experimental metastasis assay. Our results indicate that the novel cyclic peptide analog VQ can exert a remarkable antitumor and antimetastatic effect in a preclinical model of breast carcinoma. Loop conformation of the peptide seems to be essential for interaction with V2 receptor and for the biological activity of the compound.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5473.
Abstract 5479: Glycogen synthase kinase-3 (GSK3) differently targets in MLL leukemia cells
Authors: Hur Eun-Hye , Kim Dae-Young , Kang Mun-Jung , Lee Je-Whan 
Published: February 2011

Abstract
Propose: We evaluated the anti-leukemic effect of GSK3 inhibitor for specific type of MLL-tranlocated cell line.
Materials and methods:
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GSK3 inhibitor: LiCl, SB216763, GSK3-IX
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Cell line: MV4-11 [human lymphoblast, t(4:11)]
MOLM-13 [human acute myeloid leukemia, ins(9:11)(q23;p22p23)]
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Cell proliferation assay: XTT assay, Clonogenic assay
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GSK3i activity & detection of histone acetylation and H3K4 methylation: Immunoblotting
Summary:
MLL gene encodes an enzyme which methylates histone H3 DNA-binding protein and positively regulates the expression of target genes in normal tissue. MLL rearrangement which is found in acute myeloid leukemia (AML), especially therapy-related AML, encodes fusion proteins that have lost H3 lys4-specific (H3K4) methyltransferase activity, and causes a transformation of hematopoietic cells into leukemia stem cells.
GSK3, a serine/threonine kinase, plays a key role in glycogen metabolism and is constitutively expressed in resting cell. Although it has been thought that the inhibition of GSK3 causes apoptosis in neurons and other tissues, a paradoxical and unexpected cell death effect of GSK3 inhibition were reported recently in leukemic cell line with MLL translocation, especially t(4;11).
Regarding the mechanism of the cytotoxic effect of GSK3 inhibitor, various molecules associated with the signaling pathway around MLL gene have been investigated. Acetylation of H3 peptides stimulates the activity of SET domain in MLL. MLL gene is cleaved at 2 conserved sites by taspase-1; N-terminal 320 kD fragment (N320) and a C-terminal 180 kD fragment (C180). RNA interference-mediated knockdown of taspase-1 resulted in an unprocessed MLL, and finally a loss of proper HOX gene expression. However, the exact mechanism has been still unknown and it remains to be uncertain whether GSK3 inhibitor shows cell death effect on various leukemic cell lines of MLL translocation with other partner gene.
We intended to determine whether the inhibition of GSK3 induced cell death in different types of leukemia cell lines with MLL translocation. We examined the apoptotic effects of GSK3 inhibitors on MV4-11 and MOLM-13 cell line. LiCl and GSK3-IX induced cell death, H3K4 methylation and histone acetylation in dose-dependent manners on MV4-11 but did not induce on MOLM-13. However, SB216763 did not induced cell death both cell lines.
Conclusion: Cell death effects with the inhibition of GSK3 may be different among leukemic cell line with MLL translocation according to the partner gene of MLL translocation.
Note: This abstract was not presented at the AACR 101st Annual Meeting 2010 because the presenter was unable to attend.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5479.
Abstract 5483: Targeted intracellular photodynamic therapy (TIP) reduces tumor mass and prolongs survival in a mouse model of cancer
Authors: Luboshitz Galia , Raisa Laptev , Arad-Yellin Rina , Green Bernard G. , Firer Michael A. 
Published: February 2011

Abstract
Targeted Intracellular Photodynamic Therapy (TIP) is a novel advance on traditional photodynamic therapy (PDT) in which photosensitizer activation is afforded by chemiluminescence rather than by laser beam. This advance allows PDT access to target cells essentially anywhere in the body. TIP also has advantages over bioluminescence as there is no need for transfection of cells with enzymes such as luciferase. It can therefore be more easily applied both in vitro and in vivo and has potential as a new targeted cancer therapeutic modality that could be applied to a wide variety of cancers. We have previously described in vitro the efficacy and specificity of TIP toward murine leukemic cells (Brit. J. Cancer, 95; 189-196, 2006). We now report that TIP is effective in vivo using a murine model of cancer.
To target the photosensitizer, Protoporphyrin IX was conjugated to Transferrin (Trnsf-PrP). Balb/c mice were injected subcutaneously with the mouse hybridomas U13.6 or U7.6, both of which overexpress the Transferrin receptor CD71. The use of Trnsf-PrP resulted in rapid uptake of photosensitizer into cells and conjugate was retained for over 48hrs. Animals were treated with TIP by injecting Trnsf-PrP and the chemiluminescent agent Luminol (LM) under reduced light conditions. Experiments were performed whereby different parameters of the system were varied, including: time of treatment initiation after tumor cell inoculation; dose and number of Trnsf-PrP and luminol treatments; and time intervals between treatments. Initial experiments in which TIP was performed at the time of tumor inoculation showed that this procedure completely abolished tumor growth. In subsequent experiments where tumors were palpable before treatment began, various treatment protocols were tested. TIP reduced tumor mass by over 40% and increased survival by 50%. These results demonstrate that TIP is active against cancer cells in vivo and encourages the further development of the modality as a targeted cancer therapy.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5483.
Abstract 5486: Developing homing aptamers for targeted therapy in neuroblastoma
Authors: Barman Jharna , Beckstead Wesley , Song Young , Wei Jun , Metaferia Belhu , Khan Javed 
Published: February 2011

Abstract
Neuroblastoma is the most common extracranial solid tumour in children. It accounts for 7-10% of malignancies in patients younger than 15 years and 15% of childhood oncology deaths. Each year, there are about 650 new cases of neuroblastoma occurring in the US. The survival rate is 70 - 95 % for low stage (stage 1, 2, 3) tumors. Unfortunately more than 50% of the patients present with advanced stage and the overall survival rate is less than 40% (less than 30% of the children over 1 year old) despite current aggressive multimodal therapies. We have reached the maximal tolerated dosage for most of the chemotherapeutic agents currently used to treat neuroblastoma. Therefore, better targeted therapeutic agents are required to reduce the toxicity related to the therapies. To identify specific targeting agents for neuroblastoma cells, we have undertaken nucleic acid based approach, known as aptamers.
Aptamers are short single stranded nucleic acid ligands which can bind specifically to target protein or small molecules because of their unique 3D structures. Low or no immunogenicity together with high specificity makes aptamers potential candidates for therapeutic agents. In our study we have applied Systematic Evolution of Ligands by EXponential Enrichment (SELEX) to isolate RNA aptamers that target neuroblastoma. A modified RNA pool containing a theoretical 109 unique molecules was generated from a synthetic combinatorial library of nucleic acids, by using 2′-F pyrimidine and 2′-OH purine nucleotides in order to increase the stability toward nucleases.
We performed 13 rounds of selection against one of the aggressive stage 4 neuroblastoma cell lines, SK-NA-S. After preliminary analysis we have identified 15 modified RNA sequences and performed binding affinity studies by labeling those sequences with 33P. The apparent dissociation constant (Kd) values are in nanomolar range.
The aptamers with the lowest Kd values are chosen for further study in order to visualize the site of binding as well as to identify the target protein they are binding to. Once a neuroblastoma specific aptamer is verified, it will be evaluated for targeted therapeutics in neroblastoma by conjugating it with the polymerized liposomal nanoparticles containing small molecule drugs.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5486.
Abstract 5492: The effects of whole body hyperthermia on tumor growth by a novel far infrared emitter
Authors: Uemura Hirotsugu , Ushida Hiroshi , Asahi Chiori , Miyazaki Yuka , Yoshikawa Kazuhiro , De Velasco Marco A. 
Published: February 2011

Abstract
Whole body hyperthermia (WBH) has been used alone or as an adjunct to radio- and/or chemotherapy for the treatment of various malignant diseases. The therapeutic effect of WBH in these conditions has been hypothesized to involve direct or indirect activation of the immune system and heat shock proteins (HSPs). In this study, we investigate the effects of hyperthermia in vitro and in vivo using BioRubber (BR, Yamamoto Bio-Technology Inc., Anaheim, CA), a revolutionary far infrared emitter on tumor growth. BR is a pliable state-of-the-art biomaterial that emits FIR in the 4-25μm spectral ranges.
For the in vitro experiments, cell growth assays and cell cycle analysis was performed in a total of twelve different cancer cell lines (HeLa, bladder, prostate and renal) sandwiched between BR. BR had no inhibitory effects on any of the tumor cells grown in vitro.
To determine the effects of BR therapy on tumor and normal tissue in vivo, KU7/GFP-bearing nude mice were housed in cages lined with BR for 28 days. Tumor size and core body temperature were recorded weekly. The core body temperatures of mice exposed to BR increased significantly by 1oC (P&lt;0.05) after 2 weeks of exposure to BR. Although not significant, tumors of mice exposed to BR showed a clear tendency in tumor size reduction. Tumors were collected and anlyzed for histopathology, TUNEL and PCNA immunohistochemical analysis. Proliferation and apoptotic rates in tumors from mice exposed to BR were similar to control mice. Further histopathological analysis showed that BR-exposed tumors had remarkable granulocyte infiltration accompanied by increased necrosis. This suggest that BR exposure was indeed able to induce and sustain mild hyperthermia in vivo with reduced tumor growth. However, no direct inhibitory on the tumor cells resulted form BR-induced hyperthermia but rather appeared to have been an indirect effect of immuno-stimulation achieved from sustained WBH.
To further investigate the immunological component of hyperthermia-induced immune response, a syngeneic tumor model was carried out using mouse RENCA cells in immunocompetent and immunodeficient mice. Similar tumor growth inhibitory effects were seen in both immunocompetent and immunodeficient mice thus suggesting an innate immune response as a result of sustained WBH.
Together, these data suggest that BR may be a promising biomaterial in for use hyperthermia therapy: however, more research has to be conducted to elucidate the specific mechanisms involved in immuno-stimulation and whether the effects from BR-induced hyperthermia can be maximized with combination therapies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5492.