bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1386: A novel approach to develop anti-VEGFR2/KDR therapeutics: characterizing and targeting the G-quadruplex
Authors: Gaerig Vanessa C. , Fortin Jessica S. , Brown Robert V. , Brooks Tracy A. 
Published: February 2011

Abstract
The anti-angiogenic approach is traditionally considered for solid malignancies, but increasing evidence has also highlighted its involvement in the progression of hematological oncologies. Angiogenesis, including expression of key proteins, is aberrant in blood cancers such as leukemias, lymphomas, and myelomas, in addition to many solid malignancies, including pancreatic cancer. The most critical mediator of oncogenic angiogenesis is vascular endothelial growth factor (VEGF), which is recognized by two high-affinity receptor tyrosine kinases, VEGFR1 and VEGFR2 (KDR gene). VEGFR2 is necessary for the survival, growth, and differentiation of endothelial cells as its downstream effects include activation of the MAPK and the PI3K pathways, and its upregulation is observed under conditions of pathological angiogenesis. While VEGF/VEGFR2 signaling is known to act in a paracrine manner on endothelial cells, autocrine signaling has been observed in both malignant cells and hematopoietic stem cells. For endothelial and hematological malignancies, both autocrine and paracrine pathways can be targeted with anti-VEGFR2 therapies, potentially doubling the clinical efficacy. Intriguingly, the promoter region of KDR contains a GC-rich region of DNA within its the core promoter located −120 to −31 basepairs (bp) upstream of the transcriptional start site (TSS), putatively able to form several G-quadruplexes. These are unique DNA secondary structures that often serve as transcriptional silencer elements. In the present study, G-quadruplex formation has been isolated −80 to −38 bp upstream of the TSS, which contains five strings of guanines that form a mixed parallel/anti-parallel G-quadruplex, as determined by circular dichroism. The cleavage pattern of DMS footprinting and the major stop product of the polymerase stop assay confirmed that the dominant isoform is a parallel G-quadruplex occurring within the four 3’ runs of guanines. Mutant studies were performed to further determine guanines integral to G-quadruplex formation. An electrophoretic mobility shift assay was used to confirm the formation of a biologically relevant intramolecular structure. High-throughput screening identified a novel KDR-interactive agent, NSC643735, which thermally stabilized the G-quadruplex. This compound is currently being tested in vitro, and has high potential to transcriptionally downregulate KDR mRNA and, subsequently, VEGFR2 protein. These data characterizing the formation of a unique secondary structure in an important oncogene are promising to develop novel and specific anti-KDR therapy for the treatment of hematological and solid malignancies.
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 1386.
Abstract 1398: Aurora kinase A inhibition with MLN8054 radiosensitizes prostate cancer by inducing cell cycle arrest leading to increased prolonged DNA damage and apoptosis
Authors: Schleicher Stephen M. , Moretti Luigi , Hwang Misun , Kopsombut Prapaporn , Kim Kwang Woon , Spratt Daniel , Jaboin Jerry , Lu Bo 
Published: February 2011

Abstract
The purpose of this study is to investigate a potential new radioenhancer for the treatment of prostate cancer. Despite multiple promising treatment modalities, prostate cancer remains a significant cause of diminished quality of life and cancer death, indicating the need for more aggressive, targeted therapy. Aurora kinase A (AURKA) is a promising treatment target, but its inhibition has never been investigated in combination with radiotherapy in prostate cancer. Using the selective AURKA inhibitor, MLN8054, we performed clonogenic assay to investigate in vitro radiosensitization, cell cycle analysis to observe changes induced by AURKA inhibition, tumor growth delay to study in vivo effects, and histologic active caspase staining to measure apoptosis. We demonstrated radiosensitizing effects in vitro in PC3 and DU145 prostate cancer cell lines, which was confirmed in vivo by tumor growth delay in PC3 xenografts in nude mice. In addition, we investigated a potential mechanism for radiosensitization. We report that MLN8054 induces cell cycle arrest at G2/M and polyploidy in both prostate cancer cell lines, which is associated with sustained DNA damage from radiation as seen by increased immunofluorescence for γ-H2AX, a measure of DNA double-strand breaks. Staining for caspase-3 in xenograft samples showed increased apoptosis in irradiated samples pre-treated with MLN8054 compared to irradiation or inhibitor alone. Our findings support the potential use of AURKA inhibition with MLN8054 to enhance the effectiveness of radiation therapy for the treatment of prostate cancer, and suggest a potential mechanism underlying its radiosensitization effects.
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 1398.
Abstract 1400: Mitigation of radiation-induced injury with the nitric oxide synthase co-factor, tetrahydrobiopterin
Authors: Wang Jing , Lin Peck-Sun , Mikkelsen Ross B. , Gewirtz David , Anscher Mitchell S. , Graves Paul R. 
Published: February 2011

Abstract
The purpose of this study was to determine the effect of modulation of the nitric oxide (NO) and the cGMP/PKG signaling pathway on radiation-induced myofibroblast differentiation and radiation-induced injury in mice. Nitric oxide (NO) is a diverse second messenger critical for a variety of cell functions produced by nitric oxide synthases (NOS). NOS activity is regulated in part by the availability of co-factors including tetrahydrobiopterin (BH4). In the absence of BH4, NOS can become ‘uncoupled’ to produce superoxide anion which upon reaction with NO can form peroxynitrite, a highly reactive molecule known to contribute to protein tyrosine nitration. BH4 is approved for human consumption and therefore may represent a safe, viable strategy to reduce tissue injury from radiation. We show here that BH4 administration to mice prior to whole body irradiation with 9.5 Gy significantly increases mouse survival. In contrast, inhibition of NOS activity either before or after irradiation significantly reduced survival. We also show that the phosphodiesterase 5 inhibitor, sildenafil, inhibits the radiation-induced differentiation of human myofibroblasts. The mechanisms underlying the protective effects of BH4 and the role of NOS in radiation-induced tissue injury will be discussed.
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 1400.
Abstract 1404: Mitochondrial-targeted nitroxide JP4-039 ameliorates irradiation-induced delay in bone wound healing and inhibits orthotopic tumor growth
Authors: Rwigema Jean-Claude , Gokhale Abhay , Epperly Michael , Glowackie Julie , Wang Hong , Dixon Tracy , Patrene Ken , Wipf Peter , Greenberger Joel S. 
Published: February 2011

Abstract
In the case of a nuclear explosion, combined injuries will result from radiation dispersal resulting in burns and cellular damage as well as a concussion wave resulting in traumatic bone fractures. Currently no available drugs are available to protect against both irradiation damage and traumatic bone damage. A new mitochondrial targeted small molecule hemigramicidin S nitroxide JP4-039 has been developed and shown to protect against total body irradiation. JP4-039 was tested to determine its effects on irradiation-induced delay of osseous wound healing.
A model for osseous would healing was used where the right hind legs of C57BL/6NHsd female mice were irradiated to doses 0 to 30 Gy 24 hours prior to drilling tibial wounds. JP4-039 (10 mg/kg) was injected either 10 min before or after irradiation. Mice were sacrificed weekly after wounding; tibiae were removed and radiographed for measurement of hole diameter. The left non-irradiated leg served as a control for the irradiated right leg. To determine whether JP4-039 might enhance tumor growth while stimulating bone growth, we injected Lewis lung carcinoma cells subcutaneously above the knee in both legs. The tumor on the right leg was within the 10Gy irradiation field. Tumor growth was monitored daily with calipers. Tukey's test was used to assess statistical significance between control and treated groups.
Mice treated with JP4-039 before bone drilling showed significant improvement in osseous wound healing at 14 days and 21 days after drilling (0.55 ± 0.3 and 0.47 ± 0.04 mm, respectively), compared with 0.84 ± 0.05 and 0.64 ± 0.05 mm, respectively for control, untreated mice (p&lt;0.05). Mice treated with JP4-039 prior to 20 Gy irradiation showed improved bone healing compared with controls at 21 days; Mice treated with JP4-039 after 20Gy showed improved bone healing at 21 and 28 days(p&lt;0.05). Mice bearing orthotopic tumors treated with JP4-039 prior to irradiation and bone drilling showed significantly less increase in tumor volume compared with control group in both irradiated and non-irradiated legs (p &lt; 0.05).
Thus, treatment with JP4-039 enhanced osseous bone healing when administered before wounding. Furthermore, JP4-039 enhanced healing when administered before or after irradiation. Finally, JP4-039 inhibited tumor growth and may have useful applications in 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 1404.
Abstract 1406: Involvement of DNA repair pathways in DAG-lactone radiosensitization of human LNCaP cells
Authors: Galvin David J. , Thin Tin H. , Truman Jean-Paul , Shenker Larissa , Kolesnick Richard , Fuks Zvi , Haimovitz-Friedman Adriana 
Published: February 2011

Abstract
We previously demonstrated that pre-treatment of human androgen-dependent prostate cancer cell line LNCaP with either 12-0-tetradecanoylphorbol 13-acetate (TPA, a known protein kinase C activator), or diacylglycerol-lactone (DAG-lactone) radiosensitized these cells. This effect was mediated by down-regulation of ATM protein levels, thus de-repressing the enzyme ceramide synthase (CerS), ceramide generation and apoptosis. Here we assessed whether ATM down-regulation affected DNA repair pathways. LNCaP cells were pretreated for 16 hr with 10μM DAG-lactone and irradiated with 20 or 40Gy. Pre-treatment with DAG-lactone significantly enhanced apoptosis at 48 hours from 1.1% to 13.9% (20Gy) and 19.9% (40Gy) respectively. γ-H2AX and BRCA1 foci formation at 1 and 8 hours post-radiation were scored. Immunofluorescent staining for γ-H2AX demonstrated a dose-dependent increase in γ-H2AX foci formation at 20Gy and 40Gy for both 1hr and 8 hr time points. Our data also shows that 40Gy alone produces the same amount of DNA double strand breaks (dsbs; as measured by γ-H2AX at 8 hr) as 20Gy+DAG-lactone, yet 40Gy alone does not induce apoptosis in LNCaP cells, while 20Gy+DAG-lactone does, indicating that ATM down-regulation is necessary for the apoptotic response. Similarly there was a dose-dependent response in the generation of BRCA1 foci at 20Gy and 40 Gy at 8hr post-radiation. There was no difference in the BRCA1 foci between pre-treatment with DAG-lactone either at 20Gy or at 40 Gy at both 1 hr or at 8 hr post-radiation. While apoptotic degradation is associated with γ-H2AX phosphorylation, in LNCaP cells these events would be expected at 24-48 hr. Therefore the foci observed here are unlikely to be associated with apoptotic DNA degradation and most likely result from DNA dsbs. Our recent data showed that unrepaired DNA dsbs trigger post-transcriptional activation of CerS via a mechanism that remains unknown. Accordingly MRE 11, ATM or DNA-PKcs (SCID) deficiencies sensitize mice towards CerS-mediated apoptosis in crypt stem cells clonogens.
Although these studies indicate that HR is active, further experiments need to be carried out to explore whether non-homologous end-joining (NHEJ) is or is not functional in LNCaP treated with DAG-lactone and radiation. Hence, the trigger for CerS activation still needs to be established.
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 1406.
Abstract 1409: C20orf52 regulates cell death by ionizing radiation via modulation of ROS generation in the mitochondria
Authors: So Kwangsup , Yoo Young Do , Um Hong-Duck , Park Jong Kuk 
Published: February 2011

Abstract
It is known that ROS exerts an important role in various intracellular physiological phenomena. Mitochondria and its molecules are one of major intracellular ROS source. Generation of ROS in normal cell condition is mainly caused by intracellular metabolic processes, but several extra-cellular stresses including ionizing radiation (IR) also increase ROS production. In this study, we tried to identify new molecular target that regulate ROS generation after IR irradiation, and confirmed the C20orf52 (also named as MTMG and Romo-1) as one of the new candidate. In recent report, C20orf52 was identified a regulator of ROS generation in the mitochondria, and it is located at integral mitochondrial inner-membrane. We constructed C20orf52 over-expressing HEK293 cell, and then showed that this C20orf52 over-expressing cells have a radio-resistance via suppression of ROS production by IR. Down-regulation of C20orf52 by siRNA treatment in several cancer cells increased cell death by IR. C20orf52 over-expression also increased mitochondrial potential and JNK phosphorylation in MAPKinase pathway induced by IR. Therefore we suggest that C20orf52 might modulate ROS production by IR and regulates cell death.
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 1409.
Abstract 1423: SatB2, targeted by miR31, is a modulator in cancer microenvironment
Authors: Yu Xiang , Aprelikova Olga , Palla John , John Simone , Yi Ming , Stephens Robert , Risinger John I. , Jazaeri Amir , Niederhuber John 
Published: February 2011

Abstract
Cancer growth and metastasis involve an active interaction between primary tumor cells and the tumor's microenvironment, which consists of fibroblasts, vascular cells and inflammatory cells. Such interactions between the cancer and the cells within the microenvironment induce differential expression of genes that act to foster the growth, invasion and spread of tumor cells. This study utilizes pair-wise primary cultures of fibroblasts from normal and cancerous human endometrial tissues of the same patients to investigate the potential factors in the tumor microenvironment and their role in carcinogenesis. Both microRNA and mRNA profiling were performed on paired normal and cancer fibroblasts. SatB2 emerged as a promising candidate when its expression was shown to be significantly increased in fibroblasts surrounding the tumor tissues in all but one patients tested (n=8). Further investigation documented that SatB2 is a target for miR31, via 2 binding sites located within the SATB2 3’ UTR region. In concordance, miR31 is down-regulated in tumor fibroblasts, which further implicates the potential role of SatB2 in promoting a favorable environment for tumors. Ectopic expression of SATB2 in normal fibroblasts does not affect the growth rate of an endometrial cancer cell line (EC-1) in co-culture experiments; however, it did increase the motility of EC-1 cells towards these fibroblasts by multiple folds in both in vitro migration and invasion assays. A reduction of SATB2 expression in cancer activated fibroblasts (CAFs) by shRNA attenuated the migratory ability of EC-1 cells, further supporting the role of SatB2 in tumor aggression. Our observations also indicated that the conditioned media from CAFs were sufficient to induce the motility changes in the EC-1 cells. We believe the elucidation of SatB2 pathway(s) will assist in uncovering the intricate connections between tumors and their microenvironments, leading to new targets for treating tumor progression.
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 1423.
Abstract 1439: De novo expression of c-kit in prostate cancer cells interacting with the bone microenvironment
Authors: Zhe Xiaoning , Nabha Sanaa M. , Mukundan Anju , Giroux Craig N. , Cher Michael L. , Bonfil R. Daniel 
Published: February 2011

Abstract
Specific cellular and molecular interactions between prostate cancer (PC) cells and the bone microenvironment lead to expansion of the metastatic deposit, disease progression, and ultimately significant morbidity and mortality. We recently reported an association between expression of the tyrosine kinase receptor c-kit and clinical PC progression, with the highest expression seen in clinical metastatic bone specimens. Moreover, we found that intraosseous tumors formed by otherwise c-kit negative PC3 cells injected into human bone xenografts in SCID mice (SCID-hu model) expressed c-kit. To determine the relevance of these findings, we examined additional human PC cell lines, namely LNCaP, C42b, and DU145, for the expression of c-kit in vitro and in vivo. While none of the cultured PC cells expressed c-kit at the message or protein level, immunostaining for c-kit in intraosseous tumors produced by these cells in the SCID-hu model revealed a distinctive and specific reactivity in the cancer cell compartment. The induction of c-kit expression in PC cells growing within the bone microenvironment was emulated by co-culture of PC3 cells and bone-derived cells embedded in Matrigel, as demonstrated by RT-PCR analysis. In an attempt to mimic the de novo c-kit expression observed in the SCID-hu model and to identify potential signaling pathways triggered by c-kit activation by its ligand stem cell factor (SCF), normally expressed by the bone microenvironment, we transiently transfected PC3 cells with wild-type c-kit. Activation of c-kit was confirmed by immunoblotting for phosphorylated c-kit. Using the whole human genome Agilent microarray, we found that 220 genes were differentially expressed when SCF-treated and non-treated c-kit-transfected PC3 cells were compared, resulting in discrete functional sub-networks that were coordinately up or down-regulated. Most notably, pathway and genetic network analysis revealed that c-kit activation resulted in an up-regulated fibroblast growth factor-2-mediated sub-network. Taken together, these results suggest that c-kit induction in PC cells in the bone microenvironment modulates cell-cell interaction pathways and growth factor signaling systems that ultimately lead to expansion of bone metastasis.
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 1439.
Abstract 1440: Pediatric pulmonary microenvironment differs from adults: Implications for pulmonary metastasis
Authors: Hayes-Jordan Andrea Anita , Wang Yong Xin 
Published: February 2011

Abstract
Background: Ewing's sarcoma (ES) is the second most common bone tumor in children. Still, despite multimodal therapy, lung metastasis are the most common cause of demise. Older age has been found to portend a poorer survival in ES. Here we identify differences in the pulmonary micro-environment comparing pediatric to adult lung tissue.
Purpose: To identify molecular differences in the pediatric and adult lung micro-environment.
Methods: To evaluate whether adult lungs provide a more permissive metastatic environment compared to pediatric lungs, we measured the migration and invasion of ES cells in a modified Boyden chamber assay. ES TC-71 cells, know to have moderate metastatic potential and ES LM-7 cells which are highly metastatic, were compared normal lung epithelial cells (CRL2300). Lungs from 4 week old adolescent and 9 week old adult nude mice, were morselated and placed in a modified Boyden chamber. To compare expression of metastatic genes in pediatric compared to adult lung, RNA was extracted from 4 week and 9 week nude mouse lung and a focused microarray of 128 genes were evaluated for differential expression.
Results: The TC-71 cell line and the CRL2300 cells had equal area of migration to adolescent and adult lung. Whereas, LM-7 had a significantly larger area of cell migration to the adult lung compared to the adolescent lung.(p=0.033) The focused gene expression profile demonstrated significant differential expression of 2 genes, Interleukin 1-beta (IL1-B), and Integrin beta-3 (ItgB3). IL1-B was significantly under-expressed and ItgB3 was significantly over-expressed in adolescent lung tissue compared to adult lung tissue.
Conclusions: Highly metastatic ES LM-7 cells have a significantly decreased migration to the adolescent/pediatric lung compared to adult lung tissue. This implies a different microenvironment in adolescent lung which does not have the same affinity for metastatic Ewing's sarcoma cells as the adult lung. Furthermore, differential gene expression of IL1-B and ItgB3 and may contribute to the cause of this difference since ItgB3 regulates cell adhesion, invasion and low doses of IL1-B can cause tumor cell eradication.
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 1440.