bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of Selective Checkpoint Kinase 1 Inhibition on Cytarabine Cytotoxicity in Acute Myelogenous Leukemia Cells In Vitro
Authors: Schenk Erin L. , Koh Brian D. , Flatten Karen S. , Peterson Kevin L. , Parry David , Hess Allan D. , Smith B. Douglas , Karp Judith E. , Karnitz Larry M. , Kaufmann Scott H. 
Published: August 2012

Abstract
Purpose: Previous studies have shown that the replication checkpoint, which involves the kinases ataxia telangiectasia mutated and Rad3 related (ATR) and Chk1, contributes to cytarabine resistance in cell lines. In the present study, we examined whether this checkpoint is activated in clinical acute myelogenous leukemia (AML) during cytarabine infusion in vivo and then assessed the impact of combining cytarabine with the recently described Chk1 inhibitor SCH 900776 in vitro.
Experimental design: AML marrow aspirates harvested before and during cytarabine infusion were examined by immunoblotting. Human AML lines treated with cytarabine in the absence or presence of SCH 900776 were assayed for checkpoint activation by immunoblotting, nucleotide incorporation into DNA, and flow cytometry. Long-term effects in AML lines, clinical AML isolates, and normal myeloid progenitors were assayed using clonogenic assays.
Results: Immunoblotting revealed increased Chk1 phosphorylation, a marker of checkpoint activation, in more than half of Chk1-containing AMLs after 48 hours of cytarabine infusion. In human AML lines, SCH 900776 not only disrupted cytarabine-induced Chk1 activation and S-phase arrest but also markedly increased cytarabine-induced apoptosis. Clonogenic assays demonstrated that SCH 900776 enhanced the antiproliferative effects of cytarabine in AML cell lines and clinical AML samples at concentrations that had negligible impact on normal myeloid progenitors.
Conclusions: These results not only provide evidence for cytarabine-induced S-phase checkpoint activation in AML in the clinical setting, but also show that a selective Chk1 inhibitor can overcome the S-phase checkpoint and enhance the cytotoxicity of cytarabine. Accordingly, further investigation of the cytarabine/SCH 900776 combination in AML appears warranted. Clin Cancer Res; 18(19); 5364–73. ©2012 AACR.
A Locked, Dimeric CXCL12 Variant Effectively Inhibits Pulmonary Metastasis of CXCR4-Expressing Melanoma Cells Due to Enhanced Serum Stability
Authors: Takekoshi Tomonori , Ziarek Joshua J. , Volkman Brian F. , Hwang Sam T. 
Published: August 2012

AbstractThe CXC chemokine receptor-4 (CXCR4) plays a critical role in cancer by positively regulating cancer cell metastasis and survival. We previously showed that high concentrations of the CXCR4 ligand, wild-type CXCL12 (wtCXCL12), could inhibit colorectal cancer metastasis in vivo, and we have hypothesized that wtCXCL12 dimerizes at high concentration to become a potent antagonist of CXCR4. To address this hypothesis, we engineered a covalently locked, dimeric variant of CXCL12 (CXCL122). Herein, we show that CXCL122 can not only inhibit implantation of lung metastasis of CXCR4-B16-F10 melanoma cells more effectively than AMD3100, but that CXCL122 also blocks the growth of established pulmonary tumors. To identify a basis for the in vivo efficacy of CXCL122, we conducted Western blot analysis and ELISA analyses, which revealed that CXCL122 was stable for at least 12 hours in serum, whereas wtCXCL12 was quickly degraded. CXCL122 also maintained its antagonist properties in in vitro chemotaxis assays for up to 24 hours in serum, whereas wtCXCL12 was ineffective after 6 hours. Heat-inactivation of serum prolonged the stability and function of wtCXCL12 by more than 6 hours, suggesting enzymatic degradation as a possible mechanism for wtCXCL12 inactivation. In vitro analysis of amino-terminal cleavage by enzymes dipeptidylpeptidase IV (DPPIV/CD26) and matrix metalloproteinase-2 (MMP-2) resulted in 25-fold and 2-fold slower degradation rates, respectively, of CXCL122 compared with wtCXCL12. In summary, our results suggest CXCL122 possesses greater potential as an antimetastatic drug as compared with AMD3100 or wtCXCL12, potentially due to enhanced serum stability in the presence of N-terminal degrading enzymes. Mol Cancer Ther; 11(11); 2516–25. ©2012 AACR.
Cdk4/6 Inhibition Induces Epithelial–Mesenchymal Transition and Enhances Invasiveness in Pancreatic Cancer Cells
Authors: Liu Fang , Korc Murray 
Published: August 2012

AbstractAberrant activation of Cyclin D-Cdk4/6 signaling pathway is commonly found in pancreatic ductal adenocarcinoma (PDAC). Here, we show that PD-0332991, a highly specific inhibitor for Cdk4 and Cdk6, exerted growth inhibitory effects on three human PDAC cell lines. Microarray analysis revealed that PD-0332991 downregulated cell-cycle–related genes, but upregulated genes implicated in extracellular matrix (ECM) remodeling and pancreatic cancer cell invasion and metastasis. Moreover, PD-0332991 enhanced invasion in TGF-β–responsive PDAC cell lines that harbor a wild-type SMAD4 gene (COLO-357, PANC-1), but not in TGF-β–resistant AsPC-1 cells that harbor a mutated SMAD4. PD-0332991 also induced epithelial–mesenchymal transition (EMT) in COLO-357 and PANC-1, but not in AsPC-1 cells. Inhibition of CDK4/6 using shRNA mimicked the effects of PD-0332991 on EMT induction. Furthermore, PD-0332991 increased Smad transcriptional activity in luciferase readout assays and activated TGF-β signaling. SB-505124, an inhibitor of the type-I TGF-β receptor (TβRI) kinase, completely blocked EMT induction by PD-0332991. When combined with PD-0332991, SB-505124 inhibited the growth of COLO-357 and PANC-1 cells. Taken together, these data suggest that anti-Cdk4/6 therapy could induce EMT and enhance pancreatic cancer cell invasion by activating Smad-dependent TGF-β signaling, and that combining PD-0332991 and SB-505124 may represent a novel therapeutic strategy in PDAC. Mol Cancer Ther; 11(10); 2138–48. ©2012 AACR.
Quantifying Pulmonary Regurgitation and Right Ventricular Function in Surgically Repaired Tetralogy of Fallot
Authors: Mercer-Rosa Laura , Yang Wei , Kutty Shelby , Rychik Jack , Fogel Mark , Goldmuntz Elizabeth 
Published: August 2012

Background—
Patients with repaired tetralogy of Fallot are monitored for pulmonary regurgitation (PR) and right ventricular (RV) function. We sought to compare measures of PR and RV function on echocardiogram to those on cardiac magnetic resonance (CMR) and to develop a new tool for assessing PR by echocardiogram.

Methods and Results—

Patients with repaired tetralogy of Fallot (n=143; 12.5±3.2 years) had an echocardiogram and CMR within 3 months of each other. On echocardiogram, RV function was assessed by (1) Doppler tissue imaging of the RV free wall and (2) myocardial performance index. The ratio of diastolic and systolic time-velocity integrals measured by Doppler of the main pulmonary artery was calculated. CMR variables included RV ejection fraction, RV volumes, and pulmonary regurgitant fraction (RF). Pulmonary regurgitation was graded as mild (RF<20%), moderate (RF=20–40%), and severe (RF>40%). On CMR, RF was 34+17% and RV ejection fraction was 61+8%. Echocardiography had good sensitivity identifying cases with RF>20% (sensitivity 97%; 95% CI: 92–99%) but overestimated the amount of PR when RF<20% (false-positive rate 36%; 95% CI: 18–57%). The diastolic and systolic time-velocity integrals on echocardiogram showed moderate correlation with RF on CMR (
R
=0.60;
P
<0.0001). On CMR, RF of 20% and 40% corresponded with a diastolic and systolic time-velocity integral of 0.49 (95% CI: 0.44–0.56) and 0.72 (95% CI: 0.68–0.76), respectively. RV myocardial performance index correlated modestly with RV ejection fraction (
r
=−0.33;
P
<0.001).

Conclusions—
This study suggests that the diastolic and systolic time-velocity integrals ratio may make a modest contribution to the overall assessment of PR in patients with repaired tetralogy of Fallot and warrants further investigation. However, echocardiography continues to have a limited ability to quantify PR and RV function as compared with CMR.
Implantable Cardioverter-Defibrillators Have Reduced the Incidence of Resuscitation for Out-of-Hospital Cardiac Arrest Caused by Lethal Arrhythmias
Authors: Hulleman Michiel , Berdowski Jocelyn , de Groot Joris R. , van Dessel Pascal F.H.M. , Borleffs C. Jan Willem , Blom Marieke T. , Bardai Abdenasser , de Cock Carel C. , Tan Hanno L. , Tijssen Jan G.P. , Koster Rudolph W. 
Published: August 2012

Background—
Over the last decades, a gradual decrease in ventricular fibrillation (VF) as initial recorded rhythm during resuscitation for out-of-hospital cardiac arrest (OHCA) has been noted. We sought to establish the contribution of implantable cardioverter-defibrillator (ICD) therapy to this decline.

Methods and Results—

Using a prospective database of all OHCA resuscitation in the province North Holland in the Netherlands (Amsterdam Resuscitation Studies [ARREST]), we collected data on all patients in whom resuscitation for OHCA was attempted in 2005–2008. VF OHCA incidence (per 100 000 inhabitants per year) was compared with VF OHCA incidence data during 1995–1997, collected in a similar way. We also collected ICD interrogations of all ICD patients from North Holland and identified all appropriate ICD shocks in 2005–2008; we calculated the number of prevented VF OHCA episodes, considering that only part of the appropriate shocks would result in avoided resuscitation. VF OHCA incidence decreased from 21.1/100 000 in 1995–1997 to 17.4/100 000 in 2005–2008 (
P
<0.001). Non-VF OHCA increased from 12.2/100 000 to 19.4/100 000 (
P
<0.001). VF as presenting rhythm declined from 63% to 47%. In 2005–2008, 1972 ICD patients received 977 shocks. Of these shocks, 339 were caused by a life-threatening arrhythmia. We estimate that these 339 shocks have prevented 81 (minimum, 39; maximum, 152) cases of VF OHCA, corresponding with 33% (minimum, 16%; maximum, 63%) of the observed decline in VF OHCA incidence.

Conclusions—
The incidence of VF OHCA decreased over the last 10 years in North Holland. ICD therapy explained a decrease of 1.2/100 000 inhabitants per year, corresponding with 33% of the observed decline in VF OHCA.
Interactions between Shallow and Deep Convection under a Finite Departure from Convective Quasi Equilibrium
Authors: Yano Jun-Ichi , Plant Robert 
Published: August 2012

Abstract
The present paper presents a simple theory for the transformation of nonprecipitating, shallow convection into precipitating, deep convective clouds. To make the pertinent point a much idealized system is considered, consisting only of shallow and deep convection without large-scale forcing. The transformation is described by an explicit coupling between these two types of convection. Shallow convection moistens and cools the atmosphere, whereas deep convection dries and warms the atmosphere, leading to destabilization and stabilization, respectively. Consequently, in their own stand-alone modes, shallow convection perpetually grows, whereas deep convection simply damps: the former never reaches equilibrium, and the latter is never spontaneously generated. Coupling the modes together is the only way to reconcile these undesirable separate tendencies, so that the convective system as a whole can remain in a stable periodic state under this idealized setting. Such coupling is a key missing element in current global atmospheric models. The energy cycle description used herein is fully consistent with the original formulation by Arakawa and Schubert, and is suitable for direct implementation into models using a mass flux parameterization. The coupling would alleviate current problems with the representation of these two types of convection in numerical models. The present theory also provides a pertinent framework for analyzing large-eddy simulations and cloud-resolving modeling.
A Numerical Study of the Impacts of Dry Air on Tropical Cyclone Formation: A Development Case and a Nondevelopment Case
Authors: Fritz Cody , Wang Zhuo 
Published: August 2012

Abstract
The impacts of dry air on tropical cyclone formation are examined in the numerical model simulations of ex-Gaston (2010) and pre-Fay (2008). The former, a remnant low downgraded from a short-lived tropical cyclone, can be regarded as a nondeveloping system because it failed to redevelop, and the latter developed into a tropical cyclone despite lateral dry air entrainment and a transient upper-level dry air intrusion. Water vapor budget analysis suggests that the mean vertical moisture transport plays the dominant role in moistening the free atmosphere. Backward trajectory analysis and water budget analysis show that vertical transport of dry air from the middle and upper troposphere, where a well-defined wave pouch is absent, contributes to the midlevel drying near the pouch center in ex-Gaston. The midlevel drying suppresses deep convection, reduces moisture supply from the boundary layer, and contributes to the nondevelopment of ex-Gaston. Three-dimensional trajectory analysis based on the numerical model simulation of Fay suggests that dry air entrained at the pouch periphery tends to stay off the pouch center because of the weak midlevel inflow or gets moistened along its path even if it is being wrapped into the wave pouch. Lateral entrainment in the middle troposphere thus does not suppress convection near the pouch center or prevent the development of Tropical Storm Fay. This study suggests that the upper troposphere is a weak spot of the wave pouch at the early formation stage and that the vertical transport is likely a more direct pathway for dry air to influence moist convection near the pouch center.
Structural and Surface Features of Arc-Shaped Radar Echoes along an Outer Tropical Cyclone Rainband
Authors: Yu Cheng-Ku , Tsai Chia-Lun 
Published: August 2012

Abstract
This study uses ground-based dual-Doppler radar and surface observations to document the structural and surface features of the arc-shaped radar echoes (ASREs) evident along an outer rainband of Typhoon Longwang as it approached northern Taiwan on 1 October 2005. The particular aim of this study is to explore the possible distinction between the present case, previously documented tropical cyclone rainbands (TCRs), and squall lines. The dual-Doppler-derived fields show that the leading precipitation of the studied ASREs exhibited a convective nature with a sharp horizontal gradient of reflectivity and a significant vertical extent. The regions behind the leading convection were characterized by band-relative rear-to-front flow at low levels and were associated with a broader area of stratiform precipitation. The deep layer of front-to-rear flow extending from the surface to the upper troposphere was generally present ahead of the ASREs. This flow appears to be lifted upward at and immediately ahead of the leading edge of the low-level rear-to-front flow to form rearward-tilting updrafts. These airflow patterns are similar to those of the convective region of squall lines but differ fundamentally from those of previously documented TCRs that were located closer to the inner core of cyclones. The detailed analyses of surface fluctuations during the passage of one of the studied ASREs further show an abrupt pressure rise (2 mb), a temperature drop (4°C), and a pronounced deceleration of inflow air coincident with the leading heavy precipitation. The evaluation presented suggests that the convectively generated cold pool may be important in influencing the structures and propagation of the studied ASREs.
A Sensitivity Analysis of Surface Biophysical, Carbon, and Climate Impacts of Tropical Deforestation Rates in CCSM4-CNDV*
Authors: Gotangco Castillo C. Kendra , Gurney Kevin Robert 
Published: August 2012

Abstract
The biophysical–climate and combined biophysical and carbon–climate feedbacks of tropical deforestation rates are explored through sensitivity analyses using the Community Climate System Model 4 with prognostic carbon–nitrogen and dynamic vegetation. Simulations test 5%, 2%, 1%, and 0.5% annual deforestation rates, each paired with preservation targets of 10% per tropical tree type. Perturbations are applied over pan-tropical land but analyses also investigate responses over the subcontinental areas of the Amazon basin, central Africa, and Southeast Asia. Sensitivities [expressed as the change in a variable per million square kilometers (Mkm2) of change in tree cover] and means of selected biophysical, carbon, and climate variables during and after deforestation are compared across rates. The most apparent effect of the rates is in hastening/postponing climate change, but otherwise results show no consistent differences across rates and vary more across subcontinents (with the Amazon basin reflecting highest sensitivities in albedo and ground temperatures, and Southeast Asia for total ecosystem carbon). Additionally, biophysical feedbacks alone were found to have significant impact on climate over subcontinental scales. In the Amazon, ground temperature increase due to biophysical feedbacks is as much as 55%, and precipitation decrease up to 61%, of combined biophysical and carbon impacts. Replication with other models is required. Although it is still unclear whether a slow but prolonged deforestation differs in impacts from one that is rapid but short, the rate can still be relevant to planning with regards to the timing of impacts.
Trend Analysis of Precipitation in the Jinsha River Basin in China
Authors: Wang Shunjiu , Zhang Xinli , Liu Zhigang , Wang Deming 
Published: August 2012

Abstract
According to the mean seasonal and annual precipitation from 30 meteorological stations in the periods of 1961–2008, the precipitation trends are analyzed by using the Mann–Kendall (MK) test in the Jinsha River basin (JRB). Both the temporal and spatial distribution characteristics of precipitation trends in different regions in the JRB are studied for the first time in this paper. There is a slight and insignificant increasing trend in seasonal and annual precipitation except for autumn precipitation, and the annual precipitation has increased by 0.7634 mm yr−1 during the last 48 years. The increasing precipitation trends in spring seem more significant than those in the other three seasons, and autumn is the only season showing a slight and insignificant decreasing precipitation trend. There are more than 80% of stations exhibiting increasing trends for annual precipitation, and it goes to 90% for spring precipitation. The increasing precipitation trends in the headwater and the middle reaches are more dominant than those in the upper and lower reaches. The largest increase magnitude occurred in the less precipitation area, while the largest decrease magnitude occurred in the more precipitation area. The increasing trend of minimum precipitation series and decreasing trend of maximum precipitation series could result in a decreasing trend for the range series in the JRB. In general, the increasing trends of precipitation in the tributary (the Yalong River) are more significant than those in the mainstream (the Jinsha River). The results of this study will provide further knowledge for understanding on the climate change in the JRB.
Using CloudSat Cloud Retrievals to Differentiate Satellite-Derived Rainfall Products over West Africa
Authors: Tompkins Adrian M. , Adebiyi Adeyemi A. 
Published: August 2012

Abstract
Daily precipitation retrievals from three algorithms [the Tropical Rainfall Measuring Mission 3B42 rain product (TRMM-3B42), the Climate Prediction Center morphing technique (CMORPH), and the second version (RFEv2) of the Famine Early Warning System (FEWS)] and CloudSat retrievals of cloud liquid water, ice amount, and cloud fraction are used to document the cloud structures associated with rainfall location and intensity in the West African monsoon. The different rainfall retrieval approaches lead to contrasting cloud sensitivities between all three algorithms most apparent in the onset period of June and July. During the monsoon preonset phase, CMORPH produces a precipitation peak at around 12°N associated with upper-level cirrus clouds, while FEWS and TRMM both produce rainfall maxima collocated with the tropospheric–deep convective cloud structures at 4°–6°N. In July similar relative displacements of the rainfall maxima are observed. Conditional sampling of several hundred convection systems proves that, while upper-level cirrus is advected northward relative to the motion of the convective system cores, the reduced cover and water content of lower-tropospheric clouds in the northern zone could be due to signal attenuation as the systems there appear to be more intense, producing higher ice water contents. Thus, while CMORPH may overestimate rainfall in the northern zone due to its reliance on cloud ice, TRMM and FEWS are likely underestimating precipitation in this zone, potentially due to the use of infrared based products in TRMM and FEWS when microwave is not available. Mapping the CloudSat retrievals as a function of rain rate confirms the greater sensitivity of CMORPH to ice cloud and indicates that high-intensity rainfall events are associated with systems that are deeper and of a greater spatial scale.
Seasonality of Vertical Structure in Radar-Observed Precipitation over Southern Switzerland
Authors: Rudolph James V. , Friedrich Katja 
Published: August 2012

AbstractOperational radar data reveal that precipitation systems occurring on the southern side of the Alps near Locarno, Switzerland, follow seasonal patterns of vertical reflectivity structure. Storms occurring in summer are more convective than winter season storms as indicated by more frequent observation of reflectivity at higher altitudes during summer. Individual precipitation events occurring year-round are classified by comparison to average seasonal vertical reflectivity structure. Seasonal classification of individual storms reveals a transition between winter- and summer-type storms during spring and fall that follows changes in average daily surface temperature. In addition to distinct vertical structure, summer- and winter-type storms have differences in duration, intensity, and interval between storms. Although summer- and winter-type storms result in a similar amount of total precipitation, summer-type storms have shorter duration, and therefore greater intensity. The dependence of storm types on temperature has implications for intensification of the hydrologic cycle due to climate change. Warmer winter, spring, or fall surface temperatures may affect average precipitation intensity by increasing the number of days per year that experience more intense convective precipitation while decreasing the probability of less intense stratiform precipitation.