bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-125: Germline mutations in BAP1 predispose to melanocytic nevi and melanoma
Authors: Wiesner Thomas , Obenauf Anna , Murali Rajmohan , Fried Isabella , Griewank Klaus , Ulz Peter , Windpassinger Christian , Loy Shea , Wackernagel Werner , Wolf Ingrid , Becker Juergen , Viale Agnes , Lash Alex , Pirun Mono , Socci Nick , Ruetten Arno , Palmedo Gabrielle , Ott Arthur , Abramson David , Offit Kenneth , Cerroni Lorenzo , Kutzner Heinz , Bastian Boris , Speicher Michael 
Published: June 2012

Abstract
We describe an autosomal-dominant syndrome characterized by multiple non-pigmented, exophytic melanocytic nevi and an increased susceptibility for melanoma, caused by germline mutations in the histone deubiquitinase BAP1. To identify the causative alterations, we performed comprehensive genomic analyses in two unrelated families with numerous dermal nevi composed largely of large, epithelioid melanocytes with abundant amphophilic cytoplasm and large, pleomorphic, vesicular nuclei with prominent nucleoli. Both families each had one proband with uveal melanoma, and three probands in one family had cutaneous melanoma. Array-based comparative genomic hybridization (aCGH) revealed losses of parts of or the entire chromosome 3 in 11 of 22 neoplasms studied. Genotypic analyses revealed that the deletions invariably affected the chromosome from the unaffected parent. Genome partitioning of the minimally deleted region on chromosome 3p21 followed by massively parallel sequencing revealed two different inactivating germline mutations of the BAP1 tumor suppressor gene that in both families segregated with the phenotype. In almost all tumors the remaining wild type BAP1 allele was eliminated by deletion, separate inactivating mutations, or loss of heterozygosity. 35 of 40 nevi (88%) showed mutations in BRAF, while the uveal melanomas had mutations in GNAQ.
Our data identify BAP1 as a highly penetrant susceptibility gene for melanocytic neoplasia. Somatic BAP1 mutations have recently been reported in uveal melanoma and linked to the metastatic phenotype. Our observation of frequent bi-allelic inactivation of BAP1 in nevi indicates that the role of BAP1 in melanocytic neoplasia is more complex, and may differ depending on other factors such as the type of melanocyte (uveal or cutaneous) and the co-existing oncogenic mutation.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-125. doi:10.1158/1538-7445.AM2011-LB-125
Abstract LB-15: Overexpression of Pak1 and Pak4 contributes to endometrial carcinogenesis
Authors: Siu Michelle KY , Kong Daniel SH , Chan Hoi Yan , Ngai Sheila YP , Jiang Lili , Wong Esther SY , Ngan Hextan YS , Cheung Annie NY 
Published: June 2012

Abstract
Introduction: Endometrial cancer is the most common gynaecological cancer worldwide and its incidence in Asia is rising. It can be classified into two major types: the estrogen dependent type I endometrioid carcinoma that comprises about 80% of endometrial cancers and the type II non-endometroid carcinoma, which is estrogen-independent, including serous carcinoma and clear cell carcinoma. p21-activated kinases (Paks) are major effectors of the small Rho GTPases Rac1 and Cdc42 that play important roles in cell morphology, cytoskeletal reorganization, apoptosis, survival and angiogenesis. This study investigated the expression patterns, clinical significance, functional roles and putative downstream targets of Pak1 and Pak4 in endometrial cancer. Methods and Results: Immunohistochemical study of Pak1, Pak4 and p-Pak4 Ser474 (the activated form) was performed on 10 normal atrophic endometrium, 16 hyperplastic endometrium without atypia, 17 atypical complex hyperplasia and 67 endometrial carcinomas. Pak1 was expressed in cytoplasm whereas Pak4 and p-Pak4 were expressed in both cytoplasm and nucleus. Significantly higher Pak1, Pak4 and p-Pak4 expression was detected in hyperplastic endometrium and endometrial carcinomas than normal atrophic endometrium. Moreover, endometrioid carcinomas showed significantly higher Pak1 expression than non-endometrioid carcinomas. In endometrial carcinomas, expression of Pak4 was found to be correlated with proliferation markers, MCM7 and Ki67. By quantitative real-time polymerase chain reaction, significantly higher Pak1 and Pak4 mRNA expression was observed in endometrial cancer samples when compared with the corresponding non-tumor counterparts. Up-regulation of Pak1 and Pak4 mRNA and protein expression was also found in cancer cell lines compared with normal endometrial cells. Knockdown of Pak1 by siRNA in RL-95–2, an endometrial cancer cell line with relatively high Pak1 expression, inhibited cell proliferation along with down-regulation of estrogen receptor alpha mRNA and protein expression. Conclusion: This is the first report revealing the expression of Pak1 and Pak4 in normal atrophic, hyperplastic endometrium and endometrial carcinomas, suggesting Pak1 and Pak4 to be useful markers in detection of endometrial carcinoma in postmenopausal women and potential therapeutic targets in endometrial cancer.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-15. doi:10.1158/1538-7445.AM2011-LB-15
Abstract LB-215: Inhibition of Polo-like kinase 4 as an anti-cancer strategy
Authors: Mason Jacqueline , Wei Sam , Luo Xunyi , Nadeem Vincent , Kiarash Reza , Huang Ping , Awrey Don , Leung Genie , Beletskaya Irina , Feher Miklos , Forrest Bryan , Laufer Radek , Sampson Peter , Li Sze-Wan , Liu Yong , Lang Yunhui , Pauls Henry , Mak Tak , Pan James Guohua 
Published: June 2012

Abstract
Polo-like kinase 4 or PLK4 is a member of a conserved family of serine/threonine protein kinases that regulate multiple cellular processes, such as cell division and checkpoint regulation of mitosis. These kinases are often deregulated in cancer. PLK4 is the most structurally divergent PLK, localizes to centrosomes and is a critical regulator of centriole duplication. Over-expression of PLK4 leads to centrosome amplification and results in chromosome instability (CIN), a common characteristic observed in many types of cancers. We found that PLK4 is upregulated in breast cancer, specifically in the basal-like subtype. PLK4 expression is induced by hypoxia and suppressed by p53 in cancer cells. Consistent with this observation, PLK4 expression in cancer cells is upregulated when they are implanted and grown as xenografts in vivo. Furthermore, RNAi-mediated depletion of PLK4 inhibits the growth of cancer cells, but not normal cells (HMEC), in vitro, and tumor growth in vivo. Interestingly, siRNA knockdown of PLK4 sensitizes cancer cells to hypoxia. These findings suggest that targeting PLK4 may be a good therapeutic strategy in treating certain cancers. To this end, we initiated a discovery program that resulted in the identification of potent PLK4 inhibitors. These novel inhibitors are potent anti-prolifeartives, cause loss of mitotic checkpoint followed by apoptotic cell death, and suppress tumor growth in xenograft models. Mechanistically, inhibition of PLK4 suppresses phosphorylation of PLK4 and Histone H3, leads to failure of centrosome clustering and formation of multipolar spindles. Interestingly, breast cancer cell response to PLK4 inhibition appears to differ among subtypes of breast cancer cells and to be influenced by receptor and mutation status, such as ER and PTEN. Since multipolar division in cancer cells is not viable, due to massive missegregation of chromosomes, inhibition of PLK4 and formation of multipolar division followed by cell death may be a unique strategy for killing cancer cells. Implications of these findings in treating cancer will also be discussed.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-215. doi:10.1158/1538-7445.AM2011-LB-215
Abstract LB-223: Dissecting the therapeutic determinants of MET inhibition in Glioblastoma: HGF-autocrine loop predicts sensitivity to MET inhibitor
Authors: Xie Qian , Bradley Robert , Kang Liang , Koeman Julie , Worschech Andrea , De Giorgi Valeria , Wang Ena , Kefene Lisa , Su Yanli , Essenburg Curt , Kaufman Dafna , DeKoning Tom , Enter Mark , J.O'Rourke Timothy , Marincola Francesco , Vande Woude George F. 
Published: June 2012

Abstract
Due to its invasive nature, glioblastoma (GBM) is the most aggressive brain cancer. Hepatocyte growth factor (HGF) binds to MET tyrosine kinase receptor and induces invasive tumor growth. As MET inhibitors are entering clinical trials against several types of cancer including GBM, it is compelling to identify therapeutic determinants which could indicate which patient subsets are suitable for this therapy. We investigated in vivo four types of GBM models for their sensitivity to MET (SGX523*) or EGFR (erlotinib*) inhibitors: 1) Tumors sustained by an HGF-autocrine loop; 2) tumors displaying paracrine HGF tumor growth; and 3) tumors with polysomy MET amplification. 4) In addition, GBM tumors with epidermal growth factor receptor (EGFR) amplification were included, as this occurs frequently in GBM patients and often in association with MET aberrancy. Of the four tumor types, we observed that HGF-autocrine loop expression correlates with p-MET levels in the HGF autocrine cell lines, which in turn are extremely sensitive to MET inhibition in vivo. Moreover, serum HGF levels in HGF-autocrine loop GBM xenografts correlate with MET inhibition. Paracrine HGF can enhance GBM growth in vivo, but they were not significantly sensitive to MET inhibition. In type 4, EGFR VIII amplification predicted sensitivity to erlotinib, but MET polysomy in the same tumor did not display MET activity and the cells did not show sensitivity to MET inhibition. We conclude that HGF-autocrine loop GBM tumors bear an activated MET signaling pathway that may be used to predict sensitivity to MET inhibitors in GBM patients. However, targeting MET alone may not be sufficient for treating GBM and the combination of MET with other RTK inhibitors, especially EGFR inhibitors should be considered.
*SGX523, a selective small molecule MET inhibitor, was obtained from Eli Lilly and Company, Indianapolis IN.
*Erlotinib inhibits EGFR and was a generous gift from OSI Pharmaceuticals, Long Island N.Y.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-223. doi:10.1158/1538-7445.AM2011-LB-223
Abstract LB-278: Transcriptomic profiling of castrate resistant prostate cancer cells: identification of transcription factors associated with androgen resistance
Authors: Prencipe Maria , Madden Stephen , O'Neill Amanda , Culhane Aedin , O'Connor Darran , Klocker Helmut , Gallagher William M. , Watson William 
Published: June 2012

Abstract
Locally advanced and metastatic prostate cancer are treated by hormone ablation therapy. However, despite an initial response, the majority of men relapse within 2–3 years to develop a castrate resistant disease for which there are no effective treatments; therefore defining the mechanisms of resistance represents a significant question.
Androgen-independent (AI) sublines were derived from the androgen-dependent (AD) LNCaP cells. Previous studies in our laboratory have shown a complex interplay between changes in pro and anti-apoptotic proteins in the development of this resistance. Manipulating individual genes has only minor alterations in the resistant phenotype so we hypothesise that targeting the central signalling pathways and transcription factors (TFs) would represent a better therapeutic targeting approach.
We have undertaken a transciptomic analysis of the LNCaP parental (AD), LNCaP Abl (AI) and Hof (AI) cell lines, using the Affymetrix HG U133 Plus 2.0 GeneChip. Using a combination of correspondence analysis, between group analysis and co-inertia analysis, we have generated a transriptomic profile showing 900 genes associated with androgen resistance. Most importantly, we have predicted a list of TFs including HSF1, CDP, VDR-RXR, SRF and PBX1, which may be responsible for the differential gene expression observed in the AI compared to the AD cells. Taqman validation of 32 genes, including 6 TFs, has confirmed our gene chip results. Further validation of VDR-RXR and SRF activity was performed using luciferase assays. We are currently focusing on SRF, which has recently been associated with prostate cancer development (1). We have confirmed its up-regulation in the AI cell lines by WB.
Due to the heterogeneous nature of prostate cancer and the complex changes associated with the development of androgen resistance, the upstream TFs may represent better therapeutic targets to reverse this resistance.
Reference
1. Gorlov et al. Prioritizing genes associated with prostate cancer development. BMC Cancer 2010, 10:599
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr LB-278. doi:10.1158/1538-7445.AM2011-LB-278
Abstract A14: Invalidation of the inflammasome within breast tumor microenvironment impairs tumor growth
Authors: Guey Baptiste , Goutagny Nadege , Puisieux Isabelle , Caux Christophe , Tschopp Jurg , Renno Toufic , Pétrilli Virginie 
Published: June 2012

Abstract
Tumor microenvironment plays an essential role in modulating and supporting tumor growth. Solid tumors are frequently infiltrated with innate immune cells as illustrated by the strong macrophages infiltration observed in breast tumors. In fact, infiltrating macrophages in breast tumors are associated with poor prognosis. IL-1beta (IL-1 b) is a proinflammatory cytokine produced mostly by macrophages and dendritic cells which detection in advance breast tumor stage is also correlated with bad prognosis. Furthermore, mouse studies using the orthotopic implantation of the mammary tumor cell line 4T1 have suggested a role for IL-1b in tumor growth and vascularization. IL-1b is a peculiar cytokine as its production is tightly controlled. First, proinflammatory signals induce the production of the proIL-1 b. To be active, the cytokine has to be cleaved by the caspase-1 within a complex named the inflammasome. Finally the cleaved cytokine is secreted outside the cells. By and large, the inflammasome is composed of a scaffold receptor, for instance NLRP3, an adaptor, ASC, and caspase-1. The NLRP3 inflammasome is mainly expressed by macrophages and dendritic cells and gets activated upon detection of pattern-associated molecular pattern but also danger-associated molecular pattern such as extracellular ATP or uric acid. As the inflammasome controls the biological activity of IL-1b, we speculated that the inflammasome should play an important role in the breast tumor microenvironment. To test our hypothsesis, we used the mouse mammary model of breast cancer using orthotopic implantation of 4T1 cells within the mammary gland of either wild-type or inflammasome deficient mice. Our results show that tumor growth is delayed in caspase-1 deficient mice suggesting that the presence of the inflammasome in the tumor microenvironment supports tumor growth.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr A14.
Abstract A15: Inflammation-dependent deregulation of the tumor suppressor Pdcd4
Authors: Schmid Tobias , Rübsamen Daniela , Blees Johanna S. , Bajer Magdalena M. , Milke Larissa , Schulz Kathrin , Henrich Curtis J. , McMahon James B. , Colburn Nancy H. , Brüne Bernhard 
Published: June 2012

Abstract
Tumor suppressor Pdcd4 was shown to inhibit the helicase activity of eIF4A and consequently to suppress the translation of mRNAs with structured 5′UTRs. As a result, Pdcd4 inhibits transformation, migration, and invasion in vitro and tumorigenesis in vivo. Recent reports indicate that Pdcd4 protein levels are attenuated in various human tumor types. Loss of Pdcd4 was not attributable to mutational inactivation, instead miR-21-dependent translational repression and p70S6K1-mediated, phosphorylation-dependent attenuation of Pdcd4 protein stability emerged as important mechanisms of Pdcd4 regulation.
In this study, we characterize the mechanism of Pdcd4 regulation under inflammatory, tumor-promoting conditions. Our data indicate that Pdcd4 protein is lost in human tumor cells exposed to an inflammatory environment generated by activated macrophages. Downregulation of Pdcd4 required activation of PI3K-mTOR-p70S6K1-signaling and was attributable to a markedly reduced Pdcd4 protein half-life resulting from increased proteasomal degradation. Functionally, Pdcd4 protein levels inversely correlated with AP-1 transactivation, migration, and invasion. Based on the proposed mechanism of Pdcd4 regulation, we further developed an assay to identify compounds interfering with tumor-promoter induced degradation of Pdcd4. Identified hit compounds will provide a source for novel, translation-oriented approaches for tumor therapies.
In summary, we suggest that p70S6K1-dependent phosphorylation and subsequent proteasomal degradation of Pdcd4 protein is a key mechanism in the regulation of the tumor suppressor Pdcd4 under inflammation-associated, tumor-promoting conditions. Consequently, we put forward stabilization of Pdcd4 as a novel tumor therapeutic approach and identify novel compounds disrupting Pdcd4's phosphorylation-dependent destabilization during tumorigenesis.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr A15.
Abstract A2: Differential dependency of human cancer cells on vascular endothelial growth factor-mediated autocrine growth and survival
Authors: Lee Jungwhoi , Lee Jungsul Lee , Yu Hana , Choi Chulhee , Choi Kyungsun 
Published: June 2012

Abstract
Analysis using the public microarray database Gene Expression Omnibus indicates significantly higher mRNA expression of VEGF and VEGFRs in colorectal cancer and high-grade astrocytoma but not in hepatocellular carcinoma compared to normal tissue. Human malignant astrocytoma cell lines (U251-MG and U373-MG) and HT-1080 fibrosarcoma cells expressed relatively higher levels of VEGF and VEGFRs compared to hepatocellular and colorectal cancer cell lines. Administration of exogenous VEGF-A induced cell growth in a dose-dependent fashion in astrocytoma and fibrosarcoma cells but not in colorectal and hepatocellular cancer cells. The blockade of VEGF inhibited cell survival only in U251-MG, U373-MG and HT-1080 cells. These results collectively suggest the role of autocrine VEGF signaling in various cancer cells and provide a basis for the variable clinical responses to antiangiogenic therapy observed in different types of malignancies.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr A2.
Abstract A20: Differential rates of proliferation and apoptosis observed in human cutaneous T-cell lymphoma cell lines, in response to treatment with 9-cis UAB30, a novel rexinoid analog
Authors: Verney Zoe M. , Atigadda Venkatram R. , Elmets Craig A. , Muccio Donald D. , Grubbs Clinton J. 
Published: June 2012

Abstract
Cutaneous T-cell lymphoma (CTCL) designates a heterogeneous group of malignancies, characterized by the infiltration and detection of transformed T-cell lymphocytes in the skin. Although there is no cure for CTCL, a wide range of treatment options have been developed for use in the clinical setting. Bexarotene, a retinoid X receptor (RXR) agonist or rexinoid, is a commonly used treatment modality for CTCL. However, documented increases in the levels of triglycerides of CTCL patients, resulting from treatment with bexarotene, point to concerns over the long-term use and efficacy of this anticancer agent. We have recently synthesized a novel rexinoid, 9-cis UAB30, which does not elevate triglycerides in vivo and have begun evaluating its use as a potential chemotherapeutic agent for the treatment of CTCL. In this study, we compared the efficacy of 9-cis UAB30 to that of bexarotene in reducing cell proliferation and inducing apoptosis, in the three human CTCL cell lines HH, MJ, and Hut78. A standard XTT assay was used to determine the rate of cell proliferation of CTCL cells. In all three lines, 9-cis UAB30 was equally and sometimes more effective than bexarotene at suppressing cell proliferation. Using an annexin V binding assay, we next analyzed the rate of apoptosis in these human CTCL lines. Interestingly, we observed the MJ cell line to be resistant to apoptosis, when treated with either compound. The HH cell line exhibited a similar increase in apoptosis, whether treated with 9-cis UAB30 or bexarotene. Finally, the Hut78 cell line showed a greater sensitivity to apoptosis, when treated with 9-cis UAB30 as compared to bexarotene. Taken together, these preliminary results indicate that 9-cis UAB30 appears to be equally if not more effective than bexarotene at suppressing cell proliferation and appears to exert differential effects on the rate of apoptosis that may be cell-line specific. These differential responses of human CTCL cells have implications for the development of next-generation, rexinoid-based therapies and reveal that 9-cis UAB30 may be a better alternative for the treatment of CTCL.
Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the Second AACR International Conference on Frontiers in Basic Cancer Research; 2011 Sep 14-18; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2011;71(18 Suppl):Abstract nr A20.