bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-263: Effects of black raspberry diet on the metabolomic profile of C57BL/6J mouse tissues
Authors: Skaer Chad W. , Pan Pan , Young Matthew , Wang Hsin Tzu , Oshima Kiyoko , Huang Yi-Wen , Stoner Gary D. , Lechner John , Wang Li-Shu 
Published: August 2015

Abstract
In our previous work, a diet containing 5% freeze-dried black raspberries (BRB) was shown to significantly inhibit colorectal cancer in ApcMin mice. Studies in recent years have shown that metabolomics may help to elucidate the anti-cancer effects of dietary factors. Initially, therefore, we evaluated the effects of black raspberries on the metabolomic profiles of C57BL/6J mice, the mouse strain from which ApcMin mice were derived. In this study, we report the effects of the BRB diet on the metabolomic profiles from C57BL/6J mice. After 8 weeks on a 5% BRB or control AIN-76A diet, feces, liver, and colon mucosa tissues from 9 BRB-fed mice and 7 control-diet fed mice were collected and profiled using mass spectrometry. A total of 424 named metabolites were observed in the liver, feces, and colon mucosa, with 115 metabolites whose levels were significantly different between BRB and control-diet mice (P&lt;0.05). Of these 115 differentiated metabolites, 41 were altered in the colon mucosa, and 38 and 44 metabolites were different in the feces and liver, respectively. Almost all of the changed metabolites in the colon mucosa (36 of 41) were downregulated by the BRB diet, whereas in the feces and liver the majority were upregulated (58 of 82). Included in the upregulated metabolites were lipids and amino acids in the feces and liver tissue. Benzoate derivatives, the product of gut bacteria metabolism of BRB polyphenols, were also up in all tissues. Among the downregulated metabolites were lipids in the colon mucosa and lysolipids in the liver. The decreased levels of lipid metabolites, particularly fatty acids, in the colon mucosa of mice indicates that antagonizing fatty acid synthesis is a potential mechanism by which the BRB diet is altering energy utilization in the colon mucosa of mice.
Citation Format: Chad W. Skaer, Pan Pan, Matthew Young, Hsin Tzu Wang, Kiyoko Oshima, Yi-Wen Huang, Gary D. Stoner, John Lechner, Li-Shu Wang. Effects of black raspberry diet on the metabolomic profile of C57BL/6J mouse tissues. [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 LB-263. doi:10.1158/1538-7445.AM2015-LB-263
Abstract LB-266: Suppression of colitis-associated colon carcinogenesis by the natural triterpenoid celastrol
Authors: Choi Sung Hee , Baker Emily , Kim Byung-Gyu , Tochtrop Gregory , Letterio John J. 
Published: August 2015

Abstract
Celastrol is a natural triterpenoid isolated from the medicinal herb Triptyrgium wilfordii, commonly known as the Thunder of God vine. Celastrol has been shown to have a broad range of anti-inflammatory and anti-cancer activities. Here we investigated whether celastrol administered as a dietary supplement can inhibit both colitis and colitis-associated colon cancer (CAC) in either genetic or chemically-induced CAC mouse models. As a genetic and spontaneous, inflammatory-driven intestinal neoplasia model, we generated a Smad4TKO / p27Kip1-/- (DKO) mouse in which a germ line p27Kip1 gene deletion (p27Kip1-/-) was combined with the T cell-restricted deletion of the Smad4 gene (Smad4TKO). All DKO mice developed spontaneous gastrointestinal inflammation and colon carcinoma by 3 months of age. Administration of celastrol as a dietary supplement (2 mg/day) to DKO mice increased survival and suppressed intestinal epithelial neoplasia by decreasing production of inflammatory mediators, including TNF-alpha, IL-6, IL-1beta and iNOS. We investigated the chemopreventive activity of celastrol in the chemically induced CAC mouse model using dextran sulfate sodium (DSS)/azoxymethane (AOM). Mice (C57/BL6, ages 6-8 weeks) received intraperitoneal injections with 10 mg/kg AOM, followed by exposure to 2% DSS in drinking water for 7 days. We repeated 3 cycles of 2% DSS, with 10 days of normal drinking water provided between cycles. Mice were either maintained on control diet or given celastrol (2 mg/day) diet beginning with first administration of DSS and continuing until termination of the experiment. Mice receiving celastrol diet showed less loss in body weight compared with the control diet group and marked protection from AOM/DSS-induced colon cancer. The incidence and number of colonic tumors in mice in the celastrol diet group were also significantly lower than those in control diet group. These results were accompanied by decreased expression of iNOS and lower production of pro-inflammatory cytokines. Our data demonstrate the protective effects of celastrol in the chemoprevention of CAC, was and this effect correlated with a dampening of iNOS expression and with a decrease of inflammatory cytokine production. These results highlight the potential of celastrol as an effective agent for the chemoprevention of CAC in humans.
Citation Format: Sung Hee Choi, Emily Baker, Byung-Gyu Kim, Gregory Tochtrop, John J. Letterio. Suppression of colitis-associated colon carcinogenesis by the natural triterpenoid celastrol. [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 LB-266. doi:10.1158/1538-7445.AM2015-LB-266
Abstract LB-297: Integrative analysis identifies driver lncRNAs in prostate cancer
Authors: Guo Haiyang , Ahmed Musaddeque , Hua Junjie , Liang Yi , Langstein Jens , He Housheng Hansen 
Published: August 2015

Abstract
Genome-Wide Association Studies (GWAS) and whole-genome resequencing studies identified thousands of germline risk variants and somatic mutations in cancer. However, efforts to interpret these data have mainly focused on protein coding genes, despite the fact that majority of these genetic alterations locate outside of coding gene exons. A recent curation of over seven thousand RNA-seq data characterized more than fifty-eight thousand expressed long noncoding RNAs (lncRNAs) in human genome, twice as large as the number of protein coding genes. In this study, we integrated lncRNA gene expression, epigenetic and genetic alteration data to nominate potential driver lncRNAs in prostate cancer. We have identified eleven lncRNAs that are regulated by risk SNPs and somatic mutations through both cis and trans actions. The function of two of these lncRNAs in prostate cancer development and progression has been characterized. Our data suggests that lncRNAs may function as driving factors in prostate cancer development and progression.
Note: This abstract was not presented at the meeting.
Citation Format: Haiyang Guo, Musaddeque Ahmed, Junjie Hua, Yi Liang, Jens Langstein, Housheng Hansen He. Integrative analysis identifies driver lncRNAs in 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 LB-297. doi:10.1158/1538-7445.AM2015-LB-297
Abstract LB-301: MicroRNA target screen identifies NEK9 pathway as a crucial component regulating proliferation of cancer cells lacking functional p53
Authors: Tsuchiya Naoto 
Published: August 2015

Abstract
An abnormality of TP53 is one of the hallmarks of human cancer, and a major cause of human cancer development. Therefore, selective elimination of p53-inactivated cancer cells represents an ideal therapeutic strategy. We previously identified miR-22 as a tumor-suppressive miRNA, which induces apoptosis in p53 wild type (WT) cancer cells, but it causes cell cycle arrest in p53-deficient cancer cells (Cancer Res. 2011). This finding led us to hypothesize that miR-22 has a unique set of target genes that determined the fate of cancer cells according to p53 mutation status. In this study, using miR-22 as a screening tool, we tried to identify factors that play important roles in proliferation and cell cycle progression of p53-inactivated cancer cells. The screen identified NIMA-related kinase 9 (NEK9) as such a crucial regulator. Both in vitro and in vivo, depletion of NEK9 selectively inhibited cell proliferation of p53-inactivated cancer cells, and expression of the NEK9 open reading frame restored proliferation. The resultant cell cycle arrest occurred pre-dominantly in G1 phase and exhibited features of pre-mature senescence. Furthermore, repression of NEK9 affected expression of a wide range of genes encoding factors involved in mRNA processing, receptor signaling and cell cycle regulation, suggesting that NEK9 plays a role in controlling these processes in p53-deficient cells. Importantly, high level expression of both NEK9 and p53 mutant proteins in lung adenocarcinoma specimens were associated with poor prognosis, suggesting that NEK9 confers some advantages for malignant progression of p53 mutant cancer. Collectively, our findings indicated that a novel NEK9 network, which is specifically activated in p53-deficient context, is a crucial cellular component responsible for the growth capacity of cancer cells lacking functional p53.
Citation Format: Naoto Tsuchiya. MicroRNA target screen identifies NEK9 pathway as a crucial component regulating proliferation of cancer cells lacking functional p53. [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 LB-301. doi:10.1158/1538-7445.AM2015-LB-301
Abstract LB-303: Identification of a mammalian sterile-20 like kinase 4 (MST4) inhibitor to target pituitary tumorigenesis
Authors: Xiong Weipeng , Matheson Chris , Backos Donald S. , Xu Mei , Kiseljak-Vassiliades Katja , Salian-Mehta Smita , Reigan Philip , Wierman Margaret E. 
Published: August 2015

Abstract
Pituitary tumors of the gonadotrope lineage are often large and invasive, resulting in hypopituitarism. There are no medical treatments currently available. Using a combined genetic and genomic screen of human pituitary tumor samples, we identified the Mammalian sterile-20 like kinase 4 (MST4) as a pro-tumorigenic effector, driving increased pituitary cell proliferation and survival in response to a hypoxic microenvironment. MST4 is a member of the germinal center kinase III subfamily of Ste-20 kinases with limited data available concerning its role in tumorigenesis. To identify selective inhibitors of the MST4 kinase, computational-based virtual library screening was employed to dock the commercially available SelleckChem kinase inhibitor library into the ATP binding site of the MST4 crystal structure. Several candidate MST4 kinase inhibitors were identified with the potential to bind with high affinity. Using a newly developed TRFRET in vitro kinase assay, one of the small molecule compounds exhibited a potent inhibition of the MST4 kinase (IC50 = 6.18 nM +/- 2.2 nM). To determine the ability of this inhibitor to antagonize MST4 actions, a hypoxic LβT2 gonadotrope pituitary cell model was used. Under chronic hypoxia (5% O2), cells stably overexpressing MST4 showed an increased rate of proliferation (at 7 days, 3.16-fold, p = 0.006) compared to vector control cells as assessed by BrdU staining. These effects were completely blocked by the inhibitor at 50nM (-2.61-fold, p = 0.01, NS from controls). Similarly, MST4 protection from hypoxia induced apoptosis under 1% O2 for 17h was also inhibited at the same dose as assessed by TUNEL staining (-2.72-fold, p&lt;0.001, NS from controls). Analysis of transfectants expressing wildtype and Mst4-mutants (K53E-kinase dead, T178A-loss of autophosphorylation, and C-terminus deletion) confirmed the inhibitory effect was dependent on the kinase sequence. Together, these data identify a potent inhibitor of the MST4 kinase with the capacity to selectively block pituitary cell growth under a hypoxic microenvironment and support future studies of its ability to modulate pituitary tumor growth in rodent models.
Citation Format: Weipeng Xiong, Chris Matheson, Donald S. Backos, Mei Xu, Katja Kiseljak-Vassiliades, Smita Salian-Mehta, Philip Reigan, Margaret E. Wierman. Identification of a mammalian sterile-20 like kinase 4 (MST4) inhibitor to target pituitary tumorigenesis. [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 LB-303. doi:10.1158/1538-7445.AM2015-LB-303
Abstract SY01-04: Chloroquine derivatives as anticancer agents
Authors: Amaravadi Ravi K. 
Published: August 2015

Abstract
Mouse models of cancer have demonstrated that therapy-induced autophagy in advanced cancer can promote tumor cell survival and resistance to therapy. Chloroquine derivatives impair autophagy by impairing lysosomal function. Preclinical studies in many, but not all, cancer models have shown that combining chloroquine derivatives with other anticancer agents produces autophagic vesicle accumulation followed by enhanced cancer cell death. Based on these results, clinical trials involving the hydroxychloroquine (HCQ) have been launched for patients with refractory malignancies. The results of the first 6 HCQ clinical trials (5 in humans, 1 in dogs) represent the first deliberate attempt to modulate autophagy therapeutically in patients. These studies indicate that autophagy can be modulated therapeutically with HCQ in patients. While the majority of patients did not experience unexpected toxicity, specific HCQ- chemotherapy combinations did produce enhanced myelosuppression, indicating treatment with HCQ and other chloroquine derivatives should continue to only be considered in the context of clinical trials. Encouraging antitumor activity of HCQ based combinations was observed in patients with melanoma, colon cancer, renal cell carcinoma, and in pet dogs, but randomized studies will be needed to determine if the activity can be attributed to the addition of HCQ. Preliminary results of currently enrolling or more recently completed clinical trials involving hydroxychloroquine will be highlighted. A serum-based approach based on secretome analysis of melanoma cells grown in three dimensional culture has identified potential quantitative biomarkers of low and high tumor cell autophagy. This approach could potentially lead to predictive and pharmacodynamic assays of response to autophagy modulation. To improve the potency of chloroquine derivatives against cancer we have previously reported a dimeric chloroquine Lys05, which is being evaluated for clinical development. Based on analysis of 70 new derivatives of Lys05, compounds which localize to the lysosome, inhibit autophagy and exhibit nanomolar cytotoxicity profiles have been identified. Finally we will discuss ongoing efforts to develop a more detailed understanding of the mechanism of action chloroquine as an anticancer agent.
Citation Format: Ravi K. Amaravadi. Chloroquine derivatives as anticancer agents. [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 SY01-04. doi:10.1158/1538-7445.AM2015-SY01-04
Abstract SY10-04: Histone tail alterations in cellular senescence
Authors: Duarte Luis F. , Young Andrew R. J. , Wang Zichen , Wu Hsan-Au , Panda Taniya , Kou Yan , Kapoor Avnish , Hasson Dan , Mills Nicholas R. , Ma'ayan Avi , Narita Masashi , Bernstein Emily 
Published: August 2015

Abstract
The process of cellular senescence generates a repressive chromatin environment, however, the role of histone tail modifications, histone variants and histone proteolytic cleavage in senescence remains unclear. Using well-characterized senescence models in human primary lung fibroblasts and melanocytes, we are investigating how chromatin alterations contribute to the senescence phenotype. Here we report novel histone H3 tail cleavage events in oncogene-induced and replicative senescence models mediated by the protease Cathepsin L. We find that cleaved forms of H3 are nucleosomal and that H3.3 is the preferred cleaved form of H3 - an H3 histone variant that is deposited independent of DNA replication. Ectopic expression of H3.3 and its cleavage product (H3.3cs1), which lacks the first twenty-one amino acids of the H3 tail, is sufficient to induce senescence. Furthermore, we find that chromatin incorporation of H3.3cs1 is mediated by the HUCA (HIRA/UBN1/CABIN1/ASF1a) histone chaperone complex. Genome-wide transcriptional profiling revealed that H3.3cs1 facilitates transcriptional silencing of cell cycle regulators including RB/E2F target genes, likely via the permanent removal of H3K4me3. Collectively, our studies have identified histone H3.3 and its proteolytically processed forms as key regulators of cellular senescence.
Citation Format: Luis F. Duarte, Andrew R. J. Young, Zichen Wang, Hsan-Au Wu, Taniya Panda, Yan Kou, Avnish Kapoor, Dan Hasson, Nicholas R. Mills, Avi Ma'ayan, Masashi Narita, Emily Bernstein. Histone tail alterations in cellular senescence. [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 SY10-04. doi:10.1158/1538-7445.AM2015-SY10-04
Abstract SY11-04: Genetics of immune escape
Authors: Hacohen Nir 
Published: August 2015

Abstract
How the genomic landscape of a tumor shapes and is shaped by anti-tumor immunity has not been systematically explored. Using large-scale genomic datasets of solid tissue tumor biopsies, we quantified the cytolytic activity of the local immune infiltrate and identified associated properties across 18 tumor types. The number of predicted MHC Class I-associated neoantigens was correlated with cytolytic activity and was lower than expected in colorectal and other tumors, suggesting immune-mediated elimination. We identified recurrently mutated genes that showed positive association with cytolytic activity, including beta-2-microglobulin (B2M), HLA-A, -B and -C and Caspase 8 (CASP8), highlighting loss of antigen presentation and blockade of extrinsic apoptosis as key strategies of resistance to cytolytic activity. Genetic amplifications were also associated with high cytolytic activity, including immunosuppressive factors such as PDL1/2 and ALOX12B/15B. Our genetic findings thus provide evidence for immunoediting in tumors and uncover mechanisms of tumor-intrinsic resistance to cytolytic activity.
Citation Format: Nir Hacohen. Genetics of immune escape. [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 SY11-04. doi:10.1158/1538-7445.AM2015-SY11-04
Abstract SY12-03: Obesity, inflammation and breast cancer
Authors: Dannenberg Andrew J. 
Published: August 2015

Abstract
Obesity is a risk factor for the development of hormone receptor-positive breast cancer in postmenopausal women. In addition to its impact on breast cancer risk, obesity has been recognized as a poor prognostic factor among breast cancer survivors. Obesity causes subclinical inflammation in visceral and subcutaneous white adipose tissue, characterized by macrophages surrounding dead or dying adipocytes forming crown-like structures (CLS). Estrogen synthesis is catalyzed by aromatase, which is encoded by CYP19. Several pro-inflammatory mediators including PGE2 and TNF-alpha are known inducers of aromatase. Utilizing a combination of preclinical models and human breast tissue samples, we demonstrated that obesity was associated with increased numbers of CLS in the breast (CLS-B), activation of the NF-κB transcription factor, increased levels of pro-inflammatory mediators and elevated aromatase expression. These findings raise the possibility that the obesity-inflammation-aromatase axis is important for understanding the link between obesity and hormone receptor-positive breast cancer in postmenopausal women. To further explore the potential clinical significance of breast adipose inflammation, a retrospective study was carried out to investigate the relationship between CLS-B and breast cancer recurrence. The presence of CLS-B at the time of index mastectomy was associated with shortened recurrence free survival in women who develop recurrent breast cancer. Whether white adipose inflammation promotes the progression of breast cancer via local effects, systemic mechanisms, e.g., hyperinsulinemia or both is uncertain. Given the apparent significance of white adipose inflammation (CLS-B) in the pathogenesis of disease, a blood-based biomarker discovery effort has been initiated. Elevated levels of CRP, IL-6 and insulin as well as altered levels of numerous metabolites correlate with the presence of breast white adipose inflammation. Finally, the connection between obesity, adipose inflammation and cancer provides a strong rationale for attempting to develop effective anti-inflammatory interventions. This will be illustrated with findings from a recent preclinical study that utilized caloric restriction to reverse adipose inflammation and related molecular changes in the mammary glands of obese mice.
Citation Format: Andrew J. Dannenberg. Obesity, inflammation and breast 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 SY12-03. doi:10.1158/1538-7445.AM2015-SY12-03