bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract 97: A novel PTPRK-FILIP1 fusion gene in invasive mucinous adenocarcinoma of lung without known driver mutations
Authors: Hong Sung-Hye , Lee Geon Kook , Song Sang Hoon , Lee Seung Youn , Kim Jin Young , Han Ji-Youn
Published: July 2016

Invasive mucinous adenocarcinoma (IMA) accounts for 2 to 10% of all adenocarcinoma cases of the lung and has a poor prognosis. The KRAS mutation is the most commonly detected genetic alteration in IMAs. Recent progress has permitted the identification of novel fusions such as NRG1. In an effort to further discovery of new driver oncogenes, we have carried out whole-transcriptome sequencing of IMA. To exclude IMA cases with known driver oncogenes, we performed targeted sequencing using the Ion AmpliSeq Cancer Hotspot Panel. We also tested other currently known fusion genes in lung cancer including CD74-NRG1, TPM3-ROS1, SDC4-ROS1, SLC34A2-ROS1, CD74-ROS1, EZR-ROS1, LRIG-ROS1, KIF5B-RET, CCDC6-RET1, EZR-ERBB4, TRIM24-BRAF, KIAA1468-RET, EML4-ALK, and KIF5B-ALK using RT-PCR. Finally we found 10 IMA cases without known driver oncogenes and performed transcriptome paired-end sequencing (the Illumina HiSeq platform). We utilized and compared 3 bioinformatic pipelines, FusionMap, deFuse, and ChimeraScan to identify fusion events. Of 10 IMA cases tested, we found 2 novel fusions, PTPRK-FILIP1 and CEP85L-RNGTT, from a never-smoking female patient. They were shared across all three fusion-finder and never reported in TCGA fusion gene data portal. Only PTPRK-FILIP1 was showed an in-frame fusion between exon 2 of PTPRK and 5’ UTR of FILIP1. It was confirmed by RT-PCR analysis and Sanger sequencing. This precise fusion was not present in the matched normal tissue. The reading frame is preserved that both the start codon of PTPRK and FILIP1. However, PTPRK mRNA expression is increased until exon 2 because of the fusion includes only two exons of PTPRK. Otherwise, expression analysis showed significant increase of FILIP1 mRNA expression in the affected tumor pair sample. The protein product from FILIP1 is closely associated with the protein filamin A, which is associated with tumor proliferation, cell migration, and metastasis. Many studies have reported that filamin A as a poor prognostic factor. Considering its implication in tumor proliferation, cell migration, and metastasis, PTPRK-FILIP1 could be a novel target for IMA. This is the first report of PTPRK-FILIP1 fusion gene in IMA without known driver mutations. Further functional validation of FILIP1 fusion is planned.

Citation Format: Sung-Hye Hong, Geon Kook Lee, Sang Hoon Song, Seung Youn Lee, Jin Young Kim, Ji-Youn Han. A novel PTPRK-FILIP1 fusion gene in invasive mucinous adenocarcinoma of lung without known driver mutations. [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 97.
Abstract 971: A novel long noncoding RNA, onco-lncRNA 230, induces apoptosis and invasion in lung squamous cell carcinoma
Authors: Tang Cynthia Y. , Silva-Fisher Jessica M. , Dang Ha X. , White Nicole M. , Maher Christopher A.
Published: July 2016

Long non-coding RNAs (lncRNAs) are RNAs that are longer than 200 base pairs and do not translate into proteins but have been shown to play roles in all aspects of biological regulation. LncRNAs have also been shown to regulate gene expression including chromatin organization, transcriptional regulation, and post-transcriptional control. In addition, they are now emerging to be important players in our understanding of cancer and have been shown to promote tumorigenesis. However, the mechanisms driving the advancement of tumor progression to metastasis is poorly understood. To identify lncRNAs critical to tumorigenesis, our lab conducted a pan-cancer analysis of normal and primary tumor tissues from The Cancer Genome Atlas to discover lncRNAs that are commonly altered across cancer types, which we termed ‘onco-lncRNAs’. During our analysis, we discovered a novel unannotated onco-lncRNA, onco-lncRNA-230, that was significantly up regulated in head and neck squamous cell carcinoma (HNSC), lung adenocarcinoma (LUAD), and lung squamous cell carcinoma (LUSC) tumors relative to matched adjacent normal tissues, when available. We chose to focus on onco-lncRNA-230 as it displayed more than seven fold increase in LUAD and more than thirty seven fold change in LUSC tumors relative to adjacent normal. First, we validated this finding by quantitative PCR which revealed greater than a two fold enrichment of onco-lncRNA-230 expression in two out of seven LUAD and all six LUSC cells lines compared to a normal lung cell line. Because we observed the greatest increase in expression in HCC95 LUSC cells, we next sought to determine if modulating the expression of onco-lncRNA-230 promotes oncogenic phenotypes. Silencing of onco-lncRNA-230 in HCC95 cells did not change cellular proliferation but significantly increased apoptosis. Furthermore, silencing onco-lncRNA-230 resulted in a decrease in cellular invasion by transwell assay. Taken together, this represents the first study reporting that onco-lncRNA-230 is dysregulated in multiple cancer types, significantly up-regulated in lung cancer patient samples and lung cancer cell lines, and confers oncogenic phenotypes. Moving forward, we intend to explore how onco-lncRNA-230 mechanistically promotes lung cancer with the objective of utilizing onco-lncRNA-230 as a novel cancer diagnostic and therapy.

Citation Format: Cynthia Y. Tang, Jessica M. Silva-Fisher, Ha X. Dang, Nicole M. White, Christopher A. Maher. A novel long noncoding RNA, onco-lncRNA 230, induces apoptosis and invasion in lung squamous cell carcinoma. [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 971.
Abstract 979: Identification of a novel long noncoding RNA within the LCK gene locus that regulates prostate cancer cell growth
Authors: Ta Huy Q. , Jackson Samuel R. , Whitworth Hilary , Bhadel Shriti , Gioeli Daniel
Published: July 2016

Prostate cancer remains the second most common type of cancer and frequent cause of cancer-related mortality in American men. Even though many patients with metastatic prostate cancer will initially respond to androgen deprivation therapy, virtually all patients will relapse and develop lethal castration-resistant prostate cancer. Long noncoding RNAs (lncRNAs) are emerging as critical regulatory elements of many cellular biological processes, and there is increasing evidence demonstrating that dysregulation of lncRNAs is associated with many human cancers, including cancers of the prostate, breast, and lung. We have discovered in a high-throughput RNAi screen identifying regulators of prostate cancer cell growth that knockdown of lymphocyte-specific protein tyrosine kinase (LCK) significantly decreases growth of prostate cancer cells in the presence and absence of androgen. Surprisingly, immunoprecipitation and western blot analyses show that LCK is not expressed at the protein level in prostate cancer cells. Rapid amplification of cDNA ends (RACE) and sequencing have revealed that a previously unannotated lncRNA lies within exon six and the 3’UTR of the LCK gene. While short hairpin RNAs (shRNAs) targeting the carboxy-terminus of the LCK gene decreases cell growth, expression of shRNAs specific for the amino-terminus has no effect on growth. Furthermore, only quantitative polymerase chain reaction (qPCR) primers directed toward the 3’ section of the LCK gene yield detectable levels of transcript. These data provide further validation for the existence of a lncRNA within the LCK gene locus. Remarkably, the lncRNA situated within the LCK gene is dramatically upregulated in response to androgen. Therefore, we have labeled this lncRNA “HULLK” for Hormone-upregulated lncRNA within LCK. Cellular fractionation and qPCR show that HULLK predominantly localizes to the cytoplasm. In addition to the effects on prostate cancer cell growth, we have data that alludes to the increase in transcript levels of several Src family members following depletion of HULLK. Thus, these studies indicate that the LCK gene contains a lncRNA involved in the regulation of prostate cancer cell growth and perhaps transcription. While additional analyses will be required to fully characterize HULLK, our data suggest that it may serve as a novel regulator of prostate cancer proliferation.

Citation Format: Huy Q. Ta, Samuel R. Jackson, Hilary Whitworth, Shriti Bhadel, Daniel Gioeli. Identification of a novel long noncoding RNA within the LCK gene locus that regulates prostate cancer cell growth. [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 979.
Abstract 991: Long non-coding RNA LINC01133 inhibits epithelial-mesenchymal transition and metastasis in colorectal cancer by interacting with SRSF6
Authors: Kong Jianlu , Zhang Honghe , Xu Enping , Huang Qiong , Chen Jian , Lai Maode
Published: July 2016

Objective Long non-coding RNAs (lncRNAs) play crucial roles in many biological and pathological processes, including tumor metastasis. The aim of this study was to investigate the expression and molecular function of LINC01133 in colorectal cancer (CRC).

Design LINC01133 expression was assessed in CRC cell lines and 219 clinical tissue samples by quantitative RT-PCR. Small interfering RNA-mediated knockdown was used to probe the biological functions of LINC01133, and its binding protein was isolated and identified using ChIRP-MS combined with western blot, and further validated by RNA immunoprecipitation assays.

Results We found that LINC01133 inhibited CRC cell migration and invasion by regulating the epithelial-mesenchymal transition (EMT), and was downregulated by TGF-β. We then showed that SRSF6 directly bound to LINC01133. Furthermore, we confirmed that that the EMT process regulated by LINC01133 in CRC cells depended on the presence of SRSF6. The expression of LINC01133 was markedly downregulated in CRC tissues relative to their corresponding normal mucosal tissues, and patients with tumors displaying higher LINC01133 expression had a better clinical outcome.

Conclusion These data suggest that LINC01133 inhibits the EMT and metastasis by directly binding to SRSF6 as a target mimic, and may serve as a prognostic biomarker and/or an effective target for anti-metastasis therapies for CRC.

Citation Format: Jianlu Kong, Honghe Zhang, Enping Xu, Qiong Huang, Jian Chen, Maode Lai. Long non-coding RNA LINC01133 inhibits epithelial-mesenchymal transition and metastasis in colorectal cancer by interacting with SRSF6. [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 991.
Abstract 995: The functional involvement of H19, a Long noncoding RNA, in human colorectal cancer
Authors: LING HUI , Ohtsuka Masahisa , Pichler Martin , Ivan Cristina , Matsushita Daisuke , Calin George
Published: July 2016

The clinical significance of long noncoding RNAs (lncRNAs), defined as transcripts longer than 200 bp that do not code for proteins, in colorectal cancer (CRC) remains largely uncharacterized. We selected 10 lncRNAs associated with CRC, analyzed their expression association with patient survival using The Cancer Genome Atlas (TCGA) CRC data, and identified H19 as the one significantly associated with CRC patient survival. Experimental data using CRC cell line models showed that downregulation of H19 significantly reduced cancer cell proliferation, anchorage-independent growth, and cell migration capacity. Flow cytometric analysis suggested a clear G1 arrest of CRC cells following depletion of H19 expression. Our mechanism study suggests that H19 is pivotal in maintaining Wnt signaling and notch signaling. These finding represent a novel mechanism of H19 function in colorectal cancer, and strongly support the translational importance of this lncRNA as cancer marker and therapeutic target.

Citation Format: HUI LING, Masahisa Ohtsuka, Martin Pichler, Cristina Ivan, Daisuke Matsushita, George Calin. The functional involvement of H19, a Long noncoding RNA, in human colorectal cancer. [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 995.
Abstract CT152: Food effect on the pharmacokinetics of 200-mg abemaciclib in healthy subject
Authors: Turner Kellie , Chappell Jill , Kulanthaivel Palaniappan , Ng Wee Teck , Royalty Jane
Published: July 2016

Abemaciclib is an oral, selective, and potent small-molecule inhibitor of cyclin-dependent kinases 4 and 6 (CDK4 and CDK6) being investigated for the treatment of patients with refractory hormone-receptor positive (HR+) advanced or metastatic breast cancer. The absolute bioavailability and effect of food on pharmacokinetics (PK) following a single 200-mg oral dose of abemaciclib in healthy subjects were evaluated in three studies (Table 1). Abemaciclib plasma concentrations were measured serially pre-dose through 192 hours post-dose. Non-compartmental analysis was used to calculate PK parameters, and a mixed-effects model was used for statistical inference. In Study 1 the absolute bioavailability of a 200-mg dose of abemaciclib was 45% (90% CI: 40%, 51%). In Study 2 the ratios of AUC0-? after a high-fat or standard meal compared to fasting showed no effect (90% CIs within 0.80, 1.25). However, Cmax increased by 24% and 25% following high-fat and standard meals, respectively, compared to fasting (upper 90% CIs >1.25). No differences were found in the AUC0-? and Cmax of abemaciclib following a high-fat meal compared to a standard meal (90% CI within 0.80, 1.25). The median tmax was delayed by 2 hours following a high-fat meal compared to fasting (p = 0006). However, there was no difference in median tmax between the standard meal and fasting (p = .7197). Abemaciclib terminal half-life was similar across fed and fasted conditions. The late-breaking Study-3 results will be presented. In conclusion, abemaciclib oral bioavailability is sufficient to achieve therapeutic exposure. Food with abemaciclib does not reduce or increase the inter-individual PK variability and does not have a clinically-relevant impact on the PK of abemaciclib. Therefore, abemaciclib may be administered without regard to food. Table 1Designs for three open-label clinical studies of abemaciclib as a single 200-mg oral dose administered to healthy subjectsStudy ParametersNCT02327143a (Study 1)I3Y-MC-JPBSNCT02059148a (Study 2)I3Y-MC-JPBGNCT02482935a (Study 3)I3Y-MC-JPBUCompleted subjects (N)82329Overall designs and formulationsAbsolute bioavailability, 4 x 50-mg (25% w/w) capsules and tracer IVbPilot food effect, randomized crossover 3 period, 6 sequence 4 x 50-mg (50% w/w) capsulesPivotal food effect, randomized crossover 2 period, 2 sequence 2 x 100-mg (25% w/w) capsulesMeal conditionFastedFastedStandard mealHigh-fat, high-calorie mealFastedHigh-fat, high-calorie meal

Citation Format: Kellie Turner, Jill Chappell, Palaniappan Kulanthaivel, Wee Teck Ng, Jane Royalty. Food effect on the pharmacokinetics of 200-mg abemaciclib in healthy subject. [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 CT152.
Abstract LB-056: Discovery of novel small molecule inhibitors of the DCN1-Ubc12 interaction by high throughput screening technology
Authors: Min Jaeki , Scott Daniel C. , Chai Sergio C. , Goktug Asli N. , Hammill Jared T. , Huang Guochang , Connelly Michele C. , Matheny Amy , Shelat Anang , Singh Bhuvanesh , Chen Taosheng , Schulman Brenda A. , Guy R. Kiplin
Published: July 2016

Ubiquitination of protein is well known mechanism for the regulation of cellular proteins by the ubiquitin-proteasome system (UPS). The ubiquitin-proteasome system (UPS) plays a crucial role in regulating cellular protein degradation and turnover. Dysregulation of the UPS has been associated with a wide variety of diseases including cancers, neurodegenerative disorders, and viral and bacterial infections. Recently, there are emerging evidences show that targeting this UPS by small molecule modulator is a useful anticancer strategy based on the previous successes of proteasome inhibitors, E3 inhibitors and the NEDD8 E1 inhibitor. In particular, we are targeting NEDD8 ligation to cullins via inhibition of DCN1 as a small molecule target. DCN1 was known to interacts with cullins and is required for neddylation in vivo. Furthermore, dysregulation of DCN1 is associated with a number of human cancers. DCN1 activity is controlled by its interaction with UBC12. Therefore, we have developed biochemical assay utilizing TR-FRET technology for the purpose of high-throughput screening (HTS) to identify the small molecule inhibitors that disrupt the DCN1-UBC12 protein-protein interaction and use them to elucidate the biological effects of DCN1 mediated UPS regulation. Herein, we report our progress including design, procedure and result of HTS with post-screen analysis to discover small molecule inhibitors of the DCN1 from our in-house library compounds (∼600K). Following hit identification and validation, we identified three novel scaffolds as novel DCN1 inhibitors by biochemical, biophysical, and crystallographic studies to follow for further hit optimization. To the best of our knowledge, this is the first work to report small molecule DCN1 inhibitors.

Citation Format: Jaeki Min, Daniel C. Scott, Sergio C. Chai, Asli N. Goktug, Jared T. Hammill, Guochang Huang, Michele C. Connelly, Amy Matheny, Anang Shelat, Bhuvanesh Singh, Taosheng Chen, Brenda A. Schulman, R. Kiplin Guy. Discovery of novel small molecule inhibitors of the DCN1-Ubc12 interaction by high throughput screening technology. [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 LB-056.
Abstract LB-094: A comparative study of PD-L1 diagnostic assays and the classification of patients as PD-L1 positive and PD-L1 negative
Authors: Ratcliffe Marianne J. , Sharpe Alan , Midha Anita , Barker Craig , Scorer Paul , Walker Jill
Published: July 2016

Background: PD-1/PD-L1 directed antibodies are emerging as effective therapeutics in multiple oncology settings. Keynote 001 and Checkmate 057 have shown more frequent response to PD-1 targeted therapies in NSCLC patients with high tumour PD-L1 expression than patients with low or no PD-L1 expression. Multiple diagnostic PD-L1 tests are available using different antibody clones, different staining protocols and diverse scoring algorithms. It is vital to compare these assays to allow appropriate interpretation of clinical outcomes. Such understanding will promote harmonization of PD-L1 testing in clinical practice.

Methods: Approximately 500 tumour biopsy samples from NSCLC patients, including squamous and non-squamous histologies, will be assessed using three leading PD-L1 diagnostics assays. PD-L1 assessment by the Ventana SP263 assay that is currently being used in Durvalumab clinical trials (positivity cut off: ≥25% tumour cells with membrane staining) will be compared with the Dako 28-8 assay (used in the Nivolumab Checkmate 057 trial at the 1%, 5% and 10% tumour membrane positivity cut offs), and the Dako 22C3 assay (used in the Pembrolizumab Keynote 001 trial) at the 1% and 50% cut offs).

Results: Preliminary data from 81 non-squamous patients indicated good concordance between the Ventana SP263 and Dako 28-8 assays. Optimal overall percent agreement (OPA) was observed between Dako 28-8 at the 10% cut off and the Ventana SP263 assay (OPA; 96%, Positive percent agreement (PPA); 91%, Negative percent agreement (NPA); 98%), where the Ventana SP263 assay was set as the reference. Data on the full cohort will be presented for all three assays, and a lower 95% confidence interval calculated using the Clopper-Pearson method.

Conclusions: This study indicates that the patient population defined by Ventana SP263 at the 25% cut off is similar to that identified by the Dako-28-8 assay at the 10% tumour membrane cut off. This, together with data on the 22C3 assay, will enable cross comparison of studies using different PD-L1 tests, and widen options for harmonization of PD-L1 diagnostic testing. Table 1Reference: Ventana SP-263 (≥25% tumour membrane staining)Dako 28-8 assay cut offPPA (%)NPA (%)OPA (%)>1%5810081>5%7210090>10%919896

Citation Format: Marianne J. Ratcliffe, Alan Sharpe, Anita Midha, Craig Barker, Paul Scorer, Jill Walker. A comparative study of PD-L1 diagnostic assays and the classification of patients as PD-L1 positive and PD-L1 negative. [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 LB-094.
Abstract LB-130: STAT3/PIAS3 as “early signature” gene pathways in the development of ovarian high grade serous carcinoma from the fallopian tube
Authors: Saini Uksha , Wallbillich John , Riley Maria Riley , Fowler John M. , Wanner Ross , Lester Jenny , Karlan Beth , Goodfellow Paul , Suarez Adrian , Cohn David , Selvendiran Karuppaiyah
Published: July 2016

Objectives: Our recent studies in human samples have demonstrated constitutive activation of STAT3 Tyr705 and loss of protein inhibitor of activated STAT3 (PIAS3) in STICs in the fallopian tubes and advanced HGSC tissues. The goal of this current study is to identify and elucidate the molecular mechanisms leading to the initiation and development of HGSC through STAT3 activation and low levels or absence of PIAS3 in the fallopian tube (FT).

Methods: Human tissues–benign normal FTs, STICs (without ovarian cancer) and HGSC—were evaluated for expression of STAT3/PIAS3 (as compared with their known TP53 signature) and their target proliferation genes. Isolated primary fallopian tubal serous epithelial carcinoma (FTSEC) cells from FT and immortalized FT cells were also utilized and were evaluated with real time PCR, IHC, ICC, western blots, cloning and orthotopic mouse models.

Results: We observed high-level expression of pSTAT3 Tyr705, and decreased levels of PIAS3, in dysplastic areas of FT obtained from patients with and without cancer and advanced stage HGSC (as compared to high PIAS3 low pSTAT3 expression in normal benign FT). In addition, FT cells transfected with a STAT3 overexpression construct showed translocation of pSTAT3 and c-Myc into the nucleus. Further, the in vivo experiments demonstrated that the overexpression of STAT3 in FTSECs promoted tumor progression and metastasis, mimicking the clinical disease observed in patients with HGSC. In contrast, STAT3 knockdown in ovarian cancer cells was associated with reduced tumor growth and metastasis in vivo.

Conclusions: The STAT3 pathway may play a critical role in the development of STIC lesions and their progression to HGSC. We will further screen more FT samples and number of human tissues from various stages of HGSC along with an in vivo mouse model of HGSC in order to establish the oncogenic role of STAT3 and expression levels of PIAS3 in ovarian HGSC. Our current and future findings offer an opportunity to address the clinically important questions that are critical for cancer prevention and early detection in deadly HGSC.

Citation Format: Uksha Saini, John Wallbillich, Maria Riley Riley, John M. Fowler, Ross Wanner, Jenny Lester, Beth Karlan, Paul Goodfellow, Adrian Suarez, David Cohn, Karuppaiyah Selvendiran. STAT3/PIAS3 as “early signature” gene pathways in the development of ovarian high grade serous carcinoma from the fallopian tube. [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 LB-130.
Abstract LB-206: A bromodomain-swap allele demonstrates that on-target chemical inhibition of BRD9 limits the proliferation of acute myeloid leukemia cells
Authors: Hohmann Anja F. , Martin Laetitia J. , Minder Jessica , Roe Jae-Seok , Shi Junwei , Steurer Steffen , Bader Gerd , McConnell Darryl , Pearson Mark , Gerstberger Thomas , Gottschamel Teresa , Thompson Diane , Suzuki Yutaka , Koegl Manfred , Vakoc Christopher
Published: July 2016

Recent studies have revealed vital roles of SWI/SNF complexes in leukemia and a variety of other cancers, making this chromatin remodeler a candidate drug target in human malignancy. Chemical modulation of SWI/SNF activity, however, remains to be achieved. Given the success of pharmacological bromodomain inhibition, we evaluated the role of bromodomain-carrying SWI/SNF subunits and identified Bromodomain-containing protein 9 (BRD9) as critical for the growth of Acute Myeloid Leukemia (AML). In AML cells, BRD9 binds the enhancer of the MYC proto-oncogene and sustains MYC transcription, rapid cell proliferation, as well as a block in differentiation. Based on these observations, we derived a small-molecule inhibitor of the BRD9 bromodomain, which partially displaces BRD9 from MYC enhancer elements and selectively suppresses the proliferation of mouse and human AML cell lines.

Given the known role of other bromodomains, namely those of BRD4, in leukemia growth, ruling out potential off-target activity of our BRD9 inhibitor was critical. Traditionally, bromodomain inhibitor selectivity is tested using in vitro binding assays that examine a subset of other bromodomains. To sample the entire space of potential off-target proteins, we sought an in-cell selectivity assay. To this end, we engineered a bromodomain-swap allele of BRD9, which retains functionality despite a radically altered bromodomain pocket. Expression of this allele in AML cells confers resistance to the anti-proliferative effects of our BRD9 inhibitor, thus establishing BRD9 as the relevant cellular target. Furthermore, we used an analogous domain-swap strategy to generate an inhibitor-resistant allele of EZH2.

Our study provides the first evidence for a role of BRD9 in cancer and further highlights a simple genetic strategy for constructing resistance alleles to demonstrate on-target activity of chemical probes in cells.

Citation Format: Anja F. Hohmann, Laetitia J. Martin, Jessica Minder, Jae-Seok Roe, Junwei Shi, Steffen Steurer, Gerd Bader, Darryl McConnell, Mark Pearson, Thomas Gerstberger, Teresa Gottschamel, Diane Thompson, Yutaka Suzuki, Manfred Koegl, Christopher Vakoc. A bromodomain-swap allele demonstrates that on-target chemical inhibition of BRD9 limits the proliferation of acute myeloid leukemia cells. [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 LB-206.
Abstract LB-212: Therapeutic efficacy of the paradox-breaking panRAF and SRC drug CCT3833/BAL3833 in KRAS-driven cancer models
Authors: Saturno Grazia , Lopes Filipa , Girotti Maria Romina , Niculescu-Duvaz Ion , Niculescu-Duvaz Dan , Zambon Alfonso , Davies Lawrence , Johnson Louise , Preece Natasha , Viros Amaya , Pedersen Malin , McLeary Robert , Knight Ruth , Lee Rebecca , Holovanchuk Denys , Lorigan Paul , Dhomen Nathalie , Marais Richard , Springer Caroline
Published: July 2016

KRAS is mutated in ∼80% of pancreatic ductal adenocarcinoma (PDAC), ∼35% of colorectal cancer (CRC) and ∼20% of non-small-cell lung cancer (NSCLC). KRAS remains an intractable drug target and targeting the downstream pathway component is ineffective because feedback mechanisms or parallel pathways provide alternative routes to cell proliferation and/or survival. Here we show that a new panRAF/SRC inhibitor, CCT3833, is active in KRAS-mutant PDAC, CRC and NSCLC. We demonstrate that CCT3833 inhibits tumor growth in several KRAS-driven cancers via inhibition of RAF and SRC, eliciting therapeutic efficacy at well-tolerated doses in mouse models of human cancer. CCT3833 has already entered clinical trials (NCT02437227) for BRAF mutant and BRAF inhibitor-resistant melanomas and these new data show that it is also effective in KRAS mutant cancers, potentially providing a new therapeutic option for these patients.

Citation Format: Grazia Saturno, Filipa Lopes, Maria Romina Girotti, Ion Niculescu-Duvaz, Dan Niculescu-Duvaz, Alfonso Zambon, Lawrence Davies, Louise Johnson, Natasha Preece, Amaya Viros, Malin Pedersen, Robert McLeary, Ruth Knight, Rebecca Lee, Denys Holovanchuk, Paul Lorigan, Nathalie Dhomen, Richard Marais, Caroline Springer. Therapeutic efficacy of the paradox-breaking panRAF and SRC drug CCT3833/BAL3833 in KRAS-driven cancer models. [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 LB-212.
CYP2J2-Derived EETs Attenuated Angiotensin II-Induced Adventitial Remodeling via Reduced Inflammatory Response
Authors: Zhou Chi , Huang Jin , Chen Junxiong , Lai Jinsheng , Zhu Fasheng , Xu Xizhen , Wang Dao Wen
Published: July 2016

Background: Cytochrome P450 (CYP) epoxygenases metabolize arachidonic acids (AA) to form epoxyeicosatrienoic acids (EETs), which exert beneficial roles in the treatment of cardiovascular diseases, but little is known about its role on adventitial remodeling. Methods: We used C57BL/6J mice in vivo and primary rat adventitial fibroblasts (AFs) in vitro treated with Angiotensin II to investigate the effects of CYP2J2 gene delivery and exogenous EETs administration on adventitial remodeling. Results: CYP/sEH system was found to exist in human adventitia, and involved in adventitial remodeling process. Exogenous EETs administration significantly inhibited Ang II-induced AFs activation, characterized by differentiation, proliferation, migration, and collagen synthesis. These protective effects were partially reversed by PPARγ antagonist GW9662 pretreatment or SOCS3 siRNA transfection. EETs suppressed Ang II-induced IκBα phosphorylation, subsequent NF-κB nuclear translocation via PPARγ dependent signaling pathway in AFs. Additionally, EETs reduced Ang II-induced JAK2, STAT3 phosphorylation and subsequent phosphor-STAT3 nuclear translocation, which were mediated by SOCS3 induction but independent of PPARγ activation. Furthermore, rAAV-CYP2J2 gene delivery reduced vessel wall thickening, AFs differentiation, proliferation and collagen deposition in aortic adventitia induced by Ang II infusion, which were mediated by NF-κB and SOCS3/JAK/STAT signaling pathways in blood pressure dependent and independent manner, respectively. Conclusion: We concluded that CYP2J2 overexpression attenuated Ang II-induced adventitial remodeling via PPARγ-dependent NF-κB and PPARγ-independent SOCS3/JAK/STAT inflammatory signaling pathways.
The Clinical Significance of miR-34a in Pancreatic Ductal Carcinoma and Associated Molecular and Cellular Mechanisms
Authors: Long Li-Min , Zhan Jun-Kun , Wang Hai-Qin , Li Shuang , Chen Yi-Yin , Liu You-Shuo
Published: July 2016

Background: Pancreatic ductal adenocarcinoma (PDAC) exhibits poor prognosis and resistance to chemotherapy. This study was to identify the biomarkers associated with the progression, poor prognosis and chemoresistance of PDAC. Methods: miR-34a and miR-150 levels in the plasma and tissues from PDAC patients were measured by real-time PCR. Xenograft PDAC tumor models were established in mice by inoculation of CD133+ stem cells isolated from PDAC tumors. Protein expression was measured by Western blot. Results: The plasma miR-34a and miR-150 levels were significantly lower in PDAC patients than in patients with benign pancreatic lesions and in healthy subjects. The miR-34a and miR-150 levels in the tumor tissues were significantly lower than in pancreatic tissues with benign lesions. The protein levels of CD133, Notch1, Notch2 and Notch4 receptors in PDAC tumor tissues were significantly higher than in pancreatic tissues with benign lesions. miR-34a injection significantly inhibited the tumor growth of PDAC tumors and sensitized the anticancer effects of 5-fluorouracil (5-FU). miR-34a significantly inhibited Notch1, Notch2 and Notch4 expression in xenograft tumor tissues in vivo and BxPC-3 cells in vitro. miR-34a and miR-150 significantly induced apoptosis and inhibited proliferation, invasion and migration in BxPC-3 cells. miR-34a, but not miR-150, significantly sensitized the anticancer effect of 5-FU in BxPC-3 cells in vitro. Conclusion: A loss of expression of miR-34a, but not of miR-150, is associated with disease progression and poor prognosis in PDAC patients, and may be involved in the chemoresistance of PDAC cells.
Ecological Hypothesis of Dentin and Root Caries
Authors: Takahashi Nobuhiro , Nyvad Bente
Published: July 2016

Recent advances regarding the caries process indicate that ecological phenomena induced by bacterial acid production tilt the de- and remineralization balance of the dental hard tissues towards demineralization through bacterial acid-induced adaptation and selection within the microbiota - from the dynamic stability stage to the aciduric stage via the acidogenic stage [Takahashi and Nyvad, 2008]. Dentin and root caries can also be partly explained by this hypothesis; however, the fact that these tissues contain a considerable amount of organic material suggests that protein degradation is involved in caries formation. In this review, we compiled relevant histological, biochemical, and microbiological information about dentin/root caries and refined the hypothesis by adding degradation of the organic matrix (the proteolytic stage) to the abovementioned stages. Bacterial acidification not only induces demineralization and exposure of the organic matrix in dentin/root surfaces but also activation of dentin-embedded and salivary matrix metalloproteinases and cathepsins. These phenomena initiate degradation of the demineralized organic matrix in dentin/root surfaces. While a bacterial involvement has never been confirmed in the initial degradation of organic material, the detection of proteolytic/amino acid-degrading bacteria and bacterial metabolites in dentin and root caries suggests a bacterial digestion and metabolism of partly degraded matrix. Moreover, bacterial metabolites might induce pulpitis as an inflammatory/immunomodulatory factor. Root and dentin surfaces are always at risk of becoming demineralized in the oral cavity, and exposed organic materials can be degraded by host-derived proteases contained in saliva and dentin itself. New approaches to the prevention and treatment of root/dentin caries are required.
Notes on the occurrence of Mortonagrion aborense Laidlaw, 1914 (Odonata: Coenagrionidae) from lower West Bengal, India
Authors: Payra Arajush , Tiple Ashish D.
Published: July 2016

A new distribution record of an Odonata species from lower West Bengal. Mortonagrion aborense laidlaw, 1914 is recorded for the first time from Purba Medinipur district, lower West Bengal. Previously the species was recorded only from north-east India (Mizoram, West Bengal, Assam and Nagaland). Diagnostic characters with photographic details of male anal appendages are also given for easy identification of this rare damselfly species.
Ablation of Atrial Fibrillation
Authors: Link Mark S. , Haïssaguerre Michel , Natale Andrea
Published: July 2016

Atrial fibrillation (AF) is the most common arrhythmia encountered by cardiologists and is a major cause of morbidity and mortality. Risk factors for AF include age, male sex, genetic predisposition, hypertension, diabetes mellitus, sleep apnea, obesity, excessive alcohol, smoking, hyperthyroidism, pulmonary disease, air pollution, heart failure, and possibly excessive exercise. The management of AF involves decisions about rate versus rhythm control. Asymptomatic patients are generally managed with rate control and anticoagulation. Symptomatic patients will desire rhythm control. Rhythm control options are either antiarrhythmic agents or ablation, with each having its own risks and benefits. Ablation of AF has evolved from a rare and complex procedure to a common electrophysiological technique. Selection of patients to undergo ablation is an important aspect of AF care. Patients with the highest success rates of ablation are those with normal structural hearts and paroxysmal AF, although those with congestive heart failure have the greatest potential benefit of the procedure. Although pulmonary vein isolation of any means/energy source is the approach generally agreed on for those with paroxysmal AF, optimal techniques for the ablation of nonparoxysmal AF are not yet clear. Anticoagulation reduces thromboembolic complications; the newer anticoagulants have eased management for both the patient and the cardiologist. Aggressive management of modifiable risk factors (hypertension, diabetes mellitus, sleep apnea, obesity, excessive alcohol, smoking, hyperthyroidism, pulmonary disease, air pollution, and possibly excessive exercise) after ablation reduces the odds of recurrent AF and is an important element of care.
Association of Parental Hypertension With Arterial Stiffness in Nonhypertensive Offspring
Authors: Andersson Charlotte , Quiroz Rene , Enserro Danielle , Larson Martin G. , Hamburg Naomi M. , Vita Joseph A. , Levy Daniel , Benjamin Emelia J. , Mitchell Gary F. , Vasan Ramachandran S.
Published: July 2016

High arterial stiffness seems to be causally involved in the pathogenesis of hypertension. We tested the hypothesis that offspring of parents with hypertension may display higher arterial stiffness before clinically manifest hypertension, given that hypertension is a heritable condition. We compared arterial tonometry measures in a sample of 1564 nonhypertensive Framingham Heart Study third-generation cohort participants (mean age: 38 years; 55% women) whose parents were enrolled in the Framingham Offspring Study. A total of 468, 715, and 381 participants had 0 (referent), 1, and 2 parents with hypertension. Parental hypertension was associated with greater offspring mean arterial pressure (multivariable-adjusted estimate=2.9 mm Hg; 95% confidence interval, 1.9–3.9, and 4.2 mm Hg; 95% confidence interval, 2.9–5.5, for 1 and 2 parents with hypertension, respectively;
P
<0.001 for both) and with greater forward pressure wave amplitude (1.6 mm Hg; 95% confidence interval, 0.6–2.7, and 1.9 mm Hg; 95% confidence interval, 0.6–3.2, for 1 and 2 parents with hypertension, respectively;
P
=0.003 for both). Carotid–femoral pulse wave velocity and augmentation index displayed similar dose-dependent relations with parental hypertension in sex-, age-, and height-adjusted models, but associations were attenuated on further adjustment. Offspring with at least 1 parent in the upper quartile of augmentation index and carotid–femoral pulse wave velocity had significantly higher values themselves (
P
≤0.02). In conclusion, in this community-based sample of young, nonhypertensive adults, we observed greater arterial stiffness in offspring of parents with hypertension. These observations are consistent with higher vascular stiffness at an early stage in the pathogenesis of hypertension.
Relations of Arterial Stiffness and Brachial Flow–Mediated Dilation With New-Onset Atrial Fibrillation
Authors: Shaikh Amir Y. , Wang Na , Yin Xiaoyan , Larson Martin G. , Vasan Ramachandran S. , Hamburg Naomi M. , Magnani Jared W. , Ellinor Patrick T. , Lubitz Steven A. , Mitchell Gary F. , Benjamin Emelia J. , McManus David D.
Published: July 2016

The relations of measures of arterial stiffness, pulsatile hemodynamic load, and endothelial dysfunction to atrial fibrillation (AF) remain poorly understood. To better understand the pathophysiology of AF, we examined associations between noninvasive measures of vascular function and new-onset AF. The study sample included participants aged ≥45 years from the Framingham Heart Study offspring and third-generation cohorts. Using Cox proportional hazards regression models, we examined relations between incident AF and tonometry measures of arterial stiffness (carotid–femoral pulse wave velocity), wave reflection (augmentation index), pressure pulsatility (central pulse pressure), endothelial function (flow-mediated dilation), resting brachial arterial diameter, and hyperemic flow. AF developed in 407/5797 participants in the tonometry sample and 270/3921 participants in the endothelial function sample during follow-up (median 7.1 years, maximum 10 years). Higher augmentation index (hazard ratio, 1.16; 95% confidence interval, 1.02–1.32;
P
=0.02), baseline brachial artery diameter (hazard ratio, 1.20; 95% confidence interval, 1.01–1.43;
P
=0.04), and lower flow-mediated dilation (hazard ratio, 0.79; 95% confidence interval, 0.63–0.99;
P
=0.04) were associated with increased risk of incident AF. Central pulse pressure, when adjusted for age, sex, and hypertension (hazard ratio, 1.14; 95% confidence interval, 1.02–1.28;
P
=0.02) was associated with incident AF. Higher pulsatile load assessed by central pulse pressure and greater apparent wave reflection measured by augmentation index were associated with increased risk of incident AF. Vascular endothelial dysfunction may precede development of AF. These measures may be additional risk factors or markers of subclinical cardiovascular disease associated with increased risk of incident AF.
Does Contralateral Delay Activity Reflect Working Memory Storage or the Current Focus of Spatial Attention within Visual Working Memory?
Authors: Berggren Nick , Eimer Martin
Published: July 2016

During the retention of visual information in working memory, event-related brain potentials show a sustained negativity over posterior visual regions contralateral to the side where memorized stimuli were presented. This contralateral delay activity (CDA) is generally believed to be a neural marker of working memory storage. In two experiments, we contrasted this storage account of the CDA with the alternative hypothesis that the CDA reflects the current focus of spatial attention on a subset of memorized items set up during the most recent encoding episode. We employed a sequential loading procedure where participants memorized four task-relevant items that were presented in two successive memory displays (M1 and M2). In both experiments, CDA components were initially elicited contralateral to task-relevant items in M1. Critically, the CDA switched polarity when M2 displays appeared on the opposite side. In line with the attentional activation account, these reversed CDA components exclusively reflected the number of items that were encoded from M2 displays, irrespective of how many M1 items were already held in working memory. On trials where M1 and M2 displays were presented on the same side and on trials where M2 displays appeared nonlaterally, CDA components elicited in the interval after M2 remained sensitive to a residual trace of M1 items, indicating that some activation of previously stored items was maintained across encoding episodes. These results challenge the hypothesis that CDA amplitudes directly reflect the total number of stored objects and suggest that the CDA is primarily sensitive to the activation of a subset of working memory representations within the current focus of spatial attention.
“Blödigkeit” und “Unbedachtsamkeit”: Vorankündigungen anthropologischen Erzählens in Sibylla Schwarz’ pastoraler Liebeserzählung Faunus
Authors: Wels Ulrike
Published: July 2016

The article offers a rereading of Sibylla Schwarz’s prose eclogue, Faunus. By describing the circumstances and the development of a young love in detail, Schwarz directs the reader’s attention to the fact, that Christian moral and ethical standards are external, and, therefore, are to be rejected. Instead, she places the ‘anthropological’ dimension in the foreground, the interest in human beings and their emotional motivations. Affective control and adaptation to conventions are less important. In that regard, this short text can be seen as an integral part of a prehistory of ‘literary anthropology,’ which ultimately evolved only in the course of the 18th century, although, as will be shown, its precursors can already be found in the 17th century.
Migrants’ Cultural Rights at the Confluence of International Human Rights Law and International Cultural Heritage Law
Authors: Chechi Alessandro
Published: July 2016

Contemporary migration flows and the related humanitarian emergency have received overwhelming media coverage and political attention. It appears, however, that the sorrow provoked by the heart-breaking stories of migrants has been all too often quickly replaced by the rhetoric that describes this influx as the principal cause for the problems that Western States face today – unemployment, crime, drugs and violent extremism – and as a threat for national culture and identity. This article looks at the cultural rights of migrants and at the international instruments that regulate one or more aspects of the phenomenon of migration and the protection of cultural heritage. Its objective is to challenge existing prejudices against migrant communities and to answer the question whether migration and migrants are a burden or a blessing for the culture of receiving States.
A review of the genus Eotmethis (Orthoptera, Acridoidea, Pamphagidae) with two new species and key to known species of the genus from China
Authors: LI XIN-JIANG , SHI JIAN-PING , DANG YAN
Published: July 2016

Two new species of the genus Eotmethis Bey-Bienko, 1948, namely Eotmethis inditibialis sp. nov. and Eotmethis shizuishanensis sp. nov. from the Ningxia Hui Autonomous Region are described in this paper. The new species Eotmethis inditibialis sp. nov. differs from all known species of the genus by inner side of hind tibia purple in the middle. The new species Eotmethis shizuishanensis sp. nov. is similar to Eotmethis xiai Ye, Shi & Zhi, 2015, differs from latter by tegmina of male shorter, reaching to 4th abdominal tergite, R vein without branch, M vein with one branch, Cu vein without branch and lower knee-lobe of hind femur yellow on inner side. The type specimens are deposited in College of Life Sciences, Hebei University, Baoding, China. Key to known species of the genus Eotmethis Bey-Bienko, 1948 is given.
Do Inflatable Bounce Houses Pose Heat-Related Hazards to Children?
Authors: Duzinski Sarah
Published: July 2016

Inflatable bounce houses provide a popular summer activity for children. Injuries such as sprains and fractures are widely acknowledged, but there is less awareness about possible hazards from excessive heat exposure. This study aims to identify whether conditions in the bounce house are more oppressive than ambient conditions on a typical summer day in Athens, Georgia. Results show that maximum air temperatures in the bounce house can reach up to 3.7°C (6.7°F) greater than ambient conditions, and peak heat index values may exceed outdoor conditions by 4.5°C (8.1°F). When considered within the context of the National Weather Service heat index safety categories, the bounce house reached the “danger” level in more than half of the observations, compared with only 7% of observations for ambient conditions. Parents and caregivers should be aware of heat-related hazards in bounce houses and closely monitor children, adjusting or canceling activities as conditions become more oppressive.