bluuebunny/crossref_metadata_2025_split huggingface dataset:
Discovery and Characterization of Novel Mutant FLT3 Kinase Inhibitors
Authors: Weisberg Ellen , Choi Hwan Geun , Barrett Rosemary , Zhou Wenjun , Zhang Jianming , Ray Arghya , Nelson Erik A. , Jiang Jingrui , Moreno Daisy , Stone Richard , Galinsky Ilene , Fox Edward , Adamia Sophia , Kung Andrew L. , Gray Nathanael S. , Griffin James D. 
Published: September 2010

Abstract
For a subpopulation of acute myeloid leukemia (AML) patients, the constitutively activated tyrosine kinase, mutant FLT3, has emerged as a promising target for therapy. The development of drug resistance, however, is a growing concern for mutant FLT3 inhibitors, such as PKC412. Potential therapeutic benefit can arise from the combination of two structurally diverse inhibitors that target—but bind differently to—the same protein or from two inhibitors with completely different mechanisms of action. Thus, there is a need for identification and development of novel FLT3 inhibitors that have the ability to positively combine with PKC412 or standard chemotherapeutic agents used to treat AML as a way to suppress the development of drug resistance and consequently prolong disease remission. Here, we report the effects of the novel type II ATP-competitive inhibitors, HG-7-85-01 and HG-7-86-01, which potently and selectively target mutant FLT3 protein kinase activity and inhibit the proliferation of cells harboring FLT3-ITD or FLT3 kinase domain point mutants via induction of apoptosis and cell cycle inhibition. Antileukemic activity of HG-7-85-01 was shown in vivo to be comparable with that observed with PKC412 in a bioluminescence assay using NCr nude mice harboring Ba/F3-FLT3-ITD-luc+ cells. HG-7-85-01 was also observed to override PKC412 resistance. Finally, HG-7-85-01 and HG-7-86-01 synergized with PKC412 and standard chemotherapeutic agents against mutant PKC412-sensitive and some PKC412-resistant, FLT3-positive cells. Thus, we present a structurally novel class of FLT3 inhibitors that warrants consideration for clinical testing against drug-resistant disease in AML patients. Mol Cancer Ther; 9(9); 2468–77. ©2010 AACR.
Cells expressing FLT3/ITD mutations exhibit elevated repair errors generated through alternative NHEJ pathways: implications for genomic instability and therapy
Authors: Fan Jinshui , Li Li , Small Donald , Rassool Feyruz 
Published: September 2010

AbstractThe internal tandem duplication (ITD) mutations of the FMS-like tyrosine kinase-3 (FLT3) receptor found in acute myeloid leukemia patients are associated with poor prognosis. Although DNA double-strand breaks (DSBs) are mainly repaired by the DNA-PK–dependent nonhomologous end-joining (NHEJ) pathway in normal mammalian cells, an alternative and less well-defined NHEJ pathway, characterized by microhomology at the repair junctions, play a role in the generation of deletions and translocations leading to cancer progression. Here we report that in FLT3/ITD-expressing cell lines and bone marrow mononuclear cells from FLT3/ITD knock-in mice, end-joining of DSBs occurs at microhomologous sequences resulting in a high frequency of DNA deletions. Strikingly, levels of Ku proteins, key components of the main NHEJ pathway, are decreased in FLT3/ITD+ cell lines and murine FLT3/ITD bone marrow mononuclear cells. Concomitantly, levels of DNA ligase IIIα, a component of ALT NHEJ, are increased in FLT3/ITD-expressing cells. Cells treated with a FLT3 inhibitor demonstrate decreased DNA ligase IIIα and a reduction in DNA deletions, suggesting that FLT3 signaling regulates the pathways by which DSBs are repaired. Thus, therapy to inhibit FLT3/ITD signaling and/or DNA ligase IIIα may lead to repair that reduces repair errors and genomic instability.
Bone marrow myeloid-derived suppressor cells (MDSCs) inhibit graft-versus-host disease (GVHD) via an arginase-1–dependent mechanism that is up-regulated by interleukin-13
Authors: Highfill Steven L. , Rodriguez Paulo C. , Zhou Qing , Goetz Christine A. , Koehn Brent H. , Veenstra Rachelle , Taylor Patricia A. , Panoskaltsis-Mortari Angela , Serody Jonathan S. , Munn David H. , Tolar Jakub , Ochoa Augusto C. , Blazar Bruce R. 
Published: September 2010

AbstractMyeloid-derived suppressor cells (MDSCs) are a well-defined population of cells that accumulate in the tissue of tumor-bearing animals and are known to inhibit immune responses. Within 4 days, bone marrow cells cultured in granulocyte colony-stimulating factor and granulocyte-macrophage colony-stimulating factor resulted in the generation of CD11b+Ly6GloLy6C+ MDSCs, the majority of which are interleukin-4Rα (IL-4Rα+) and F4/80+. Such MDSCs potently inhibited in vitro allogeneic T-cell responses. Suppression was dependent on L-arginine depletion by arginase-1 activity. Exogenous IL-13 produced an MDSC subset (MDSC-IL-13) that was more potently suppressive and resulted in arginase-1 up-regulation. Suppression was reversed with an arginase inhibitor or on the addition of excess L-arginine to the culture. Although both MDSCs and MDSC-IL-13 inhibited graft-versus-host disease (GVHD) lethality, MDSC-IL-13 were more effective. MDSC-IL-13 migrated to sites of allopriming. GVHD inhibition was associated with limited donor T-cell proliferation, activation, and proinflammatory cytokine production. GVHD inhibition was reduced when arginase-1-deficient MDSC-IL-13 were used. MDSC-IL-13 did not reduce the graft-versus-leukemia effect of donor T cells. In vivo administration of a pegylated form of human arginase-1 (PEG-arg1) resulted in L-arginine depletion and significant GVHD reduction. MDSC-IL-13 and pegylated form of human arginase-1 represent novel strategies to prevent GVHD that can be clinically translated.
Deficits in fine motor skills in a genetic animal model of ADHD
Authors: Qian Yu , Lei Gefei , Castellanos Francisco X , Forssberg Hans , Heijtz Rochellys Diaz 
Published: September 2010

Abstract

Background
In an attempt to model some behavioral aspects of Attention Deficit/Hyperactivity Disorder (ADHD), we examined whether an existing genetic animal model of ADHD is valid for investigating not only locomotor hyperactivity, but also more complex motor coordination problems displayed by the majority of children with ADHD.

Methods
We subjected young adolescent Spontaneously Hypertensive Rats (SHRs), the most commonly used genetic animal model of ADHD, to a battery of tests for motor activity, gross motor coordination, and skilled reaching. Wistar (WIS) rats were used as controls.

Results
Similar to children with ADHD, young adolescent SHRs displayed locomotor hyperactivity in a familiar, but not in a novel environment. They also had lower performance scores in a complex skilled reaching task when compared to WIS rats, especially in the most sensitive measure of skilled performance (i.e., single attempt success). In contrast, their gross motor performance on a Rota-Rod test was similar to that of WIS rats.

Conclusion
The results support the notion that the SHR strain is a useful animal model system to investigate potential molecular mechanisms underlying fine motor skill problems in children with ADHD.
Aerodynamic Noise Reduction for Small Wind Turbine Rotors
Authors: Clifton-Smith M. J. 
Published: September 2010

Noise emissions are detrimental to the take-up of wind turbine technology. This is important for small wind turbine technology, as many are located close to dwellings. This paper presents a method of reducing turbine noise whilst retaining power production performance of small wind turbines using the numerical optimisation technique called differential evolution. The differential evolution technique coupled an empirical noise prediction model with a blade element-momentum analysis for predicting power performance. For the small wind turbine rotor at a design tip speed ratio of 5.5, a 2 dBA reduction in the total sound pressure levels was possible for a 1% reduction in power coefficient. This noise reduction was attributed to an increase in angle of attack and Reynolds number. The noise minimisation was then combined with starting time minimisation to improve low wind speed performance. At a tip speed ratio of 5.5, the best trade offs for a maximum of 1% decrease in power coefficient were a simultaneous decrease in total sound pressure level and starting time of 4% (2 dBA) and 6% respectively, or a decrease in total sound pressure level and starting time of 1% (0.7 dBA) and 16% respectively.
Improvement of water resistance and dimensional stability of wood through titanium dioxide coating
Authors: Sun Qingfeng , Yu Haipeng , Liu Yixing , Li Jian , Lu Yun , Hunt John F. 
Published: September 2010

Abstract
Moisture absorption and dimensional distortion are the major drawbacks of wood utilization as building material. In this study, poplar wood coated with a thin layer of titanium dioxide (TiO2) was prepared by the cosolvent-controlled hydrothermal method. Subsequently, its moisture absorption and dimensional stability were examined. Scanning electron microscopy analysis revealed that the wood substrate was closely and entirely covered with the TiO2 coat. Microscale features were visible despite masking of the ultrastructural features of the cell wall. To explore the effects of TiO2 coating on the water-repellency and dimensional stability of wood, a 90-day water immersion test was carried out. Results showed that water absorption and thickness swelling of TiO2-coated wood increase very slowly and minimally. Weight change after 90 days of water immersion was reduced to 20.5%, nearly one-tenth of untreated control wood, and that maximum cross-sectional relative swelling was only 1.2%. Specimens were conditioned for 3 months at 20%, 30%, 40%, 50%, 60%, 70%, 80%, and 90% relative humidity (RH) to determine the effects of RH on moisture absorption and dimensional swelling of TiO2-coated wood. There was no change in weight after 3 months of being exposed to humidity conditions below 60%, whereas there was linear weight increase above 60% RH, but the maximum change was less than 6%. Cross-sectional relative swelling was less than 0.3% below 60% RH but increased as RH exceeded 60%. The maximum change was approximately 3%. Anisotropic thickness swelling of wood was almost eliminated after coating. It is obvious that TiO2 coating can act as a moisture barrier for wood and is an exceptionally strong water vapor-inhibiting shield under very humid conditions.
Prostaglandin E2-Induced Synaptic Plasticity in Neocortical Networks of Organotypic Slice Cultures
Authors: Koch Henner , Huh Sung-Eun , Elsen Frank P. , Carroll Michael S. , Hodge Rebecca D. , Bedogni Francesco , Turner Michael S. , Hevner Robert F. , Ramirez Jan-Marino 
Published: September 2010

Traumatic brain injury (TBI) is a major cause of epilepsy, yet the mechanisms underlying the progression from TBI to epilepsy are unknown. TBI induces the expression of COX-2 (cyclooxygenase-2) and increases levels of prostaglandin E2 (PGE2). Here, we demonstrate that acutely applied PGE2 (2 μm) decreases neocortical network activity by postsynaptically reducing excitatory synaptic transmission in acute and organotypic neocortical slices of mice. In contrast, long-term exposure to PGE2 (2 μm; 48 h) presynaptically increases excitatory synaptic transmission, leading to a hyperexcitable network state that is characterized by the generation of paroxysmal depolarization shifts (PDSs). PDSs were also evoked as a result of depriving organotypic slices of activity by treating them with tetrodotoxin (TTX, 1 μm; 48 h). This treatment predominantly increased postsynaptically excitatory synaptic transmission. The network and cellular effects of PGE2 and TTX treatments reversed within 1 week. Differences in the underlying mechanisms (presynaptic vs postsynaptic) as well as occlusion experiments in which slices were exposed to TTX plus PGE2 suggest that the two substances evoke distinct forms of homeostatic plasticity, both of which result in a hyperexcitable network state.PGE2 and TTX (alone or together with PGE2) also increased levels of apoptotic cell death in organotypic slices. Thus, we hypothesize that the increase in excitability and apoptosis may constitute the first steps in a cascade of events that eventually lead to epileptogenesis triggered by TBI.
Clinical Outcomes After Treatment of Non‐Contained Intrabony Defects With Enamel Matrix Derivative or Guided Tissue Regeneration: A 12‐Month Randomized Controlled Clinical Trial
Authors: Siciliano Vincenzo Iorio , Andreuccetti Gianmaria , Siciliano Alessandro Iorio , Blasi Andrea , Sculean Anton , Salvi Giovanni E. 
Published: September 2010

Background: The purpose of this study is to compare the healing of deep, non‐contained intrabony defects (i.e., with a ≥80% 1‐wall component and a residual 2‐ to 3‐wall component in the most apical part) treated with either an enamel matrix derivative (EMD) or guided tissue regeneration (GTR) after 12 months.Methods: In this randomized, controlled clinical trial, 40 subjects with 40 defects affecting single‐rooted teeth were treated. The defects were treated with EMD alone or with a non‐resorbable titanium‐reinforced membrane. No grafting materials were used. At baseline and after 12 months, clinical parameters including probing depths (PDs) and clinical attachment levels (CAL) were recorded. The difference in CAL gain was the primary outcome.Results: At baseline, the intrabony component of the defects amounted to 8.5 ± 2.2 mm at EMD‐treated sites and 8.6 ± 1.7 mm at GTR‐treated sites (P = 0.47). The mean CAL gain at sites treated with GTR was significantly greater (P <0.001) than that at sites treated with EMD (4.1 ± 1.4 mm versus 2.4 ± 2.2 mm, respectively). GTR therapy, compared to EMD application alone, significantly (P = 0.01) increased the probability of CAL gain ≥4 mm (79.2% versus 11.3%, respectively) and significantly (P = 0.01) decreased the probability of residual PDs ≥6 mm (3% versus 79.3%, respectively).Conclusion: Although the outcomes of open‐flap debridement alone were not investigated, the application of EMD alone appeared to yield less PD reduction and CAL gain compared to GTR therapy in the treatment of deep, non‐contained intrabony defects.
Aggressive and Chronic Periodontitis Correlate With Distinct Cellular Sources of Key Immunoregulatory Cytokines
Authors: Lima Patrícia Maria A. , Souza Paulo Eduardo A. , Costa José Eustáquio , Gomez Ricardo Santiago , Gollob Kenneth John , Dutra Walderez Ornelas 
Published: September 2010

Background: Chronic periodontitis (CP) and aggressive periodontitis (AP) are inflammatory diseases and the main cause of dental loss in adults. We aimed to investigate the expression of adhesion molecules and the source of proinflammatory and anti‐inflammatory cytokines in circulating mononuclear cells from patients with CP and AP.Methods: Peripheral blood mononuclear cells from healthy controls and CP or AP patients were collected. The expression of the cell adhesion molecules CD11a and CD11b, and the cellular sources of interleukin (IL)‐4, IL‐10, IL‐12, interferon‐γ, and tumor necrosis factor‐α by distinct subpopulations of circulating leukocytes were determined using flow cytometry.Results: The expression of CD11a, but not CD11b, was significantly higher within the CD4+ and CD8+ T cells in CP and AP than in healthy controls. The frequencies of tumor necrosis factor‐α–expressing CD4+ T cells and CD14+ cells were higher in AP and CP, compared to healthy controls, respectively. Moreover, the frequency of IL‐10 expressing CD14+ cells was higher in CP, but not AP, compared to healthy controls CD4+ T cells committed to IL‐4 production was higher in CP than in healthy controls.Conclusion: These results suggest the participation of CD11a in the pathogenesis of periodontal lesions and show distinct cellular sources of immunoregulatory cytokines in AP versus CP.
A Survey of United States Periodontists' Knowledge, Attitudes, and Behaviors Related to Tobacco‐Cessation Interventions
Authors: Patel Amit M. , Blanchard Steven B. , Christen Arden G. , Bandy Robert W. , Romito Laura M. 
Published: September 2010

Background: Because of the clear causal relationship between smoking and periodontal disease, and the negative effect of smoking on wound healing, it is of great importance to evaluate the tobacco‐cessation interventions provided by periodontal practices. The use of tobacco‐cessation interventions in clinical practice can be measured by whether the practitioner uses any of the “5 A's” defined by the 2008 United States Public Health Services Clinical Practice Guideline.Methods: Surveys were mailed to 1,000 active members of the American Academy of Periodontology. The surveys assessed the periodontists' demographic information, educational and professional background, knowledge and attitudes about tobacco cessation, and use of interventions in the daily practice of periodontics.Results: Data were collected from 231 periodontists via a self‐administered survey. Most (92%) believed that tobacco cessation is a responsibility of the dental profession. A pattern of declining levels of involvement was seen as the providers moved through the suggested “5 A's” for promoting tobacco cessation. Providers with formal tobacco‐cessation training were more likely to perform interventions. The primary perceived barriers to providing tobacco‐cessation interventions were low patient acceptance of treatment, lack of time, and lack of training.Conclusion: The findings of this study indicate that periodontists believe that tobacco‐cessation interventions are a responsibility of the dental profession; however, because of several perceived barriers, reported rates of comprehensive tobacco interventions in periodontal practices are low.
Aerobic Exercise Capacity and Pulmonary Function in Athletes With and Without Type 1 Diabetes
Authors: Komatsu William R. , Barros Neto Turibio L. , Chacra Antonio R. , Dib Sergio A. 
Published: September 2010

OBJECTIVE
To compare the aerobic exercise capacity and pulmonary function between athletes with and without type 1 diabetes.

RESEARCH DESIGN AND METHODS
Fifty-one adult age-matched individuals were assessed in random order to the maximum volume of O2 consumption (Vo2peak max) (ml/kg/min), anaerobic threshold (ml/kg/min), peak pulmonary ventilation (Ve), heart rate (beats per min), time to exhaustion (min), forced vital capacity (FEV) (%), forced expiratory volume in the first second (FEV1) (%), total lung capacity (TLC) (%), and lung diffusion capacity for carbon monoxide (DLCO) (%). Individuals were 27 with type 1 diabetes: 15 athletes (ADM) and 12 nonathletes (NADM); and 24 healthy individuals: 12 ADM and 12 NADM. Duration of diabetes was 14.6 ± 6.2 and 15.2 ± 6.7 years in ADM and NADM, respectively.

RESULTS
Vo2peak max was higher in ADM than in NADM (P &lt; 0.001). The anaerobic threshold was lower in subjects with type 1 diabetes than in control subjects (P &lt; 0.001). FEV1 was lower in ADM than in other groups (NADM, athletes control, and nonathletes control, P &lt; 0.001).

CONCLUSIONS
Aerobic capacity in subjects with type 1 diabetes with programmed exercise is similar to the capacity of normal athletes despite lower anaerobic threshold and FEV1.
Gestational Diabetes Mellitus Alone in the Absence of Subsequent Diabetes Is Associated With Microalbuminuria
Authors: Bomback Andrew S. , Rekhtman Yelena , Whaley-Connell Adam T. , Kshirsagar Abhijit V. , Sowers James R. , Chen Shu-Cheng , Li Suying , Chinnaiyan Kavitha M. , Bakris George L. , McCullough Peter A. 
Published: September 2010

OBJECTIVE
Women with gestational diabetes mellitus (GDM) maintain a higher risk for recurrent GDM and overt diabetes. Overt diabetes is a risk factor for development of chronic kidney disease (CKD), but GDM alone, without subsequent development of overt diabetes, may also pose a risk for CKD.

RESEARCH DESIGN AND METHODS
This cross-sectional analysis included Kidney Early Evaluation Program (KEEP) participants from 2000 to 2009. Patient characteristics and kidney function among three categories (GDM alone, overt diabetes, and no history of diabetes) were compared. The prevalence of microalbuminuria, macroalbuminuria, and CKD stages 1–2 and 3–5 was assessed using logistic regression.

RESULTS
Of 37,716 KEEP female participants, 571 (1.5%) had GDM alone and 12,100 (32.1%) had overt diabetes. Women with GDM had a higher rate of microalbuminuria but not macroalbuminuria than their nondiabetic peers (10.0 vs. 7.7%) that was substantially lower than the 13.6% prevalence in diabetic women. In multivariate analysis, women with GDM alone, compared with nondiabetic women, demonstrated increased odds of CKD stages 1–2 (multivariate odds ratio 1.54 [95% CI 1.16–2.05]) similar to the odds for women with overt diabetes (1.68 [1.55–1.82]). In stratified analyses, age, race, BMI, and hypertension modified the odds for CKD stages 1 –2 but not CKD stages 3–5 among women with GDM.

CONCLUSIONS
Women with GDM alone have a higher prevalence of microalbuminuria than women without any history of diabetes, translating to higher rates of CKD stages 1–2. These results suggest that GDM, even in the absence of subsequent overt diabetes, may increase the risk for future cardiovascular and kidney disease.
Thermal antinociceptive effect of orally administered gabapentin in healthy cats
Authors: Pypendop Bruno H. , Siao Kristine T. , Ilkiw Jan E. 
Published: September 2010

Abstract
Objective—To determine the thermal antinociceptive effect of various single doses of gabapentin administered orally in cats.
Animals—6 healthy adult domestic shorthair cats.
Procedures—Baseline skin temperature and baseline thermal threshold were determined via application of a thermal probe to the thorax of each cat prior to oral administration (in random order) of an empty capsule (placebo) or a capsule containing 5, 10, or 30 mg of gabapentin/kg (4 experiments/cat). After each treatment, thermal threshold was determined at intervals during an 8-hour period. Plasma gabapentin concentration was measured prior to and at 1-hour intervals after drug administration. Dose and time effects were analyzed by use of a repeated-measures ANOVA.
Results—Peak plasma gabapentin concentration increased with increasing gabapentin dose. After administration of the 5, 10, and 30 mg/kg doses, median interval until the greatest gabapentin concentration was detected was 60, 120, and 90 minutes, respectively (interval ranges were 60 to 120 minutes, 60 to 120 minutes, and 60 to 180 minutes, respectively). In the experiments involving administration of the placebo or increasing doses of gabapentin, mean ± SD baseline skin temperature and thermal threshold were 36.8 ± 1.21°C and 45.8 ± 4.4°C, 36.9 ± 1.1°C and 43.1 ± 2.4°C, 37.0 ± 0.7°C and 44.0 ± 1.5°C, and 36.1 ± 1.7°C and 43.3 ± 3.3°C, respectively. There was no significant effect of treatment on thermal threshold.
Conclusions and Clinical Relevance—At the doses evaluated, orally administered gabapentin did not affect the thermal threshold in healthy cats and therefore did not appear to provide thermal antinociception. (Am J Vet Res 2010;71:1027–1032)