bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 492: Hepatic oxidative stress activates the Gadd45b gene via degradation of the transcriptional repressor STAT3
Authors: Kim Jung-Hwan , Qu Aijuan , Reddy Janardan K. , Gao Bin , Gonzalez Frank J. 
Published: May 2015

Abstract
Growth arrest and DNA damage-inducible beta (GADD45b) plays an important role in many intracellular events, such as cell cycle arrest, DNA repair, cell survival, apoptosis, and senescence. However, its mechanism of transcriptional regulation remains unclear. In this study the mechanism of proliferator-activated receptor a (PPARa) ligand induction of the Gadd45b gene in mouse liver was investigated. Gadd45b messenger RNA (mRNA) was markedly induced by the PPARa agonist, Wy-14,643, in wild-type mice but not in Ppara-null mice. Signal transducer and activator of transcription 3 (STAT3) was found to be a repressor of the Gadd45b gene through binding to upstream regulatory elements. The role of STAT3 in control of Gadd45b was confirmed using liverspecific Stat3-null mice. Wy-14,643 treatment stimulated STAT3 ubiquitination leading to activation of the Gadd45b gene as a result of loss of Gadd45b repression by STAT3.
STAT3 degradation was induced by forced overexpression of the PPARa target geneencoded enzyme ACOX1, which produces increased H2O2 as a byproduct of fatty acid b-oxidation. H2O2 also stimulated expression of Gadd45b in cultured cells. In conclusion, these studies revealed that PPARa indirectly induces the Gadd45b gene in liver through promoting degradation of the repressor STAT3 as a result of elevated oxidative stress.
Note: This abstract was not presented at the meeting.
Citation Format: Jung-Hwan Kim, Aijuan Qu, Janardan K. Reddy, Bin Gao, Frank J. Gonzalez. Hepatic oxidative stress activates the Gadd45b gene via degradation of the transcriptional repressor STAT3. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 492. doi:10.1158/1538-7445.AM2014-492
Abstract 4921: X-ray irradiation induced bio luminescence: Ex vivo and endoscopic imaging of radiobioluminescence
Authors: Papineni Rao V. 
Published: May 2015

Abstract
Accurate dose delivery to malignant tissue in radiotherapy is essential for enhancing the treatment efficacy while minimizing morbidity of surrounding normal tissues. Advances in therapeutic strategies and diagnosis technologies along with our understanding of the biology of tumor response to radiation therapy have paved way to allow nearly 60% of current cancer patients to be treated with Radiation Therapy. The confluence of molecular imaging and nanotechnology fields are bridging physics and medicine and are quickly making strides in opening new avenues and therapeutic strategies that complement radiation therapy- with a distinct footprint in immunotherapy, adoptive cell therapy, and targeted chemotherapy. Incorporating optical imaging in radiation therapy in my laboratory, endogenous bioluminescence resulting from whole body irradiation in different organs, which is distinct from the cherenkov radiation, is described here. Mice were subjected to 5 - 10 Gy X-ray irradiation doses using commercially available X-RAD 320 irradiator (1Gy/min; F2 beam hardening filter 1.5mm Al, 0.25mm Cu, 0.75mm Sn; Precision X-ray inc, USA). The endogenous bioluminescence in response to irradiation, described here as radiobioluminescence, was captured using cooled CCD camera from live subjects, and from the excised organs/tissues. Significant increase (up to 100 fold) in the amounts of photons released as bioluminescence was detected during 5 -10 min capture from the mice subjected to irradiation compared to that of the control. The GI tract contributed significant portion of this radiobioluminescence and was confirmed both by ex-vivo and minimally invasive rectal endoscopic imaging. Other organs and tissues displaying such robust increase in radiobioluminescence include skin, and fat depots. The role, evaluation, and future assessment of nutrients, nutriceuticals, microbiome, and metabolites during the course of radiation therapy become highlighted with these findings. Thus such molecular imaging methodologies and modalities described will be useful tools in radiation treatment design and process.
Citation Format: Rao V. Papineni. X-ray irradiation induced bio luminescence: Ex vivo and endoscopic imaging of radiobioluminescence. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4921. doi:10.1158/1538-7445.AM2014-4921
Abstract 4930: Quantitative PET imaging of tissue factor expression using 18F-labeled active site inhibited factor VIIa
Authors: Nielsen Carsten H. , Erlandsson Maria , Jensen Mette M. , Madsen Jacob , Petersen Lars C. , Kjaer Andreas 
Published: May 2015

Abstract
Objectives: Tissue factor (TF) is up regulated in many solid tumors and its expression is linked to tumor angiogenesis, invasion, metastasis and prognosis. Hence it would be of clinical relevance if one could assess tumor TF expression status non-invasively. Here we report the development of a new PET tracer for specific imaging of TF using a derivative of factor VII, the natural ligand to TF, labeled with 18F.
Methods: Active site inhibited factor VIIa (ASIS) was radiolabeled with N-succinimidyl 4-18F-fluorobenzoate ([18F]SFB) and purified. Nude mice (n=5) with subcutaneous human pancreatic xenograft tumors (BxPC-3) underwent small animal PET/CT imaging 1, 2 and 4 hours after injection of 7.3-9.3 MBq [18F]ASIS (∼37 µg) in 160 µL saline. Mice were euthanized following the last imaging session, and their tumors and major organs were resected for ex vivo gamma well counting. Tumor tissue was preserved for molecular analysis. A blocking experiment was performed in a second set of mice. The blocking group (n=3) received 500 µg non-labeled ASIS before injection of [18F]ASIS and was imaged after 4 hours. The expression pattern of TF in the tumors was visualized by immunohistochemistry and the amount of TF in tumor homogenates was measured by ELISA.
Results: The PET images showed high uptake of [18F]ASIS in the tumor regions with a mean uptake of 2.40 ±0.18, 2.56 ±0.20 and 2.54 ±0.27 %ID/g (Mean ±SEM) at 1, 2 and 4 hours after injection of [18F]ASIS and with an average maximum uptake in the tumors of 7.08 ±0.72 %ID/g at 4 hours. In comparison, the muscle uptake was 0.19 ±0.01 %ID/g at 4 hours. At 4 hours the tumors had the highest uptake of any organ. Blocking with cold ASIS significantly reduced the uptake of [18F]ASIS from 2.51 ±0.06 to 1.29 ±0.07 %ID/g (p&lt;0.001). Importantly, the uptake of [18F]ASIS measured in vivo by PET imaging correlated (r=0.72, p&lt;0.02) with TF expression at the protein level measured ex vivo in tumor homogenates by ELISA.
Conclusion: PET/CT imaging with [18F]ASIS can be used for specific, non-invasive imaging of TF expression.
Research Support: This work was supported by at grant from the Danish National Advanced Technology Foundation.
Citation Format: Carsten H. Nielsen, Maria Erlandsson, Mette M. Jensen, Jacob Madsen, Lars C. Petersen, Andreas Kjaer. Quantitative PET imaging of tissue factor expression using 18F-labeled active site inhibited factor VIIa. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4930. doi:10.1158/1538-7445.AM2014-4930
Abstract 4954: Hematogenous metastasis of ovarian cancer: Re-thinking mode of spread
Authors: Pradeep Sunila , Kim Seung Wook , Wu Sherry , Masato Nishimuara , Miyake Takahito , Hyun-Jin Choi , Rupaimoole Rajesha , Liu Jinsong , Fidler Isahai , Lopez Gabriel , Sood Anil 
Published: May 2015

Abstract
Background: Most patients with ovarian cancer have widely metastatic disease within the abdominal cavity at primary diagnosis; historically, this was thought to occur via intraperitoneal “seeding”. Here, we report unexpected findings related to hematogenous ovarian cancer metastasis with a strong tropism for the omentum.
Methods: We established a novel parabiosis model where the skin of female mice was fused surgically from the shoulder to the hip joint. Two weeks later, the “host” parabiont mice were injected with tumor cells into ovary. Once the host mice became moribund, the parabionts were separated, and the host mice were euthanized. Tumor development and patterns of metastasis were analyzed in the host mice. A series of additional in vitro and in vivo experiments were carried out to decipher the underlying mechanisms.
Results: The parabiosis models demonstrated that tumor cells injected into the ovary of each “host” mouse metastasized to the corresponding “guest” mouse, predominantly to the omentum. Using high-throughput transcriptome analysis and phospho-proteome arrays, we demonstrated that ErbB3, an EGFR family receptor tyrosine kinase (RTK) was highly expressed in the ovarian cancer cells that hematogenously metastasized to the omentum (SKOV3-OM3) compared to parental cells. The ErbB3-NRG1 axis activated Src/PI3K/AKT signaling pathway, which in turn induced loss of polarity and increased invasion of ovarian cancer cells. Depletion of murine NRG1 using target specific siRNAs almost completely abolished omental metastasis. In contrast, overexpression of ErbB3 resulted in enhanced tumor formation and omental metastatic spread, which confirms the role of ErbB3 in hematogenous omental metastasis. Additional studies with a function-blocking antibody specific to ErbB3 led to substantial reduction in hematogenous metastasis of ovarian cancer cells.
Conclusions:
Collectively, our results provide the first evidence that ovarian cancer cells are capable of hematogenous metastasis, but with strong tropism for the omentum. These findings not only provide a new understanding of ovarian cancer metastasis, but also identify novel therapeutic targets.
Citation Format: Sunila Pradeep, Seung Wook Kim, Sherry Wu, Nishimuara Masato, Takahito Miyake, Choi Hyun-Jin, Rajesha Rupaimoole, Jinsong Liu, Isahai Fidler, Gabriel Lopez, Anil Sood. Hematogenous metastasis of ovarian cancer: Re-thinking mode of spread. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4954. doi:10.1158/1538-7445.AM2014-4954
Abstract 4955: Role of Angiotensin II in prostate cancer metastasis
Authors: Chakroborty Debanjan , Sarkar Chandrani 
Published: May 2015

Abstract
Introduction: At the initial stages prostate cancer development depends on a crucial level of androgenic stimulation but at later stages when it becomes androgen independent the perturbation from androgen receptor axis leads to the development of more aggressive phenotypes with greater metastatic potential. At this stage the growth and progression of prostate cancer is regulated by various local growth factors and neuro-hormones which are altered in prostate cancer microenvironment. Therefore, identifying these factors which are aberrantly expressed in the tumor microenvironment and understanding how these factors are involved in regulating the tumor progression are essential for developing better targeted therapeutic strategy for the treatment of advanced stages of prostate cancer.
Objective: As emerging reports suggest the importance of tissue based renin angiotensin system (RAS) in pathophysiology of the prostate and as studies indicate a lower incidence of cancer and cancer related deaths in patients taking angiotensin receptor blockers (ARBs) (as medication for hypertension), we intend to study the role played by this system in the progression of prostate cancer.
Methods and Results: Our results show that there is limited expression of RAS components, Angiotensin II (AT II), the main bioactive effector peptide of RAS and its receptors, and its receptor Angiotensin receptor type 1( AT1R) and Angiotensin receptor type 2 (AT2R) , in mouse prostate tissues. However, RAS becomes activated in prostate cancer. The expressions of ATII and AT1R are significantly higher in androgen independent orthotopic PC3 prostate tumor tissues. The expression of AT2R remains unaltered during the development of tumor. Therefore to evaluate the role of ATII in prostate cancer progression, in vitro experiments using two androgen independent orthotopic cell lines, PC3 and C4-2 were performed. Both these cell lines express AT1R. Our results indicate that ATII acting through AT1R promotes metastatic behavior such as invasion and migration of prostate cancer cells and inhibition of ATII by blocking AT1R receptor abrogates this action of ATII.
Conclusions: This study identifies a new role of local RAS in the metastatic progression of prostate cancer and will eventually help to develop newer and effective therapeutic strategies in treatment of androgen independent prostate cancer by targeting ATII or AT1R. This strategy can be used either alone or in combination with existing therapeutic strategies in treatment of the disease.
Citation Format: Debanjan Chakroborty, Chandrani Sarkar. Role of Angiotensin II in prostate cancer metastasis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4955. doi:10.1158/1538-7445.AM2014-4955
Abstract 4957: Role of tumor-derived exosomes in growth and metastasis of breast cancer
Authors: Munagala Radha , Gupta Ramesh 
Published: May 2015

Abstract
Breast cancer (BC) mortality rates have decreased over last 30 years, largely due to early detection and improved treatment modalities, particularly targeted therapies. However, metastasis relentlessly drives mortality. The pervasive mortality from metastasis highlights the shortcomings of traditionally accepted hypotheses on the metastatic process. The mechanisms by which malignant tumors leave the primary tumor site, invade lymphatics, and metastasize to regional lymph nodes are complex and interrelated. Exosomes are biological nanovesicles (∼30-100 nm) of endocytic origin. Exosomes mediate local and horizontal transfer of information, such as mRNAs, miRNAs and proteins. They are indicated to play a significant role in the genesis of tumor, growth and metastasis. Recent advances in the exosome biology suggest that tumor-derived exosomes (TDEs) are critical mediators of tumorigenesis and can incite a pro-angiogenic signaling program capable of remodeling tissue matrices. However, the role of TDEs in BC metastasis remains elusive. In this study, we examined the role of exosomes in breast cancer metastasis using cell culture studies. We made the following observations: i) exosomes derived from BC cells had a mean size of 92 nm and carried exosomal marker proteins CD63 and CD81, ii) uptake of exosomes from highly metastatic BC cells (MDA-MB-231) by non-metastatic recipient cells (BT474 and T47D), iii) faster wound healing rate, increased migratory behavior, and invasiveness in recipient cells treated with metastatic BC exosomes, iv) increased endothelial cell tube formation, reflective of angiogenesis ability with exosomes from metastatic BC cells, v) modulation in expression levels of key EMT-associated proteins in non-metastatic cells treated with metastatic BC exosomes favoring EMT shift, vi) difference in metastasis-associated miRNAs levels in exosomes from invasive and non-invasive BC cells. Our data that suggest exosomes from metastatic BC cells carry the cargo essential for EMT and have the ability to change phenotypic traits of the recipient cells. Determining the role of exosomes in BC metastasis and characterization of BC exosomes components (proteins, mRNA and miRNA) will have great potential to uncover new targets and lead to new therapies for metastatic disease.
Citation Format: Radha Munagala, Ramesh Gupta. Role of tumor-derived exosomes in growth and metastasis of breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4957. doi:10.1158/1538-7445.AM2014-4957
Abstract 4963: In vivo and in vitro effect of a nutrient mixture on murine 4T1 breast cancer
Authors: Roomi M. Waheed , Cha John , Roomi Nusrath , Niedzwiecki Aleksandra , Rath Matthias 
Published: May 2015

Abstract
Breast cancer patients often have detectable or occult metastases at diagnosis and most patients will develop metastatic lesions during the course of the disease. We investigated the effect of a nutrient mixture (NM) containing ascorbic acid, lysine, proline, and green tea extract on murine breast cancer 4T1, a unique metastatic breast cancer model that has the capacity to metastasize efficiently to sites affected in human breast cancer. After one week of isolation, 5-6 week old female Balb/C mice were inoculated with 5x105 4T1 cells into the mammary pad and randomly divided into two groups; group A was fed a regular diet and group B a regular diet supplemented with 0.5% NM. After four weeks, the mice were sacrificed and their tumors, lungs, livers, kidneys, hearts and spleens were excised and processed for histology. Dimensions (length and width) of tumors were measured using a digital caliper, and the tumor burden was calculated using the following formula: 0.5 x length x width. We also tested the effect of NM in vitro on 4T1 cells, measuring cell proliferation by MTT assay, MMP secretion by zymography, invasion through Matrigel , migration by scratch test and morphology by H&E staining. NM inhibited tumor weight and burden of 4T1 tumors by 50% (p =0.02) and 53.4% (p&lt;0.0001), respectively. Lung metastasis was profoundly inhibited by NM supplementation: mean number of colonies was reduced by 87% (p&lt;0.0001) and mean weight of lungs by 60% (p=0.0001) compared to control mice. Metastasis to liver, spleen, kidney and heart was significantly reduced with NM supplementation. In vitro, NM exhibited 50% toxicity over the control at 250 and 500 µg/ml concentrations. Zymography demonstrated MMP-2 and MMP-9 secretion which was inhibited by NM in a dose dependent fashion, with virtual total inhibition of both at 1000 µg/ml. Migration by scratch test and Invasion through Matrigel were inhibited in a dose dependent manner with total block of invasion at 250 µg/ml and of migration at 1000 µg/ml. These results suggest that NM has therapeutic potential in treatment of breast cancer.
Citation Format: M. Waheed Roomi, John Cha, Nusrath Roomi, Aleksandra Niedzwiecki, Matthias Rath. In vivo and in vitro effect of a nutrient mixture on murine 4T1 breast cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4963. doi:10.1158/1538-7445.AM2014-4963
Abstract 4971: Splicing factor kinase regulates metastatic dissemination of human prostate cancer
Authors: Bond David J. , Stoletov Konstantin , Leong Hon Sing , Woolner Emma , Liu Shuhong , Bismar Tarek , Zijlstra Andries , Lewis John D. 
Published: May 2015

Abstract
Metastasis causes the vast majority of cancer-associated deaths. Despite its clinical significance, the molecular mechanisms that regulate this multi-step process are poorly understood. To successfully disseminate a cancer cell must escape the primary tumor, travel to a distant site, arrest, enter the stroma and grow in a new microenvironment. The presence of circulating tumor cells in patients with metastatic disease and experimental animals with metastatic cancers suggests that tumor invasion is a critical, rate-limiting step in the metastatic process. To identify the key molecular determinants that regulate invasive metastatic lesion formation we performed the first whole-genome, in vivo RNAi screen in an avian embryo model using advanced intravital imaging techniques. We identified numerous novel regulators of cancer cell invasion, including JL1, a splicing factor kinase.
In secondary assays, we demonstrated that JL1-depletion inhibits migration of several human cancer cell lines with no effect on proliferation or survival. Furthermore, JL1-deficient human cancer cells display diminished metastatic potential in chicken embryo and mouse models of metastasis. Cancer microarray database mining shows that JL1 gene expression is strongly associated with indicators of poor clinical outcome in prostate cancer, including pathological Gleason score and metastasis. To experimentally determine JL1 association with advanced disease we performed histological examinations of prostate cancer tissue and determined that JL1 staining strongly correlates with prostate cancer progression. JL1 kinase regulates alternative splicing of numerous cellular transcripts in response to stress and growth signals. To examine the molecular mechanism behind JL1 regulation of cancer cell metastasis, we performed exon level microarray analysis on JL1-depleted cancer cell lines. Subsequent interactome analysis identified an enrichment of key regulatory proteins in pro-metastatic networks. Therefore, we hypothesize that abrogated JL1 activity directly promotes prostate cancer cell migration and invasion. In summary, JL1 is a novel regulator of cancer cell metastasis that represents a potential pathological marker for prostate cancer progression, and novel drug target to block invasion and metastasis.
Citation Format: David J. Bond, Konstantin Stoletov, Hon Sing Leong, Emma Woolner, Shuhong Liu, Tarek Bismar, Andries Zijlstra, John D. Lewis. Splicing factor kinase regulates metastatic dissemination of human prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4971. doi:10.1158/1538-7445.AM2014-4971