bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract B31: Sulindac inhibition of tumor cell transformation
Authors: Liang Zhipin , Feng Xiangling , Chang Hong , Yi Bin , Ma Ruixia , Xi Yaguang 
Published: November 2016

Abstract
Cell transformation is the process in which normal cells acquire the properties of cancer. Sulindac Sulfide (SS) is one of non-steroidal anti-inflammatory drugs (NSAIDs), and its anticancer activity in prevention of tumor occurrence and progression has been documented in various human cancers. In this study, we observed the anti-transformative activity of SS in NIH/3T3 cells by using a two-stage transformation assay induced by the carcinogens, 3-methylcholanthrene (MCA) and 2-O-tetradecanoylphorbol-13-acetate (TPA) in which foci formation is used to characterize the transformed cells. We found that SS could inhibit foci formation by attenuation of TPA's promotive effect. K-Ras was upregulated in the transformed cells, while SS treatment could selectively inhibit the growth of transformed cell in which K-Ras was suppressed significantly. Loss-of-function study demonstrated that knockdown of K-Ras in NIH/3T3 cells could significantly reduce foci formation, which support that K-Ras might be one of the key targets involved in SS inhibiting tumor cell transformation. When studying the mechanism by which SS regulates K-Ras, we triggered two tumor suppressor miRNAs, let-7b and let-7g, which were previously reported to target K-Ras and repress its expression through the post-transcriptional or translational modulation. We found that let-7b and let-7g could be upregulated in the transformed cells by SS treatment. However, the inhibitory effect of SS on foci formation was significantly attenuated when let-7b and let-7g were knocked down by CRISPR/cas9. In parallel, K-Ras maintained static expression in the transformed cells, regardless of SS treatment. These results suggest that upregulation of let-7b and let-7g is the key step for SS to inhibit tumor transformation. In addition, we demonstrated that SS could suppress the expression of Lin28 that interacts with let-7 through a documented feedback loop. Given our previous studies reporting that SS was able to inhibit the transcriptional activity of NF-kappaB that is involved in regulation of Lin28 expression, our study demonstrates that the NF-kappaB/Lin28/Let-7/K-Ras axis addresses a new mechanism responsible for anti-transformative activity of SS. These results will provide novel insights into understanding the mechanisms involved in tumorigenesis and benefiting identification of new targets for drug development in prevention of tumor progression. This study is supported by the NIH/NCI R01 Grant (1R01CA192395) and the American Cancer Society Research Scholar Grant (RSG-13-265-01-RMC).
Citation Format: Zhipin Liang, Xiangling Feng, Hong Chang, Bin Yi, Ruixia Ma, Yaguang Xi. Sulindac inhibition of tumor cell transformation. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Cancer Cell Cycle - Tumor Progression and Therapeutic Response; Feb 28-Mar 2, 2016; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(11_Suppl):Abstract nr B31.
Abstract B32: Oncogenic role of snoRD93 in breast cancer cells
Authors: Ma Ruixia , Zhao Hongyou , Patterson Dillon , Borchert Glen , Xi Yaguang 
Published: November 2016

Abstract
Noncoding RNAs (ncRNAs) play key roles in many essential processes of human diseases through regulating gene expression. Small nucleolar RNA (snoRNA) is a relatively large group of ncRNAs with diversified functions in mammalian cells, although many of them have not been well-characterized. Recent studies have revealed the alterations of different snoRNAs in prostate, breast, and lung malignancies; however, their mechanistic roles in tumorigenesis and progression have not been well-studied yet. In this study, we compared the transcriptome profiles of human breast cancer cell lines, MCF-7 and MDA-MB-231, by using the next generation sequencing (NGS). MCF-7 cells were derived from the primary breast tumor, while MDA-MB-231 cells are highly metastatic. Our sequencing results showed that 13 snoRNAs was significantly overexpressed in MDA-MB-231 cells versus MCF-7 cells. In particular, we are interested in snoRD93, given its expression showing 27-time higher in MDA-MB-231 cells than MCF-7 cells. We further studied the oncogenic role of snoRD93 in MDA-MB-231 cells by using loss-of-function strategy. By employing cell viability assay, we found that the repression of snoRD93 by transfection of the antisense inhibitors could significantly inhibit the tumor cell growth. In addition, downregulation of snoRD93 could result in relatively low motility of MDA-MB-231 cells as shown in the matrigel invasion assay. Therefore, our data support the oncogenic role of snoRD93 in breast cancer cells and suggest that snoRD93 can be triggered a potential target for development of new anticancer drugs.
Citation Format: Ruixia Ma, Hongyou Zhao, Dillon Patterson, Glen Borchert, Yaguang Xi. Oncogenic role of snoRD93 in breast cancer cells. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Cancer Cell Cycle - Tumor Progression and Therapeutic Response; Feb 28-Mar 2, 2016; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(11_Suppl):Abstract nr B32.
Abstract B33: The membrane associated cyclin D1 promotes contact-independent growth via phosphorylation of Akt1 Ser 473
Authors: Jiao Xuanmao , Chen Ke , Xu Shaohua , Ju Xiaoming , Ertel Adam , Tian Lifeng , Yu Zuoren , Sante Gabriele Di , Wang Min , Li Zhiping , Pestell Timothy , Casimiro Mathew , Shen Duanwen , Achilefu Samuel , Pestell Richard 
Published: November 2016

Abstract
The serine threonine kinase Akt plays a pivotal role in the control of cellular metabolism, survival, growth and cellular migration. Cyclin D1 encodes the regulatory subunit of a holoenzyme that phosphorylates and inactivates pRb, to promote cell cycle progression and functions as a nuclear collaborative oncogene. Herein, genetic deletion of cyclin D1 reduced and overexpression induced Akt1 activity in tissue culture and in vivo. Endogenous cyclin D1 augmented both the rate of onset and maximal cellular Akt1 activity. The cytoplasmic membrane-associated pool of cyclin D1, augmented Akt1 kinase activity, to thereby induce cell cycle progression, cellular migration, proliferation and contact independent growth. The induction of Akt1 kinase activity, via Ser 473, was dependent upon a single residue of cyclin D1 (K112) in vitro, and in vivo in mammary epithelial cell targets tissue specific transgenic mice. Distinct subcellular compartments of cell cycle proteins convey distinct functions to augment cellular growth.
Our data identified the function of the membrane associated cyclin D1 pool is to phosphorylate and activate AKT1, thereby, inducing cell cycle progression, contact independent growth and cellular migration. Membrane mounted cyclin D1 is a novel targetable vulnerability aberrant growth control.
Citation Format: Xuanmao Jiao, Ke Chen, Shaohua Xu, Xiaoming Ju, Adam Ertel, Lifeng Tian, Zuoren Yu, Gabriele Di Sante, Min Wang, Zhiping Li, Timothy Pestell, Mathew Casimiro, Duanwen Shen, Samuel Achilefu, Richard Pestell. The membrane associated cyclin D1 promotes contact-independent growth via phosphorylation of Akt1 Ser 473. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Cancer Cell Cycle - Tumor Progression and Therapeutic Response; Feb 28-Mar 2, 2016; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(11_Suppl):Abstract nr B33.
Abstract IA07: Targeting the cyclin D-CDK4/6 pathway for cancer therapy
Authors: Abraham Robert T. 
Published: November 2016

Abstract
The cyclin D-CDK4/6 kinase complex plays a pivotal role in the stimulation of cellular proliferation through phosphorylation and functional inactivation of the retinoblastoma protein (pRb), which leads to commitment of G1-phase cells to enter S phase, and ultimately to complete the mitotic cell cycle. Cancer cells frequently escape normal constraints on cell proliferation via persistent inactivation of pRb, through dysregulation of cyclin D-CDK4/6 kinase activity or loss of pRb expression. Interestingly, estrogen-positive (ER+) breast cancer cells rarely show loss of pRb, and hence rely on inappropriate activation of cyclin D-CDK4/6 to drive malignant proliferation. ER+ breast cancer therefore represents an enriched patient population in which to test the efficacy of cyclin D-CDK4/6 inhibition as a therapeutic strategy. Palbociclib, a selective cyclin D-CDK4/6 inhibitor, was approved by the FDA in 2015 for the treatment of women with advanced ER+/HER2- breast cancer. The drug is administered in combination with an anti-hormonal agent, which underscores the critical, collaborative roles of dysregulated estrogen receptor and cyclin D-CDK4/6 activities in driving tumor growth in this breast cancer subtype. This presentation will review the cellular pharmacology of palbociclib, with a particular emphasis on the phenotypic outcomes of combined estrogen receptor and cyclin D-CDK4/6 inhibition in human breast cancer cell lines. In addition, we will provide an update on the clinical activities of palbociclib in breast cancer, as well as prospects for therapeutic targeting of cyclin D-CDK4/6 activity in other cancer subtypes.
Citation Format: Robert T. Abraham. Targeting the cyclin D-CDK4/6 pathway for cancer therapy. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Cancer Cell Cycle - Tumor Progression and Therapeutic Response; Feb 28-Mar 2, 2016; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(11_Suppl):Abstract nr IA07.
Abstract IA09: A drug delivery method selective for senescent cells
Authors: Serrano Manuel 
Published: November 2016

Abstract
The accumulation of senescent cells occurs in multiple human degenerative pathologies and are also present within tumors. Senescent cells, although not proliferating, are very active in secreting cytokines that may fuel the growth of tumor cells. Therefore, the selective elimination of senescent cells may bring benefits to the treatment of many diseases, including cancer. I will present a strategy to selective deliver drugs to senescent cells in vivo.
Citation Format: Manuel Serrano. A drug delivery method selective for senescent cells. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Cancer Cell Cycle - Tumor Progression and Therapeutic Response; Feb 28-Mar 2, 2016; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(11_Suppl):Abstract nr IA09.
Abstract IA16: Breaking the balance between E2F activators and atypical repressors: Consequences to development and cancer
Authors: Leone Gustavo W. 
Published: November 2016

Abstract
E2F transcriptional activators and repressors regulate cell cycle-dependent gene expression. Using a series of loss- and gain-of-function alleles to dial E2F transcriptional output we show that mouse development is relatively insensitive to alterations in E2F levels and composition. However, modest increases in E2F output resulted in spontaneous hepatocellular carcinoma (HCC) without additional organ involvement, whereas decreases protected against HCC. Cell type- and temporal-specific gene ablation strategies defined a cell-autonomous oncogenic role for E2F1/3B and a tumor suppressor role for E2F7/8 in hepatocytes. Genetic, biochemical and profiling studies suggest a mechanism involving E2F1/3B-mediated activation and E2F7/8-mediated repression of a common set of targets during early post-natal liver development, which are associated with HCC progression. Thus, while overall development is sufficiently robust, the liver is uniquely sensitive to perturbations in E2Fs. In summary, we identified the critical network components in immature hepatocytes that control E2F output and foster a cancer-free life span.
Citation Format: Gustavo W. Leone. Breaking the balance between E2F activators and atypical repressors: Consequences to development and cancer. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Cancer Cell Cycle - Tumor Progression and Therapeutic Response; Feb 28-Mar 2, 2016; Orlando, FL. Philadelphia (PA): AACR; Mol Cancer Res 2016;14(11_Suppl):Abstract nr IA16.
Menopausal Hot Flashes and Carotid Intima Media Thickness Among Midlife Women
Authors: Thurston Rebecca C. , Chang Yuefang , Barinas-Mitchell Emma , Jennings J. Richard , Landsittel Doug P. , Santoro Nanette , von Känel Roland , Matthews Karen A. 
Published: November 2016

Background and Purpose—
There has been a longstanding interest in the role of menopause and its correlates in the development of cardiovascular disease (CVD) in women. Menopausal hot flashes are experienced by most midlife women; emerging data link hot flashes to CVD risk indicators. We tested whether hot flashes, measured via state-of-the-art physiologic methods, were associated with greater subclinical atherosclerosis as assessed by carotid ultrasound. We considered the role of CVD risk factors and estradiol concentrations in these associations.

Methods—
A total of 295 nonsmoking women free of clinical CVD underwent ambulatory physiologic hot flash assessments; a blood draw; and carotid ultrasound measurement of intima media thickness and plaque. Associations between hot flashes and subclinical atherosclerosis were tested in regression models controlling for CVD risk factors and estradiol.

Results—

More frequent physiologic hot flashes were associated with higher carotid intima media thickness (for each additional hot flash: β [SE]=0.004 [0.001];
P
=0.0001; reported hot flash: β [SE]=0.008 [0.002];
P
=0.002, multivariable) and plaque (eg, for each additional hot flash, odds ratio [95% confidence interval] plaque index ≥2=1.07 [1.003–1.14];
P
=0.04, relative to no plaque, multivariable] among women reporting daily hot flashes; associations were not accounted for by CVD risk factors or by estradiol. Among women reporting hot flashes, hot flashes accounted for more variance in intima media thickness than most CVD risk factors.

Conclusions—
Among women reporting daily hot flashes, frequent hot flashes may provide information about a woman’s vascular status beyond standard CVD risk factors and estradiol. Frequent hot flashes may mark a vulnerable vascular phenotype among midlife women.
Infarct in a New Territory After Treatment Administration in the ESCAPE Randomized Controlled Trial (Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion With Emphasis on Minimizing CT to Recanalization Times)
Authors: Ganesh Aravind , Al-Ajlan Fahad S. , Sabiq Farahna , Assis Zarina , Rempel Jeremy L. , Butcher Kenneth , Thornton John , Kelly Peter , Roy Daniel , Poppe Alexandre Y. , Jovin Tudor G. , Devlin Thomas , Baxter Blaise W. , Krings Timo , Casaubon Leanne K. , Frei Donald F. , Choe Hana , Tampieri Donatella , Teitelbaum Jeanne , Lum Cheemun , Mandzia Jennifer , Phillips Stephen J. , Bang Oh Young , Almekhlafi Mohammed A. , Coutts Shelagh B. , Barber Philip A. , Sajobi Tolulope , Demchuk Andrew M. , Eesa Muneer , Hill Michael D. , Goyal Mayank , Menon Bijoy K. 
Published: November 2016

Background and Purpose—
Infarct in a new previously unaffected territory (INT) is a potential complication of endovascular treatment. We applied a recently proposed methodology to identify and classify INTs in the ESCAPE randomized controlled trial (Endovascular Treatment for Small Core and Anterior Circulation Proximal Occlusion With Emphasis on Minimizing CT to Recanalization Times).

Methods—
The core laboratory identified INTs on 24-hour follow-up imaging, blinded to treatment allocation, after assessing all baseline imaging. INTs were classified into 3 types (I–III) and 2 subtypes (A/B) based on size and if catheter manipulation was likely performed across the vessel territory ostium. Logistic regression was used to understand the effect of multiple a priori identified variables on INT occurrence. Ordinal logistic regression was used to analyze the effect of INTs on modified Rankin Scale shift at 90 days.

Results—

From 308 patients included, 14 INTs (4.5% overall; 2.8% on follow-up noncontrast computed tomography, 11.7% on follow-up magnetic resonance imaging) were identified (5.0% in endovascular treatment arm versus 4.0% in control arm [
P
=0.7]). The use of intravenous alteplase was associated with a 68% reduction in the odds of INT occurrence (3.0% with versus 9.1% without; odds ratio, 0.32; 95% confidence interval, 0.11–0.96; adjusted for age, sex, and treatment type). No other variables were associated with INTs. INT occurrence was associated with reduced probability of good clinical outcome (common odds ratio, 0.25; 95% confidence interval, 0.09–0.74; adjusted for age, type of treatment, and follow-up scan).

Conclusions—
INTs are uncommon, detected more frequently on follow-up magnetic resonance imaging, and affect clinical outcome. In experienced centers, endovascular treatment is likely not causal, whereas intravenous alteplase may be therapeutic.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT01778335.
Moist Formulations of the Eliassen–Palm Flux and Their Connection to the Surface Westerlies
Authors: Dwyer John G. , O’Gorman Paul A. 
Published: November 2016

Abstract
The Eliassen–Palm (EP) flux is an important diagnostic for wave propagation and wave–mean flow interaction in the atmosphere. Here, two moist formulations of the EP flux are compared with the traditional dry EP flux, and their links to the surface westerlies are analyzed using reanalysis data and simulations with GCMs. The first moist formulation of the EP flux modifies only the static stability to account for latent heat release by eddies, while the second moist formulation simply replaces all potential temperatures with equivalent potential temperatures. For reanalysis data, the peak upward EP flux in the lower troposphere is farther equatorward and stronger when the moist formulations are used, with greater changes for the second moist formulation. The moist formulations have the advantage of giving a closer relationship over the seasonal cycle between the latitudes of the peak surface westerlies and the peak upward EP flux. In simulations with a comprehensive GCM, the dry and moist upward EP fluxes shift poleward by a similar amount as the climate warms. In simulations over a wider range of climates with an idealized GCM, the surface westerlies can shift both poleward and equatorward with warming, and they are influenced by an anomalous region of dry EP flux divergence near the subtropical jet. Using moist EP fluxes weakens this anomalous divergence in the idealized GCM simulations, and the shifts in the surface westerlies can then be understood through changes in the preference for equatorward or poleward wave propagation.
Influence of the Ocean and Greenhouse Gases on Severe Drought Likelihood in the Central United States in 2012
Authors: Rupp David E. , Li Sihan , Mote Philip W. , Massey Neil , Sparrow Sarah N. , Wallom David C. H. 
Published: November 2016

Abstract
The impacts of sea surface temperature (SST) anomalies and anthropogenic greenhouse gases on the likelihood of extreme drought occurring in the central United States in the year 2012 were investigated using large-ensemble simulations from a global atmospheric climate model. Two sets of experiments were conducted. In the first, the simulated hydroclimate of 2012 was compared to a baseline period (1986–2014) to investigate the impact of SSTs. In the second, the hydroclimate in a world with 2012-level anthropogenic forcing was compared to five “counterfactual” versions of a 2012 world under preindustrial forcing. SST anomalies in 2012 increased the simulated likelihood of an extreme summer precipitation deficit (e.g., the deficit with a 2% exceedance probability) by a factor of 5. The likelihood of an extreme summer soil moisture deficit increased by a similar amount, due in great part to a large spring soil moisture deficit carrying over into summer. An anthropogenic impact on precipitation was detectable in the simulations, doubling the likelihood of what would have been a rainfall deficit with a 2% exceedance probability under preindustrial-level forcings. Despite this reduction in rainfall, summer soil moisture during extreme drought was essentially unaffected by anthropogenic forcing because of 1) evapotranspiration declining roughly one-to-one with a decrease in precipitation due to severe water supply constraint and despite higher evaporative demand and 2) a decrease in stomatal conductance, and therefore a decrease in potential transpiration, with higher atmospheric CO2 concentrations.
Persistence and switching patterns of oral migraine prophylactic medications among patients with chronic migraine: A retrospective claims analysis
Authors: Hepp Zsolt , Dodick David W , Varon Sepideh F , Chia Jenny , Matthew Nitya , Gillard Patrick , Hansen Ryan N , Devine Emily Beth 
Published: November 2016

Background Migraine prevention guidelines recommend oral prophylactic medications for patients with frequent headache. This study examined oral migraine preventive medication (OMPM) treatment patterns by evaluating medication persistence, switching, and re-initiation in patients with chronic migraine (CM). Methods A retrospective US claims analysis (Truven Health MarketScan® Databases) evaluated patients ≥18 years old diagnosed with CM who had initiated an OMPM between 1 January, 2008 and 30 September, 2012. Treatment persistence was measured at six and 12 months’ follow-up. Time-to-discontinuation was assessed for each OMPM and compared using Cox regression models. Among those who discontinued, the proportion that switched OMPMs within 60 days or re-initiated treatment between 61 to 365 days, and their associated persistence rates, were also assessed. Results A total of 8707 patients met the inclusion/exclusion criteria. Persistence to the initial OMPM was 25% at six months and 14% at 12 months. Based on Kaplan-Meier curves, a sharp decline of patients discontinuing was observed by 30 days, and approximately half discontinued by 60 days. Similar trends in time-to-discontinuation were seen following the second or third OMPM. Amitriptyline, gabapentin, and nortriptyline had significantly higher likelihood of non-persistence compared with topiramate. Among patients who discontinued, 23% switched to another prophylactic and 41% re-initiated therapy within one year. Among patients who switched, persistence was between 10 to 13% and among re-initiated patients, persistence was between 4 to 8% at 12 months. Conclusions Persistence to OMPMs is poor at six months and declines further by 12 months. Switching between OMPMs is common, but results indicate that persistence worsens as patients cycle through various OMPMs.