bluuebunny/crossref_metadata_2025_split huggingface dataset:
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

Abstract
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 &gt;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

Abstract
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

Abstract
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 (%)&gt;1%5810081&gt;5%7210090&gt;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

Abstract
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

Abstract
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

Abstract
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.
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

AbstractInflatable 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.
Revision Meniscal Allograft Transplantation in the Lateral Compartment
Authors: Lee Bum-Sik , Bin Seong-Il , Kim Jong-Min , Kim Won-Kyeong , Kim Jae Hyan 
Published: July 2016

Background: Little is known about clinical outcomes after revision meniscal allograft transplantation (RMAT), and there are no studies on magnetic resonance imaging (MRI) evaluations during the early remodeling period. Hypothesis: The objective imaging results, as determined by MRI evaluation, would be inferior to those of published data on primary meniscal allograft transplantations (MATs), although short-term clinical improvement would be achieved after RMAT. Study Design: Case series; Level of evidence, 4. Methods: We retrospectively reviewed 9 consecutive patients (6 male and 3 female) who underwent RMAT from 2010 to 2014. The mean patient age was 33 years (range, 28-45 years). All patients had prior failed MATs in the lateral compartment. None of the patients had malalignment or ligament instability, and 7 patients had grade 3 or higher chondral degeneration. We assessed the RMAT with routine MRI evaluations during the remodeling period of the first postoperative year to determine graft healing and the mode of refailures, if any. We also investigated the problems specific for revision operations, as well as clinical outcomes. Results: Four of the 9 RMAT patients had significant intra-articular fibrosis with or without motion limitations at the time of RMAT. MRI evaluations demonstrated that the overall early refailure rate was 33.3% (3/9) during the first year; bucket-handle displacement with no meniscocapsular healing was the mode of all failures. Insufficient meniscal healing was also found in 2 other RMATs without premature failure. After a mean follow-up of 29.2 months (range, 21-45 months) in the 6 patients with preserved RMATs, Lysholm and International Knee Documentation Committee subjective scores showed significant improvements over preoperative scores (from 53.3 ± 6.0 to 87.7 ± 2.9 [ P = .028] and from 53.4 ± 9.0 to 69.9 ± 4.8 [ P = .043], respectively; Wilcoxon signed rank test). Conclusion: The MRI findings showed that poor or insufficient meniscal healing to the host joint capsule was the major drawback of RMAT. Although more than half of our patients experienced clinical improvement after RMAT, the short-term graft survival was inferior to that of primary MATs in the literature. Our findings suggest that this challenging revision procedure requires great caution, especially with regard to the effects of poor host tissue quality on meniscal healing. Although RMAT can be an effective treatment, close observation with routine MRI evaluation is necessary during the early remodeling period to assess the status of the revised meniscal allograft.
Time-dependent ROC methodology to evaluate the predictive accuracy of semiparametric multi-state models in the presence of competing risks: An application to peritoneal dialysis programme
Authors: Teixeira Laetitia , Cadarso-Suárez Carmen , Rodrigues Anabela , Mendonça Denisa 
Published: July 2016

Abstract: The evaluation of peritoneal dialysis (PD) programmes requires the use of statistical methods that suit the complexity of such programmes. Multi-state regression models taking competing risks into account are a good example of suitable approaches. In this work, multi-state structured additive regression (STAR) models combined with penalized splines (P-splines) are proposed to evaluate peritoneal dialysis programmes. These models are very flexible since they may consider smooth estimates of baseline transition intensities and the inclusion of time-varying and smooth covariate effects at each transition. A key issue in survival analysis is the quantification of the time-dependent predictive accuracy of a given regression model, which is typically assessed using receiver operating characteristic (ROC)’based methodologies. The main objective of the present study is to adapt the concept of time-dependent ROC curve, and their corresponding area under the curve (AUC), to a multi-state competing risks framework. All statistical methodologies discussed in this work were applied to PD survival data. Using a multi-state competing risks framework, this study explored the effects of major clinical covariates on survival such as age, sex, diabetes and previous renal replacement therapy. Such multi-state model was composed of one transient state (peritonitis) and several absorbing states (death, transfer to haemodialysis and renal transplantation). The application of STAR models combined with time-dependent ROC curves revealed important conclusions not previously reported in the nephrology literature when using standard statistical methodologies. For practical application, all the statistical methods proposed in this article were implemented in R and we wrote and made available a script named as NestedCompRisks.