bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 1524: BCL6 modulates the TP53 and STAT pathways in glioma
Authors: Chen Ye , Xu Liang , Dutra-Clarke Marina , Mayakonda Anand , Lin De-Chen , Koh Lynnette , Chong Yuk Kien , Sandanaraj Edwin , Madan Vikas , Yang Henry , Doan Ngan , Said Jonathan W. , Yong William H. , Müschen Markus , Ang Beng Ti , Tang Carol , Breunig Joshua J. , Koeffler Phillip 
Published: July 2017

Abstract
Glioblastoma multiforme (GBM) remains the most aggressive brain malignancy with little improvement in prognosis or therapy for decades. Recently, we identified BCL6, also known as ZBTB27, to be a novel oncogene in GBM. In this study, we performed IHC analysis of 153 primary human glioma specimens and 8 normal brain samples. BCL6 expression is robustly elevated in tumor samples and positively correlated with glioma pathological grade. High BCL6 expression strongly predicts a worse prognosis of GBM patients. Depletion of BCL6 in human GBM cells reduced the incorporation of BrdU, promoted the cellular senescence and inhibited the growth of human GBM cells in vivo. Next, genome-wide occupancy of BCL6 in GBM cells was characterized by ChIP-seq assay. Genomic regions centered on BCL6 peaks are co-enriched with RNA-Pol II and flanked with strong H3K27ac and H3K4me3 modifications. MYC and two long non-coding RNAs MALAT1 and NEAT1 were identified as novel BCL6 targets in GBM. Moreover, pathway enrichment analysis of BCL6 peak-associated genes reveals a significant enrichment of JAK-STAT, TP53, ERBB and MAPK pathways. We demostrated further that BCL6 represses the TP53 pathway and promotes the JAK-STAT pathway activation in GBM cells. Together, our findings uncover potential downstream targets and provide a better understanding of BCL6 function in GBM.
Citation Format: Ye Chen, Liang Xu, Marina Dutra-Clarke, Anand Mayakonda, De-Chen Lin, Lynnette Koh, Yuk Kien Chong, Edwin Sandanaraj, Vikas Madan, Henry Yang, Ngan Doan, Jonathan W. Said, William H. Yong, Markus Müschen, Beng Ti Ang, Carol Tang, Joshua J. Breunig, Phillip Koeffler. BCL6 modulates the TP53 and STAT pathways in glioma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1524. doi:10.1158/1538-7445.AM2017-1524
Abstract 1529: Scutellaria baicalensis targets the hypoxia-inducible factor-1α and attenuates ovarian cancer growth
Authors: Hussain Imran , Waheed Sana , Ahmad Kashif A. , Pirog John E. , Syed Viqar 
Published: July 2017

Abstract
Hypoxia-inducible factor-1alpha (HIF-1α), a transcription factor important for maintaining cellular oxygen homeostasis, is aberrantly upregulated in many tumors and implicated in angiogenesis, metastasis and drug resistance. Therefore, developing treatments that target HIF-1α may be a viable therapeutic approach. For centuries, traditional Chinese medicine has used herbs, such as Scutellaria baicalensis (SB), as a natural remedy for tumors. However, the mechanisms by which SB inhibits tumor growth are not known. We have previously reported that SB inhibits cancer cell proliferation and targets NF-κB in endometrial and ovarian cancers and TGF-β in endometrial cancers. In this study, we examined the effects of SB on HIF-1α protein levels in three ovarian cancer cell lines, SKOV3, OVCA 429, and OVCA 420, grown under normoxic and hypoxic conditions. When treated daily with SB, cancer cells showed a decrease in HIF-1α expression after 48 hours. Investigation into the molecular mechanisms of SB-induced inhibition revealed a significant reduction of HIF-1α accumulation in cells treated with cycloheximide, a protein synthesis inhibitor. Further decrease of HIF-1α accumulation was seen when cycloheximide was combined with SB. Additionally, SB- induced HIF-1α proteasomal degradation was prevented by treatment of cells with proteasomal inhibitor MG132 and chloroquine, lysosome inhibitor, abrogated SB-induced inhibition of HIF-1α. Activation of PI3K/AKT and MAPK/ERK is shown in cancers. SB reduced levels of phospho-AKT and phospho-extracellular signal-related kinase (ERK) in ovarian cancer cells. Furthermore, pretreatment of cells with LY294002 (phosphoinositide 3-kinase inhibitor) and PD98059 (mitogen-activated protein kinase kinase inhibitor) reduced HIF-1α expression comparable to SB-treated cells. Hypoxia-induced cisplatin resistance is a major challenge in therapy of ovarian tumors. SB reduces the proliferation and reverses cisplatin resistance in ovarian cancer cells by attenuating the expression of HIF-1α. Taken together, the findings suggest that targeting HIF-1α with SB could be an effective treatment strategy for ovarian cancer and that SB can improve the sensitivity of cells to cisplatin.
Note: This abstract was not presented at the meeting.
Citation Format: Imran Hussain, Sana Waheed, Kashif A. Ahmad, John E. Pirog, Viqar Syed. Scutellaria baicalensis targets the hypoxia-inducible factor-1α and attenuates ovarian cancer growth [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1529. doi:10.1158/1538-7445.AM2017-1529
Abstract 1536: CRISPR/Cas9 biased mutagenesis in the mouse genome: Is it useful or harmful for cancer therapeutics
Authors: Shin Ha Youn 
Published: July 2017

Abstract
Advances in CRISPR/Cas9 genome editing have provided unprecedented opportunities to interrogate the functional significance of any given genomic site. While this technology is rapidly spreading and extended to with almost 4,000 PubMed entries as of today, there is a paucity of data on the extent of unexpected and undesired molecular consequences established upon targeting the mouse genome. We have introduced deletions at more than 20 genomic sites including CTCF and STAT5 transcription factor binding sites, screened over 500 founder mice and established and analyzed more than 50 lines. These data sets revealed hitherto unknown deletion patterns, unexpected large deletions using single sgRNAs and the consistent deletion of sequences bridging distant loci that were targeted simultaneously. Our findings provide guidelines for the application of CRISPR/Cas9 in the mouse germline and provide the insight into designing CRISPR-based cancer therapeutics.
Note: This abstract was not presented at the meeting.
Citation Format: Ha Youn Shin. CRISPR/Cas9 biased mutagenesis in the mouse genome: Is it useful or harmful for cancer therapeutics [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1536. doi:10.1158/1538-7445.AM2017-1536
Abstract 1537: 3p13-14 FOXP1-SHQ1 deletion spanning multiple potential tumor suppressor genes cooperates with PTEN loss in cancer
Authors: Hieronymus Haley , Iaquinta Philip J. , Wongvipat John , Gopalan Anuradha , Murali Rajmohan , Mao Ninghui , Carver Brett S. , Sawyers Charles L. 
Published: July 2017

Abstract
The recurrent 3p13-14 deletion spanning from FOXP1 to SHQ1 occurs frequently in prostate cancer and is broadly lost in a range of cancer types, but this deletion has unknown tumor suppressive potential. FOXP1-SHQ1 deletion significantly co-occurs with PTEN loss in prostate cancer and other cancers. We find that FOXP1-SHQ1 deletion cooperates with PTEN loss to accelerate prostate cancer development in mice, resulting in tumors with increased proliferation and highly anaplastic dedifferentiation. FOXP1-SHQ1 deletion in these PTEN null tumors results in selective mTORC1 pathway hyperactivation beyond that mediated by PTEN loss alone. FOXP1-SHQ1 deletion also partially rescues AR target gene inhibition caused by PTEN loss, circumventing the repression of the androgen axis seen upon PI3K pathway activation. Clinically, combined FOXP1 and PTEN loss is associated with increased prostate cancer recurrence, and this finding extends to other cancer types, most notably breast cancer.
Citation Format: Haley Hieronymus, Philip J. Iaquinta, John Wongvipat, Anuradha Gopalan, Rajmohan Murali, Ninghui Mao, Brett S. Carver, Charles L. Sawyers. 3p13-14 FOXP1-SHQ1 deletion spanning multiple potential tumor suppressor genes cooperates with PTEN loss in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1537. doi:10.1158/1538-7445.AM2017-1537
Abstract 1543: Caspase-10 suppresses tumorigenesis by targeting ATP-citrate lyase
Authors: Kumari Rajni , Das Sanjeev 
Published: July 2017

Abstract
p53 fosters metabolic reprogramming, which restricts metabolic adaptation of tumor cells under energy stress conditions. However, modulation and directionality of underlying cascades to induce or restrict metabolism are determined by the downstream target of p53. To explore the role of p53 in tumor metabolism upon metabolic stress, we performed a microarray screen in the presence or absence of p53 under glucose starvation. We observed caspase-10 to be upregulated by p53 upon metabolic stress. Caspase-10 belongs to the class of initiator caspases and is poorly understood in terms of substrate specificities. Emerging evidences also suggest intrinsic activation of caspase-10, distinct from its homologue caspase-8. Moreover, inactivating mutations as well as downregulation of caspase-10 in several carcinomas are suggestive of its role in tumorigenesis. Thus, we investigated the function of caspase-10 as a tumor suppressor. Our results indicated that caspase-10, upregulated in a p53-dependent manner in response to metabolic stress, was activated by homodimerization-induced intrinsic activation mechanism involving Adenylate Kinase 2 and FADD. We further performed a proteomic screen to identify novel caspase-10 substrates. We observed that several anabolic enzymes are caspase-10 interacting partners. However, in vitro and in vivo assays confirmed only ATP-Citrate Lyase (ACLY) as a novel substrate of caspase-10. Cleavage of ACLY by caspase-10 abrogates enzymatic conversion of cytosolic citrate to acetyl-CoA, leading to overall decrease in nucleocytosolic acetyl-CoA pool. Decrease in cytosolic acetyl-CoA levels suppress lipogenesis upon metabolic stress. Moreover, decreased levels of nuclear acetyl-CoA alter global histone acetylation. Further studies using RNAi established that alteration in histone acetylation is GCN5-dependent. Caspase-10-dependent abrogation of histone acetylation reprograms the epigenetic profile of metastatic and proliferative genes, leading to their diminished expression under metabolic stress. Concomitant suppression of both cytosolic lipogenesis and nuclear histone acetylation by caspase-10-mediated ACLY cleavage decreases proliferation capacity, migration potential and invasiveness of tumor cells. Further, studies in mouse tumor models confirmed that caspase-10 restricts tumorigenesis and metastases under metabolic stress via ACLY and GCN5. Taken together, our findings establish caspase-10 as a novel integrator of metabolism and epigenetics, by regulating acetyl-CoA levels. Hence, it functions as a tumor suppressor by disrupting lipogenesis-mediated metabolic reprogramming and GCN5-mediated epigenetic reprogramming.
Citation Format: Rajni Kumari, Sanjeev Das. Caspase-10 suppresses tumorigenesis by targeting ATP-citrate lyase [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1543. doi:10.1158/1538-7445.AM2017-1543
Abstract 1545: Loss of glycogen debranching enzyme (AGL) promotes rapid growth of non-small cell lung cancer cells
Authors: Meier David R. , Weinhaus Benjamin , Oldenburg Darby , Guin Sunny 
Published: July 2017

Abstract
Glycogen Debranching Enzyme (AGL) is involved in glycogen breakdown. Compromise in glycogen breakdown due to loss of function mutations in the AGL gene lead to metabolic disease - Glycogen Storage Disease Type III. We have previously shown that loss of AGL results in rapid growth of bladder cancer cells using extensive in vitro and in vivo experiments. Here we test whether AGL regulate growth of non-small cell lung cancer (NSCLC) cells. We show that loss of AGL promotes rapid growth of NSCLC cells using anchorage independent growth assay. Loss of AGL also resulted in rapid xenograft growth of NSCLC cells when injected subcutaneously in immunocompromised mice. Whereas overexpression of AGL reduce the growth of these NSCLC cells. Further loss of glycogen phosphorylase the other enzyme involved in glycogen breakdown does not promote aggressive growth of these cancer cells. This observation is similar to our findings in bladder cancer which confirms that AGL regulates tumor growth independent of its role in glycogen metabolism. Thus using in vitro and in vivo experiments we show that AGL can regulate the growth of multiple tumor types such as bladder cancer and NSCLC. The exact mechanism on how AGL regulates NSCLC growth needs further investigation.
Citation Format: David R. Meier, Benjamin Weinhaus, Darby Oldenburg, Sunny Guin. Loss of glycogen debranching enzyme (AGL) promotes rapid growth of non-small cell lung cancer cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1545. doi:10.1158/1538-7445.AM2017-1545
Abstract 1551: GULP1 is an epigenetically altered and functional tumor suppressor in urothelial carcinoma through regulation of Nrf2-Keap1 signaling axis
Authors: Hayashi Masamichi , Guida Elisa , Goldberg Rachel , Inokawa Yoshikuni , Reis Leonardo , Oki Akira , Izumchenko Evgeny , Maldonado Leonel , Marchionni Luigi , Brait Mariana , Bivalacqua Trinity , Baras Alexander , Netto George J. , Koch Wayne , Sidransky David , Hoque Mohammad O. 
Published: July 2017

Abstract
We identified GULP1 as a novel tumor suppressor gene (TSG) selectively silenced during urothelial cancer (UC) progression through promoter hypermethylation (PH) analyzed by quantitative methylation specific PCR (QMSP) and novel methylation specific digital droplet PCR (ddPCR) assay. Numerous cell based assays revealed that GULP1 silencing confers growth advantage to tumor cells. Correspondently, in vivo tumorigenicity after xenotransplantation of GULP1 knockdown T24 cells was significantly higher than control cells. Further mechanistic analysis revealed that GULP1 has a crucial role in the regulation of Nrf2-Keap1 axis, maintaining actin cytoskeleton architecture and helping Keap1 to scaffold Nrf2 in the cytoplasm. Moreover, GULP1 silencing induces constitutive activation of Nrf2 target signature, responsible for chemoresistance of UCs. Additionally, we analyzed GULP1 PH and expression in cisplatin-based therapy responsive and resistant primary UC samples, and in isogenic cisplatin sensitive and resistant T24 cell lines. Interestingly, GULP1 expression at transcription level was lower in both resistant primary UC samples and resistant T24 cell line. Cell lines with lower expressions of GULP1 (SW780 and UM-UC-3) also showed higher resistance to cisplatin than those with higher expression (T24 and BFTC905). Altogether, our findings determined that GULP1 is an epigenetically silenced potential TSG in UC and GULP1 expression and/or PH may guide in selecting candidate patients for cisplatin based neo-adjuvant therapy.
Citation Format: Masamichi Hayashi, Elisa Guida, Rachel Goldberg, Yoshikuni Inokawa, Leonardo Reis, Akira Oki, Evgeny Izumchenko, Leonel Maldonado, Luigi Marchionni, Mariana Brait, Trinity Bivalacqua, Alexander Baras, George J. Netto, Wayne Koch, David Sidransky, Mohammad O. Hoque. GULP1 is an epigenetically altered and functional tumor suppressor in urothelial carcinoma through regulation of Nrf2-Keap1 signaling axis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1551. doi:10.1158/1538-7445.AM2017-1551
Abstract 1556: Algorithms for discovery of somatic single nucleotide mutation display specific artifacts and different detection capabilities under the effect of read coverage and sample heterogeneity
Authors: Xiao Wenming , Wu Leihong , Yavas Gokhan , Hong Huixiao , Ning Baitang , Tong Weida , Donaldson Eric F. , Tezak Zivana , Philip Reena , Jacob Howard , Staudt Louis M. 
Published: July 2017

Abstract
Understanding the performance and capability of different bioinformatics algorithms used for the discovery of somatic variants is very important for helping scientists choose an appropriate tool for cancer research. In this study, we developed a comparison approach and created a series of data sets that could be used to provide such guidance. We mixed reads from two well characterized individuals, NA12878 and NA24385, and generated a series of data sets with different coverages and sample heterogeneity. We then used these data sets to evaluate five commonly utilized somatic mutation detection tools. Our results indicate that read coverage has a significant impact on the accuracy and capability of mutation calling by individual bioinformatics algorithms. The mutation caller that performs well with high read coverage may perform poorly with low read coverage. On the other hand, the tool that performed well in calling variants in a relatively higher homogeneity sample may not have the same power to detect rare variants with low mutation allele frequency. In addition, we demonstrated that different mutation calling algorithms are associated with specific artifacts that were sensitive to read coverage. Furthermore, there were large numbers of false positives and false negatives shared by five callers, indicating that other factors, such as read alignment, library preparation, and even the properties of the sequencing platform could be the sources of false discovery for somatic variants. We observed similar behavior of the five variant calling algorithms using the sequencing data of a pair of matched tumor/normal cell lines, confirming the findings from the comparative analyses on the mixture of reads from the two normal individuals. Our findings are expected to facilitate selection of bioinformatics pipelines that fit for specific purposes in cancer research based on sequencing data.
Citation Format: Wenming Xiao, Leihong Wu, Gokhan Yavas, Huixiao Hong, Baitang Ning, Weida Tong, Eric F. Donaldson, Zivana Tezak, Reena Philip, Howard Jacob, Louis M. Staudt. Algorithms for discovery of somatic single nucleotide mutation display specific artifacts and different detection capabilities under the effect of read coverage and sample heterogeneity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1556. doi:10.1158/1538-7445.AM2017-1556
Abstract 1558: Data-driven approach to detecting novel gene interactions in cancer with applications to drug response prediction and cancer stratification
Authors: Magen Assaf , Das Avinash , Lee Joo , Hannenhalli Sridhar , Ruppin Eytan 
Published: July 2017

Abstract
The effect of a gene’s activity on a phenotype depends on the context of a complex network of functionally interacting genes. Several genetic interactions (GIs), such as Synthetic lethality and Synthetic Rescues, have been reported to have a significant functional role in cancer progression and provide potential candidates for selective cancer treatments. However, numerous other types of GIs with potential clinical significance are yet to be explored. In this work we generalize the concept of GI and detect ~70,000 GIs of different types with both molecular and clinical signature. We demonstrate their clinical predictive value as well as their ability to stratify breast cancer patients into refined clinical subtypes that might allow for better diagnosis and modified course of treatment. These results compare favorably with previous sequence based approaches and provide evidence for the importance of context specific genomic events and their effect on tumor progression. Additionally, the GI network accurately predicts patients’ drug response, where difference GI types are found to be predictive of distinct drugs in a complementary manner. This work provides the basis for future exploration of novel GI types as well as individual interactions with major impact on cancer progression.
Citation Format: Assaf Magen, Avinash Das, Joo Lee, Sridhar Hannenhalli, Eytan Ruppin. Data-driven approach to detecting novel gene interactions in cancer with applications to drug response prediction and cancer stratification [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1558. doi:10.1158/1538-7445.AM2017-1558
Abstract 1571: Decrypting the transcriptome profile of Pak4 using next generation sequencing
Authors: Rane Chetan , Patel Misaal , Cai Li , Minden Audrey 
Published: July 2017

Abstract
The PAK4 (p-21 Activated Kinase 4) protein kinase has long been associated with cancer because of its key roles in regulating cell proliferation, cell cycle progression and cell morphology. The PAK4 gene is amplified in different types of cancers, including breast cancer. PAK4 overexpression is associated with oncogenic transformation in several breast cancer cell lines, while PAK4 inhibition has been shown to significantly reduce their tumorigenic potential. However, there is limited information available on PAK4’s mechanism of action in promoting tumorigenesis. To gain an insight into PAK4 downstream signaling pathways, we performed Next Generation Sequencing (NGS) on RNA samples collected from non-transformed immortalized mouse mammary epithelial cells (WT iMMECs) and iMMECs overexpressing PAK4. Research from our lab has shown that unlike WT iMMECs, iMMECs overexpressing PAK4 formed tumors when injected into mammary fat pads of mice, suggesting a central role for PAK4 in tumor formation. Previous studies to delineate PAK4 signaling pathways have mostly focused on substrates phosphorylated by PAK4. This study, however, takes into account genes which may act downstream of PAK4 and play an important role in mediating long term PAK4 function. RNA-seq analysis offers the ability to discover new genes and splice variants and measure transcript expression. mRNA was isolated in triplicates from WT iMMECs and iMMECs overexpressing PAK4; mRNA from each condition was then sequenced using Illumina NextSeq platform. The RNA-seq data generated was analyzed using Top Hat and Cufflinks software, which created a list of genes whose expression was significantly different in these two cell types, and previously unknown to be regulated by PAK4 (26 genes were up regulated and 51 genes were down regulated by more than a log2 fold change of 3). A qPCR analysis of 8 of these genes validated the sequencing data. Among the different genes we identified, we chose to focus on ParvB, which is consistently down regulated by almost seven fold in the iMMECs overexpressing PAK4. Previous studies have suggested a tumor suppressor role for ParvB in regulating breast tumorigenicity. We hypothesize that PAK4 mediates mammary tumor formation through ParvB downregulation. Additional studies investigating the role of ParvB in the PAK4 signaling pathway are under investigation. Future studies will also involve studying the other genes we found to be regulated by PAK4 overexpression and determining their role in tumorigenesis.
Citation Format: Chetan Rane, Misaal Patel, Li Cai, Audrey Minden. Decrypting the transcriptome profile of Pak4 using next generation sequencing [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1571. doi:10.1158/1538-7445.AM2017-1571