bluuebunny/crossref_metadata_2025_split huggingface dataset:
Does the DSA reconstruction kernel affect hemodynamic predictions in intracranial aneurysms? An analysis of geometry and blood flow variations
Authors: Berg P , Saalfeld S , Voß S , Redel T , Preim B , Janiga G , Beuing O 
Published: May 2017

BackgroundComputational fluid dynamics (CFD) blood flow predictions in intracranial aneurysms promise great potential to reveal patient-specific flow structures. Since the workflow from image acquisition to the final result includes various processing steps, quantifications of the individual introduced potential error sources are required.MethodsThree-dimensional (3D) reconstruction of the acquired imaging data as input to 3D model generation was evaluated. Six different reconstruction modes for 3D digital subtraction angiography (DSA) acquisitions were applied to eight patient-specific aneurysms. Segmentations were extracted to compare the 3D luminal surfaces. Time-dependent CFD simulations were carried out in all 48 configurations to assess the velocity and wall shear stress (WSS) variability due to the choice of reconstruction kernel.ResultsAll kernels yielded good segmentation agreement in the parent artery; deviations of the luminal surface were present at the aneurysm neck (up to 34.18%) and in distal or perforating arteries. Observations included pseudostenoses as well as noisy surfaces, depending on the selected reconstruction kernel. Consequently, the hemodynamic predictions show a mean SD of 11.09% for the aneurysm neck inflow rate, 5.07% for the centerline-based velocity magnitude, and 17.83%/9.53% for the mean/max aneurysmal WSS, respectively. In particular, vessel sections distal to the aneurysms yielded stronger variations of the CFD values.ConclusionsThe choice of reconstruction kernel for DSA data influences the segmentation result, especially for small arteries. Therefore, if precise morphology measurements or blood flow descriptions are desired, a specific reconstruction setting is required. Furthermore, research groups should be encouraged to denominate the kernel types used in future hemodynamic studies.
Spike-timing-dependent plasticity in lower-limb motoneurons after human spinal cord injury
Authors: Urbin M. A. , Ozdemir Recep A. , Tazoe Toshiki , Perez Monica A. 
Published: May 2017

Recovery of lower-limb function after spinal cord injury (SCI) likely depends on transmission in the corticospinal pathway. Here, we examined whether paired corticospinal-motoneuronal stimulation (PCMS) changes transmission at spinal synapses of lower-limb motoneurons in humans with chronic incomplete SCI and aged-matched controls. We used 200 pairs of stimuli where corticospinal volleys evoked by transcranial magnetic stimulation (TMS) over the leg representation of the motor cortex were timed to arrive at corticospinal-motoneuronal synapses of the tibialis anterior (TA) muscle 2 ms before antidromic potentials evoked in motoneurons by electrical stimulation of the common peroneal nerve (PCMS+) or when antidromic potentials arrived 15 or 28 ms before corticospinal volleys (PCMS−) on separate days. Motor evoked potentials (MEPs) elicited by TMS and electrical stimulation were measured in the TA muscle before and after each stimulation protocol. After PCMS+, the size of MEPs elicited by TMS and electrical stimulation increased for up to 30 min in control and SCI participants. Notably, this was accompanied by increases in TA electromyographic activity and ankle dorsiflexion force in both groups, suggesting that this plasticity has functional implications. After PCMS−, MEPs elicited by TMS and electrical stimulation were suppressed if afferent input from the common peroneal nerve reduced TA MEP size during paired stimulation in both groups. In conclusion, PCMS elicits spike-timing-dependent changes at spinal synapses of lower-limb motoneurons in humans and has potential to improve lower-limb motor output following SCI. NEW & NOTEWORTHY Approaches that aim to enhance corticospinal transmission to lower-limb muscles following spinal cord injury (SCI) are needed. We demonstrate that paired corticomotoneuronal stimulation (PCMS) can enhance plasticity at spinal synapses of lower-limb motoneurons in humans with and without SCI. We propose that PCMS has potential for improving motor output in leg muscles in individuals with damage to the corticospinal tract.
Phase I and Preliminary Phase II Study of TRC105 in Combination with Sorafenib in Hepatocellular Carcinoma
Authors: Duffy Austin G. , Ma Chi , Ulahannan Susanna V. , Rahma Osama E. , Makarova-Rusher Oxana , Cao Liang , Yu Yunkai , Kleiner David E. , Trepel Jane , Lee Min-Jung , Tomita Yusuke , Steinberg Seth M. , Heller Theo , Turkbey Baris , Choyke Peter L. , Peer Cody J. , Figg William D. , Wood Brad J. , Greten Tim F. 
Published: May 2017

Abstract
Purpose: Endoglin (CD105) is an endothelial cell membrane receptor highly expressed on proliferating tumor vasculature, including that of hepatocellular carcinoma (HCC), and is associated with poor prognosis. Endoglin is essential for angiogenesis, and its expression is induced by hypoxia and VEGF pathway inhibition. TRC105 is a chimeric IgG1 CD105 mAb that inhibits angiogenesis and causes antibody-dependent cellular cytotoxicity and apoptosis of proliferating endothelium.
Experimental Design: Patients with HCC (Child–Pugh A/B7), ECOG 0/1, were enrolled in a phase I study of TRC105 at 3, 6, 10, and 15 mg/kg every 2 weeks given with sorafenib 400 mg twice daily. Correlative biomarkers included DCE-MRI and plasma levels of angiogenic factors, including soluble endoglin. Pharmacokinetics were assessed in serum.
Results: Twenty-six patients were enrolled, of whom 25 received treatment, 15 with cirrhosis. Hep B/C: 3/15; M:F 19:6; mean age of 60 (range, 18–76); 1 DLT (grade 3 AST) occurred at 10 mg/kg. The most frequent toxicity was low-grade epistaxis, a known toxicity of TRC105. One patient experienced an infusion reaction and was replaced. One patient with coronary stenosis developed a fatal myocardial infarction, and one patient developed G3 cerebral tumor hemorrhage. MTD was not established and DL4 (15 mg/kg) was expanded. The overall response rate in 24 evaluable patients at all 4 dose levels was 21% [95% confidence interval (CI), 7.1–42.2], and 25% (95% CI, 8.7–49.1) in patients with measureable disease. Four patients had confirmed stable disease, one of whom was treated for 22 months. Median progression-free survival (PFS) for 24 patients evaluable for PFS was 3.8 months (95% CI, 3.2–5.6 months); median overall survival was 15.5 months (95% CI, 8.5–26.3 months).
Conclusions: TRC105 combined with sorafenib was well tolerated at the recommended single agent doses of both drugs. Encouraging evidence of activity to date (PR rate 25%) was observed, and the study is now continuing to recruit in the phase II stage as a multicenter study to confirm activity of the combination. Clin Cancer Res; 23(16); 4633–41. ©2017 AACR.
Cell-Free DNA from Ascites and Pleural Effusions: Molecular Insights into Genomic Aberrations and Disease Biology
Authors: Husain Hatim , Nykin David , Bui Nam , Quan Daniel , Gomez German , Woodward Brian , Venkatapathy Sumathi , Duttagupta Radha , Fung Eric , Lippman Scott M. , Kurzrock Razelle 
Published: May 2017

Abstract
Collection of cell-free DNA (cfDNA) from the blood of individuals with cancer has permitted noninvasive tumor genome analysis. Detection and characterization of cfDNA in ascites and pleural effusions have not yet been reported. Herein, we analyzed cfDNA in the ascites and pleural effusions from six individuals with metastatic cancer. In all cases, cfDNA copy number variations (CNV) were discovered within the effusate. One individual had a relevant alteration with a high copy amplification in EGFR in a never smoker with lung cancer, who showed only MDM2 and CDK4 amplification in a prior tissue biopsy. Another subject with metastatic breast cancer had cytology-positive ascites and an activating PIK3CA mutation identified in the tissue, blood, and ascites collectively. This individual had tumor regression after the administration of the mTOR inhibitor everolimus and had evidence of chromotripsis from chromosomal rearrangements noted in the cell-free ascitic fluid. These results indicate that cfDNA from ascites and pleural effusions may provide additional information not detected with tumor and plasma cell-free DNA molecular characterization, and a context for important insights into tumor biology and clonal dynamic change within primary tumor and metastatic deposits. Mol Cancer Ther; 16(5); 948–55. ©2017 AACR.
Abstract A09: The role of pre-mRNA splicing factor in Glioblastoma Multiforme by regulating EGFRvIII
Authors: Oh Young Taek , Hong Jun Hee , Park Jong Bae 
Published: May 2017

Abstract
Glioblastoma (GBM) heterogeneity in the genomic and phenotypic properties has potentiated personalized approach against specific therapeutic targets of each GBM patient. Therefore, there is a critical unmet need to predict therapeutic responses for individual patients. There is 50% of GBM patient has EGFR over-expression and mutation. Because of this reason, there are various EGFRvIII target inhibitor for GBM patient. However, the efficacy of EGFRvIII specific drugs is not good because of autophosphorylation. We found Tra2β, which is pre-mRNA splicing factor, can bind in first intron and there are 9 consensus sequences. Because of EGFRvIII has deletion of second exon, Tra2β can regulate the expression of EGFRvIII. We validated low WTAP expression level in differentiated GBM stem cells, and confirmed the tumorigenic function of Tra2β in GBM cells. Furthermore, we are going to find the mechanism of Tra2β that can regulated by CDC-like kinase. As a result, we connected Tra2β function and EGFR specific drug resistance problem. This study could be helpful on personalized treatment approach based on genetic characteristics of each GBM could make better treatment outcomes of GBMs.
Citation Format: Young Taek Oh, Jun Hee Hong, Jong Bae Park. The role of pre-mRNA splicing factor in Glioblastoma Multiforme by regulating EGFRvIII. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr A09.
Abstract A23: AMPK's role in glioblastoma survival: An insight into its regulation on transcription factors and mTOR
Authors: Chhipa Rishi Raj , Dasgupta Biplab 
Published: May 2017

Abstract
AMP kinase (AMPK) is an evolutionarily conserved enzyme required for adaptive responses to various physiological and pathological conditions. The multisubunit structure and sensitivity to various stresses confer complexity to AMPK function which scores beyond energy sensing. Here we show that inhibition of AMPK reduces viability of patient-derived primary Glioblastoma Multiforme (GBM) lines and tumors. We demonstrate that primary GBM cells coopt the AMPK-CREB1 pathway to coordinate global bioenergetics program through control of the transcription factors HIF1alpha and GABPA. But a growing number of AMPK activators are being developed to treat human diseases such as cancer and diabetes. This may be because AMPK activity can inhibit biosynthetic kinases like mammalian target of rapamycin (mTOR) and acetyl Co-A carboxylase (ACC). We found that AMPK silencing in glioma cells did not affect mTOR or downstream targets. AMPK is not absolutely necessary for mTOR inhibition, suggesting that in certain contexts, activated AMPK and mTOR may coexist. Indeed, this is what we observed in glioblastoma suggesting that basally active AMPK may not be sufficient to put a brake on mTOR. Further analysis of our preliminary data from primary tumor cells on Cap-dependent and well reported procancer IRES dependent translation under tumor microenvironment context will demonstrate significance of AMPK in translational machinery in GBM and will benefit in finding new therapeutic targets.
Citation Format: Rishi Raj Chhipa, Biplab Dasgupta. AMPK's role in glioblastoma survival: An insight into its regulation on transcription factors and mTOR. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr A23.
Abstract A39: Expression of DNA methylation-related proteins in metastatic breast cancer
Authors: Yukyung Lee , Eun-Sol Kim , Seung Koo Ja 
Published: May 2017

Abstract
Purpose: To investigate the expressions of methylation-related proteins (5-methylcytosine [5-meC] and DNA [cytosine-5-]-methyltransferase 1 [DNMT1]) in metastatic breast cancers of variable sites and their associations with clinicopathologic factors.
Methods: A total of 126 metastatic breast cancers (31, 36, 11, and 48 bone, brain, liver, and lung metastases, respectively) were made into tissue microarrays, and immunohistochemical staining was performed for estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor-2 (HER-2), Ki-67, 5-meC, and DNMT1. Molecular classification was made on the basis of the immunohistochemical staining results of ER, PR, HER-2, and Ki-67, as luminal A, luminal B, HER-2-positive, and triple-negative breast cancers.
Results: Methylation-related proteins were differentially expressed based on the metastatic sites. Tumoral and stromal 5-meC showed the lowest expression in bone metastases (P &lt; 0.001), while tumoral DNMT1 showed the lowest expression in bone metastases and the highest expression in brain metastases (P &lt; 0.001). Expression of DNMT1 correlated with ER-negativity (P = 0.004), PR-negativity (P = 0.011), HER-2-positivity (P = 0.016), higher Ki-67 labeling indices (P = 0.016), and non-luminal A type (P = 0.017). Univariate analysis revealed that DNMT1-positivity was associated with shorter overall survival in patients with bone (P = 0.017) and lung metastases (P = 0.028).
Conclusion: In metastatic breast cancer, methylation-related proteins are differentially expressed according to the metastatic sites. Tumoral and stromal 5-meC showed the lowest expression in bone metastases, while tumoral DNMT1 expression was low in bone metastases and the highest in brain metastases.
Citation Format: Lee Yukyung, Kim Eun-Sol, Koo Ja Seung. Expression of DNA methylation-related proteins in metastatic breast cancer. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr A39.
Abstract B06: Translational control of mitochondria through mTORC1/4E-BP signaling pathway
Authors: Morita Masahiro , Prudent Julien , McBride Heidi , Bergeron John , Sonenberg Nahum 
Published: May 2017

Abstract
mRNA translation is the most energy consuming process in the cell. Translation and energy metabolism are dysregulated in a variety of diseases including cancer. However, the mechanisms which coordinate translation and energy metabolism remain largely unknown. The mechanistic/mammalian target of rapamycin complex 1 (mTORC1) stimulates mRNA translation and other anabolic processes in response to a variety of extracellular signals and intracellular cues (e.g., growth factors, nutrients, oxygen), ultimately accelerating cellular growth and proliferation. mTORC1 is frequently hyper-activated in a series of cancer, thereby it is targeted for the cancer treatment.
We previously carried out a genome-wide polysome profiling analysis using mTORC1 inhibitors, such as rapamycin and active-site mTOR inhibitors. These experiments revealed that mRNAs whose translation is regulated by mTORC1 are enriched in those encoding mitochondrial proteins. Here, by using a combination of pharmacological, genetic, biochemical and metabolomic approaches, we demonstrate that mTORC1 modulates mitochondrial functions and dynamics through translational regulation of mRNAs encoding mitochondrial proteins. Mechanistically, we indicate that the effects of mTORC1 on mitochondria are mediated by the eukaryotic translation initiation factor 4E (eIF4E) binding proteins (4E-BPs). Stimulation of translation of mitochondria-related mRNAs engendered an increase in ATP production, which is required as an energy source for translation.
These data support a feed-forward loop model, whereby the mTORC1/4E-BP pathway promotes translation of mitochondria-related mRNAs to increase mitochondrial ATP production to meet the high energy demand of protein synthesis in proliferating cells. This represents a novel paradigm for understanding how cellular energy homeostasis is maintained via direct coordination of energy consumption (translation) and energy production (ATP production in mitochondrion). Thereby, our findings provide a new mechanism linking aberrant mTOR signaling to conditions of abnormal cellular energy metabolism such as neoplasia. In this presentation, we will introduce our recent data and discuss the role of mTORC1/4E-BP signaling pathway on mitochondrial function, cellular metabolism and proliferation.
Citation Format: Masahiro Morita, Julien Prudent, Heidi McBride, John Bergeron, Nahum Sonenberg. Translational control of mitochondria through mTORC1/4E-BP signaling pathway. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr B06.
Abstract B28: Discovery of 2-acetylpyridine-[N-(3-hydroxy-2-naphthoyl)]hydrazone analogs as glycine N-methyltransferase (GNMT) inducers for the treatment of hepatocellular carcinoma (HCC)
Authors: Tzeng Cherng-Chyi , Tseng Chih-Hua , Chen Yeh-Long 
Published: May 2017

Abstract
Hepatocellular carcinoma (HCC) is the sixth most common cancer worldwide and the third most common cause of cancer mortality. Because of the late diagnosis, poor treatment options and high recurrence, the incidence still nearly equals to the mortality rate. Therefore, the discovery of novel therapeutic agents and/or drug combination strategies is urgently needed. Glycine N-methyltransferase (GNMT) is a tumor suppressor gene for HCC. Literatures revealed that the expression of GNMT is significantly down-regulated in HCC patients. Therefore, discovery of small molecule compounds that are able to enhance GNMT expression will have important implications for the treatment of HCC. Recently, we have identified a small molecule, 2-acetylpyridine-[N-(3-hydroxy-2-naphthoyl)]hydrazone (1), as a hit from a collective drug library containing more than 20,000 compounds using a GNMT gene expression-oriented screen platform. Preliminary results indicated that compound 1 is capable of inducing GNMT expression strongly with 7.57 folds to control in 2.5 micromole.
In order to discover novel lead compounds based on the initial hit, we have synthesized more than 100 analogs of compound 1 and evaluated for their effects on GNMT promoter activity. Results indicated certain newly synthesized compounds are more active than compound 1. A comprehensive Structure-activity relationships (SAR) study will be presented.
Citation Format: Cherng-Chyi Tzeng, Chih-Hua Tseng, Yeh-Long Chen. Discovery of 2-acetylpyridine-[N-(3-hydroxy-2-naphthoyl)]hydrazone analogs as glycine N-methyltransferase (GNMT) inducers for the treatment of hepatocellular carcinoma (HCC). [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr B28.
Abstract B45: Insights into the anti-prostate cancer activity of pterostilbene
Authors: Tolba Mai F. , Omar Hany A. 
Published: May 2017

Abstract
Castration-resistant prostate cancer (PC) is one of the most challenging cancers with limited therapeutic options. Angiogenesis is a key mechanism required for the progression of advanced metastatic stage of PC. Interference with angiogenesis halts prostate tumor progression and metastases. Estrogen receptor alpha (ER-α) is upregulated in PC compared to normal tissues. ER-α is implicated in tumor angiogenesis through activating vascular endothelial growth factor (VEGF) transcription. Pterostilbene (PT) is an active component of blueberries that exhibits anti-proliferative and antimetastatic effects in PC. The impact of PT on pro-angiogenic signals is not known. The current study tested the hypothesis that PT exhibits sensitizes prostate cancer (PC) cells to chemotherapy. We also examined the underlying mechanisms by which PT exhibits cytotoxic effects in PC with special emphasis on ER-α, Akt activity and angiogenesis signals. PT is cytotoxic against LNCaP, DU-145 and PC-3 with IC50 of 33.76, 41.17 and 58.9 µM. PT synergized doxorubicin in both LNCaP and PC-3 cells. Molecular docking indicated that PT interacts with ER-α active site with a comparable affinity to estradiol. Since, ER-α is implicated in the progression of PC. The effect of PT on PC migration and invasion was investigated and results showed significant reduction in both functions. PT suppressed ER-α expression, ER-α(Ser-167) and Akt(Ser473) phosphorylations in PC-3 cells. PT opposed the release of the pro-angiogenic growth factors VEGF, IGF-1 and TGF-β by 41.5, 36.5 and 28.8% (P&lt;0.05). Our findings suggest that PT could serve as a promising antiangiogenic therapy/ adjuvant for the management of advanced stage PC.
Citation Format: Mai F. Tolba, Hany A. Omar. Insights into the anti-prostate cancer activity of pterostilbene. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr B45.
Abstract IA21: New technologies to monitor and understand RNA-binding proteins in cancer cells
Authors: Hentze Matthias W. 
Published: May 2017

Abstract
Based on the development of “RNA interactome capture”, we recently discovered that hundreds of cellular proteins, previously well known for other biological functions, also unexpectedly bind RNA (termed “enigmRBPs” for enigmatic RNA-Binding Proteins) (1-4). Since many enigmRBPs are conserved from yeast to humans, their existence raises pressing questions—for benign as well as for cancer cells.
One of the most stunning surprises was the discovery that almost all enzymes of the glycolytic pathway are conserved as enigmRBPs. Overall, more than 50 metabolic enzymes were found to bind RNA. Could the combination of enzymatic and RNA-binding functions represent a general biological principle for coordination between gene expression and metabolism? (5,6). Applying a newly developed technique, RBDmap, to identify the RNA-binding domains of enigmRBPs, we uncovered new RNA-binding architectures yielding functional insights (7). Integrating all information, we discuss a possible new function for genomes in addition to their classical role in driving protein biosynthesis via mRNAs, rRNAs, and tRNAs and their associated modifying and regulatory RNAs. I will also reflect on how RNA interactome capture and RBDmap can advance our understanding of cancer cell biology.
(1) Castello et al., Cell 149, 1393-1406, 2012
(2) Castello et al., Nature Protoc. 8, 491-500, 2013
(3) Kwon et al., Nature Struc. Mol. Biol. 20, 1122-1132, 2013
(4) Beckmann et al., Nature Communications, 2015
(5) Hentze and Preiss, TiBS 35, 423-426, 2010
(6) Castello et al., Trends in Endocrin. Metab., 2015
(7) Castello et al., Mol. Cell, 2016
Citation Format: Matthias W. Hentze. New technologies to monitor and understand RNA-binding proteins in cancer cells. [abstract]. In: Proceedings of the AACR Special Conference on Translational Control of Cancer: A New Frontier in Cancer Biology and Therapy; 2016 Oct 27-30; San Francisco, CA. Philadelphia (PA): AACR; Cancer Res 2017;77(6 Suppl):Abstract nr IA21.