bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pleiotropic Effects of PPARD Accelerate Colorectal Tumorigenesis, Progression, and Invasion
Authors: Liu Yi , Deguchi Yasunori , Tian Rui , Wei Daoyan , Wu Ling , Chen Weidong , Xu Weiguo , Xu Min , Liu Fuyao , Gao Shen , Jaoude Jonathan C. , Chrieki Sarah P. , Moussalli Micheline J. , Gagea Mihai , Morris Jeffrey , Broaddus Russell R. , Zuo Xiangsheng , Shureiqi Imad 
Published: January 2019

Abstract

APC mutations activate aberrant β-catenin signaling to drive initiation of colorectal cancer; however, colorectal cancer progression requires additional molecular mechanisms. PPAR-delta (PPARD), a downstream target of β-catenin, is upregulated in colorectal cancer. However, promotion of intestinal tumorigenesis following deletion of PPARD in Apcmin mice has raised questions about the effects of PPARD on aberrant β-catenin activation and colorectal cancer. In this study, we used mouse models of PPARD overexpression or deletion combined with APC mutation (ApcΔ580) in intestinal epithelial cells (IEC) to elucidate the contributions of PPARD in colorectal cancer. Overexpression or deletion of PPARD in IEC augmented or suppressed β-catenin activation via up- or downregulation of BMP7/TAK1 signaling and strongly promoted or suppressed colorectal cancer, respectively. Depletion of PPARD in human colorectal cancer organoid cells inhibited BMP7/β-catenin signaling and suppressed organoid self-renewal. Treatment with PPARD agonist GW501516 enhanced colorectal cancer tumorigenesis in ApcΔ580 mice, whereas treatment with PPARD antagonist GSK3787 suppressed tumorigenesis. PPARD expression was significantly higher in human colorectal cancer–invasive fronts versus their paired tumor centers and adenomas. Reverse-phase protein microarray and validation studies identified PPARD-mediated upregulation of other proinvasive pathways: connexin 43, PDGFRβ, AKT1, EIF4G1, and CDK1. Our data demonstrate that PPARD strongly potentiates multiple tumorigenic pathways to promote colorectal cancer progression and invasiveness.

Significance:
These findings address long-standing, important, and unresolved questions related to the potential role of PPARD in APC mutation-dependent colorectal tumorigenesis by showing PPARD activation enhances APC mutation-dependent tumorigenesis.
The Antitumor Drug LB-100 Is a Catalytic Inhibitor of Protein Phosphatase 2A (PPP2CA) and 5 (PPP5C) Coordinating with the Active-Site Catalytic Metals in PPP5C
Authors: D'Arcy Brandon M. , Swingle Mark R. , Papke Cinta M. , Abney Kevin A. , Bouska Erin S. , Prakash Aishwarya , Honkanen Richard E. 
Published: January 2019

Abstract
LB-100 is an experimental cancer therapeutic with cytotoxic activity against cancer cells in culture and antitumor activity in animals. The first phase I trial (NCT01837667) evaluating LB-100 recently concluded that safety and efficacy parameters are favorable for further clinical testing. Although LB-100 is widely reported as a specific inhibitor of serine/threonine phosphatase 2A (PP2AC/PPP2CA:PPP2CB), we could find no experimental evidence in the published literature demonstrating the specific engagement of LB-100 with PP2A in vitro, in cultured cells, or in animals. Rather, the premise for LB-100 targeting PP2AC is derived from studies that measure phosphate released from a phosphopeptide (K-R-pT-I-R-R) or inferred from the ability of LB-100 to mimic activity previously reported to result from the inhibition of PP2AC by other means. PP2AC and PPP5C share a common catalytic mechanism. Here, we demonstrate that the phosphopeptide used to ascribe LB-100 specificity for PP2A is also a substrate for PPP5C. Inhibition assays using purified enzymes demonstrate that LB-100 is a catalytic inhibitor of both PP2AC and PPP5C. The structure of PPP5C cocrystallized with LB-100 was solved to a resolution of 1.65Å, revealing that the 7-oxabicyclo[2.2.1]heptane-2,3-dicarbonyl moiety coordinates with the metal ions and key residues that are conserved in both PP2AC and PPP5C. Cell-based studies revealed some known actions of LB-100 are mimicked by the genetic disruption of PPP5C. These data demonstrate that LB-100 is a catalytic inhibitor of both PP2AC and PPP5C and suggest that the observed antitumor activity might be due to an additive effect achieved by suppressing both PP2A and PPP5C.
A Kinase Inhibitor with Anti-Pim Kinase Activity is a Potent and Selective Cytotoxic Agent Toward Acute Myeloid Leukemia
Authors: Bjørnstad Ronja , Aesoy Reidun , Bruserud Øystein , Brenner Annette K. , Giraud Francis , Dowling Tara Helen , Gausdal Gro , Moreau Pascale , Døskeland Stein Ove , Anizon Fabrice , Herfindal Lars 
Published: January 2019

Abstract
More than 40 years ago, the present standard induction therapy for acute myeloid leukemia (AML) was developed. This consists of the metabolic inhibitor cytarabine (AraC) and the cytostatic topoisomerase 2 inhibitor daunorubucin (DNR). In light of the high chance for relapse, as well as the large heterogeneity, novel therapies are needed to improve patient outcome. We have tested the anti-AML activity of 15 novel compounds based on the scaffolds pyrrolo[2,3-a]carbazole-3-carbaldehyde, pyrazolo[3,4-c]carbazole, pyrazolo[4,3-a]phenanthridine, or pyrrolo[2,3-g]indazole. The compounds were inhibitors of Pim kinases, but could also have inhibitory activity against other protein kinases. Ser/Thr kinases like the Pim kinases have been identified as potential drug targets for AML therapy. The compound VS-II-173 induced AML cell death with EC50 below 5 μmol/L, and was 10 times less potent against nonmalignant cells. It perturbed Pim-kinase–mediated AML cell signaling, such as attenuation of Stat5 or MDM2 phosphorylation, and synergized with DNR to induce AML cell death. VS-II-173 induced cell death also in patients with AML blasts, including blast carrying high-risk FLT3-ITD mutations. Mutation of nucleophosmin-1 was associated with good response to VS-II-173. In conclusion new scaffolds for potential AML drugs have been explored. The selective activity toward patient AML blasts and AML cell lines of the pyrazolo-analogue VS-II-173 make it a promising drug candidate to be further tested in preclinical animal models for AML.
Combined MEK and BCL-2/XL Inhibition Is Effective in High-Grade Serous Ovarian Cancer Patient–Derived Xenograft Models and BIM Levels Are Predictive of Responsiveness
Authors: Iavarone Claudia , Zervantonakis Ioannis K. , Selfors Laura M. , Palakurthi Sangeetha , Liu Joyce F. , Drapkin Ronny , Matulonis Ursula A. , Hallberg Dorothy , Velculescu Victor E. , Leverson Joel D. , Sampath Deepak , Mills Gordon B. , Brugge Joan S. 
Published: January 2019

AbstractMost patients with late-stage high-grade serous ovarian cancer (HGSOC) initially respond to chemotherapy but inevitably relapse and develop resistance, highlighting the need for novel therapies to improve patient outcomes. The MEK/ERK pathway is activated in a large subset of HGSOC, making it an attractive therapeutic target. Here, we systematically evaluated the extent of MEK/ERK pathway activation and efficacy of pathway inhibition in a large panel of well-annotated HGSOC patient–derived xenograft models. The vast majority of models were nonresponsive to the MEK inhibitor cobimetinib (GDC-0973) despite effective pathway inhibition. Proteomic analyses of adaptive responses to GDC-0973 revealed that GDC-0973 upregulated the proapoptotic protein BIM, thus priming the cells for apoptosis regulated by BCL2-family proteins. Indeed, combination of both MEK inhibitor and dual BCL-2/XL inhibitor (ABT-263) significantly reduced cell number, increased cell death, and displayed synergy in vitro in most models. In vivo, GDC-0973 and ABT-263 combination was well tolerated and resulted in greater tumor growth inhibition than single agents. Detailed proteomic and correlation analyses identified two subsets of responsive models—those with high BIM at baseline that was increased with MEK inhibition and those with low basal BIM and high pERK levels. Models with low BIM and low pERK were nonresponsive. Our findings demonstrate that combined MEK and BCL-2/XL inhibition has therapeutic activity in HGSOC models and provide a mechanistic rationale for the clinical evaluation of this drug combination as well as the assessment of the extent to which BIM and/or pERK levels predict drug combination effectiveness in chemoresistant HGSOC.
Nanoparticle Delivery of miR-708 Mimetic Impairs Breast Cancer Metastasis
Authors: Ramchandani Divya , Lee Seung Koo , Yomtoubian Shira , Han Myung Shin , Tung Ching-Hsuan , Mittal Vivek 
Published: January 2019

Abstract
Triple-negative breast cancer (TNBC) patients exhibit the worst clinical outcome due to its aggressive clinical course, higher rate of recurrence, and a conspicuous lack of FDA-approved targeted therapies. Here, we show that multilayered nanoparticles (NPs) carrying the metastasis suppressor microRNA miR-708 (miR708-NP) localize to orthotopic primary TNBC, and efficiently deliver the miR-708 cargo to reduce lung metastasis. Using a SOX2/OCT4 promoter reporter, we identified a population of miR-708low cancer cells with tumor-initiating properties, enhanced metastatic potential, and marked sensitivity to miR-708 treatment. In vivo, miR708-NP directly targeted the SOX2/OCT4-mCherry+ miR-708low tumor cells to impair metastasis. Together, our preclinical findings provide a mechanism-based antimetastatic therapeutic approach for TNBC, with a marked potential to generate miR-708 replacement therapy for high-risk TNBC patients in the clinic. To our knowledge, this gold nanoparticle-based delivery of microRNA mimetic is the first oligonucleotide-based targeted therapy for TNBC.
Vascular Risk Factors and Findings on Brain MRI of Elderly Adult American Indians: The Strong Heart Study
Authors: Shibata Dean  , Suchy-Dicey Astrid , Carty Cara L. , Madhyastha Tara  , Ali Tauqeer , Best Lyle  , Grabowski Jr. Thomas J. , Longstreth Jr. W.T. , Buchwald Dedra 
Published: January 2019

<b><i>Background:</i></b> Clinical stroke is prevalent in American Indians, but the risk factors for cerebrovascular pathology have not been well-studied in this population. The purpose of this study was to correlate abnormalities on brain magnetic resonance imaging (MRI) with clinical risk factors in a cohort of elderly American Indians. <b><i>Methods:</i></b> Brain MRI scans from 789 participants of the Strong Heart Study were analyzed for infarcts, hemorrhage, white matter disease, and measures of cerebral atrophy including ventricular and sulcal grade and total brain volume. Clinical risk factors included measures of hypertension, diabetes, and high levels of low-density lipoprotein (LDL) cholesterol. Regression models adjusted for potential confounders were used to estimate associations between risk factors and brain MRI outcomes. <b><i>Results:</i></b> ­Hypertension was associated with the presence of infarcts (<i>p</i> = 0.001), ventricle enlargement (<i>p</i> = 0.01), and increased white matter hyperintensity volume (<i>p</i> = 0.01). Diabetes was associated with increased prevalence of cerebral atrophy (<i>p</i> &#x3c; 0.001), ventricular enlargement (<i>p</i> = 0.001), and sulcal widening (<i>p</i> = 0.001). High LDL was not significantly associated with any of the measured cranial imaging outcomes. <b><i>Conclusions:</i></b> This study found risk factors for cerebrovascular disease in American Indians similar to those seen in other populations and provides additional evidence for the important roles of hypertension and diabetes in promoting cerebral infarcts and brain atrophy, respectively.
HETEROGENEITY OF PROTEINS IN BIRDSâ€™ EGG-WHITES
Authors: Hashim Hayder Obayes , Al-Shuhaib Mohammed Baqur Sahib , Ewadh Mufeed Jaleel 
Published: January 2019

Little is known about the comparative heterogeneity of protein compounds among a wide variety of birdsâ€™ egg white, particularly, an analysis of their detailed, in-parallel protein composition. Hence this research is conducted mainly to evaluate the extent of variability among 42 types of birdsâ€™ egg white. To improve the perception of these biological fluids, the main phenotypic variations of egg whites were evaluated using the discontinuous denaturing polyacrylamide gel electrophoresis (SDS-PAGE), Gradient SDS-PAGE, Native-PAGE, cellulose acetate electrophoresis, and the reverse-phase high-performance liquid chromatography (RP-HPLC). The results showed that the Native-PAGE and SDS-PAGE produced better screening results than other methods in identifying protein. Although Â Native-PAGE and SDS-PAGE did not show remarkable variability in terms of hydrophobicity, several electrophoretic differences of egg-white proteins were observed. Several unknown proteins in the egg white samples of different bird species were also identified through the electrophoretic experiments. Hence, it might be possible, as in the case of egg white samples, to provide a characterized assessment among birds by using only the available gel electrophoresis techniques. This study also provided a rapid snapshot of the initial identification of several unknown components of egg white proteins. Accordingly, this study constituted the first large-scale comparative proteomics investigation performed among the largely varying types of egg whites from commercial stores and bird keepers in the middle Euphrates areas in Iraq.
Seawater Icicles of the Adriatic Sea
Authors: Malačič Vlado , Žagar Nedjeljka 
Published: January 2019

AbstractThe marine icicles that form on coastal constructions (e.g., piers and railings) are very common in polar and subpolar areas. The occasional formation of icicles in the coastal zones of the Mediterranean Sea occurs in relation to cold-air outbreaks from the polar region, such as the one presented in this paper in February 2018. The air temperatures over the northern Adriatic Sea, the northernmost part of the Mediterranean, dropped below –2.1°C, a necessary condition for seawater to freeze, with salinity between 38.0 and 38.5 PSU. The formation of icicles on the coastal structures was further enabled by the bora wind and related high seas along the coast. Measurements presented in this paper confirm that the icicles in the Bay of Piran in the Gulf of Trieste (45.55°N) were formed from the seawater. The measured salinity level of the melted icicles, around 9 PSU, is a typical value reported for marine icicles in polar regions.
The Impact of the QBO on MJO Convection in Cloud-Resolving Simulations
Authors: Martin Zane , Wang Shuguang , Nie Ji , Sobel Adam 
Published: January 2019

Abstract
This study examines the relationship between the Madden–Julian oscillation (MJO) and the stratospheric quasi-biennial oscillation (QBO) in a limited-area cloud-resolving model with parameterized large-scale dynamics. The model is used to simulate two consecutive MJO events that occurred during the late fall and early winter of 2011. To test the influence of the QBO on the simulated MJO events, various QBO states are imposed via the addition of characteristic wind and temperature anomalies. In experiments with only QBO temperature anomalies imposed (without corresponding zonal wind anomalies) the strength of convection during MJO active phases is amplified for the QBO easterly phase [an anomalously cold tropical tropopause layer (TTL)] compared to the westerly QBO phase (a warm TTL), as measured by outgoing longwave radiation, cloud fraction, and large-scale ascent. This response is qualitatively consistent with the observed MJO–QBO relationship. The response of precipitation is weaker, and is less consistent across variations in the simulation configuration. Experiments with only imposed QBO wind anomalies (without corresponding temperature anomalies) show much weaker effects altogether than those with imposed temperature anomalies, suggesting that TTL temperature anomalies are a key pathway through which the QBO can modulate the MJO. Sensitivity tests indicate that the QBO influence on MJO convection depends on both the amplitude and the height of the QBO temperature anomaly: lower-altitude and larger-amplitude temperature anomalies have more pronounced effects on MJO convection.
Power-Law Scaling in the Internal Variability of Cumulus Cloud Size Distributions due to Subsampling and Spatial Organization
Authors: Neggers R. A. J. , Griewank P. J. , Heus T. 
Published: January 2019

AbstractIn this study, the spatial structure of cumulus cloud populations is investigated using three-dimensional snapshots from large-domain LES experiments. The aim is to understand and quantify the internal variability in cloud size distributions due to subsampling effects and spatial organization. A set of idealized shallow cumulus cases is selected with varying degrees of spatial organization, including a slowly organizing marine precipitating case and five more quickly organizing diurnal cases over land. A subdomain analysis is applied, yielding cloud number distributions at sample sizes ranging from severely undersampled to nearly complete. A strong power-law scaling is found in the relation between cloud number variability and subdomain size, reflecting an inverse linear relation. Scaling subdomain size by cloud size yields a data collapse across time points and cases, highlighting the role played by cloud spacing in controlling the stochastic variability. Spatial organization acts on top of this baseline model by increasing the maximum cloud size and by enhancing the variability in the number of smallest clouds. This reflects that the smaller clouds start to live on top of larger-scale thermodynamic structures, such as cold pools, which favor or inhibit their formation. Compositing all continental cumulus cases suggests the existence of a prototype diurnal time dependence in the spatial organization. A simple stochastic expression for cloud number variability is proposed that is formulated in terms of two dimensionless groups, which allows objective estimation of the degree of spatial organization in simulated and observed cumulus cloud populations.
The Annual Cycle of Northern Hemisphere Storm Tracks. Part I: Seasons
Authors: Hoskins B. J. , Hodges K. I. 
Published: January 2019

AbstractIn this paper and Part II a comprehensive picture of the annual cycle of the Northern Hemisphere storm tracks is presented and discussed for the first time. It is based on both feature tracking and Eulerian-based diagnostics, applied to vorticity and meridional wind in the upper and lower troposphere. Here, the storm tracks, as diagnosed using both variables and both diagnostic techniques, are presented for the four seasons for each of the two levels. The oceanic storm tracks retain much of their winter mean intensity in spring with only a small change in their latitude. In the summer they are much weaker, particularly in the Pacific and are generally farther poleward. In autumn the intensities are larger again, comparable with those in spring, but the latitude is still nearer to that of summer. However, in the lower troposphere in the eastern ocean basins the tracking metrics show northern and southern tracks that change little with latitude through the year. The Pacific midwinter minimum is seen in upper-troposphere standard deviation diagnostics, but a richer picture is obtained using tracking. In winter there are high intensities over a wide range of latitudes in the central and eastern Pacific, and the western Pacific has high track density but weak intensity. In the lower troposphere all the diagnostics show that the strength of the Pacific and Atlantic storm tracks are generally quite uniform over the autumn–winter–spring period. There is a close relationship between the upper-tropospheric storm track, particularly that based on vorticity, and tropopause-level winds and temperature gradients. In the lower troposphere, in winter the oceanic storm tracks are in the region of the strong meridional SST gradients, but in summer they are located in regions of small or even reversed SST gradients. However, over North America the lower-tropospheric baroclinicity and the upstream portion of the Atlantic storm track stay together throughout the year.
Theories and Practices of Federalism in Deeply Divided Societies
Authors: Dixon Rosalind , Levy Ron , Tushnet Mark 
Published: January 2019

Federal systems are often compared based on their history or origins: Riker famously distinguished between ‘coming together’ and ‘holding together’ forms of federalism. Federal systems can also be viewed as serving a variety of potential purposes: they may help promote government closer to the people, greater democratic experimentation, forms of vertical as well as horizontal political accountability, and the accommodation of diversity.This special issue of the Federal Law Review (‘FLR’), on ‘the theory and practice of federalism in deeply divided societies’, explores those federations that originate from ‘holding together’ rather than ‘coming together’ processes, and that are designed to respond to a range of ethnic, religious, racial and territorial cleavages. There is a growing comparative literature on constitution-making and practice in ‘divided societies’, which includes attention to federalism. But there is still important work to be done understanding when and how federalism succeeds in managing social and political conflict, and promoting peace, stability and democratic resilience, especially in the Asia-Pacific. This volume thus seeks to fill this gap—by encouraging a wide-ranging exploration of these issues and contributing to a global debate on constitutionalism and constitutional design.
Genotoxic effects of photodynamic therapy in laryngeal cancer cells – Anin vitrostudy
Authors: Dailton Guedes de Oliveira Moraes Carlos , Henrique Godoi Bruno , Chaves Silva Carvalho Isabel , Cristina Pinto Jessica , Carvalho Rossato Rafaella , Soares da Silva Newton , Pacheco Soares Cristina 
Published: January 2019

Photodynamic therapy provides the formation of reactive oxygen species that are capable of inducing cell death. Human laryngeal carcinoma (HEp-2) cells have been evaluated in this study under PDT treatment. Cells were treated with photosensitizer aluminum phthalocyanine tetrasulfonate (AlPcS4) and irradiated with a Biopdi/Irrad-Led5 660 LED with 660 nm wavelength, intensity of delivered light of 25 mW/cm2, power of 70 mW, fluence of 5 J/cm2for 24 h and 48 h, and then evaluated. Cell population was not increased by PDT treatment after the tested period. The apoptosis assay demonstrated that control groups exhibit approximately 60% of living cells in the 24 h and 48 h periods, however. A significant increase in apoptotic cells was observed after the photodynamic therapy treatments, for both 24 and 48 h groups. Over 50% of cells were under apoptosis after photodynamic therapy, evidencing a death process generated from the oxidative damage of the treatment. Comet assay and micronucleus assessments, both of which evaluate genotoxicity, demonstrated favorable results to damages caused by the photodynamic therapy treatment. Thus, photodynamic therapy is proposed to damage nuclear cells and the subcellular structure of carcinogenic cells.Impact statementRecently, the use of photodynamic therapy grows as an alternative treatment for cancer, since it has a noninvasive characteristic and affinity to the tumor tissue. Accordingly, understanding the therapy’s foci of action is important for the technique improvement. This work aims to understand the genotoxic effect triggered by the therapy action, thus evidencing the permanent changes caused to the genetic material of the tumor cell after the treatment. Therefore, to increase the knowledge in this study field, the methodology of the comet assay and count of micronucleus formed after the therapy was adopted in order to understand if the damage caused to the DNA of tumor cell makes its replication process unfeasible in future generations. The study allows a better therapeutic approach to the cancer treatment, making the process of association between therapies a more effective option during the disease treatment.