bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 4996: The m6A hallmark of cancer: RNA demethylase ALKBH5 maintains tumorigenicity of glioblastoma stem-like cells by sustaining FOXM1 expression and cell proliferation
Authors: Zhang Sicong , Zhou Aidong , Bogler Oliver , Majumder Sadhan , Huang Suyun 
Published: July 2017

Abstract
N6-methyladenosine (m6A) is the most prevalent internal modification on mRNA, but its functions in human diseases are poorly understood. The dynamic and reversible m6A modification installed and erased by N6-methyltransferases and demethylases regulates cell fate and gene expression. We show that the m6A demethylase ALKBH5 is highly expressed in patient-derived glioblastoma stem-like cells (GSCs) and informs poor survival of patients with glioblastoma. Silencing ALKBH5 suppresses the proliferation of GSCs in vitro and in vivo. Results of integrated transcriptome and m6A-seq analyses reveal a global change of gene expression enriched in cell cycle and altered expression of select ALKBH5 targets. Among these targets, Ingenuity’s upstream regulator analysis identified FOXM1, an essential transcription factor for GSC proliferation, as a key mediator responsible for the disrupted proliferation program. Using multiple molecular and biochemical approaches, we demonstrate that ALKBH5 binds to and demethylates FOXM1 nascent transcripts. This promotes the interaction of FOXM1 pre-mRNA with HuR, thereby maintaining FOXM1 expression. Further, a long noncoding RNA antisense to the FOXM1 (FOXM1-AS) interacts with ALKBH5 as well as FOXM1 pre-mRNA and promotes their interaction. Depleting ALKBH5 and FOXM1-AS abolishes GSC tumorigenesis through the FOXM1 axis. The vulnerability of GSCs to disruptions in ALKBH5-dependent gene expression suggests that m6A has a central role in tumor development and provides a rationale for therapeutically targeting epitranscriptomic modulators in patients with glioblastoma.
Citation Format: Sicong Zhang, Aidong Zhou, Oliver Bogler, Sadhan Majumder, Suyun Huang. The m6A hallmark of cancer: RNA demethylase ALKBH5 maintains tumorigenicity of glioblastoma stem-like cells by sustaining FOXM1 expression and cell proliferation [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 4996. doi:10.1158/1538-7445.AM2017-4996
Abstract 4997: Specialized microRNP and translation mechanisms in quiescent cancer cells
Authors: Bukhari Syed I. , Truesdell Samuel S. , Lee Sooncheol , Kollu Swapna , Classon Anthony , Boukhali Myriam , Jain Esha , Mortensen Richard D. , Yanagiya Akiko , Sadreyev Ruslan , Haas Wilhelm , Vasudevan Shobha 
Published: July 2017

Abstract
Quiescence (G0) represents an assortment of reversible, cell cycle-arrested states that are resistant to unfavorable conditions and associated with cancer persistence. G0 involves regulated gene expression with selective mRNA expression and decreased canonical translation. Low mTOR activity in G0 activates the cap complex inhibitor, eIF4EBP, and impairs canonical translation. The alternative translation mechanisms in G0 remain to be uncovered. Our data show that microRNAs, regulatory, non-coding RNAs that target distinct mRNAs to alter gene expression, can associate with alternative complexes and translation factors to regulate specific mRNA translation in G0. One subset of transcripts expressed in G0 includes specific mRNAs recruited by an FXR1a-associated microRNP (microRNA-protein complex) for translation activation in G0 mammalian cells. MicroRNPs predominantly mediate repression and downregulation; however, FXR1a-microRNP lacks conventional microRNP repressors, and instead, contains a specific RNA binding protein isoform, FXR1a. FXR1a promotes translation and is overexpressed and associated with poor prognosis in several cancers. Our data reveal that microRNA-mediated activation requires target mRNAs with unadenylated/ shortened poly(A) tails to avoid the roles of PABP in enhancing microRNA-mediated downregulation and in canonical translation that is impaired in G0. Instead of canonical translation factors that are inhibited by eIF4EBP in G0, we find alternative translation factors—a non-canonical 5’cap binding factor and an eIF4G homolog that interacts with the ribosome—are recruited by the 3’-UTR binding FXR1a-microRNP, and promote specific mRNA translation. Our data show that G0 leukemic cells are chemoresistant and their translation profile is similar to surviving leukemic cells that are isolated after clinical therapy. We find expression of critical cytokines and immune regulators in G0. Significantly, inhibiting these immune regulators in resistant G0 cancer cells reduces their survival and chemoresistance. These data reveal a specialized translation mechanism in G0 cancer cells that promotes specific mRNA translation in these conditions of reduced canonical translation, and is important for chemoresistance.
Citation Format: Syed I. Bukhari, Samuel S. Truesdell, Sooncheol Lee, Swapna Kollu, Anthony Classon, Myriam Boukhali, Esha Jain, Richard D. Mortensen, Akiko Yanagiya, Ruslan Sadreyev, Wilhelm Haas, Shobha Vasudevan. Specialized microRNP and translation mechanisms in quiescent 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 4997. doi:10.1158/1538-7445.AM2017-4997
Abstract 5: The effects of SIRT1 inhibitors nicotinamide and Ex-527 on lymphoma cells
Authors: Guardi Manuela , Pistoni Mariaelena , Frazzi Raffaele 
Published: July 2017

Abstract
SIRT1 is a well-known lysine-deacetylase, having both histone and non-histone proteins as molecular targets. SIRT1 may function as a tumor promoter as well as a tumor suppressor in a context-dependent manner. We previously demonstrated that the treatment with resveratrol at concentrations able to induce apoptosis leads to SIRT1 down-regulation in lymphoma cells. Here we look for SIRT1 inhibition in order to investigate the effects on proliferation potential, apoptosis induction and targets modulation at a molecular level. The aim is to study whether SIRT1 inhibition affects cell cycle and proliferation capability of lymphoma cells. Experimental procedures. Diffuse large-B cell lymphoma derived cell line Toledo; human lymphoblastoid cell line GGB #7; SIRT1 inhibitors: nicotinamide (NAM) and Ex-527; cell cycle analysis; caspase-3 activity fluorimetric assay; genotoxicity assay gamma-H2AX; fluorescence-activated cell sorting intracellular staining for acetylated-H4K16 histone. New data. We found that the calculated IC50s for SIRT1 inhibition is 50mM for NAM and 343μM for Ex-527. The treatment with either NAM or Ex-527 leads to cell cycle arrest in both Toledo and GGB#7 cells, although in a different fashion. Namely, NAM causes an S-phase accumulation of Toledo while it leads GGB #7 to G0/G1 phase arrest with a concomitant decrease in S-phase already after 10mM. In both cell lines NAM 50mM induces apoptosis as demonstrated by caspase-3 activation and sub-G1 peak appearance in the cell cycle profiles. Ex-527 causes an accumulation in the S phase of Toledo cells and a decrease of G2/M in GGB#7 cells. No induction of apoptosis at the IC50 concentration was observed in both cell lines. Genotoxicity of the above mentioned treatments was investigated through the quantitation of gamma-H2AX histone released by treated cells. No genotoxic effects have been observed upon the treatments with these two inhibitors even at the concentration where NAM induces apoptosis. In order to correlate the observed changes with SIRT1 inhibition, we studied the acetylated H4K16 histone, a direct target of SIRT1 deacetylation. Our preliminary data indicate that NAM treatment increases the percentage of acetylated H4K16. Conclusions. Lymphoma and lymphoblastoid cells are affected by SIRT1 inhibition. NAM and Ex-527 cause cell cycle arrest and growth inhibition. Only NAM 50mM induces apoptosis without genotoxic effects. Overall, our data suggest the direct involvement of SIRT1 during the observed cell cycle arrest and growth inhibition mediated by these inhibitors.
Citation Format: Manuela Guardi, Mariaelena Pistoni, Raffaele Frazzi. The effects of SIRT1 inhibitors nicotinamide and Ex-527 on lymphoma 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 5. doi:10.1158/1538-7445.AM2017-5
Abstract 5003: Serum parathyroid hormone and risks of colorectal adenoma, adenoma recurrence and colorectal cancer, results from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial
Authors: Zhu Xiangzhu , Shrubsole Martha J. , Giovannucci Edward , Edwards Todd L. , Dai Qi 
Published: July 2017

Abstract
Background: Serum parathyroid hormone (PTH) may be related to risk of incident colorectal cancer. However, no study has prospectively examined whether serum PTH is differentially related to risks of different stages of colorectal carcinogenesis (incident adenoma and metachronous adenoma). Further, it is unclear if PTH is associated with risk of incident colorectal neoplasia in individuals receiving endoscopic screenings. To address these important scientific inquiries, we have conducted three nested case-control studies within the Prostate, Lung, Colorectal, and Ovarian (PLCO) cancer screening trial.
Methods: The PLCO is a large, multicenter, population-based randomized trial designed to determine the effects of screening on cancer-related mortality with a median of 12.5 years of follow up. We evaluated the associations between serum PTH and the risks of incident colorectal adenoma (755 cases and 514 controls), metachronous adenoma (755 cases and 755 controls) and incident colorectal cancer (755 cases and 514 controls) within PLCO participants aged 55 to 74 years. Odds ratios (OR) and 95% confidence intervals (95%CIs) were estimated using unconditional logistic regression models after adjusting for potential confounding factors.
Results: Compared to low serum PTH (&lt;30 ng/L), higher concentrations of serum PTH were associated with significantly reduced risk of incident colorectal cancer with the ORs (95% CIs) being 0.65(0.48-0.88) and 0.52(0.35-0.76) for PTH ≥30 ng/L and PTH≥65 ng/L (p for trend, 0.001). The inverse associations appeared significant for both women and men. However, overall, serum PTH was not related to risk of incident adenoma and metachronous adenoma.
Conclusion: In conclusion, compared to the lowest PTH levels, higher serum PTH were related to reduced risks of incident colorectal cancer among an US population who received endoscopy, but not incident colorectal adenoma and metachronous adenoma.
Citation Format: Xiangzhu Zhu, Martha J. Shrubsole, Edward Giovannucci, Todd L. Edwards, Qi Dai. Serum parathyroid hormone and risks of colorectal adenoma, adenoma recurrence and colorectal cancer, results from the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial [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 5003. doi:10.1158/1538-7445.AM2017-5003
Abstract 501: Tyrosyl-DNA phosphodiesterase I cellular function dependent on its N-terminal residues
Authors: Cuya Selma M. , Waardenburg Robert C.A.M. Van 
Published: July 2017

Abstract
Tyrosyl-DNA phosphodiesterase I (Tdp1) is a highly conserved eukaryotic DNA repair enzyme that catalyzes the resolution of 3’ and 5’ phospho-DNA adducts. Tdp1 has been implicated in the repair of DNA topoisomerase I (Top1)-DNA covalent complexes reversibly stabilized by FDA approved camptothecins (CPTs) derivatives topotecan and irinotecan. Tdp1 activity relies on two catalytic histidines that function as a nucleophile and an acid-base residue. A mutation of the acid-base His to Arg (H493R) in human Tdp1 is associated with the rare recessive ataxia SCAN1. We defined alternative substitution of either catalytic histidine that induce cytotoxicity, reduce catalytic activity and enhances the requisite Tdp1-DNA covalent adduct lifetime in the cell. The phenotypes of the catalytic mutants provide excellent tools to study Tdp1 cellular function. Biochemical studies revealed that Tdp1 catalysis in vitro is independent of the N-terminal domain. Among Tdp1 proteins, the N-terminal domain is poorly conserved in sequence and size (79aa for yeast and 148aa for human Tdp1). Conversely, the N-terminal domain regulates the in vitro activity of these Tdp1 mutants. Additionally, we investigated the role of the N-terminal domain for Tdp1 activity in the yeast and human cell models. Expression of N-terminal truncated proteins showed similar cellular distribution as the full-length proteins. However, these N-terminal truncated Tdp1 mutants did not display the toxicity that was observed with the full-length Tdp1 mutant proteins. Our data suggests that the N-terminal domain is required to resolve protein-DNA covalent complexes, such as Top1. Indeed, preliminary results suggest that this domain is also critical to process Top2-DNA covalent complexes, but only in the presences of etoposide. We are currently investigating other protein-DNA adducts that are resolved by Tdp1. These results suggests that the N-terminal domain is a critical determinate of Tdp1 cellular function. However, further studies are necessary to ensure that these constructs are properly distributed and retain their catalytic activity. Additionally, the N-terminal domain of human Tdp1 is post-translational modified, while our preliminary results suggest that this domain is important for protein-protein interaction and Tdp1 recruitment to its substrates. Understanding Tdp1 substrate and protein-interactions are important in the development of Tdp1 as therapeutic target. This work is in part supported by the ADDA, UAB Cancer Comprehensive Center (P30CA013148), ACS-IRG-60-001-53, DOD OCRP (W81XWH-15-1-0198).
Citation Format: Selma M. Cuya, Robert C.A.M. Van Waardenburg. Tyrosyl-DNA phosphodiesterase I cellular function dependent on its N-terminal residues [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 501. doi:10.1158/1538-7445.AM2017-501
Abstract 5021: Semaphorin signal via MICAL3 induces symmetrical cell division of cancer stem-like cells to confer aggressiveness in breast cancer
Authors: Tominaga Kana , Yano Masao , Tada Kei-ichiro , Tojo Arinobu , Gotoh Noriko 
Published: July 2017

Abstract
Breast cancer stem cells (BCSCs) are thought to be maintained in cancerous tissues by increased frequency of symmetric cell division at the expense of asymmetric cell divisionin the cancer tissues, although how this occurs it remain largely unknown. Here, we discovered that molecules interactinging with CasL 3 (MICAL3) contributed to tumor sphere formation in patient-derived breast cancer cells and tumor initiating activity in a patient-derived xenograft (PDX) model. Semaphorin (Sema)-stimulation induced complex formation involving MICAL3 and collapsin response mediator protein 2 (CRMP2), leading to stabilization of Numb in breast cancer cells. Neuropillin-1 (NP1), a receptor for Sema, and Numb were specifically expressed and colocalized at high levels in a BCSC-enriched population that induce tumor sphere formation. MICAL3 knockdown decreased symmetric cell division and increased asymmetric division of in NP1-high cancer stem-like cells that express high level of Numb at high levels. Thus, MICAL3/CRMP2/Numb pathway appears to play a critical role in the symmetric division of NP1-high cancer stem-like cells to expand the pool of BCSCs. Finally, we showed that breast cancer patients with higher expression levels of NP1 and Numb in cancer tissues show poor prognosis compared with those with lower expression levels of NP1 and Numb by using tissue microarray of breast cancer tissues. We provide a rationale for eradicating BCSC by blocking the symmetric division of BCSC by targeting molecules in Sema/NP1/MICAL3 pathway.
Citation Format: Kana Tominaga, Masao Yano, Kei-ichiro Tada, Arinobu Tojo, Noriko Gotoh. Semaphorin signal via MICAL3 induces symmetrical cell division of cancer stem-like cells to confer aggressiveness in breast 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 5021. doi:10.1158/1538-7445.AM2017-5021
Abstract 5024: Unmasking heterogeneity within the adult mammary stem cell compartment
Authors: Fu Nai Yang , Rios Anne , Pal Bhupinder , Law Charity , Jamieson Paul , Vaillant Francois , Smyth Gordon K. , Ritchie Matthew E. , Lindeman Geoffrey J. , Visvader Jane E. 
Published: July 2017

Abstract
Breast cancer is a highly heterogeneous disease at both the molecular and pathological levels. To understand this heterogeneity and ‘cells of origin’ of breast cancer, it is important to dissect the normal mammary epithelial hierarchy. Despite accumulating evidence for a mammary differentiation hierarchy, the basal compartment comprising stem cells remains poorly characterized. Through gene expression profiling of Lgr5+ versus Lgr5– basal epithelial cells, we identify a novel marker that led to the fractionation of three distinct mammary stem cell (MaSC) subsets in the adult gland. These exist in a largely quiescent state but differ in their repopulating ability, spatial localisation, and their molecular signatures. Interestingly, the dormant MaSC subset localises to the proximal region of the gland throughout life. These cells appear to originate from the embryonic mammary primordia before switching to a quiescent state post-natally but can be recruited into the cell cycle in response to hormones. Single cell gene expression analyses have also revealed unexpected complexity within the basal and luminal compartments. Moreover, analyses at different stages of development have provided insights into the earliest ‘lineage priming’ events.
Citation Format: Nai Yang Fu, Anne Rios, Bhupinder Pal, Charity Law, Paul Jamieson, Francois Vaillant, Gordon K. Smyth, Matthew E. Ritchie, Geoffrey J. Lindeman, Jane E. Visvader. Unmasking heterogeneity within the adult mammary stem cell compartment [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 5024. doi:10.1158/1538-7445.AM2017-5024
Abstract 5038: Comparison of the dose response of malignant peripheral nerve sheath tumor in vitro growth inhibition of 30 drugs to reported Cmax values
Authors: Reilly Karlyne M. , Tuskan Robert G. , Widemann Brigitte C. 
Published: July 2017

Abstract
In this study we aim to identify drugs that can be repurposed to inhibit malignant peripheral nerve sheath tumor (MPNST), a rare and deadly sarcoma associated with Neurofibromatosis type 1 (NF1). Inhibition of MPNST cell growth in vitro was tested for 30 drugs that have previously been through human clinical trials such that the maximum concentration of compound in human serum (Cmax) at the maximum tolerated dose has been determined. Drugs were compared to the chemotherapeutic doxorubicin. Six MPNST cell lines from human and mouse were tested and dose response curves were compared to Cmax for each drug.
For most compounds tested, inhibition of MPNST viability occurred at drug concentrations higher than Cmax. Doxorubicin was one of the best compounds tested. Several compounds with less specific molecular targets appear promising, however, currently available inhibitors of receptor tyrosine kinase signaling pathways required concentrations above Cmax to inhibit MPNST viability. These data suggest that difficulty in developing therapy for MPNST may be due to the requirement for high concentrations of drugs to inhibit MPNST cells.
Citation Format: Karlyne M. Reilly, Robert G. Tuskan, Brigitte C. Widemann. Comparison of the dose response of malignant peripheral nerve sheath tumor in vitro growth inhibition of 30 drugs to reported Cmax values [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 5038. doi:10.1158/1538-7445.AM2017-5038
Abstract 5043: Population pharmacokinetic model for OT-101 - A TGF-β2-specific antisense oligonucleotide in cancer patients
Authors: Wang Wen , Ng Kevin , Nam David , Trieu Vuong , Hwang Larn 
Published: July 2017

Abstract
Background: OT-101 (Trabedersen) is a phosphorothioate antisense oligodeoxynucleotide specifically inhibiting the expression of transforming growth factor-beta 2 (TGF-β2), whose overexpression is a pivotal factor for malignant progression in solid tumors. In the clinical Phase I/II study, plasma pharmacokinetic (PK) profile of OT-101 administered intravenously was evaluated in patients with advanced tumors. A population PK model was built to further understand the factors contributing to the variability in PK of OT-101.
Methods: A total of 61 patients with pancreatic cancer (n=37), malignant melanoma (n=19), or colorectal carcinoma (n=5) were treated with OT-101 with escalating doses in 2 treatment schedules (1st schedule: 7-days on, 7-days off; 2nd schedule: 4-days on, 10-days off; up to 10 cycles). The PK analysis was only performed on Cycle 1 and, when applicable, Cycle 2. Blood samples were collected from patients at planned time points from before start of infusion to 7 days (1st schedule) or 10 days (2nd schedule) after stop of infusion. The plasma concentration data of OT-101 were used to build a population PK model using Phoenix NLME software. The influence of age, gender, body mass index (BMI), body weight (BW), height, cancer type, and treatment schedule as covariates on PK was evaluated.
Results: With exclusion of protocol deviations, a total of 1444 plasma sample concentration data from 100 patient cycles were examined. The concentration time course of OT-101 was best described by a two-compartment model. The model estimated the PK parameters as follows: total body clearance, 0.17 mL/h; distribution volume of the central compartment, 4.69 L; inter-compartmental clearance, 3.31 L/h; distribution volume of the peripheral compartment, 5046.44 L. BW was identified as a covariate on OT-101 inter-compartmental clearance, with KBW as -ve 1.48.
Conclusion: The PK parameters of OT-101 were best described by a two-compartment model. OT-101 was largely distributed in the peripheral tissues. The influence of age, gender, BMI, height, cancer type and treatment schedule on the PK of OT-101 was not identified. The model will be used for a sparse population PK study during the planned phase III trial of OT-101 in pancreatic cancer.
Citation Format: Wen Wang, Kevin Ng, David Nam, Vuong Trieu, Larn Hwang. Population pharmacokinetic model for OT-101 - A TGF-β2-specific antisense oligonucleotide in cancer patients [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 5043. doi:10.1158/1538-7445.AM2017-5043