tbuckley/cabot-search huggingface dataset:
Abstract 4607: Mediator kinase module as a transducer of oncogenic Wnt/beta-catenin signaling
Authors: Alison Clark, Marieke Oldenbroek, Yao Wang, Jason Spaeth, Fangjian Gao, Victor X. Jin, Thomas Boyer
Journal: Cancer Research (2016)

Abstract Dysregulation of Wnt/β-catenin signaling promotes colorectal cancer (CRC) and other types of malignancies through unprogrammed changes in gene transcription that drive tumorigenesis. CDK8 is a CRC oncoprotein whose amplification-dependent overexpression identifies a significant subset of CRC patients with poor prognosis. CDK8 kinase activity, along with Cyclin C (CycC), drives tumorigenesis by stimulating β-catenin transcriptional activity. Thus, inhibition of CDK8 kinase function offers a promising therapeutic approach for CDK8-overexpressing CRCs. CycC-CDK8, along with MED12 and MED13, compose a four-subunit “kinase” module within Mediator, a conserved multiprotein interface between gene-specific transcription factors and RNA Polymerase II. We have previously identified a network of physical and functional interactions within the Mediator kinase module critical for oncogenic Wnt/β-catenin signaling. Mechanistically, β-catenin binds directly to MED12 in Mediator, thus activating CycC-dependent CDK8 kinase activity and β-catenin transcriptional activity. More specifically, MED12-dependent CDK8 activation occurs through a direct interaction involving the MED12 N-terminus and a phylogenetically conserved surface groove on CycC. Here, we demonstrate that mutagenic disruption of the MED12/CycC interface in CRC cell lines leads to uncoupling of CycC-CDK8 to MED12 and core Mediator, and concomitant loss of Mediator-associated CDK8 activity. Transcriptome analysis of cells lacking CDK8 kinase function revealed downregulation of Wnt/β-catenin signaling and other oncogenic pathways, consequently impairing CRC cell proliferation and clonogenicity. Our studies therefore identify the MED12/CycC interface as a critical transducer of oncogenic Wnt/β-catenin signaling. By validating MED12/CycC as a potential therapeutic target, our findings have significant implications in current methods of treating CRC as they pave a way for development of novel, targeted inhibitors of Wnt/β-catenin signaling to treat colorectal and other CDK8-driven driven malignancies. Supported by MH085320-05 (TGB), RP140435 (TGB) and T32DE14318 (ADC). Citation Format: Alison Clark, Marieke Oldenbroek, Yao Wang, Jason Spaeth, Fangjian Gao, Victor X. Jin, Thomas Boyer. Mediator kinase module as a transducer of oncogenic Wnt/beta-catenin signaling. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4607.
Abstract 3985: First case of B LAL with <i>MLL - MAML2</i> rearrangement
Authors: Fabrice Usseglio, Nathalie Beaufils, Régis Costello, Jean Gabert
Journal: Cancer Research (2016)

Abstract Over 70 MLL partner genes have been reported so far. MLL gene (or 11q23) translocation is occurring in 7-10% of B acute lymphoblastic leukemias and AF4 being the most frequent partner gene. The prognostic is usually bad, specially for AF4 partner. A rare partner gene, mastermind like 2 (MAML2) gene has been reported in 4 cases of myeloid neoplasms after chemotherapy so far: 2 AML and 2 MDS. Here we report a case with MLL - MAML2 discovered by NGS analysis in front of an inv11 (q21q23) present in a 47 years old female previously treated for a sarcoma in 2014. It is, to our knowledge, the first case of B acute lymphoblastic leukemia (CD79a, CD22, CD19, CD45, CD10-) with this fusion gene. At the molecular level, the rearrangement consists in the fusion of exons 7 and 2 of the MLL and MAML2 genes respectively. We will discuss the biological, clinical, physiological and therapeutic consequences of this rare event. Its prognostic impact is unknown as the reported cases are too rare. Citation Format: Fabrice Usseglio, Nathalie Beaufils, Régis Costello, Jean Gabert. First case of B LAL with MLL - MAML2 rearrangement. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3985.
Predominance of Cryptococcus neoformans var. grubii multilocus sequence type 5 and emergence of isolates with non-wild-type minimum inhibitory concentrations to fluconazole: a multi-centre study in China
Authors: X. Fan, M. Xiao, S. Chen, F. Kong, H.-T. Dou, H. Wang, Y.-L. Xiao, M. Kang, Z.-Y. Sun, Z.-D. Hu, Z. Wan, S.-L. Chen, K. Liao, Y.-Z. Chu, T.-S. Hu, G.-L. Zou, X. Hou, L. Zhang, Y.-P. Zhao, Y.-C. Xu, Z.-Y. Liu
Journal: Clinical Microbiology and Infection (2016)
Preoperative Circulating sCD40L And Vascular Redox State in LIMA Grafts, Predict The Development Of Atrial Fibrillation Post-Coronary Artery Bypass Grafting
Authors: C A Antoniades, T van-Assche, J Diesch, A S Antonopoulos, D Tousoulis, C Stefanadis, B Casadei, D Taggart, K M Channon, P Leeson
Journal: Journal of the American College of Cardiology (2009)
Abstract 3048: Drug repurposing: Validation of sulfasalazine as a radiosensitizer in melanoma by blocking system Xc−
Authors: Hilde Elise Førde, Linda Sleire, Heidi Espedal, Jan Ingemann Heggdal, Frode Selheim, Paal-Henning Pedersen, Per Øyvind Enger
Journal: Cancer Research (2016)

Abstract Melanoma is a cancer that has become increasingly frequent over the last decades in the western world. Initial treatment for primary and locoregional melanoma is surgery. In metastatic disease, systematic treatment and recently immunotherapy has been the mainstay. At this stage however, the prognostic outlook is still bleak. Thus, new treatments are urgently needed. Melanoma is considered to be a radioresistant cancer. The mechanisms underlying radioresistance are multiple and incompletely characterized. In some tumors, radioresistance is mediated by increased synthesis of anti-oxidants that scavenge reactive oxygen species (ROS), induced by radiotherapy. Glutathione (GSH) is an anti-oxidant synthesized from cystine and constitutes a major defense system against oxidative stress in mammalian cells. Cystine is taken up through system Xc− (SXC), an anti-port transmembrane protein with catalytic subunit xCT. Sulfasalazine, a drug approved in the 1950s for treatment of rheumatoid arthritis and inflammatory bowel disease, has been shown to block SXC. Based on previous reports by others, and our own recent findings, we hypothesize that: I) xCT represents a mechanism for radioresistance and is expressed in radioresistant melanoma cancer and II) xCT inhibitors can act as radiosensitizers to potentiate the efficacy of radiotherapy. Expression of the catalytic subunit of SXC, xCT, was found in tissue micro array of primary and secondary melanoma biopsies. In addition, SAS treatment dramatically reduced cystine-uptake and GSH levels in melanoma cells in vitro, and markedly increased the levels of reactive oxygen species (ROS). Furthermore, SAS and radiation synergistically increased DNA double-strand breaks and increased glioma cell death, whereas adding the anti-oxidant N-acetyl-L-cysteine (NAC) reversed cell death. Moreover, SAS and irradiation synergistically reduced subcutaneous melanoma tumor growth in vivo, compared to controls or either treatment alone. Thus, future experimental studies are warranted to validate SAS as a radiosensitizer in the treatment of metastatic melanoma. Future studies will also be aimed at assessing the effect on pulmonary melanoma metastasis. Citation Format: Hilde Elise Førde, Linda Sleire, Heidi Espedal, Jan Ingemann Heggdal, Frode Selheim, Paal-Henning Pedersen, Per Øyvind Enger. Drug repurposing: Validation of sulfasalazine as a radiosensitizer in melanoma by blocking system Xc−. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3048.
Abstract 4205: Targeting a variety of cancers with NOTA-derivatized pH (low) insertion peptide (pHLIP) complexes with 64Cu and 18F: What cancers are targetable
Authors: Dustin W. Demoin, Kimberly J. Edwards, Linden C. Wyatt, Mirkka Sarparanta, Jacob Pourat, Oleg A. Andreev, Yana K. Reshetnyak, Nerissa Viola-Villegas, Jason S. Lewis
Journal: Cancer Research (2016)

Abstract Introduction: Although heterogeneous, the extracellular tumor environment is generally marked by decreased pH relative to nontumor tissues due to cancer cell metabolism. Using a pH-sensitive peptide to deliver diagnostic PET isotopes can provide clinicians with improved diagnostic tools for cancer-specific imaging and an alternative to receptor-based cancer targeting. pH (low) Insertion Peptides (pHLIPs) have previously been shown to target cancerous tissues and are able to deliver PET metals to the cancer site utilizing a NOTA-based chelator. Methods: The thiol-containing cysteine moiety on the pHLIP peptide sequence was conjugated to the NOTA chelator. The NOTA-derivatized peptides were labeled with 64CuCl2 in 100 mM NH4OAc (pH 5) solution; the [18F]-fluoride was reacted with AlCl3 before forming the [18F]-AlF-NOTA-pHLIP complexes in NH4OAc buffered reaction mixtures (pH ∼ 4.1). After purification and formulation, the radiolabeled peptides were injected intravenously into 4T1 breast, PC-3 prostate, LNCaP prostate, or B16-F10 melanoma tumor-bearing mice. Results: The 4T1 tumor-bearing mice showed significant uptake &amp;gt; 10%ID/g by 4 h p.i. and continued to show increased uptake of the 64Cu-NOTA-cysVar3 over 20 h. Tumors were visible in the 4T1 tumor-bearing mice as early as 2 h, but had the greatest tumor-to-background ratios at 24 h. Initial studies with B16-F10 tumor-bearing mice showed &amp;gt; 9%ID/g uptake in the tumor by 4 h p.i. with slight increase of 64Cu-NOTA-cysVar3 uptake over 24 h. Due to the placement of the melanoma tumors away from internal organs, tumors were visible by 1 h p.i. Additionally, the size of the melanoma tumors did not affect the%ID/g of radiotracer uptake. Conclusions: Our studies indicate that the NOTA-cys(pHLIP), specifically NOTA-cysVar3, radiolabeled with 64Cu or 18F is a viable imaging tool for detecting highly metabolic tumors in preclinical mouse models. Funding: NIH F32 CA186721 (D.W.D.), NIH R01 CA138468 (J.S.L.), NIH MSKCC Center Grant (P30-CA08748). Citation Format: Dustin W. Demoin, Kimberly J. Edwards, Linden C. Wyatt, Mirkka Sarparanta, Jacob Pourat, Oleg A. Andreev, Yana K. Reshetnyak, Nerissa Viola-Villegas, Jason S. Lewis. Targeting a variety of cancers with NOTA-derivatized pH (low) insertion peptide (pHLIP) complexes with 64Cu and 18F: What cancers are targetable. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4205.
Response to Comment on Koivusalo et al. Gestational Diabetes Mellitus Can Be Prevented by Lifestyle Intervention: The Finnish Gestational Diabetes Prevention Study (RADIEL): A Randomized Controlled Trial. Diabetes Care 2016;39:24–30
Authors: Saila Birgitta Koivusalo, Kristiina Rönö, Beata Stach-Lempinen, Johan Gunnar Eriksson
Journal: Diabetes Care (2016)

We would like to thank Dr. Bao (1) for his interest in our gestational diabetes mellitus (GDM) prevention study RADIEL (the Finnish Gestational Diabetes Prevention Study) (2). Because of the globally increasing prevalence of GDM, the findings that GDM can be prevented by a behavioral lifestyle intervention in high-risk women is indeed very promising and important from a public health point of view. Further, it will be of great interest to see whether there will be long-term metabolic advantages among the women and their offspring during a longer follow-up.

Why was the RADIEL study …
Abstract 2660: A renal CpG island methylator phenotype (R-CIMP) in kidney tumors associated with germline mutations of <i>FH</i> and <i>SDHB</i>
Authors: Christopher Ricketts, J. Keith Killian, Cathy D. Vocke, Carole Sourbier, Youfeng Yang, Maria J. Merino, Paul S. Meltzer, W. Marston Linehan.
Journal: Cancer Research (2016)

Abstract Germline mutations of the genes encoding the Krebs cycle enzymes fumarate hydratase (FH) and succinate dehydrogenase (SDHB, SDHC, SDHD) have both been associated with an increased risk of renal cell carcinoma (RCC). These renal tumors demonstrate complete loss of enzyme activity and significantly increased levels of intracellular fumarate or succinate that are predicted to infer with the actions of multiple cellular processes primarily through the inhibition of 2-oxoglutarate-dependent dioxygenases, such as the prolyl hydroxylases that regulate the HIF pathway and the TET enzymes that regulate DNA methylation. This study evaluated and compared the genome-wide methylation profiles of 33 tumor samples (including 9 FH -/- and 7 SDHB -/- tumors), 10 associated normal samples and 13 cell-lines (including cell-line models derived from FH -/- and SDHB -/- tumors) using the Illumina HumanMethylation450 BeadChip arrays. Tumors derived from patients with germline FH or SDHB mutations demonstrated a distinct pattern of hypermethylation across the genome with enrichment for hypermethylation within the CpG island regions. SDHB mutation associated tumors demonstrated that was more variable and less extensive pattern of hypermethylation than the tumors associated with germline FH mutations. Cell-line models derived from HLRCC or SDHB tumors demonstrated patterns of hypermethylation similar to the patterns observed in the tumors, yet re-expression of either wild-type FH or SDHB within these cell-line models did not alter the methylation profiles. All the HLRCC and SDHB-RCC cell lines, including the cell-line re-expressing of either wild-type FH or SDHB, demonstrated growth inhibition and reduced invasion rates in response to treatment with 5-aza-2′-deoxycytidine. Thus, renal cell carcinomas associated with FH or SDHB germline mutation demonstrate a specific R-CIMP hypermethylation profile that differentiates these tumors from tumors derived from other RCC susceptibility syndromes. These tumors represent the most aggressive types of familial-associated RCC and this could provide a useful biomarker for identifying these tumors and de-methylating agents, such as 5-aza-2′-deoxycytidine, may be effective as part of a therapeutic regime for the treatment of these tumors. Citation Format: Christopher Ricketts, J. Keith Killian, Cathy D. Vocke, Carole Sourbier, Youfeng Yang, Maria J. Merino, Paul S. Meltzer, W. Marston Linehan. A renal CpG island methylator phenotype (R-CIMP) in kidney tumors associated with germline mutations of FH and SDHB. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2660.
British Association of Dermatologists’ guidelines for the safe and effective prescribing of methotrexate for skin disease 2016
Authors: R.B. Warren, S.C. Weatherhead, C.H. Smith, L.S. Exton, M.F. Mohd Mustapa, B. Kirby, P.D. Yesudian, P.M. McHenry, K. Gibbon, D.A. Buckley, I. Nasr, V.J. Swale, C.E. Duarte Williamson, T. Leslie, E. Mallon, S. Wakelin, S. Ungureanu, P. Hunasehally, M. Cork, J. Donnelly, C. Saunders, A.G. Brain
Journal: British Journal of Dermatology (2016)

This set of guidelines has been developed using the British Association of Dermatologists' recommended methodology, 1 and with reference to the Appraisal of Guidelines Research and Evaluation (AGREE II) instrument (www.agreetrust.org). 2 Recommendations were developed for implementation in the National Health Service using a process of considered judgement based on the evidence.PubMed, MEDLINE and Embase databases and the Cochrane Library were searched for meta-analyses, randomized and nonrandomized controlled clinical trials, case series, case reports and open studies involving MTX to October 2015; search terms and strategies are detailed in the Supporting Information.Additional relevant references were also isolated from citations in reviewed literature, as well as specific targeted searches for drug interactions, combination therapy, pretreatment tests and latent tuberculosis reactivation.All identified English-language titles were screened and those relevant for first-round inclusion were selected for further scrutiny.The abstracts for the shortlisted references were then reviewed by all members of the working group and the full papers of relevant material obtained; disagreements in the final selections were resolved by discussion with the entire development group.Case reports and case series were only considered if there was no higher-quality evidence available.The structure of the guidelines was then discussed, with headings and subheadings decided; different co-authors were allocated separate subsections.Each co-author then performed a detailed appraisal of the selected literature with discussions within the GDG to resolve any issues, and all subsections were subsequently collated, circulated within the GDG and edited to produce the final guidelines. Limitations of the guidelineThis document has been prepared on behalf of the BAD and is based on the best data available when the document was prepared.It is recognized that under certain conditions it may be necessary to deviate from the guidelines and that the results of future studies may require some of the recommendations herein to be changed.Failure to adhere to these guidelines should not necessarily be considered negligent, nor should adherence to these recommendations constitute a defence against a claim of negligence.Limiting the review to Englishlanguage references was a pragmatic decision, but the authors recognize this may exclude some important information published in other languages. Plans for guideline revisionThe proposed revision date for this set of recommendations is scheduled for 2021; where necessary, important interim changes will be updated on the BAD website.
Abstract 1143: Pro-proliferative function of SIRT3 in a human melanoma xenograft mouse model
Authors: Jasmine George, Minakshi Nihal, Mary A. Ndiaye, Nihal Ahmad
Journal: Cancer Research (2016)

Abstract Melanoma is one of the most aggressive forms of skin cancer and is often lethal, if not treated early. Therefore, it is necessary to try to develop novel target-based strategies to combat this neoplasm. SIRT3 is a nicotinamide adenine dinucleotide (NAD+) -dependent mitochondrial protein deacetylase involved in metabolism- and aging- related disorders, including certain cancers. Interestingly, studies have suggested both tumor suppressor as well as tumor promoter roles of SIRT3 in cancer. However, its role in melanoma is not well-established. Previously, we have shown that SIRT3 was upregulated in human melanoma cells and its lentiviral knockdown resulted in anti-proliferative effects in human melanoma cells. We also found that SIRT3 knockdown resulted in the G1-phase arrest of the cell cycle, induction of senescence, and decrease in cell migration. This study was designed to determine the relevance of our in vitro findings to the in vivo situation, in human melanoma xenograft models. Employing immunodeficient mice (Crl:NU-Foxn1nu, homozygous; Strain 088), we first determined the effect of SIRT3-knockdown on melanoma tumorigenesis. The mice were subcutaneously implanted with shNS-SK-MEL-2 (control) and shSIRT3-SK-MEL-2 (SIRT3-knockdown) melanoma cells, followed by assessing tumorigenesis of melanoma cells. We found that compared to shNS-SK-MEL-2 cells, shSIRT3-SK-MEL-2 cells showed a significantly decreased tumorigenic potential in these mice, in terms of average tumor volume (measured weekly) and average tumor weight (measured at termination of the study). Further, the Kaplan-Meier analysis showed that SIRT3 knockdown resulted in a significant survival advantage, in terms of reaching the cutoff tumor size (2.0 cm in one dimension). In an additional strategy, we determined the tumorigenicity of SIRT3 overexpressing melanoma cells (Hs294T-SIRT3) in NU/NU mice. Our data demonstrated that compared to control Hs294T-pcDNA cells, the SIRT3 overexpressing Hs294T-SIRT3 cells demonstrated a significantly enhanced tumorigenic potential (average tumor volume and tumor weight) in NU/NU mice. Overall, our study provides evidence supporting a pro-proliferative role of SIRT3 in melanoma and suggests that SIRT3 needs to be further evaluated as a potential druggable therapeutic target for melanoma management. However, detailed mechanistic and in vivo studies in relevant melanoma models are needed to further validate our findings. Citation Format: Jasmine George, Minakshi Nihal, Mary A. Ndiaye, Nihal Ahmad. Pro-proliferative function of SIRT3 in a human melanoma xenograft mouse model. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 1143.
Prognostic impact of <i>MAD1L1</i> promoter hypermethylation in advanced ovarian cancer
Authors: R. A. Jansen, J. C. Liu, S. Liyanarachchi, A. P. Crijns, P. S. Yan, T. H. Huang, D. E. Cohn, J. M. Fowler, A. G. Van der Zee, R. Brown
Journal: Journal of Clinical Oncology (2006)

5021 Background: Aberrant methylation of GC-rich gene promoters is a frequent epigenetic event in ovarian cancer leading to silencing of tumor suppressor genes. Identification of methylation biomarkers holds promise for impacting patient survival. Methods: High-throughput screening of hypermethylated CpG islands was conducted by differential methylation hybridization on stage III and IV epithelial ovarian carcinomas. Tumor DNA methylation status was interrogated by methylation-sensitive restriction enzymes, followed by co-hybridization on a custom promoter CpG island array with pooled normal ovarian surface epithelial cell (nOSE) DNA. Microarray findings were validated by quantitative methylation-specific PCR (qMSP) on 55–79 tumor samples. Results: Methylation levels of 6 novel genes (CYP39A1, EBP, FOXD4b, GTF2A1, MAD1L1 and YY1AP1) functioning in cell cycle control, transcription and drug metabolism/transport were identified as hypermethylated in ovarian cancer versus nOSE (nonparametric Wilcoxon rank sum test, p &lt; 0.005). Using Fisher’s exact test, patients with shorter progression-free survival (PFS) (≤18 months) had higher methylation levels compared to those with longer PFS (p = 0.015) for the gene MAD1L1, a mitotic checkpoint protein and antagonist of c-myc that regulates cell proliferation and differentiation. Cox regression analysis of methylation levels and PFS identified a negative correlation for MAD1L1. This correlation achieved statistical significance when MAD1L1 methylation levels combined with chemotherapy response was tested against PFS (p = 0.021), suggesting an interaction of this gene in patient response to chemotherapy. Conclusions: Induced overexpression of MAD1L1 has been shown to delay cell proliferation and inhibit growth. Downregulation via hypermethylation of this gene results in cell cycle dysregulation, a pathway for disease progression. This epigenetic modification in MAD1L1 renders it a potential target for intervention therapies that could improve patient survival. No significant financial relationships to disclose.