bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4646: Cumin extract prevents estrogen-associated breast cancer in ACI rats
Authors: Aqil Farrukh , Jeyabalan Jeyaprakash , Munagala Radha , Gupta Ramesh C. 
Published: August 2015

Abstract
Spices are highly chemoprotective because of their antioxidant, antiproliferative, and anti-inflammatory activities. We have previously demonstrated significant chemoprotective effects of cumin seed powder (7.5%, w/w) against estrogen-induced mammary tumorigenesis in ACI rats by inhibiting cell proliferation as well as cellular and molecular markers. Here we report the inhibition of E2-mediated mammary tumorigenesis by cumin extract (1%, w/w) that is equivalent to the dietary dose in our previous study. Three extractions of cumin seeds with 80% aqueous ethanol followed by evaporation provided 13% of total dried extract (w/w). Groups of female ACI rats were given either AIN-93M diet or diet supplemented with cumin extract and then treated with subcutaneous 17ß-estradiol silastic implants (1.2 cm; 9 mg). Two additional groups were maintained on control or experimental diet. Rats received diet and water ad libitum. Five-six animals from each group were euthanized three weeks after the E2 treatment to determine the effect of interventions on early biomarkers. The remaining animals (n = 20-22) were euthanized when estrogen-treated group on control diet reached over 90% tumor incidence.
Diet consumption and body weight gain was found to be largely unaffected by the cumin extract, suggesting that it was well tolerated. The first tumor incidence in control group was after 92 days, this was significantly delayed by 35 days in cumin extract treated group. Experimental diet significantly offset estrogen-related growth of pituitary prolactinomas as early as after three weeks (p = 0.019), the effect was more pronounced at tumor time point (p &lt; 0.0001). At the end of the study (25 wks), the tumor incidence was found to be 96% in control group whereas only 45% animals had tumors in the intervention group. Significant reduction in average tumor volume (474 vs. 75 mm3) and tumor multiplicity (4.1 vs. 0.8 tumors/animal) was also observed by cumin extract compared to control. The mechanistic studies including effect on the plasma prolactin levels, and the cell proliferation marker, PCNA, estrogen-associated expression of the ERα and cyclin D1 in the mammary tissues are being evaluated. Together, our data show that cumin extract can significantly delay and prevent estrogen-mediated mammary tumorigenesis. This data further support our ultimate goal to develop these spice bioactives as clinically translatable chemopreventives and therapeutics against breast cancer. (Supported by CA-125152, Helmsley Fund, and Agnes Brown Duggan Endowment).
Citation Format: Farrukh Aqil, Jeyaprakash Jeyabalan, Radha Munagala, Ramesh C. Gupta. Cumin extract prevents estrogen-associated breast cancer in ACI rats. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4646. doi:10.1158/1538-7445.AM2015-4646
Abstract 4651: Urolithin A (UA) inhibits both androgen receptor and AKT signaling and prevents the progression of castration resistant prostate cancer
Authors: Vadhanam Manicka V. , Das Trinath P. , Suman Suman , Annamalai Lakshmanan , Damodaran Chendil 
Published: August 2015

Abstract
Current therapeutic regimens are insufficient for treating advanced and metastatic prostate cancer. Compelling evidence suggest existence of concomitant aberrations in both activation of Androgen Receptor (AR) and Protein Kinase-B (AKT) signaling pathway in advanced castration resistant prostate cancer (CRPC). Hence, simultaneous inhibition of both AR and AKT appears to be an effective strategy for the prevention and treatment of CRPC.
We are interested in identifying small molecules from natural plant origin, which targets both AR and AKT signaling for the prevention and treatment of CRPC. Ellagic acid/ellagitannins, abundantly present in the pomegranate and berries, are actively metabolized by the intestinal microflora to Urolithin-A (UA). Oral administration of UA has been equivocally shown to be highly bioavailable in the prostate gland, and is non-toxic.
In our in vitro studies, UA treatment inhibited the growth of both AR-expressing (LNCaP, C42B) and AR-negative (PC-3) prostate cancer cell lines. The molecular analyses suggested that UA transcriptionally regulated AR function and its downstream events in these cell lines. In addition, dihydrotestosterone (DHT) induced AR signaling was attenuated by UA.
While dissecting the effect of UA on AKT signaling, we found UA inhibited pAKT (Ser 473) expression and its pro-survival target genes. Phenotypic analysis confirmed UA reduces the motility and invasive potential of prostate cancer cells by inhibiting the expression of genes that are implicated in the epithelial-to-mesenchymal transition (EMT) (e.g., β-catenin, vimentin, Snail, and Slug).
We also demonstrated the in vivo efficacy of UA against CRPC. Oral administration of UA (50 mg/kg body weight) inhibited prostate tumor growth in xenografts from PC-3 and C4-2B cells. Moreover, histopathological evaluation of the xenografts revealed a marked reduction in the tumor cell density, loss of anisocytosis and anisokaryosis, and lower mitosis in animals that received UA as compared to the control group. Studies are underway to analyze the plasma and tissue levels of UA and our ongoing immunohistochemistry studies may validate the in vitro findings and confirms whether AKT/AR are the target of UA.
Together, these results suggest that targeting and thus, overriding both AR and AKT mediated pro-survival signaling could be an effective strategy for preventing the progression of CRPC.
Citation Format: Manicka V. Vadhanam, Trinath P. Das, Suman Suman, Lakshmanan Annamalai, Chendil Damodaran. Urolithin A (UA) inhibits both androgen receptor and AKT signaling and prevents the progression of castration resistant prostate cancer. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4651. doi:10.1158/1538-7445.AM2015-4651
Abstract 4669: Druggable oncogene fusions in lung invasive mucinous adenocarcinoma
Authors: Nakaoku Takashi , Tsuta Koji , Ichikawa Hitoshi , Shiraishi Kouya , Sakamoto Hiromi , Enari Masato , Furuta Koh , Shimada Yoko , Ogiwara Hideaki , Watanabe Shun-ichi , Nokihara Hiroshi , Yasuda Kazuki , Hiramoto Masaki , Nammo Takao , Kim Young Hak , Mishima Michiaki , Yokota Jun , Yoshida Teruhiko , Kohno Takashi 
Published: August 2015

Abstract
Invasive mucinous adenocarcinoma (IMA) of lung, a subtype of lung adenocarcinoma, is known to be strongly associated with KRAS mutation. Genetic aberration is unknown in IMA without KRAS mutation.
From an IMA cohort of 90 cases, consisting of 56 cases (62%) with KRAS mutations, we conducted whole-transcriptome sequencing on 32 IMAs, including 27 cases without KRAS mutation. We identified oncogenic fusions that occurred mutually exclusively with KRAS mutations: CD74-NRG1, SLC3A2-NRG1 (NRG1 fusions: 6/90), EZR-ERBB4, TRIM24-BRAF, and KIAA1468-RET.
The CD74-NRG1 and SLC3A2-NRG1 fusion proteins contained the transmembrane domain of CD74 and SLC3A2 and retained the EGF-like domain of the NRG1 protein (NRG1 III-β3 form). Membrane-tethered EGF-like domain might activate juxtacrine signaling through HER2:HER3 receptors. To reveal the mechanism of the oncogenicity, exposing EFM-19 cells which express HER2 and HER3 to conditioned media from H1299 cells expressing exogenous CD74-NRG1 fusion protein resulted in phosphorylation of HER2 and HER3, and downstream mitogen-activated kinase and AKT. The phosphorylation was suppressed by lapatinib and afatinib.
When EZR-ERBB4 or TRIM24-BRAF cDNA was exogenously expressed in NIH3T3 cells, ERBB4 or downstream mediator of BRAF was phosphorylated under serum-free condition. The expression of fusion genes induced anchorage-independent growth. The phosphorylation and growth were suppressed by the kinase inhibitors targeting fusion-induced signaling.
These results show that the NRG1, ERBB4 and BRAF fusions are novel driver mutations and potential targets. About 15% (13/90; 14.4%) of IMAs harbor druggable aberrations, taken together a small fraction of known driver aberrations.
Citation Format: Takashi Nakaoku, Koji Tsuta, Hitoshi Ichikawa, Kouya Shiraishi, Hiromi Sakamoto, Masato Enari, Koh Furuta, Yoko Shimada, Hideaki Ogiwara, Shun-ichi Watanabe, Hiroshi Nokihara, Kazuki Yasuda, Masaki Hiramoto, Takao Nammo, Young Hak Kim, Michiaki Mishima, Jun Yokota, Teruhiko Yoshida, Takashi Kohno. Druggable oncogene fusions in lung invasive mucinous adenocarcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4669. doi:10.1158/1538-7445.AM2015-4669
Abstract 4691: KRAS mutation specific alkylating pyrrole-imidazole polyamide (KR12) suppresses mutant KRAS expression and inhibits tumor growth by showing accumulation in KRAS mutant xenografts
Authors: Inoue Takahiro , Hiraoka Kiriko , Suzuki Yusei , Yoda Hiroyuki , Watanabe Takayoshi , Takatori Atsushi , Koshikawa Nobuko , Ozaki Toshinori , Nagase Hiroki 
Published: August 2015

Abstract
Constitutive active mutations of KRAS are detected in 35-40% of human colon cancers, and almost all of them are the constitutive active missense mutations at codon 12 (80%) or codon 13 (20%). Consistent with these observations, the presence of KRAS mutations has been shown to be associated with malignant properties of tumors as well as a poor clinical outcome of the patients bearing these tumors. Unfortunately, yet no effective anti-cancer drug(s) specifically targeting KRAS mutations have been developed. Hence, we synthesized an alkylating agent conjugated with the Pyrrole-Imidazole polyamide (KR12: PI-polyamide-seco-CBI), which recognized KRAS G12D or G12V mutations at codon12. We have previously found that KR12 has anti-tumor effects in vitro and in vivo. However, it still remains elusive whether KR12 exerts its selective toxicity towards colon cancer cells by penetrating into the tumor tissues and inhibiting the expression of mutant KRAS gene in mouse model of human cancer. To address this issue, we decided to examine the distribution of KR12 using FITC labeled PI polyamide. In vivo imaging of tumor-bearing mice after single intravenous administration demonstrated that the highest fluorescence intensity was seen in the tumor sites 24 hours after injection with showing nuclear localization. Quantitative RT-PCR revealed that KR12 decreased the mutated KRAS expression in tumor tissues obtained from KRAS-heterozygous-mutated-LS180-xenografted mice (G12D heterozygous mutation). Since KR12 showed long lasting accumulation in xenografts we compared the effect of single and multiple administration of KR12. Once a week injection for five to eight weeks resulted in significant suppression of tumor growth in homozygous mutant SW480 (G12V homozygous mutation) xenografts. Surprisingly, both single and multiple treatments of KR12 induced massive tumor volume reduction without affecting body weight gain. These data suggest that KR12 accumulation in colon xenograft tumor tissues may emphasize drug local effect and minimize systemic adverse effect.
Citation Format: Takahiro Inoue, Kiriko Hiraoka, Yusei Suzuki, Hiroyuki Yoda, Takayoshi Watanabe, Atsushi Takatori, Nobuko Koshikawa, Toshinori Ozaki, Hiroki Nagase. KRAS mutation specific alkylating pyrrole-imidazole polyamide (KR12) suppresses mutant KRAS expression and inhibits tumor growth by showing accumulation in KRAS mutant xenografts. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4691. doi:10.1158/1538-7445.AM2015-4691
Abstract 47: KRAS-mutation dependent effect of zoledronic acid in human NSCLC preclinical models
Authors: Kenessey István , Kói Krisztina , Cserepes Mihály , Dobos Judit , Hegedűs Balázs , Tóvári József , Tímár József 
Published: August 2015

Abstract
In non-small cell lung cancer (NSCLC) KRAS-mutant status is a negative prognostic and predictive factor of both classic and target based therapy. In human malignancies bisphosphonate drugs are applied to treat or prevent formation of bone metastases. Nitrogen-containing bisphosphonates inhibit the posttranslational modification of small G-proteins (e.g. Ras, Rac, Rho) and thus may affect proliferation and migration. In our preclinical work, we investigated the effect of an aminobisphosphonate compound (zoledronic acid) on mutant and wild type KRAS-expressing human NSCLC cell lines.
In vitro cell viability was measured by MTT assay in H358, LCLC-103H, H1650 and H1975 cells. Apoptotic cell death was quantified by flow cytometric detection of sub-G1-fraction in propidium-iodide stained cultures. Furthermore, we investigated the in vivo effect of zoledronic acid in a SCID mouse subcutaneous xenograft model. The extracted tumors were examined by traditional histological methods and the proportion of proliferating tumor cells was determined by Ki67 labeling.
KRAS-mutant H358 human NSCLC cell line showed relative resistance to zoledronic acid on proliferation, while human lung cancer cell lines carried wild type KRAS proved to be sensitive. Zoledronic acid improved the cytostatic effect of traditional anti-cancer agent cisplatin. Zoledronic acid did not induce significant apoptosis in NSCLC cell lines in vitro, rather the blockade of the cell cycle appeared. In in vivo subcutaneous animal model, zoledronic acid significantly reduced the weight of LCLC-103H xenograft tumor harboring wild type KRAS, furthermore, the treatment decreased the number of Ki67-labeled tumor. Zoledronic acid induced the expression of VEGF in LCLC-103H cells and stimulated in vivo angiogenesis.
We concluded that in human NSCLC cells the antiproliferative effect of zoledronic acid dependended on KRAS-status (wild-type or mutant). The inhibitory effect of zoledronic manifested through the in vitro and in vivo blockade of cell cycle. The in vivo angiogenic effect of zoledronic acid supported cytostatic effect of cisplatin. Our preclinical investigation suggests that patients with wild type KRAS-expressing NSCLC could potentially benefit from aminobisphosphonate therapy.
Citation Format: István Kenessey, Krisztina Kói, Mihály Cserepes, Judit Dobos, Balázs Hegedűs, József Tóvári, József Tímár. KRAS-mutation dependent effect of zoledronic acid in human NSCLC preclinical models. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 47. doi:10.1158/1538-7445.AM2015-47
Abstract 4708: Mammalian glutamine metabolism controls circadian rhythm through regulation of reactive oxygen species
Authors: Altman Brian J. , Stine Zachary E. , Hsieh Annie L. , Deberardinis Ralph J. , Dang Chi V. 
Published: August 2015

Abstract
Circadian rhythms are twenty-four hour physiologic cycles present in all eukaryotes that control a variety of organismal processes, including metabolism, but the role of metabolism in control of circadian rhythms is still not well understood. Peripheral clocks such as those present in the liver control metabolic pathways such as glucose metabolism and respiration as well as amino acid metabolism. It has been recently demonstrated that the availability of the metabolite NAD (nicotinamide adenine dinucleotide) can feed back to control circadian rhythm. There is much interest in targeting glutamine metabolism in cancer, but it is still not fully understood how inhibition of glutamine metabolism affects normal cell physiology, including circadian rhythm. Here we show using the commonly-used circadian model U2OS osteosarcoma cells and other cell lines that glutamine withdrawal blocked proper circadian oscillation of gene expression. Glutamine withdrawal led to distinct and dramatic changes in circadian gene expression in several cell lines with highly different tissue origins, which could be rescued by addition of the cell permeable TCA-intermediate α-ketoglutarate. However, cells withdrawn from glutamine did not show signs of metabolic stress or impairment of the mTOR pathway. While alterations to histone modifications possibly stemming from impairment of αKG-dependent enzymes were observed, these did not explain the observed alterations in circadian rhythm. Rather, RNA-seq analysis of genetic changes after glutamine withdrawal and α-ketoglutarate rescue revealed strong induction of several genetic pathways associated with reactive-oxygen species (ROS) induction, particularly those resulting from chemotherapy or photodynamic therapy of cancer. Further supporting the importance of ROS in regulation of circadian rhythm, addition of cell permeable antioxidants rescued the disruption of circadian oscillation in the absence of glutamine. Finally, inhibiting expression of the key ROS-defense catalase phenocopied circadian rhythm disruption observed after glutamine withdrawal. Together, these data suggest that glutamine availability and metabolism are critical to support circadian rhythm and gene expression through modulation of intracellular ROS, and furthermore that cancer treatments that lead to induction of ROS could affect normal cellular circadian rhythm.
We thank the following funding: NIH F32CA180370, NIH F32CA174148, NIH R01CA051497, LLS 610614
Citation Format: Brian J. Altman, Zachary E, Stine, Annie L. Hsieh, Ralph J. Deberardinis, Chi V. Dang. Mammalian glutamine metabolism controls circadian rhythm through regulation of reactive oxygen species. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4708. doi:10.1158/1538-7445.AM2015-4708
Abstract 4726: Gene expression signatures of isolated circulating tumor cells from metastatic breast cancer patients reveal presence of breast cancer stem cells with EMT or MET phenotypes
Authors: Fouladdel Shamileh , Yoon Hyeun Joong , Lin Eric , Kim Tae Hyun , Deol Yadwinder S. , Luther Tahra K. , Clouthier Shawn G. , Jiang Hui , Burness Monika L. , Nagrath Sunitha , Azizi Ebrahim , Wicha Max S. 
Published: August 2015

Abstract
Breast cancer stem cells are responsible for tumor recurrence, metastasis and drug resistance. One of the important steps in metastasis is entry of tumor cells into the blood circulation. These circulating tumor cells (CTCs) may serve as markers of cancer progression and as a “liquid biopsy” to provide information on tumor biology at single cell resolution. Current methods of CTC capture are not fully inclusive to isolate all phenotypic variations of cancer stem cells (CSCs) among the CTCs. Using newly developed microfluidic methods to isolate CTCs from blood samples of metastatic breast cancer patients, we assessed gene expression profiles in these cells. The gene expression signatures of isolated CTCs were determined using a highly sensitive microfluidic-based 96-plex RT-qPCR method. Analyzed multiplex RT-qPCR data revealed distinct gene expression patterns among CTCs isolated from different patients. Cancer stem cell markers such as ALDH1a1, ALDH1a2 and ALDH1a3 as well as CD44 and CD24 genes were differentially expressed in isolated CTCs. In addition, markers of the epithelial to mesenchymal (EMT) and mesenchymal to epithelial (MET) phenotypes such as Vimentin, EpCAM, HER2, CDH1, CDH2, TGFb1 and cytokeratins were also expressed variably in the CTC samples. Furthermore, MMP9, TIMP1, CD90, CD14, SPARC, BRAF, KRAS, PI3K and ERCC1 genes which play a role in cancer initiation, promotion, metastasis and drug resistance were also differentially expressed in the isolated CTCs. Overall, these studies further our understanding into the heterogeneity of CTCs and CSCs as well as providing a potential tool for real-time monitoring of cancer patients on clinical trials.
Citation Format: Shamileh Fouladdel, Hyeun Joong Yoon, Eric Lin, Tae Hyun Kim, Yadwinder S. Deol, Tahra K. Luther, Shawn G. Clouthier, Hui Jiang, Monika L. Burness, Sunitha Nagrath, Ebrahim Azizi, Max S. Wicha. Gene expression signatures of isolated circulating tumor cells from metastatic breast cancer patients reveal presence of breast cancer stem cells with EMT or MET phenotypes. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4726. doi:10.1158/1538-7445.AM2015-4726
Abstract 4730: Molecular analysis of the pediatric cancer fibrolamellar hepatocellular carcinoma
Authors: Simon Elana P. , Honeyman Joshua N. , Darcy David G. , Rosenberg Brad R. , Lim Iris I. , Murphy Jennifer M. , Farber Ben , Lalazar Gadi , Freije Catherine , La Quaglia Michael P. , Simon Sanford M. 
Published: August 2015

Abstract
Genomic analysis of the pediatric cancer fibrolamellar hepatocellular carcinoma
Fibrolamellar hepatocellular carcinoma (FLHCC) is a rare liver tumor that usually occurs in adolescents and young adults. Originally considered a variant of hepatocellular carcinoma (HCC), FLHCC is characterized by hepatocytes with deeply eosinophilic, granular cytoplasm interspersed with fibrous bands, without signs of cirrhosis as in HCC. Since little is known of its molecular pathogenesis, we performed RNA-seq and whole genome sequencing of FLHCC paired with normal liver from the same patient.
Our results demonstrated that the majority of the DNA is unremarkable with few recurrent mutations or structural variants such as amplifications or inversions The major finding is a heterogeneous deletion of ∼400 kB in chromosome 19 which produces a chimeric transcript and a fully functional protein, a fusion between the heat shock protein DNAJB1 and the catalytic subunit of protein kinase A (PRKACA). Our initial observation of this chimera in 15 out of 15 patients has now been expanded to 116 out of 116 patients. Differential expression analysis of RNA-seq revealed many changes in the gene expression in FLHCC as compared to its paired normal liver. These changes were highly consistent from patient to patient, suggesting a unifying pathogenesis. The RNA-seq from our FLHCC samples had little in common with HCC samples from the TCGA or published reports of other cancers. An analysis of protein expression correlated well with the RNA-seq results. Some observed changes can directly be linked to increased activity of PRKACA. Other changes involve pathways known to participate in the initiation and progression of other cancers, which, along with an increase of PRKACA activity, represent targets for therapeutic intervention. Several of these targets are now being explored in cellular models, genetic, and PDX mouse models, as well as clinical trials.
Citation Format: Elana P. Simon, Joshua N. Honeyman, David G. Darcy, Brad R. Rosenberg, Iris I. Lim, Jennifer M. Murphy, Ben Farber, Gadi Lalazar, Catherine Freije, Michael P. La Quaglia, Sanford M. Simon. Molecular analysis of the pediatric cancer fibrolamellar hepatocellular carcinoma. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4730. doi:10.1158/1538-7445.AM2015-4730