bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 809: BRAF wild-type melanoma survival hinges upon AKT activity and adaptive autophagic reprogramming in response to chemotherapy
Authors: Rebecca Vito W. , Massaro Renato , Fedorenko Inna , Gibney Geoffrey T. , Sondak Vernon K. , Amaravadi Ravi K. , Jin Shengkan , Maria-Engler Silvya S. , Kudchadkar Ragini , Smalley Keiran S. M. 
Published: May 2015

Abstract
Strategies for patients whose melanomas are BRAF wild-type are completely lacking. We here report on the mechanisms underlying the long-term responses (&gt;12 months) of 2 BRAF wild-type (WT) melanoma patients to the AKT inhibitor MK-2206 in combination with paclitaxel and carboplatin. A panel of 7 BRAF/NRAS-WT cell lines was leveraged to investigate strategies to overcome chemoresistance. Electron microscopy, western blotting and flow cytometry assays were integrated to simultaneously follow fluctuations in autophagic flux, reactive oxygen species levels and cytotoxicity caused from chronic treatment of cells with chemotherapy, MK-2206, lysomotropic agents and/or anti-oxidants. MK-2206 potently inhibited phospho-AKT signaling, but did not impact melanoma growth or survival. The combination of MK-2206 with paclitaxel and carboplatin induced little apoptosis following 3-day treatment, but led to cytotoxicity in long-term colony formation and 3D spheroid assays. Mechanistically the combination was noted to induce autophagy and disrupt reactive oxygen species homeostasis, as shown by increased LC3-II expression, the formation of LC3 punctae, acridine orange protonation, the accumulation of autophagosomes and increased ROS detection using DHR-123. At earlier time points, autophagy was protective with cytotoxicity enhanced following chloroquine and bafilomycin treatment as well as the increased cytotoxic effects seen in ATG5-/- MEFs. Although prolonged MK-2206/chemotherapy treatment (6-9 days) led to high levels of autophagy induction and a switch to caspase-dependent apoptosis, drug resistant clones still eventually emerged. The importance of autophagy for the escape process was suggested by the lack of ATG5-/- MEF colonies seen following combination therapy treatment. Autophagy inhibition enhanced the cell death response through increased generation of ROS and could be reversed by anti-oxidants. In summary, we demonstrate for the first time that AKT inhibition in combination with chemotherapy may have clinical activity in BRAF WT melanoma. We further show that the administration of an autophagy inhibitor may prevent resistance from emerging to this drug combination.
Citation Format: Vito W. Rebecca, Renato Massaro, Inna Fedorenko, Geoffrey T. Gibney, Vernon K. Sondak, Ravi K. Amaravadi, Shengkan Jin, Silvya S. Maria-Engler, Ragini Kudchadkar, Keiran S. M. Smalley. BRAF wild-type melanoma survival hinges upon AKT activity and adaptive autophagic reprogramming in response to chemotherapy. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 809. doi:10.1158/1538-7445.AM2014-809
Abstract 843: Methylthioadenosine phosphorylase (MTAP)-deficient T-cell ALL xenografts are sensitive to pralatrexate and 6-thioguanine alone and in combination
Authors: Tedeschi Philip M. , Kathari Yamini K. , Farooqi Iqra , Bertino Joseph R. 
Published: May 2015

Abstract
In T-cell acute lymphoblastic leukemia (ALL), the genes CDKN2A (p16 and p14) and MTAP are homozygously co-deleted, with a frequency of ∼35 %. MTAP cleaves the natural substrate, 5′-deoxy-5′-methylthioadenosine, to adenine and 5-methylthioribose-1-phosphate, which are converted to adenine nucleotides and methionine. Cells lacking MTAP are unable to salvage adenine through this pathway and rely on the de novo pathway for purine synthesis. This variation between normal MTAP+ cells and tumor MTAP-/- cells led to several studies showing that MTAP -/- cells are more sensitive to inhibitors of de novo purine synthesis.
Pralatrexate (PDX) is a second generation antifolate that targets dihydrofolate reductase and via conversion to polyglutamylates, inhibits de novo purine synthesis. 6-Thioguanine (6TG), an antimetabolite analog of guanine, also target de novo purine synthesis. MTAP-deficient ALL cells should be more sensitive to these agents, remarkably so in combination. We tested single agent PDX and 6TG as well as a combination treatment in MTAP+ (Molt4) and MTAP-/- (CEM) ALL xenografts. CEM xenografts were more sensitive to PDX treatment than MOLT4 xenografts. CEM xenografts were also much more sensitive to 6TG, while Molt4 xenografts were resistant to 6TG. Early results of the combination of PDX and 6TG in vivo show promise as an effective therapy of MTAP-/- T-cell ALL.
Citation Format: Philip M. Tedeschi, Yamini K. Kathari, Iqra Farooqi, Joseph R. Bertino. Methylthioadenosine phosphorylase (MTAP)-deficient T-cell ALL xenografts are sensitive to pralatrexate and 6-thioguanine alone and in combination. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 843. doi:10.1158/1538-7445.AM2014-843
Abstract 860: Carbon ion radiotherapy for recurrent basal cell carcinoma: preliminary report of six cases and review of the literature
Authors: Chen Yingtai , Dong Feng , Tian Yantao , Wang Chengfeng , Cui Liang , Chen Xuezhong 
Published: May 2015

Abstract
Abstract
Background: Basal cell carcinoma (BCC) is the most common malignant skin carcinoma. Although mortality is low as BCC rarely metastasizes, this malignancy has a tendency for local recurrence. As such, it is of great practical utility to assess which is the best therapeutic choice in the management of BCC recurring after different treatments. Here, we describe six cases of recurrent BCC treated with carbon ion radiotherapy and review the cases previously reported in the literature.
Methods: Case records of six patients with biopsy-proved, recurrent BCC, who were given total doses of 60-70 GyE, administered in 6-11 fractions over 6-11 days, with a fraction dose of 7-10 GyE in the therapy terminal at Heavy Ion Research Facility in Lanzhou (HIRFL) at the Institute of Modern Physics, Chinese Academy of Sciences (IMP-CAS), China, were retrospectively reviewed.
Results: Tumor response rate was 100%, including 6 CR, at 12 months after completion of carbon ion radiation. In a minimum follow-up period of 55 months, overall survival and no recurrence were achieved. No grade 3 or higher toxicity and complication occurred.
Conclusions: Carbon ion radiotherapy is well tolerated and should be considered as a potential salvage modality for recurrent BCC in certain cases.
Note: This abstract was not presented at the meeting.
Citation Format: Yingtai Chen, Feng Dong, Yantao Tian, Chengfeng Wang, Liang Cui, Xuezhong Chen. Carbon ion radiotherapy for recurrent basal cell carcinoma: preliminary report of six cases and review of the literature. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 860. doi:10.1158/1538-7445.AM2014-860
Abstract 871: Clinical utility of a plasma microRNA biomarker within lung cancer screening
Authors: Boeri Mattia , Verri Carla , Sozzi Gabriella , Roz Luca , Conte Davide , Suatoni Paola , Marchiano Alfonso , Vecchia Carlo L. , Rossi Marta , Bravi Francesca , Negri Eva , Sverzellati Nicola , Pastorino Ugo 
Published: May 2015

Abstract
Recent screening trials indicate that low-dose computed tomography (LDCT) reduces lung-cancer mortality in high risk subjects. However, high false positive rates, costs and potential harms highlight the need for complementary biomarkers. MicroRNAs (miRNAs) are tissue and disease specific molecules, actively released by cells in the circulatory system, which are associated with protein complexes and/or packaged in exosomes and microvesicles. Circulating miRNAs are rather stable and easily detectable in body fluids suggesting the possibility of using miRNAs as a new promising class of biomarkers.
Sensitivity, specificity, positive and negative predictive values (PPV and NPV, respectively) of a non-invasive plasma miRNA signature classifier (MSC) to identify lung cancer occurrence and mortality was retrospectively evaluated in samples prospectively collected from smokers within the randomized Multicentre Italian Lung Detection (MILD) trial. Plasma samples from 939 subjects including 69 lung cancer patients and 870 disease-free individuals were analyzed using a Real-Time quantitative PCR (qRT-PCR) based assay for MSC. Combined sensitivity and specificity of plasma MSC and LDCT were assessed in a blinded validation study.
MSC correctly identified patients with lung cancer at 87% sensitivity, 81% specificity, and 99% NPV, and 18 of 19 lung cancer deaths at 95% sensitivity 81% specificity, and 99.86% NPV. MSC identified 43 of 49 (88%) LDCT-detected cancers, 8 of 9 (89%) interval cancers in the LDCT arm, and 9 of 11 (82%) cancers in the observational arm. Diagnostic performance of MSC was confirmed by time dependency analysis. MSC fell to negative after lung cancer resection in 16 of 22 evaluable subjects. In lung cancer patients, there was a trend in mortality across levels of MSC (p=0.0336) and survival rate significantly differed according to MSC in all subjects (X21=49.53, p&lt;0.0001). Combination of MSC and LDCT resulted in a 5-fold reduction of LDCT false positive rate.
This large validation study highlights the clinical diagnostic and prognostic value of plasma MSC for lung cancer screening in high-risk populations. The combined use of LDCT and MSC could reduce the false positive rate of LDCT improving the efficacy of lung cancer screening.
Citation Format: Mattia Boeri, Carla Verri, Gabriella Sozzi, Luca Roz, Davide Conte, Paola Suatoni, Alfonso Marchiano, Carlo La Vecchia, Marta Rossi, Francesca Bravi, Eva Negri, Nicola Sverzellati, Ugo Pastorino. Clinical utility of a plasma microRNA biomarker within lung cancer screening. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 871. doi:10.1158/1538-7445.AM2014-871
Abstract 889: MicroRNA-21-5p upregulation in urine samples serves as novel biomarkers for early stage renal cell carcinoma patients diagnosis
Authors: Meng Wei , Alder Hansjuerg , Maclean Kirsteen , Kirste Simon , Stegmaier Petra , Grosu Anca , Chakravarti Arnab , Lautenschlaeger Tim 
Published: May 2015

Abstract
Early prevention of renal cell carcinoma needs a reliable and robust bioassay to evaluate kidney cancer patients. As a novel class of regulatory molecules in cellular activity, the recent studies showed that microRNAs had tissue-specific patterns and were able to distinguish the cancer from benign disease. We explored the diagnostic value of urine microRNAs from a cohort of 160 individuals: 80 patients with renal clear cell carcinoma and 80 normal control individuals.
Material and methods: The renal clear cell carcinomas cohort included 63% stage I cases, 10% stage II cases, 19% stage III cases, 7% stage IV cases, 1% unknown cases. Normal control cohort included 34% diverticulosis cases, 15% bariatric surgery cases, 14% diverticulitis cases, 15% hernia surgery cases, 10% hemorrhoids cases and 12% other non-cancer conditions. Every 10 urine samples were pooled together and subjected to microRNA extraction. The Norgen Biotek urine microRNA purification kit was used for total microRNA extraction (including free floating microRNAs and microRNAs from exfoliated cells) in the pooled urine samples. Urine microRNA expression profiling was performed using nCounter miRNA Expression Assay. After ligation and purification, hybridized microRNAs sequences were label by specific color codes and quantified using nCounter Digital Analyzer, then the data were normalized to the sum of the microRNAs within each pooled sample before statistic analysis.
Result: comparing to normal control urine samples, microRNA-21-5p expression showed upregulation in kidney urine samples, which is consistent with TCGA kidney cancer tissue profiling results. Some recent studies also demonstrated that microRNA-21 may act as an oncomir in prostate, lung and colorectal cancers. We also observed that microRNA-1268a and microRNA-549 were highly expressed in urine samples from renal cell carcinoma patients.
Conclusion: These findings indicate that in urine microRNA-21-5p may serve as a potential molecular marker for renal cell carcinoma and provide a new approach in the diagnosis of kidney cancer.
Note: This abstract was not presented at the meeting.
Citation Format: Wei Meng, Hansjuerg Alder, Kirsteen Maclean, Simon Kirste, Petra Stegmaier, Anca Grosu, Arnab Chakravarti, Tim Lautenschlaeger. MicroRNA-21-5p upregulation in urine samples serves as novel biomarkers for early stage renal cell carcinoma patients diagnosis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 889. doi:10.1158/1538-7445.AM2014-889
Abstract 901: Plasma proteins characterize second-line therapy response in progressive renal cell carcinoma
Authors: Hölters Sebastian , Bergmann Lothar , Grünwald Viktor , Keilholz Ulrich , Ohlmann Carsten , Staehler Michael , Schmerler Diana , Junker Kerstin 
Published: May 2015

Abstract
Introduction & Objectives: For patients with metastatic renal cell carcinoma (mRCC) vascular endothelial growth factor (VEGF)-targeted therapy represents a promising first-line therapy after tumour nephrectomy. For patients who progress during first-line therapy, inhibitors of mammalian target of rapamycin (mTOR) represent an option for second-line therapy. Within the framework of the MARC-2 clinical trial, the aim of our study is the identification and validation of marker proteins associated with second-line therapy (Everolimus) response.
Material & Methods: We included blood plasma samples from 19 mRCC patients receiving Everolimus. Therapy response was defined as stable disease and partial remission. We analysed the samples by surface-enhanced laser desorption/ionisation time-of-flight mass spectrometry (SELDI-TOF MS) using CM10 and Q10 arrays. For the identification of potential marker proteins, 2-dimensional gel electrophoresis followed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) and antibody array screening are on-going.
Results: We identified 20 mass peaks by SELDI-TOF MS with Q10 and 16 with CM10 chips for the discrimination between responders (defined as stable disease or partial remission after two month of therapy) and non-responders (defined as progressive disease after 2 month of therapy). With the Q10, but not with the CM10 chip, we obtained five peaks for the discrimination between both patient groups before the first drug application. These peaks could be useable to preselect patients for the second-line therapy with Everolimus. For therapy monitoring, we found seven mass peaks (four with Q10 and three with CM10 chips) after two weeks and 24 mass peaks (11 with Q10 and 13 with CM10 chips) after four weeks of therapy to differentiate between responders and non-responders. These mass peaks could be useful to estimate the therapy response for the patients.
Conclusion/Outlook: Our preliminary results argue for the presence of blood plasma proteins which potentially predict therapy response to Everolimus before as well as during therapy. The confirmation and identification of the SELDI-TOF MS outcomes by 2-dimensional gel electrophoresis and MALDI-TOF MS is on-going as well as the antibody array screening for angiogenesis related proteins.
Sponsored by: iOMEDICO AG
Citation Format: Sebastian Hölters, Lothar Bergmann, Viktor Grünwald, Ulrich Keilholz, Carsten Ohlmann, Michael Staehler, Diana Schmerler, Kerstin Junker. Plasma proteins characterize second-line therapy response in progressive renal cell carcinoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 901. doi:10.1158/1538-7445.AM2014-901
Abstract 935: Exome sequencing reveals BRAF mutations in papillary craniopharyngiomas
Authors: Taylor-Weiner Amaro N. , Brastianos Priscilla K. , Manley Peter E. , Jones Robert T. , Dias-Sangata Dora , Thorner Aaron , Rodriguez Fausto , Bernardo Lindsay , Schubert Laura , Stewart Chip , Keiran Mark , Hahn William C. , Resnick Adam , Louis David , Sangata Sandro , Getz Gad 
Published: May 2015

Abstract
Craniopharyngiomas are epithelial tumors that typically arise in the suprasellar region of the brain. Patients experience substantial clinical sequelae both from extension of the tumors and from therapeutic interventions which damage the optic chiasm, the pituitary stalk, and the hypothalamic area. Using whole exome sequencing we identified mutations in beta-catenin (CTNNB1) in nearly all adamantinomatous craniopharyngiomas (11/12; 92%) and recurrent mutations in BRAF (V600E) in all papillary craniopharyngiomas (3/3; 100%). Targeted genotyping revealed BRAF V600E in 95% of papillary craniopharyngiomas (36 of 39 tumors) and CTNNB1 mutation in 96% of adamantinomatous craniopharyngiomas (51 of 53 tumors). The CTNNB1 and BRAF mutations were clonal in each tumor subtype and no other recurrent mutations or genomic aberrations were detected in either subtype. Adamantinomatous and papillary craniopharyngiomas harbor mutations that are mutually exclusive and clonal. These findings have important implications for the diagnosis and treatment of these neoplasms.
Citation Format: Amaro N. Taylor-Weiner, Priscilla K. Brastianos, Peter E. Manley, Robert T. Jones, Dora Dias-Sangata, Aaron Thorner, Fausto Rodriguez, Lindsay Bernardo, Laura Schubert, Chip Stewart, Mark Keiran, William C. Hahn, Adam Resnick, David Louis, Sandro Sangata, Gad Getz. Exome sequencing reveals BRAF mutations in papillary craniopharyngiomas. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 935. doi:10.1158/1538-7445.AM2014-935
Abstract 944: Translational implications of the 19q12 bladder cancer GWAS signal for aggressive bladder cancer
Authors: Fu Yi-Ping , Kohaar Indu , Moore Lee , Lenz Petra , Figueroa Jonine D. , Tang Wei , Porter-Gill Patricia , Chanock Stephen , Hewitt Stephen M. , Silverman Debra T. , Rothman Nathaniel ,   NCI-GWAS Bladder Cancer Consortium, Prokunina-Olsson Ludmila 
Published: May 2015

Abstract
Background: A genome-wide association study (GWAS) of bladder cancer identified a genetic marker rs8102137 within the 19q12 region as a novel susceptibility variant. This marker is located upstream of the CCNE1 gene, which encodes cyclin E, a cell cycle protein.
Methods: Genetic fine mapping analysis of the CCNE1 region was performed using data from two bladder cancer GWAS, which included a total of 5,942 cases and 10,857 controls. Cyclin E protein expression was evaluated by immunohistochemistry analysis in 265 bladder tumors in relation to CCNE1 genetic variants and tumor characteristics. Functional effects of cyclin E over-expression were evaluated with cell cycle assays.
Findings: The original GWAS marker rs8102137 represents a group of 47 linked SNPs (with r2≥0.7) associated with increased bladder cancer risk. From this group we selected a functional promoter variant rs7257330, which showed strong allele-specific binding of nuclear proteins in several cell lines. In both GWAS, rs7257330 was associated only with aggressive bladder cancer (muscle-invasive or high-grade non-muscle-invasive cancer), with a per-allele odds ratio (OR) =1.18 (95%CI=1.09-1.27, p=4.67×10-5). Cyclin E protein expression was increased in aggressive bladder tumors (p=0.013) and, independently, with each rs7257330-A risk allele (ptrend=0.024). Over-expression of recombinant cyclin E in cell lines caused significant acceleration of cell cycle. Conclusions: Molecular mechanisms linking the CCNE1 GWAS signal and aggressive bladder cancer risk are related to cyclin E over-expression and cell cycle regulation. In combination with other genetic and clinical markers, CCNE1 genetic variants may be translationally useful for early prediction of aggressive bladder cancer.
Citation Format: Yi-Ping Fu, Indu Kohaar, Lee Moore, Petra Lenz, Jonine D. Figueroa, Wei Tang, Patricia Porter-Gill, Stephen Chanock, Stephen M. Hewitt, Debra T. Silverman, Nathaniel Rothman, NCI-GWAS Bladder Cancer Consortium, Ludmila Prokunina-Olsson. Translational implications of the 19q12 bladder cancer GWAS signal for aggressive bladder cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 944. doi:10.1158/1538-7445.AM2014-944
Abstract 968: β-catenin plays an important role in lung tumor development induced by EGFR mutations
Authors: Nakayama Sohei , Sng Natasha J. , Carretero Julian , Welner Robert , Hayashi Yuichiro , Yamamoto Mihoko , Alistair Tan J. , Yamaguchi Norihiro , Yasuda Hiroyuki , Danan Li , Soejima Kenzo , Ross Soo A. , Daniel Costa B. , Wong Kwok-Kin , Kobayashi Susumu S. 
Published: May 2015

Abstract
The discovery of somatic mutations in epidermal growth factor receptor (EGFR) and the development of EGFR tyrosine kinase inhibitors (TKIs), such as gefitinib and erlotinib, have revolutionized treatment for non-small cell lung cancer (NSCLC). Resistance to TKIs emerges in almost all patients, but currently no effective treatment is available.Therefore, novel strategies to either prevent or overcome resistance are sorely needed. Here we show that β-catenin is essential for development of EGFR mutated lung cancers. We found that β-catenin was upregulated, translocated to the nucleus, and subsequently activated in both EGFR mutated lung cancer cell lines and EGFR mutation driven lung tumors. We demonstrated that mutant EGFR preferentially bound to β-catenin and caused tyrosine-phosphorylation of β-catenin. Tyrosine-phosphorylation of β-catenin led to stabilization, nuclear translocation, and transcriptional activity particularly in cells harboring EGFR-L858R (LR)-T790M (TM). Pharmacological β-catenin inhibition using ICG-001, which specifically blocks the CBP-β-catenin interaction, suppressed growth of both H1975 cells harboring EGFR-LR-TM and lung tumors in EGFR-LR-TM transgenic mice. To further examine whether β-catenin plays an important role in lung tumorigenesis, we generated an EGFR-LR-TM lung cancer mouse model in which the β-catenin gene (Ctnnb1) can be conditionally deleted. Genetic deletion of Ctnnb1 dramatically reduced lung tumor formation and showed significantly longer survival. Taken together, our data suggest that β-catenin plays an important role in mutant EGFR-driven lung tumorigenesis and that targeting the β-catenin pathway may provide novel strategies to prevent lung cancer development and/or overcome resistance to EGFR TKIs.
Citation Format: Sohei Nakayama, Natasha J. Sng, Julian Carretero, Robert Welner, Yuichiro Hayashi, Mihoko Yamamoto, Tan J. Alistair, Norihiro Yamaguchi, Hiroyuki Yasuda, Li Danan, Kenzo Soejima, Soo A. Ross, Costa B. Daniel, Kwok-Kin Wong, Susumu S. Kobayashi. β-catenin plays an important role in lung tumor development induced by EGFR mutations. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 968. doi:10.1158/1538-7445.AM2014-968