bluuebunny/crossref_metadata_2025_split huggingface dataset:
Pharmacological and Protein Profiling Suggests Venetoclax (ABT-199) as Optimal Partner with Ibrutinib in Chronic Lymphocytic Leukemia
Authors: Cervantes-Gomez Fabiola , Lamothe Betty , Woyach Jennifer A. , Wierda William G. , Keating Michael J. , Balakrishnan Kumudha , Gandhi Varsha 
Published: April 2015

Abstract
Purpose: Bruton's tyrosine kinase (BTK) is a critical enzyme in the B-cell receptor pathway and is inhibited by ibrutinib due to covalent binding to the kinase domain. Though ibrutinib results in impressive clinical activity in chronic lymphocytic leukemia (CLL), most patients achieve only partial remission due to residual disease. We performed a pharmacologic profiling of residual circulating CLL cells from patients receiving ibrutinib to identify optimal agents that could induce cell death of these lymphocytes.
Experimental Design: Ex vivo serial samples of CLL cells from patients on ibrutinib were obtained prior and after (weeks 2, 4, and 12) the start of treatment. These cells were incubated with PI3K inhibitors (idelalisib or IPI-145), bendamustine, additional ibrutinib, or BCL-2 antagonists (ABT-737 or ABT-199), and cell death was measured. In vitro investigations complemented ex vivo studies. Immunoblots for BTK signaling pathway and antiapoptotic proteins were performed.
Results: The BCL-2 antagonists, especially ABT-199, induced high cell death during ex vivo incubations. In concert with the ex vivo data, in vitro combinations also resulted in high cytotoxicity. Serial samples of CLL cells obtained before and 2, 4, 12, or 36 weeks after the start of ibrutinib showed inhibition of BTK activity and sensitivity to ABTs. Among the three BCL-2 family antiapoptotic proteins that are overexpressed in CLL, levels of MCL-1 and BCL-XL were decreased after ibrutinib while ABT-199 selectively antagonizes BCL-2.
Conclusions: Our biologic and molecular results suggest that ibrutinib and ABT-199 combination should be tested clinically against CLL. Clin Cancer Res; 21(16); 3705–15. ©2015 AACR.
Diffuse Large B-cell Lymphoma Classification Tied Up Nicely with a “String”
Authors: Rimsza Lisa M. 
Published: April 2015

Abstract
Molecular classification of diffuse large B-cell lymphoma (DLBCL) is a critical biologic, prognostic, and predictive distinction. Since the discovery of two molecular types of DLBCL in otherwise morphologically indistinguishable cases, numerous methodologies for making this distinction have been published. A method and technical platform may now be reaching consensus. Clin Cancer Res; 21(10); 2204–6. ©2015 AACR.
See related article by Veldman-Jones et al., p. 2367
Efficacy of Carboplatin Alone and in Combination with ABT888 in Intracranial Murine Models of BRCA-Mutated and BRCA–Wild-Type Triple-Negative Breast Cancer
Authors: Karginova Olga , Siegel Marni B. , Van Swearingen Amanda E.D. , Deal Allison M. , Adamo Barbara , Sambade Maria J. , Bazyar Soha , Nikolaishvili-Feinberg Nana , Bash Ryan , O'Neal Sara , Sandison Katie , Parker Joel S. , Santos Charlene , Darr David , Zamboni William , Lee Yueh Z. , Miller C. Ryan , Anders Carey K. 
Published: April 2015

Abstract
Patients with breast cancer brain metastases have extremely limited survival and no approved systemic therapeutics. Triple-negative breast cancer (TNBC) commonly metastasizes to the brain and predicts poor prognosis. TNBC frequently harbors BRCA mutations translating to platinum sensitivity potentially augmented by additional suppression of DNA repair mechanisms through PARP inhibition. We evaluated brain penetrance and efficacy of carboplatin ± the PARP inhibitor ABT888, and investigated gene-expression changes in murine intracranial TNBC models stratified by BRCA and molecular subtype status. Athymic mice were inoculated intracerebrally with BRCA-mutant: SUM149 (basal), MDA-MB-436 (claudin-low); or BRCA–wild-type (wt): MDA-MB-468 (basal), MDA-MB-231BR (claudin-low). TNBC cells were treated with PBS control [intraperitoneal (IP), weekly], carboplatin (50 mg/kg/wk, IP), ABT888 (25 mg/kg/d, oral gavage), or their combination. DNA damage (γ-H2AX), apoptosis (cleaved caspase-3, cC3), and gene expression were measured in intracranial tumors. Carboplatin ± ABT888 significantly improved survival in BRCA-mutant intracranial models compared with control, but did not improve survival in BRCA-wt intracranial models. Carboplatin + ABT888 revealed a modest survival advantage versus carboplatin in BRCA-mutant models. ABT888 yielded a marginal survival benefit in the MDA-MB-436, but not in the SUM149 model. BRCA-mutant SUM149 expression of γ-H2AX and cC3 proteins was elevated in all treatment groups compared with control, whereas BRCA-wt MDA-MB-468 cC3 expression did not increase with treatment. Carboplatin treatment induced common gene-expression changes in BRCA-mutant models. Carboplatin ± ABT888 penetrates the brain and improves survival in BRCA-mutant intracranial TNBC models with corresponding DNA damage and gene-expression changes. Combination therapy represents a potential promising treatment strategy for patients with TNBC brain metastases warranting further clinical investigation. Mol Cancer Ther; 14(4); 920–30. ©2015 AACR.
Loss of miR-223 and JNK Signaling Contribute to Elevated Stathmin in Malignant Pleural Mesothelioma
Authors: Birnie Kimberly A. , Yip Yan Y. , Ng Dominic C.H. , Kirschner Michaela B. , Reid Glen , Prêle Cecilia M. , Musk Arthur W. (Bill) , Lee Y.C. Gary , Thompson Philip J. , Mutsaers Steven E. , Badrian Bahareh 
Published: April 2015

Abstract
Malignant pleural mesothelioma (MPM) is often fatal, and studies have revealed that aberrant miRNAs contribute to MPM development and aggressiveness. Here, a screen of miRNAs identified reduced levels of miR-223 in MPM patient specimens. Interestingly, miR-223 targets Stathmin (STMN1), a microtubule regulator that has been associated with MPM. However, whether miR-223 regulates STMN1 in MPM and the functions of miR-223 and STMN1 in this disease are yet to be determined. STMN1 is also regulated by c-Jun N-terminal kinase (JNK) signaling, but whether this occurs in MPM and whether miR-223 plays a role are unknown. The relationship between STMN1, miR-223, and JNK was assessed using MPM cell lines, cells from pleural effusions, and MPM tissue. Evidence indicates that miR-223 is decreased in all MPM tissue compared with normal/healthy tissue. Conversely, STMN1 expression was higher in MPM cell lines when compared with primary mesothelial cell controls. Following overexpression of miR-223 in MPM cell lines, STMN1 levels were reduced, cell motility was inhibited, and tubulin acetylation induced. Knockdown of STMN1 using siRNAs led to inhibition of MPM cell proliferation and motility. Finally, miR-223 levels increased while STMN1 was reduced following the re-expression of the JNK isoforms in JNK-null murine embryonic fibroblasts, and STMN1 was reduced in MPM cell lines following the activation of JNK signaling.
Implications: miR-223 regulates STMN1 in MPM, and both are in turn regulated by the JNK signaling pathway. As such, miR-223 and STMN1 play an important role in regulating MPM cell motility and may be therapeutic targets. Mol Cancer Res; 13(7); 1106–18. ©2015 AACR.
MYC Drives Pten/Trp53-Deficient Proliferation and Metastasis due to IL6 Secretion and AKT Suppression via PHLPP2
Authors: Nowak Dawid G. , Cho Hyejin , Herzka Tali , Watrud Kaitlin , DeMarco Daniel V. , Wang Victoria M.Y. , Senturk Serif , Fellmann Christof , Ding David , Beinortas Tumas , Kleinman David , Chen Muhan , Sordella Raffaella , Wilkinson John E. , Castillo-Martin Mireia , Cordon-Cardo Carlos , Robinson Brian D. , Trotman Lloyd C. 
Published: April 2015

Abstract
We have recently recapitulated metastasis of human PTEN/TP53–mutant prostate cancer in the mouse using the RapidCaP system. Surprisingly, we found that this metastasis is driven by MYC, and not AKT, activation. Here, we show that cell–cell communication by IL6 drives the AKT–MYC switch through activation of the AKT-suppressing phosphatase PHLPP2, when PTEN and p53 are lost together, but not separately. IL6 then communicates a downstream program of STAT3-mediated MYC activation, which drives cell proliferation. Similarly, in tissues, peak proliferation in Pten/Trp53–mutant primary and metastatic prostate cancer does not correlate with activated AKT, but with STAT3/MYC activation instead. Mechanistically, MYC strongly activates the AKT phosphatase PHLPP2 in primary cells and prostate cancer metastasis. We show genetically that Phlpp2 is essential for dictating the proliferation of MYC-mediated AKT suppression. Collectively, our data reveal competition between two proto-oncogenes, MYC and AKT, which ensnarls the Phlpp2 gene to facilitate MYC-driven prostate cancer metastasis after loss of Pten and Trp53.
Significance: Our data identify IL6 detection as a potential causal biomarker for MYC-driven metastasis after loss of PTEN and p53. Second, our finding that MYC then must supersede AKT to drive cell proliferation points to MYC inhibition as a critical part of PI3K pathway therapy in lethal prostate cancer. Cancer Discov; 5(6); 636–51. ©2015 AACR.
This article is highlighted in the In This Issue feature, p. 565
HIF2α-Dependent Lipid Storage Promotes Endoplasmic Reticulum Homeostasis in Clear-Cell Renal Cell Carcinoma
Authors: Qiu Bo , Ackerman Daniel , Sanchez Danielle J. , Li Bo , Ochocki Joshua D. , Grazioli Alison , Bobrovnikova-Marjon Ekaterina , Diehl J. Alan , Keith Brian , Simon M. Celeste 
Published: April 2015

Abstract
Two hallmarks of clear-cell renal cell carcinoma (ccRCC) are constitutive hypoxia-inducible factor (HIF) signaling and abundant intracellular lipid droplets (LD). However, regulation of lipid storage and its role in ccRCC are incompletely understood. Transcriptional profiling of primary ccRCC samples revealed that expression of the LD coat protein gene PLIN2 was elevated in tumors and correlated with HIF2α, but not HIF1α, activation. HIF2α-dependent PLIN2 expression promoted lipid storage, proliferation, and viability in xenograft tumors. Mechanistically, lipid storage maintained integrity of the endoplasmic reticulum (ER), which is functionally and physically associated with LDs. Specifically, PLIN2-dependent lipid storage suppressed cytotoxic ER stress responses that otherwise result from elevated protein synthetic activity characteristic of ccRCC cells. Thus, in addition to promoting ccRCC proliferation and anabolic metabolism, HIF2α modulates lipid storage to sustain ER homeostasis, particularly under conditions of nutrient and oxygen limitation, thereby promoting tumor cell survival.
Significance: We demonstrate that HIF2α promotes lipid storage, ER homeostasis, and cell viability in ccRCC via upregulation of the LD coat protein PLIN2, revealing a novel function for the well-documented “clear-cell” phenotype and identifying ER stress as a targetable vulnerability created by HIF2α/PLIN2 suppression in this common renal malignancy. Cancer Discov; 5(6); 652–67. ©2015 AACR.
See related commentary by Sim and Johnson, p. 584.
This article is highlighted in the In This Issue feature, p. 565
Reformulation of the Drought Code in the Canadian Fire Weather Index System Implemented in New Zealand
Authors: Yang Yang , Uddstrom Michael , Pearce Grant , Revell Mike 
Published: April 2015

AbstractThe fire danger rating system implemented in New Zealand is the Canadian Fire Weather Index (FWI) System developed 40 years ago for Canadian temperate forests. Issues have been raised in relation to this system when applied in other regions with different climate and vegetation environments. For the first time, two methods were proposed for improving the Drought Code (DC) component of the FWI System for New Zealand. The first method (PotE) employs a potential evaporation (PE) scheme that considers wind speed, surface air stability, and water vapor mixing ratio gradient. The second method (soilM) uses soil moisture. For the latter, when soil moisture is derived from observations, the calculated DC represents the actual drought status of the soil. DC and FWI have been calculated with the original and the two new DC methods at 28 climate stations in New Zealand for a pair of 2-yr periods. The Joint U.K. Land Environment Simulator (JULES) was run to provide the PE and soil moisture for the two methods. The original DC method underestimated the drought status in New Zealand, especially in summer, leading to underestimation of FWI. The PotE method significantly overestimated the drought status in summer. The errors in the calculated drought status and FWI were largely reduced by using the soilM method with simulated soil moisture from JULES. In this paper, the reasons for this reduction in error are investigated by testing the sensitivity of DC to surface evaporation and to soil parameters. Potential benefit is found from using the proposed soilM method for monitoring drought status and for FWI calculations.
Effects of Horizontal Geometrical Spreading on the Parameterization of Orographic Gravity Wave Drag. Part II: Analytical Solutions
Authors: Eckermann Stephen D. , Broutman Dave , Knight Harold 
Published: April 2015

Abstract
Effects of horizontal geometrical spreading on the amplitude variation with height of linear three-dimensional hydrostatic orographic gravity waves (OGWs) are quantified via relevant simplifications to the governing transform relations, leading to analytical solutions. The analysis is restricted to elliptical Gaussian obstacles with principal axes aligned parallel and perpendicular to unidirectional shear flow and to vertical displacement and steepness amplitudes, given their relevance to OGW drag parameterizations in global models. Two solutions are derived: a “small l” solution in which horizontal wavenumbers l orthogonal to the flow are taken to be much smaller than those parallel to the flow, and a “single k” solution in which horizontal wavenumbers k parallel to the flow have a single mean value. The resulting analytical relations, valid for arbitrary vertical profiles of upstream winds and stability, depend only on the obstacle’s elliptical aspect ratio β and a normalized height coordinate incorporating wind and stability variations. These analytical approximations accurately reproduce the salient features of the exact numerical transform solutions. These include monotonic decreases with height that asymptotically approach z−1/2 forms at large z and strong β dependence in amplitude diminution with height. Steepness singularities close to the surface are shown to be a mathematical consequence of the Hilbert transform approach to deriving complex wavefield solutions. These approximate analytical solutions for horizontal geometrical spreading effects on wave amplitude highlight the importance of this missing physics for current parameterizations of OGW drag and offer an accurate and efficient means of incorporating some of these omitted effects.
Processes Controlling Precipitation in Shallow, Orographic, Trade Wind Convection
Authors: Watson Campbell D. , Smith Ronald B. , Nugent Alison D. 
Published: April 2015

Abstract
A sharp reduction in precipitation was observed on the island of Dominica in the Caribbean during a 2011 field campaign when the trade winds weakened and convection transitioned from mechanically to thermally driven. The authors propose four hypotheses for this reduction, which relate to (i) the triggering mechanism, (ii) dry-air entrainment, (iii) giant sea-salt aerosol, and (iv) small-island-derived aerosol. The plausibility of the first three hypotheses is the focus of this study.
Aircraft observations show the dynamics of the orographic cumulus clouds at flight level are surprisingly similar, irrespective of how they are triggered. However, the orographic cumulus clouds are consistently shallower when the trade winds are weak, which the authors attribute to a drier and shallower cloud layer compared to days with stronger trade winds. The strong negative influence of dry-air entrainment in a drier environment on cumulus depth and liquid water content is qualitatively demonstrated using an entraining plume model and the WRF Model. Although the models appear more sensitive than observations to entrainment and cloud size, the sensitivity tests have some resemblance to observations. The authors also find evidence of sea-salt aerosol entering the base of marine cumulus on strong wind days using an aircraft-mounted lidar and other instruments. Although each hypothesis is plausible, the complex interplay of these processes makes determining the controlling mechanisms difficult. Ultimately, the authors’ analysis rejects the hypothesis (i) triggering, while supporting (ii) entrainment and (iii) sea-salt aerosol.
NEXRAD NWS Polarimetric Precipitation Product Evaluation for IFloodS
Authors: Cunha Luciana K. , Smith James A. , Krajewski Witold F. , Baeck Mary Lynn , Seo Bong-Chul 
Published: April 2015

AbstractThe NEXRAD program has recently upgraded the WSR-88D network observational capability with dual polarization (DP). In this study, DP quantitative precipitation estimates (QPEs) provided by the current version of the NWS system are evaluated using a dense rain gauge network and two other single-polarization (SP) rainfall products. The analyses are performed for the period and spatial domain of the Iowa Flood Studies (IFloodS) campaign. It is demonstrated that the current version (2014) of QPE from DP is not superior to that from SP mainly because DP QPE equations introduce larger bias than the conventional rainfall–reflectivity [i.e., R(Z)] relationship for some hydrometeor types. Moreover, since the QPE algorithm is based on hydrometeor type, abrupt transitions in the phase of hydrometeors introduce errors in QPE with surprising variation in space that cannot be easily corrected using rain gauge data. In addition, the propagation of QPE uncertainties across multiple hydrological scales is investigated using a diagnostic framework. The proposed method allows us to quantify QPE uncertainties at hydrologically relevant scales and provides information for the evaluation of hydrological studies forced by these rainfall datasets.
Large-Eddy Simulation and Single-Column Modeling of Thermally Stratified Wind Turbine Arrays for Fully Developed, Stationary Atmospheric Conditions
Authors: Sescu Adrian , Meneveau Charles 
Published: April 2015

AbstractEffects of atmospheric thermal stratification on the asymptotic behavior of very large wind farms are studied using large-eddy simulations (LES) and a single-column model for vertical distributions of horizontally averaged field variables. To facilitate comparisons between LES and column modeling based on Monin–Obukhov similarity theory, the LES are performed under idealized conditions of statistical stationarity in time and fully developed conditions in space. A suite of simulations are performed for different thermal stratification levels and the results are used to evaluate horizontally averaged vertical profiles of velocity, potential temperature, vertical turbulent momentum, and heat flux. Both LES and the model show that the stratification significantly affects the atmospheric boundary layer structure, its height, and the surface fluxes. However, the effects of the wind farm on surface heat fluxes are found to be relatively small in both LES and the single-column model. The surface fluxes are the result of two opposing trends: an increase of mixing in wakes and a decrease in mixing in the region below the turbines due to reduced momentum fluxes there for neutral and unstable cases, or relatively unchanged shear stresses below the turbines in the stable cases. For the considered cases, the balance of these trends yields a slight increase in surface flux magnitude for the stable and near-neutral unstable cases, and a very small decrease in flux magnitude for the strongly unstable cases. Moreover, thermal stratification is found to have a negligible effect on the roughness scale as deduced from the single-column model, consistent with the expectations of separation of scale.
An investigation of the validity of the Work Assessment Triage Tool clinical decision support tool for selecting optimal rehabilitation interventions for workers with musculoskeletal injuries
Authors: Qin Ziling , Armijo-Olivo Susan , Woodhouse Linda J , Gross Douglas P 
Published: April 2015

Objective: To evaluate the concurrent validity of a clinical decision support tool (Work Assessment Triage Tool (WATT)) developed to select rehabilitation treatments for injured workers with musculoskeletal conditions. Design: Methodological study with cross-sectional and prospective components. Setting: Data were obtained from the Workers’ Compensation Board of Alberta rehabilitation facility in Edmonton, Canada. Subjects: A total of 432 workers’ compensation claimants evaluated between November 2011 and June 2012. Main measures: Percentage agreement between the Work Assessment Triage Tool and clinician recommendations was used to determine concurrent validity. In claimants returning to work, frequencies of matching were calculated and compared between clinician and Work Assessment Triage Tool recommendations and the actual programs undertaken by claimants. The frequency of each intervention recommended by clinicians, Work Assessment Triage Tool, and case managers were also calculated and compared. Results: Percentage agreement between clinician and Work Assessment Triage Tool recommendations was poor (19%) to moderate (46%) and Kappa = 0.37 (95% CI −0.02, 0.76). The Work Assessment Triage Tool did not improve upon clinician recommendations as only 14 out of 31 claimants returning to work had programs that contradicted clinician recommendations, but were consistent with Work Assessment Triage Tool recommendations. Clinicians and case managers were inclined to recommend functional restoration, physical therapy, or no rehabilitation while the Work Assessment Triage Tool recommended additional evidence-based interventions, such as workplace-based interventions. Conclusions: Our findings do not provide evidence of concurrent validity for the Work Assessment Triage Tool compared with clinician recommendations. Based on these results, we cannot recommend further implementation of the Work Assessment Triage Tool. However, the Work Assessment Triage Tool appeared more likely than clinicians to recommend interventions supported by evidence; thus warranting further research.