bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 541: A comprehensive analysis delineating the immunotherapeutic terrain of cancer-related clinical trials
Authors: Statz Cara M. , Patterson Sara E. , Yin Taofei , Mockus Susan M. 
Published: July 2017

Abstract
Technological innovations have facilitated a greater understanding of how the tumor microenvironment contributes to cancer, leading to rapid FDA approval of four immunotherapies. To assess how these therapies are being further investigated in combination with other therapies and in tumor types outside of the current FDA approval, we performed a comprehensive analysis of the curated clinical trials in the JAX Clinical Knowledgebase (JAX-CKB). In brief, clinical trials investigating Atezolizumab, Nivolumab, Pembrolizumab, and Ipilimumab, curated from clinicaltrials.gov, were queried in the JAX-CKB and then analyzed for comparison. Further analyses were executed to illustrate possible unmet needs within the field of cancer therapeutics. Of the four immunotherapies, Pembrolizumab was identified with the greatest number of clinical trials overall, with 305 compared to Atezolizumab, 79, Nivolumab, 183, and Ipilimumab, 126. Of these trials the number of trials investigating Pembrolizumab, Atezolizumab, Nivolumab, or Ipilimumab in combination with another therapy was higher than those investigating one of the four immunotherapies as a monotherapy. Phase II trials for both single therapy and combinatorial therapies were greater than both Phase I and Phase III for the same groups, regardless of therapy. On average, 12% ± 3.8% of the combined trials for all four drugs included any advanced solid tumor. Nivolumab combined with Ipilimumab demonstrated the greatest number of trials (61) investigating an immunotherapy in combination with another immunotherapy. Among those, 30 were Phase II trials, 16 were Phase I, and 14 were Phase III. Across five cancer indications (lung, pancreatic, ovarian, prostate, and colon), lung cancer was most commonly indicated in the trials, among all four drugs. Prostate was indicated in the least number of trials, with Ipilimumab ranking the highest (10). The recent success with immunotherapies has garnered significant interest in understanding how these therapies will perform in different tumor types and whether specific combinations will have a greater impact. Interrogation of the clinical trial terrain in the JAX-CKB provides a basis for determining additional investigations that might be warranted.
Citation Format: Cara M. Statz, Sara E. Patterson, Taofei Yin, Susan M. Mockus. A comprehensive analysis delineating the immunotherapeutic terrain of cancer-related clinical trials [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 541. doi:10.1158/1538-7445.AM2017-541
Abstract 5419: The relationship between glutamatergic signaling and altered glutamine metabolism in melanoma
Authors: Shah Raj , Boreland Andrew , Chen Suzie 
Published: July 2017

Abstract
Aberrant glutamatergic signaling has been implicated in many cancer types, and is associated with dysregulated growth leading to cellular transformation and tumorigenesis. Our laboratory has previously illustrated the oncogenic properties of a neuronal receptor, metabotropic glutamate receptor 1 (GRM1) in melanocytes. Glutamate is the natural ligand of GRM1 and the major excitatory neurotransmitter in the central nervous system. Our group has demonstrated that glutamate production/release is upregulated in GRM1 expressing melanoma cells, resulting in constitutive activation of GRM1 and GRM1-associated downstream signaling pathways. We hypothesize that this activation of GRM1 in melanoma cells is associated with higher expression of c-Myc and increased enzymatic activity of glutaminase (GLS) converting glutamine to glutamate. We showed that reducing the extracellular glutamate levels by an inhibitor of glutamate release, Riluzole, led to significantly reduce melanoma cell proliferation in vitro and tumor progression in vivo. We also demonstrated that inclusion of CB-839, a potent, selective, and orally bioavailable GLS inhibitor, resulted in a significant inhibition of GRM1-expressing melanoma cell proliferation compared to GRM1 negative melanoma cell lines. Interestingly, we found that simultaneous targeting of glutamate production (CB-839) and release (Riluzole) in GRM1 expressing melanoma cells led to enhanced suppression of cell proliferation in vitro. Additionally, we found that wild type BRAF melanoma cells are more sensitive to CB-839 than mutated BRAF cells while responses to Riluzole were independent of BRAF genotypes. Furthermore, our data indicate that CB-839 acts by reducing the function, not the expression, of GLS. Currently, we are investigating the relationship between GRM1, c-Myc and GLS by genetic and pharmacological approaches, and if this cascade of events is linked with altered glutamine metabolisms described for many human cancers including melanoma.
Citation Format: Raj Shah, Andrew Boreland, Suzie Chen. The relationship between glutamatergic signaling and altered glutamine metabolism in 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 5419. doi:10.1158/1538-7445.AM2017-5419
Abstract 5420: PGAM1-REDD1 pathway promotes paclitaxel resistance through enhancing aerobic glycolysis in ovarian cancer cells
Authors: Feng Yan , Lv Weiguo , Xie Xing , Yu Yan 
Published: July 2017

Abstract
Aerobic glycolysis is a dominant pathway for energy production in cancer cells, but the association of this phenomenon with chemoresistance remains still uncertain. Here, we found that the expression of phosphoglycerate mutase 1 (PGAM1), a key catalytic enzyme in aerobic glycolysis, was significantly higher in paclitaxel-resistant ovarian cancer cell line SKOV3. Up-regulated PGAM1 expression by gene transfection and down-regulated PGAM1 expression by siRNA knockdown altered the process of aerobic glycolysis, paclitaxel sensitivity and DNA damage response 1 (REDD1) expression in ovarian cancer cells (SKOV3 and A2780). Further, the change of the concentration of pyruvic acid or lactic acid in culture medium and REDD1 expression by gene transfection or siRNA knockdown also altered the sensitivity to paclitaxel. REDD1 knockdown of by siRNA reversed partially paclitaxel resistance induced by PGAM1 over-expression in cancer cells, vice versa. Structural interaction between PGAM1 and REDD1 was predicted by molecular docking. Our results suggested that PGAM1-REDD1 pathway promotes paclitaxel resistance through enhancing aerobic glycolysis in ovarian cancer cells.
Citation Format: Yan Feng, Weiguo Lv, Xing Xie, Yan Yu. PGAM1-REDD1 pathway promotes paclitaxel resistance through enhancing aerobic glycolysis in ovarian 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 5420. doi:10.1158/1538-7445.AM2017-5420
Abstract 5424: Metformin increases PDH and suppresses HIF1A under hypoxic conditions and induces cell death in oral squamous cell carcinoma
Authors: Guimarães Talita , Farias Lucyana , Fraga Carlos , Paula Alfredo De , Santos Sergio , Gomez Ricardo , Guimaraes Andre 
Published: July 2017

Abstract
Background: Metformin is a biguanide, belonging to the oral hypoglycemic agents and is a widely used in the treatment of type 2 diabetes. Evidence indicate that Metformin inhibits cell proliferation in several human cancers and inhibits the Warburg phenomenon in tumor cells.
Objective: The present study aims to explore the effects of Metformin in hypoxic conditions. Specifically, we focused on pyruvate dehydrogenase (PDH), (hypoxia-inducible factor 1α) HIF-1α levels and the oral squamous cell carcinoma (OSCC) cell phenotype. Additionally, we also investigated a theoretical consequence of Metformin treatment.
Methods: PDH levels in patients with OSCC and oral dysplasia were evaluated. Metformin was administered in vitro to test the effect of Metformin under hypoxic conditions. The results were complemented by Bioinformatics analyses.
Results: Low PDH levels were observed in OSCC, and Metformin promotes an increase in PDH levels in hypoxic conditions. Metformin also reduced HIF-1α mRNA and protein levels. Metformin demonstrated antiproliferative effects, inhibited migration, increased the number of apoptotic cells and increased the transcription of caspase 3.
Conclusions: In conclusion, our current findings show that Metformin reduces HIF-1α gene expression and increases PDH expression. Metformin inhibits cell proliferation and migration in the OSCC cell line model. Additionally, Metformin enhances the number of apoptotic cells and caspase 3 levels. Interestingly enough, Metformin did not increase the mutant p53 levels under hypoxic conditions.
Note: This abstract was not presented at the meeting.
Citation Format: Talita Guimarães, Lucyana Farias, Carlos Fraga, Alfredo De Paula, Sergio Santos, Ricardo Gomez, Andre Guimaraes. Metformin increases PDH and suppresses HIF1A under hypoxic conditions and induces cell death in oral squamous cell carcinoma [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 5424. doi:10.1158/1538-7445.AM2017-5424
Abstract 5430: GAPDH loss in a tumorigenic human glioblastoma cell line
Authors: Gaertner Zachary , Lu Yi , Kim Jinsuh , Mohapatra Gayatry , Mehta Ankit , Lakka Sanjani , Engelhard Herbert 
Published: July 2017

Abstract
Background: Glyceraldehyde 3-phosphate dehydrogenase (GAPDH) is a ubiquitous, multifunctional 37 kDa enzyme best known for catalyzing the sixth step in glycolysis. GAPDH expression is so consistent that it has been granted “housekeeping” status, and is used as a standard (along with β-actin) for normalizing Western blots. While increased GAPDH expression has been described in hypoxia, diabetes, and some cancers, decreased expression is rare. Here we describe a new human glioblastoma cell line that exhibits GAPDH loss, while maintaining a high degree of malignancy.
Methods: Primary cultures of human glioblastoma cells were initiated and maintained in DMEM with 10% FBS. This particular cell line (designated E297) grew readily, and was passaged more than 40 times. E297 cells were confirmed to be negative for HIV, HTLV, hepatitis B and C, CMV, and mycoplasma contamination. Cells in exponential growth were stained for routine markers, and studied by DNA flow cytometry. GAPDH expression was studied by Western blot analysis using polyclonal rabbit anti-human GAPDH IgG (Abcam, Rosemont, IL), with HeLa, U138, U87 and U251 cells (as well as β-actin staining) as positive controls. For intracranial implantation into Wistar-Furth rats (male, 10-11 weeks), cells were suspended at 20 x 106 cells/ml. Using aseptic technique, rats were anesthetized, and placed into a stereotactic frame. A burr hole was drilled 3 mm right of the bregma and 25 µl of suspension injected (5 mm depth) over 10 min. by Hamilton syringe. Rats were studied by MRI and euthanized when symptomatic.
Results: E297 cells have glial/epithelioid morphology, with a doubling time of 24 + 2 hours in logarithmic growth phase, with a single DNA subpopulation with 28% S phase. They stain positively for GFAP, vimentin, bFGF, c-myc and p53, but fail to express GAPDH. 10/10 animals implanted intracerebrally developed tumors, becoming symptomatic and requiring sacrifice at 25 days (mean). Loss of GAPDH expression was confirmed by Western blot analysis.
Conclusions: The E297 human glioblastoma cell line is highly aggressive and proliferates rapidly. It is tumorigenic in nonimmunosuppressed rats but lacks GAPDH protein. We conclude that GAPDH expression is not essential for glioblastoma cell proliferation under routine culture conditions, and care needs to be taken when using GAPDH as a normalization standard for Western blots of cancer cells.
Citation Format: Zachary Gaertner, Yi Lu, Jinsuh Kim, Gayatry Mohapatra, Ankit Mehta, Sanjani Lakka, Herbert Engelhard. GAPDH loss in a tumorigenic human glioblastoma cell line [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 5430. doi:10.1158/1538-7445.AM2017-5430
Abstract 5441: Circulating exosomal microRNA-203 and microRNA-373 as non-invasive biomarkers for predicting prognosis and metastasis in human hepatocellular carcinoma
Authors: Kim Gyeonghwa , Lee Eunhye , Jang Se Young , Tak Won Young , Kweon Young Oh , Park Soo Young , Hur Keun 
Published: July 2017

Abstract
Background and Aim Hepatocellular carcinoma (HCC) is the fifth most common cancer and the most leading cause of cancer-related death worldwide. Although considerable progress has been made in treatment of HCC, early detection is still highly considered the key to improved survival. Thus, for the earlier diagnosis and accurate prediction of HCC, identification of non-invasive molecular biomarkers for HCC patients is an imperative need. Recently, cancer cell-derived extracellular vesicles (EVs) have been known to contain various intracellular biomolecules including microRNAs (miRNAs). The aim of this study was to evaluate whether exosomal miRNAs can serve as a serum-based biomarker in HCC.
Materials and Methods We isolated exosome from serum samples from HCC patients as well as normal healthy controls using ultracentrifugation, and it was confirmed by expression of exosome markers (CD9, CD63, ALIX, and TSG101) based on immunoblotting. Next, the expression of 6 miRNAs (miRNA-24, -130a, -182, -203, -373, and -423) was analyzed in the exosome samples. We also investigated expression status of the 6 miRNAs in matched HCC tissues and corresponding normal liver tissues. MiRNAs expression was determined by quantitative real-time PCR (qRT-PCR), and miRNAs expression was normalized relative to cel-miR-39 and RNU6B expression for serum and tissue samples, respectively.
Results We successfully purified exosome from serum clinical samples and detected miRNAs in the exosome. We observed that a subset of miRNAs from serum exosome, including miRNA-24, -130a, -182, -203, and -373 were enhanced in HCC patients than normal healthy controls. In further comparison between early stage and advanced stage of HCC patients, serum exosomal miRNA-203 (P&lt;0.05) and miRNA-373 (P&lt;0.05) were significantly up-regulated in advanced HCC patients. While no significant changes in the expression of other serum exosomal miRNAs (miRNA-24, -130a, -182, and -423) according to HCC progression. More interestingly, high serum exosomal miRNA-203 and miRNA-373 was associated with HCC progression (P&lt;0.01) as well as prognosis (P&lt;0.05) of HCC patients.
Conclusions We provided the novel evidence for usefulness of serum circulating exosomal miR-203 and miR-373 expressions as strong potential biomarkers for predicting prognosis and metastasis of HCC patients.
Citation Format: Gyeonghwa Kim, Eunhye Lee, Se Young Jang, Won Young Tak, Young Oh Kweon, Soo Young Park, Keun Hur. Circulating exosomal microRNA-203 and microRNA-373 as non-invasive biomarkers for predicting prognosis and metastasis in human hepatocellular carcinoma [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 5441. doi:10.1158/1538-7445.AM2017-5441
Abstract 5446: Tumor-derived miR-200c and 141 contribute to high levels of plasma microRNA-200c and 141 through exosomes
Authors: Wang Lizhong , Liu Runhua , Gao Song , Wang Yicun , Wang Meng , Li Zhi 
Published: July 2017

Abstract
Circulating microRNAs (miRs) have potential as cancer biomarkers, but their regulatory mechanisms remain elusive. Here we used a breast cancer model (Foxp3 heterozygous Scurfy mutant female mice, Foxp3sf/+) for identification of circulating miR biomarkers, and the formation and regulation of these miRs were investigated. Aging Foxp3sf/+ female mice developed spontaneous breast cancers and lung metastases. Levels of miR-200c and 141 were lower in the Foxp3sf/+ breast cancer cells than in normal breast epithelial cells, but plasma levels of miR-200c and 141 in the Foxp3sf/+ mice increased during tumor progression, especially during metastasis to the lung. Likewise, 259 participants, including patients with breast cancer or benign breast tumors, members of breast cancer families, and matched normal healthy controls, were assessed for circulating levels of candidate miRs. The results showed that: 1) the levels of miR-200c and 141 were lower in the FOXP3low breast cancer cells relative to those with FOXP3high, especially for late-stage and metastatic cancer cells; 2) the levels of miR-200c and 141 were higher in plasma of patients with metastatic breast cancer than in plasma of those with localized breast cancer, with benign breast tumors, with a family history of breast cancer, or normal healthy controls. Furthermore, in Foxp3sf/+ mice, plasma miR-200c and 141 were released from tumor cells through exosomes. Thus, plasma levels of miR-200c and 141 are potential biomarkers for early detection of metastases. MiR-200c and 141 appear to be released from breast cancer cells, through exosomes, into the circulation.
Citation Format: Lizhong Wang, Runhua Liu, Song Gao, Yicun Wang, Meng Wang, Zhi Li. Tumor-derived miR-200c and 141 contribute to high levels of plasma microRNA-200c and 141 through exosomes [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 5446. doi:10.1158/1538-7445.AM2017-5446
Abstract 545: Prognostic alternative mRNA splicing signature in non-small cell lung cancer
Authors: Li Yuan , Sun Nan , Lu Zhiliang , Sun Shouguo , Huang Jianbing , Chen Zhaoli , He Jie 
Published: July 2017

Abstract
Alternative splicing provides a major mechanism to generate protein diversity. Increasing evidence suggests a link of dysregulation of splicing associated with cancer. However, alternative splicing in non-small cell lung cancer (NSCLC) is largely unstudied. In this study, seven types of alternative splicing were profiled in 491 lung adenocarcinoma (LUAD) and 471 lung squamous cell carcinoma (LUSC) patients in TCGA using RNA sequencing data. Prognostic predictors for LUAD, LUSC and merged NSCLC patients were built by integrated survival analysis. Gene network and splicing correlation network analyses were also conducted. Overall, we detected 45,062 and 50,732 alternative splicing events in LUAD and LUSC, respectively, almost half of them were exon skipping events. A total of 3,691 and 2,403 alternative splicing events were significantly associated with patient survival in LUAD and LUSC, respectively. Gene network analysis uncovered important hub genes or nodes such as EGFR, CD44, PIK3C3, RRAS2, MAPKAP1 and FGFR2. The area under the curve (AUC) of the receiver-operator characteristic (ROC) curve for prognostic predictors in LUAD and LUSC were 0.960 and 0.940 at 2000 days of overall survival. Most relevant for clinical application, we also built the prognostic predictor for NSCLC patients with high performance. The AUC of ROC curve in NSCLC was 0.817 which were also over 0.8 in LUAD and LUSC, separately. Moreover, expression of 49 and 9 survival associated splicing factors were significantly correlated with 75 survival associated alternative splicing events in LUAD and LUSC, respectively. Interestingly, splicing correlation networks uncovered that “oncogenic“ splicing factors were up-regulated in LUAD while “tumor suppressor” splicing factors were down-regulated in LUSC. Survival associated splice factors might have opposite roles in the regulation of RNA splicing in LUAD and LUSC. In conclusion, we created prognostic predictors based on alternative splicing events with high performances for risk stratification in NSCLC patients and uncovered interesting splicing networks in LUAD and LUSC which could be underlying mechanisms.
Citation Format: Yuan Li, Nan Sun, Zhiliang Lu, Shouguo Sun, Jianbing Huang, Zhaoli Chen, Jie He. Prognostic alternative mRNA splicing signature in non-small cell lung 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 545. doi:10.1158/1538-7445.AM2017-545
Abstract 5450: Urinary microRNA as diagnostic and prognostic biomarkers for prostate cancer
Authors: Fredsøe Jacob , Rasmussen Anni K. , Thomsen Anni R. , Mouritzen Peter , Høyer Søren , Borre Michael , Ørntoft Torben F. , Sørensen Karina D. 
Published: July 2017

Abstract
Widespread use of Prostate Specific Antigen (PSA) testing for prostate cancer (PC) detection has led to extensive overdiagnosis and overtreatment. Thus, we aimed to train and validate urine-based microRNA (miRNA) biomarkers that may assist in the diagnosis and prognosis of PC. To this end, we profiled the expression levels of 92 miRNAs by RT-qPCR in exosome-enriched cell-free urine samples from 20 patients with benign prostatic hyperplasia (BPH) and 188 patients with clinically localized PC (cohort 1). The diagnostic potential of individual miRNAs and multi-miRNA ratio models were assessed by receiver operating characteristic (ROC) curve analysis. Prognostic potential was evaluated by Kaplan-Meier, uni- and multivariate Cox regression analyses using biochemical recurrence (BCR) after radical prostatectomy (RP) as endpoint. Our findings were validated in an independent cohort of 20 BPH patients and 197 patients with clinically localized PC (cohort 2). We identified and validated several deregulated miRNAs in urine samples from PC patients. In addition, we trained a novel diagnostic 3-miRNA model that distinguished BPH and PC patients with an area under the curve (AUC) of 0.95 in cohort 1, and which was successfully validated in cohort 2 (AUC=0.89). Furthermore, we trained a novel prognostic 3-miRNA model that predicted time to BCR after RP independently of routine clinicopathological parameters in cohort 1, and was successfully validated in cohort 2.
Citation Format: Jacob Fredsøe, Anni K. Rasmussen, Anni R. Thomsen, Peter Mouritzen, Søren Høyer, Michael Borre, Torben F. Ørntoft, Karina D. Sørensen. Urinary microRNA as diagnostic and prognostic biomarkers for prostate 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 5450. doi:10.1158/1538-7445.AM2017-5450