bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract LB-051: High LDHA expression predicts decreased survival in neuroblastoma
Authors: Dorneburg Carmen , Christner Lisa , Barth Thomas F. , Mueller-Klieser Wolfgang , Fischer Matthias , Barbara Hero , Beckers Anneleen , Speleman Frank , Debatin Klaus-Michael , Beltinger Christian 
Published: July 2017

Abstract
Neuroblastoma (NB) is a common pediatric malignancy that often carries a poor prognosis. Aerobic glycolysis, i.e. the Warburg effect, is a hallmark of cancers, including NB. Lactate dehydrogenase A (LDHA) catalyzes the conversion of pyruvate to lactate. It is considered a pivotal component of the LDH tetramer, which is central in the Warburg effect. LDHA is overexpressed in many cancers. Little is known about the role of LDHA in NB. We therefore determined the expression of LDHA mRNA and protein in 651 and 112 clinically annotated patient samples, respectively. We show that enhanced mRNA expression and predominant cytoplasmic protein expression of LDHA, as detected by immunohistochemistry, is markedly associated with increased tumor aggressiveness and decreased patient survival. Surprisingly, despite the proposed pivotal role of LDHA in the Warburg effect, LDHA was dispensable for aerobic glycolysis in NB cells. Complete depletion of LDHA by CRISPR/Cas9-mediated knock-out in several NB cell lines did not decrease glucose consumption and production of pyruvate and ATP. In accordance, LDH activity was maintained despite loss of LDHA, as LDHB and LDHC were still expressed, most likely compensating for the loss of LDHA. In line with LDHA being dispensable for aerobic glycolysis in NB cells, LDHA depletion did not decrease malignant characteristics of NB cells. Thus, clonogenic growth, migration and tumorigenicity remained unaffected. Extending these findings from manifest to developing NB, we show that in the TH-MYCN NB mouse model the development of NB from normal sympathetic ganglia is not associated with increased LDHA expression. Taken together, this work establishes LDHA as a novel predictive marker in NB and calls into question the pivotal role in aerobic glycolysis attributed to LDHA.
Citation Format: Carmen Dorneburg, Lisa Christner, Thomas F. Barth, Wolfgang Mueller-Klieser, Matthias Fischer, Hero Barbara, Anneleen Beckers, Frank Speleman, Klaus-Michael Debatin, Christian Beltinger. High LDHA expression predicts decreased survival in neuroblastoma [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 LB-051. doi:10.1158/1538-7445.AM2017-LB-051
Abstract LB-056: Quantitative mass spectrometry analysis of immune checkpoint protein expression and N-glycosylation in human melanoma
Authors: Betanzos Carlos Morales , Lee Hyoungjoo , Ericsson Paula I. Gonzalez , Balko Justin M. , Johnson Douglas B. , Zimmerman Lisa J. , Liebler Daniel C. 
Published: July 2017

Abstract
Quantitative assessment of key proteins that control the tumor-immune interface is one of the most formidable analytical challenges in immunotherapeutics. We developed an targeted mass spectrometry (MS) platform to quantify programmed cell death-1 (PD-1), programmed cell death 1 ligand 1 (PD-L1), and programmed cell death 1 ligand 2 (PD-L2) at fmol/microgram protein levels in formalin fixed, paraffin-embedded sections from 22 human melanomas. PD-L1 abundance ranged 50-fold, from approximately 0.03 to 1.5 fmol/microgram protein and the PRM data were largely concordant with total PD-L1-positive cell content, as analyzed by immunohistochemistry (IHC) with the E1L3N antibody. PD-1 was measured at levels up to 20-fold lower than PD-L1, but the abundances were not significantly correlated (r2 = 0.062, p = 0.264). PD-1 abundance was weakly correlated (r2 = 0.3057, p = 0.009) with the fraction of lymphocytes/histiocytes in sections. PD-L2 was measured from 0.03 to 1.90 fmol/microgram protein and the ratio of PD-L2 to PD-L1 abundance ranged from 0.03 to 2.58. In 8 samples, PD-L2 was present at more than half the level of PD-L1, which suggests that PD-L2, a higher affinity PD-1 ligand, is sufficiently abundant to contribute to T-cell downregulation. We also identified five branched mannose and N-acetylglucosamine glycans at PD-L1 position N192 in all 22 samples. Extent of PD-L1 glycan modification varied by approximately 10-fold and the melanoma with the highest PD-L1 protein abundance and most abundant glycan modification yielded a very low PD-L1 IHC estimate, thus suggesting that N-glycosylation may affect IHC measurement and PD-L1 function. Additional PRM analyses quantified immune checkpoint/co-regulator proteins LAG3, IDO1, TIM-3, VISTA and CD40, which all displayed distinct expression independent of PD-1, PD-L1 and PD-L2. Targeted MS can provide a next-generation analysis platform to advance cancer immuno-therapeutic research and diagnostics. (Supported by NIH grant U24CA159988)
Citation Format: Carlos Morales Betanzos, Hyoungjoo Lee, Paula I. Gonzalez Ericsson, Justin M. Balko, Douglas B. Johnson, Lisa J. Zimmerman, Daniel C. Liebler. Quantitative mass spectrometry analysis of immune checkpoint protein expression and N-glycosylation in human melanoma [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 LB-056. doi:10.1158/1538-7445.AM2017-LB-056
Abstract LB-064: Cheminformatics studies to analyze the therapeutic potential of alkaloids from Rhazya stricta
Authors: Sabir Jamal S. , Obaid Abdullah Obaid Y. , Voleti Sreedhara , Bora Roop S. , Hajrah Nahid H. , Omar Abdulkader M. , Saini Kulvinder S. 
Published: July 2017

Abstract
Rhazya stricta is a unique medicinal plant source for many indole alkaloids, non- alkaloids, flavonoids, triterpenes and other unknown molecules with tremendous potential for therapeutic applications against many diseases. In the present article, we generated computational data on predictive properties and activity across two key therapeutic areas of cancer and obesity, and corresponding cheminformatics studies were carried out to examine drugable properties of these alkaloids. Computed physiochemical properties of the 78 indole alkaloids from Rhazya stricta plant using industry-standard scientific molecular modeling software and their predictive anti-cancer activities from reliable web-source technologies indicate their plausible therapeutic applications. Their predictive ADME properties are further indicative of their drug-like-ness. We believe that the top-ranked molecules with anti-cancer activity are clearly amenable to chemical modifications for creating potent, safe and efficacious compounds with the feasibility of generating new chemical entities (NCEs) after pre-clinical and clinical studies.
Keywords: Rhazya stricta, Alkaloids, Physiochemical properties, Druggability, Anticancer molecules, Anti-obesity molecules.
Citation Format: Jamal S. Sabir, Abdullah Obaid Y. Obaid, Sreedhara Voleti, Roop S. Bora, Nahid H. Hajrah, Abdulkader M. Omar, Kulvinder S. Saini. Cheminformatics studies to analyze the therapeutic potential of alkaloids from Rhazya stricta [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 LB-064. doi:10.1158/1538-7445.AM2017-LB-064
Abstract LB-070: Nano self-assemblies of paclitaxel for breast cancer treatment
Authors: Nagesh Prashanth Kumar Bhusetty , Chowdhury Pallabita , Chauhan Sumeeth S. , Hatami Elham , Khan Sheema , Hafeez Bilal , Chauhan Subhash C. , Jaggi Meena , Yallapu Murali M. 
Published: July 2017

Abstract
Objectives: Breast cancer (BC) is second leading cause of cancer-related deaths in the United States. Paclitaxel (Ptx) is an FDA-approved and frequently used chemotherapeutic agent against various cancers, including BC. However its adverse side effects and chemoresistance against it, limits its use in the clinic. Minimizing the toxicity issues of Ptx through nanoparticle technology (such as Ptx bound to human serum albumin nanoformulation, i.e., Abraxane®) is feasible and has displayed encouraging outcomes. With this background, we aim to generate Ptx self-assemblies (PSAs) using various biocompatible polymers and surfactants, and to evaluate its efficacy against BC cells.
Methods: PSAs composed of Ptx dispersion or a core formation with a polymer at a weight ratio of 1:50. The extent of Ptx assembly/binding efficiency was determined using a fluorescence quenching study. FT-IR spectral study was employed to confirm the presence of Ptx in PSAs. The optimal polymers for forming PSAs were identified through measurement of particle size, zeta potential and TEM. Another check point of generating a better PSAs was evaluated by its extent of cellular internalization in BC cells and through hemolytic assay. Finally, the finalized PSAs were examined for in vitro activity in BC cells using proliferation, colony formation, and immunoblotting assays.
Results: We screened 22 biocompatible polymers for PSA formation, out of which 8 were finalized due to excellent Ptx binding profiles, appropriate particle size ranges (40-300 nm), zeta potentials (-14.0 to -4.0 mV), and superior internalization in BC cells. The optimized PSAs exhibited enhanced anti-cancer capability in MCF-7 and MDA-MB-231 BC cells in proliferation and colony formation assays, compared to free Ptx. This was further affirmed through tubulin stabilization studies. Further, PSA treatment in BC cells demonstrates a distinct induction of the expression of apoptosis-associated proteins and distinct downregulation of anti-apoptotic proteins.
Conclusion: Overall this study suggests a simple and feasible Ptxl self-assembly approach for achieving superior anti-cancer activity with Ptx.
Citation Format: Prashanth Kumar Bhusetty Nagesh, Pallabita Chowdhury, Sumeeth S. Chauhan, Elham Hatami, Sheema Khan, Bilal Hafeez, Subhash C. Chauhan, Meena Jaggi, Murali M. Yallapu. Nano self-assemblies of paclitaxel for breast cancer treatment [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 LB-070. doi:10.1158/1538-7445.AM2017-LB-070
Abstract LB-073: Proteomic characterization reveals a molecular portrait of nasopharyngeal carcinoma differentiation
Authors: Xiao Zhefeng , Zhang Guiying , Chen Yongheng 
Published: July 2017

Abstract
Nasopharyngeal carcinoma (NPC) is categorized into three different differentiated subtypes by World Health Organization (WHO). Based on an earlier comparative proteomic database of the three histological subtypes, the study was to deepen our understanding of molecular mechanisms associated with NPC differentiation through bio-information mining. Among the three subtypes were 194 differentially expressed proteins (DEPs) of 725 identified proteins. Two DEPs, heat shock protein family B (small) member 1 (HSPB1) and keratin 5 (KRT5), were validated in a series of NPC tissue samples by using immunohistochemistry. Quantified protein families including keratins, S100 proteins (S100s) and heat shock proteins exhibited characteristic expression alterations. Comparisons of predicted bio-function activation states among different subtypes, including formation of cellular protrusion, metastasis, cell death, and viral infections, were conducted. Canonical pathway analysis inferred that Rho GTPases related signaling pathways regulated the motility and invasion of dedifferentiated NPC. In conclusion, the study explored the proteomic characteristics of NPC differentiation, which could deepen our knowledge of NPC tumorigenesis and allow the development of novel targets of therapeutic and prognostic value in NPC.
Citation Format: Zhefeng Xiao, Guiying Zhang, Yongheng Chen. Proteomic characterization reveals a molecular portrait of nasopharyngeal carcinoma differentiation [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 LB-073. doi:10.1158/1538-7445.AM2017-LB-073
Abstract LB-080: The histone methyltransferase DOT1L promotes neuroblastoma by regulating gene transcription
Authors: Wong Matthew , Tee Andrew , Milazzo Giorgio , Bell Jessica , Hüttelmaier Stefan , Polly Patsie , Perini Giovanni , Scarlett Christopher J. , Liu Tao 
Published: July 2017

Abstract
Myc oncoproteins exert tumorigenic effects by regulating the expression of target oncogenes. Histone H3 lysine 79 (H3K79) methylation at Myc-responsive elements of target gene promoters is a strict prerequisite for Myc-induced transcriptional activation. DOT1L is the only known histone methyltransferase that catalyses H3K79 methylation. Here, we showed that N-Myc up-regulated DOT1L mRNA and protein expression by binding to the DOT1L gene promoter. Knocking down DOT1L reduced mRNA and protein expression of the N-Myc target genes ODC1 and E2F2. DOT1L bound to the Myc Box II domain of N-Myc protein, and knocking down DOT1L reduced histone H3K79 methylation and N-Myc protein binding at the ODC1 and E2F2 gene promoters and reduced neuroblastoma cell proliferation. Treatment with the small molecule DOT1L inhibitor SGC0946 reduced H3K79 methylation and proliferation of MYCN gene-amplified neuroblastoma cells. In mice xenografted with neuroblastoma cells stably expressing doxycycline-inducible DOT1L small hair-pin RNA, ablating DOT1L expression with doxycycline significantly reduced ODC1 and E2F2 expression, reduced tumor progression and improved overall survival. In addition, high levels of DOT1L gene expression in human neuroblastoma tissues correlated with high levels of MYCN, ODC1 and E2F2 gene expression, and independently correlated with poor patient survival. Taken together, our data identify DOT1L as a novel co-factor in N-Myc-mediated transcriptional activation of target genes and neuroblastoma oncogenesis, and DOT1L inhibitors as novel anticancer agents against MYCN-amplified neuroblastoma.
Citation Format: Matthew Wong, Andrew Tee, Giorgio Milazzo, Jessica Bell, Stefan Hüttelmaier, Patsie Polly, Giovanni Perini, Christopher J. Scarlett, Tao Liu. The histone methyltransferase DOT1L promotes neuroblastoma by regulating gene transcription [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 LB-080. doi:10.1158/1538-7445.AM2017-LB-080
Abstract LB-088: Role of histone demethylase JMJD1A in the generation of AR-V7
Authors: Fan Lingling , Zhang Fengbo , Gleave Martin , Dong Xuesen , Qi Jianfei 
Published: July 2017

Abstract
Formation of androgen receptor (AR) splicing variant, AR-V7, has been shown to contribute to the resistance of prostate cancer to androgen deprivation therapy and development of castration-resistant prostate cancer (CRPC). We and others have reported that histone demethylase JMJD1A promotes the transcriptional activity of AR by functioning as an AR co-activator. Here, we identified a new role for JMJD1A in the expression of AR-V7 in prostate cancer cells. Knockdown of JMJD1A reduced the mRNA and protein level of AR-V7 but had little effect on the full-length AR (AR-FL). Re-expression of AR-V7 in the JMJD1A-knockdown cells partly restored the expression of select AR target genes and growth of prostate cancer cells under the androgen deprivation condition in vitro and in the mouse xenograft model. Our preliminary data show that JMJD1A promotes the alternative splicing of AR-V7 and we are currently investigating the splicing factor(s) regulated by JMJD1A for the AR-V7 formation. Together, our data reveal that JMJD1A enhances the castration-resistant growth of prostate cancer cells by promoting the alternative splicing of AR-V7.
Note: This abstract was not presented at the meeting.
Citation Format: Lingling Fan, Fengbo Zhang, Martin Gleave, Xuesen Dong, Jianfei Qi. Role of histone demethylase JMJD1A in the generation of AR-V7 [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 LB-088. doi:10.1158/1538-7445.AM2017-LB-088
Abstract LB-090: p53 binding sites in normal and cancer-derived cells are characterized by distinct chromatin context
Authors: Cui Feng 
Published: July 2017

Abstract
The tumor suppressor protein p53 interacts with DNA in a sequence-dependent manner. Thousands of p53 binding sites have been mapped genome-wide in normal and cancer-derived cells. The way p53 selectively binds its cognate sites in different types of cells is not fully understood, however. We performed a comprehensive analysis of published p53 cistromes and identified 3,551 and 6,039 high-confidence normal and cancer binding sites that are enriched in genes involved in p53 signaling pathways. About 12% of these sites occur in the endogenous retrovirus 1 (ERV1) repeat family in the human genome. We further analyzed chromatin organization at the p53 binding sites in normal (GM12878) and cancer (K562) cells, and found that these sites are characterized by a high nucleosome occupancy and at the same time, by a high sensitivity to DNase I. Strikingly, compared to the sites derived from cancer cells, the p53 binding sites from normal cells are characterized by higher levels of transcriptionally active histone marks (H3K4me3 and H3K36me3) and DNA methylation. No difference was observed for the repressive histone marks (H3K27me3). These findings reveal two distinct epigenetic patterns associated with p53-DNA binding in normal and cancer-derived cells.
Citation Format: Feng Cui. p53 binding sites in normal and cancer-derived cells are characterized by distinct chromatin context [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 LB-090. doi:10.1158/1538-7445.AM2017-LB-090
Abstract LB-091: CpG island DNA methylation regulates alternative cleavage and polyadenylation
Authors: Sweet Thomas , Jin Lihua , Dermawan Josephine , Ting Angela H. 
Published: July 2017

Abstract
Abnormal DNA methylation pattern is a hallmark of human cancer, and our work in genomic profiling of DNA methylation patterns in prostate and colon cancers have identified the majority of unique DNA hypermethylation to occur outside of gene promoters. While promoter hypermethylation causes transcriptional silencing, the functions of non-promoter DNA methylation are poorly defined. Thus, we began investigating the impact of non-promoter DNA methylation on the transcriptome and specifically focused on studying the functions of DNA methylation near gene 3' ends. Using a pair of isogenic cancer cells (HCT116 and DKO cells) that differ specifically in their ability to maintain DNA methylation, we discovered an intriguing association between gene 3' end differential DNA methylation and alternative cleavage and polyadenylation (APA) events. Briefly, pre-mRNAs undergo cleavage and polyadenylation as part of normal mRNA 3' end formation, and alternative sites of cleavage and polyadenylation can be utilized to produce transcripts with varying regulatory sequences in the 3' untranslated regions (3' UTRs) or protein isoforms via APA within coding sequences. Previous studies have demonstrated that cancer cells can hijack the APA pathway to skew expression of short 3' UTRs in oncogenes to evade negative regulation, highlighting APA as an important process involved in cancer initiation and progression. By using pharmacologic inhibition of DNA methylation and reporter constructs, we demonstrated that CpG island DNA methylation near polyadenylation sites is necessary and sufficient for determining relative usage, most likely by modulating RNA polymerase II elongation rate. By leveraging the Cancer Genome Atlas (TCGA) and the Roadmap Epigenomics data, we could observe the correlation between gene 3' DNA methylation and APA at select loci in vivo. The results of our study will improve overall functional understanding of non-promoter DNA methylation, provide a novel mechanism for APA regulation, and ultimately accelerate discovery of novel targets for cancer management.
Note: This abstract was not presented at the meeting.
Citation Format: Thomas Sweet, Lihua Jin, Josephine Dermawan, Angela H. Ting. CpG island DNA methylation regulates alternative cleavage and polyadenylation [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 LB-091. doi:10.1158/1538-7445.AM2017-LB-091
Abstract LB-092: High impact of methylation accumulation on cancer risk: 5-year follow-up of a multicenter prospective cohort study
Authors: Maeda Masahiro , Nakajima Takeshi , Oda Ichiro , Shimazu Taichi , Yamamichi Nobutake , Maekita Takao , Asada Kiyoshi , Yokoi Chizu , Ando Takayuki , Yoshida Takeichi , Nanjo Sohachi , Fujishiro Mitsuhiro , Gotoda Takuji , Ichinose Masao , Ushijima Toshikazu 
Published: July 2017

Abstract
Aberrant DNA methylation can be accumulated in normal-appearing tissues, and its degree can be correlated with cancer risk [Hattori, Genome Med, 8:10, 2016]. Such accumulation is especially prominent in inflammation-associated cancers, including gastric cancer. To bring the findings into cancer risk diagnosis, we conducted a multicenter prospective cohort study with 826 patients [Asada, Gut, 64:388, 2015].
Between 2008 and 2010, 826 patients after endoscopic treatment of gastric cancer and without current H. pylori infection were enrolled, and a gastric biopsy was collected. Methylation levels of pre-defined three marker genes (miR-124a-3, EMX1 and NKX6-1) were measured by quantitative methylation-specific PCR. Patients were classified into quartiles according to methylation levels of individual genes (Q1, the lowest; Q4, the highest).
Among the 826 enrolled patients, 795 patients received annual follow-ups by endoscopy with a median period of 5.46 years (interquartile range: 3.95 - 6.09). By the end, 133 patients developed a metachronous gastric cancer, and 116 of them developed a cancer after 1 year of the enrollment (authentic metachronous cancer). Kaplan-Meier analysis showed that Q4 had a higher cumulative incidence of metachronous gastric cancer than Q1 with p-values of &lt;0.001 to 0.004 (log-rank test). Multivariate analyses adjusted for hospital, gender and age, pepsinogen index, history of endoscopic treatment, smoking and green vegetable intake also showed that Q4 had significantly high HRs compared with Q1, being 3.0 (95%CI: 1.58 to 5.72, p=0.0017) for miR-124a-3 [Maeda, Gut, online].
The results clearly showed that accumulation levels of aberrant DNA methylation can be used for cancer risk diagnosis. Even among the patients who carried a high risk of metachronous gastric cancer, cancer risk stratification was achieved. The strong influence of methylation accumulation on gastric cancer risk indicated a large contribution of aberrant DNA methylation to H. pylori infection-induced gastric carcinogenesis. Epigenetic cancer risk diagnosis is now becoming real.
Citation Format: Masahiro Maeda, Takeshi Nakajima, Ichiro Oda, Taichi Shimazu, Nobutake Yamamichi, Takao Maekita, Kiyoshi Asada, Chizu Yokoi, Takayuki Ando, Takeichi Yoshida, Sohachi Nanjo, Mitsuhiro Fujishiro, Takuji Gotoda, Masao Ichinose, Toshikazu Ushijima. High impact of methylation accumulation on cancer risk: 5-year follow-up of a multicenter prospective cohort study [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 LB-092. doi:10.1158/1538-7445.AM2017-LB-092