bluuebunny/crossref_metadata_2025_split huggingface dataset:
Tumor Vascular Maturation and Improved Drug Delivery Induced by Methylselenocysteine Leads to Therapeutic Synergy with Anticancer Drugs
Authors: Bhattacharya Arup , Seshadri Mukund , Oven Steven D. , Tóth Károly , Vaughan Mary M. , Rustum Youcef M. 
Published: June 2008

Abstract
Purpose: Our previously reported therapeutic synergy between naturally occurring seleno-amino acid methylselenocysteine (MSC) and anticancer drugs could not be shown in vitro. Studies were carried out to investigate the potential role of MSC-induced tumor vascular maturation and increased drug delivery in the observed therapeutic synergy in vivo.
Experimental Design: Mice bearing s.c. FaDu human head and neck squamous cell carcinoma xenografts were treated with MSC (0.2 mg/d × 14 days orally). Changes in microvessel density (CD31), vascular maturation (CD31/α-smooth muscle actin), perfusion (Hoechst 33342/DiOC7), and permeability (dynamic contrast-enhanced magnetic resonance imaging) were determined at the end of the 14-day treatment period. Additionally, the effect of MSC on drug delivery was investigated by determining intratumoral concentration of doxorubicin using high-performance liquid chromatography and fluorescence microscopy.
Results: Double immunostaining of tumor sections revealed a marked reduction (∼40%) in microvessel density accompanying tumor growth inhibition following MSC treatment along with a concomitant increase in the vascular maturation index (∼30% &gt; control) indicative of increased pericyte coverage of microvessels. Hoechst 33342/DiOC7 staining showed improved vessel functionality, and dynamic contrast-enhanced magnetic resonance imaging using the intravascular contrast agent, albumin-GdDTPA, revealed a significant reduction in vascular permeability following MSC treatment. Consistent with these observations, a 4-fold increase in intratumoral doxorubicin levels was observed with MSC pretreatment compared with administration of doxorubicin alone.
Conclusion: These results show, for the first time, the antiangiogenic effects of MSC results in tumor growth inhibition, vascular maturation in vivo, and enhanced anticancer drug delivery that are associated with the observed therapeutic synergy in vivo.
Advances in the Development of Cancer Therapeutics Directed against the RAS-Mitogen-Activated Protein Kinase Pathway
Authors: Sebolt-Leopold Judith S. 
Published: June 2008

Abstract
Among mammalian mitogen-activated protein kinase (MAPK) signaling cascades, the extracellular signal-related kinase (ERK) pathway has received the most attention in the oncology drug discovery arena. By virtue of its central role in promoting proliferation, survival, and metastasis, this pathway directly affects both the formation and progression of human tumors. The identification of non–ATP-competitive inhibitors of the MAPK kinase MAPK/ERK kinase (MEK) resulted in the first demonstration that the ERK pathway could be effectively shut down in a highly selective fashion. Subsequent discovery of the oncogenic nature of B-raf kinase led to the escalation of drug discovery efforts revolving around MEK and RAF. The emergence of multiple drug candidates targeting these downstream kinases provides us with the means for validating the importance of the RAS-RAF-MEK-ERK signaling cascade in human tumors. This article highlights the lessons learned in the clinical evaluation of MAPK pathway inhibitors as anticancer agents and the complexities surrounding optimization of their therapeutic potential in light of the challenges posed by genetic heterogeneity within patient populations.
Transforming Growth Factor-β Receptor Blockade Augments the Effectiveness of Adoptive T-Cell Therapy of Established Solid Cancers
Authors: Wallace Africa , Kapoor Veena , Sun Jing , Mrass Paul , Weninger Wolfgang , Heitjan Daniel F. , June Carl , Kaiser Larry R. , Ling Leona E. , Albelda Steven M. 
Published: June 2008

AbstractPurpose: Adoptive cellular immunotherapy is a promising approach to eradicate established tumors. However, a significant hurdle in the success of cellular immunotherapy involves recently identified mechanisms of immune suppression on cytotoxic T cells at the effector phase. Transforming growth factor-β (TGF-β) is one of the most important of these immunosuppressive factors because it affects both T-cell and macrophage functions. We thus hypothesized that systemic blockade of TGF-β signaling combined with adoptive T-cell transfer would enhance the effectiveness of the therapy.Experimental Design: Flank tumors were generated in mice using the chicken ovalbumin–expressing thymoma cell line, EG7. Splenocytes from transgenic OT-1 mice (whose CD8 T cells recognize an immunodominant peptide in chicken ovalbumin) were activated in vitro and adoptively transferred into mice bearing large tumors in the presence or absence of an orally available TGF-β receptor-I kinase blocker (SM16).Results: We observed markedly smaller tumors in the group receiving the combination of SM16 chow and adoptive transfer. Additional investigation revealed that TGF-β receptor blockade increased the persistence of adoptively transferred T cells in the spleen and lymph nodes, increased numbers of adoptively transferred T cells within tumors, increased activation of these infiltrating T cells, and altered the tumor microenvironment with a significant increase in tumor necrosis factor-α and decrease in arginase mRNA expression.Conclusions: We found that systemic blockade of TGF-β receptor activity augmented the antitumor activity of adoptively transferred T cells and may thus be a useful adjunct in future clinical trials.
Phase II Study of Dasatinib in Philadelphia Chromosome–Negative Acute and Chronic Myeloid Diseases, Including Systemic Mastocytosis
Authors: Verstovsek Srdan , Tefferi Ayalew , Cortes Jorge , O'Brien Susan , Garcia-Manero Guillermo , Pardanani Animesh , Akin Cem , Faderl Stefan , Manshouri Taghi , Thomas Deborah , Kantarjian Hagop 
Published: June 2008

Abstract
Purpose: Molecular characterization of Philadelphia chromosome–negative (Ph−) chronic myeloproliferative disorders, such as systemic mastocytosis (SM), has provided a clear rationale for investigating novel targeted therapies. The tyrosine kinase (TK) inhibitor dasatinib is 325-fold more potent against Bcr-Abl TK than imatinib in vitro, significantly inhibiting wild-type KIT and platelet-derived growth factor receptor β TKs, and is active against cells carrying the mutant KIT-D816V gene.
Experimental Design: In this phase 2, open-label study, the efficacy of dasatinib (140 mg/d) was investigated in 67 patients with various Ph− myeloid disorders, including SM (n = 33; 28 KIT-D816V positive).
Results: The overall response rate to dasatinib in patients with SM was 33%. Only two patients, one with SM-myelofibrosis and one with SM-chronic eosinophilic leukemia, achieved complete response (elimination of mastocytosis) lasting for 5 and 16 months, respectively. Both patients were negative for KIT-D816V mutation, had low tryptase levels, abnormal WBC counts, and anemia, and had failed prior therapy with erythropoietin. Additional nine SM patients had symptomatic response, lasting 3 to 18+ months. Complete responses were achieved in two other patients (acute myeloid leukemia and hypereosinophilic syndrome). No responses were observed among patients with myelodysplastic syndromes and primary myelofibrosis. The majority of adverse events were grade 1/2.
Conclusion: These data show that dasatinib therapy may benefit a selected group of SM patients, primarily by improving their symptoms, but it does not eliminate the disease in the patients with KIT-D816V mutation.
Soluble ErbB3 Levels in Bone Marrow and Plasma of Men with Prostate Cancer
Authors: Lin Sue-Hwa , Lee Yu-Chen , Choueiri Michel B. , Wen Sijin , Mathew Paul , Ye Xiangcang , Do Kim-Anh , Navone Nora M. , Kim Jeri , Tu Shi-Ming , Yu-Lee Li-Yuan , Logothetis Christopher J. 
Published: June 2008

Abstract
Purpose: Prostate cancer tends to metastasize to bone and induce osteoblastic lesions. We identified a soluble form of ErbB3 (sErbB3), p45-sErbB3, in bone marrow supernatant from men with prostate cancer bone metastasis and showed that p45-sErbB3 enhances bone formation. We aimed to understand clinical implications of sErbB3 by establishing an ELISA to detect sErbB3 levels in bone marrow and plasma samples.
Experimental Design: We did ELISAs on marrow from 108 men [34 with androgen-dependent disease, 30 with androgen-independent disease (AI) but negative bone scan (AI/BS−), and 44 with AI and positive bone scan (AI/BS+)], sequential marrow from 5 men during treatment, plasma from 52 men before and after docetaxel treatment, and plasma from 95 men ages ≥70 years old without prostate cancer.
Results: Some men with clinically detectable bone metastasis had high sErbB3 levels. Within the AI/BS− group, higher sErbB3 levels seemed to yield lower rates of bone metastasis. In the AI/BS+ group, detectable bone metastases took longer to appear in men with higher sErbB3 levels than in men with lower sErbB3 levels (median, 82 versus 41 months). However, high sErbB3 levels did not confer survival benefit after metastasis development. Among men with metastatic progression in bone, docetaxel treatment reduced plasma sErbB3 (P &lt; 0.0001) but did not affect bone-specific alkaline phosphatase (P = 0.206) or prostate-specific antigen (P = 0.906). sErbB3 was also detected in men without prostate cancer.
Conclusions: The apparent correlation between higher sErbB3 levels and longer time to bone metastasis suggests that sErbB3 participates in progression in bone of prostate cancer.
Springtime Intensification of the Great Plains Low-Level Jet and Midwest Precipitation in GCM Simulations of the Twenty-First Century
Authors: Cook Kerry H. , Vizy Edward K. , Launer Zachary S. , Patricola Christina M. 
Published: June 2008

Abstract
Simulations from 18 coupled atmosphere–ocean GCMs are analyzed to predict changes in the climatological Great Plains low-level jet (GPLLJ) and Midwest U.S. hydrology resulting from greenhouse gas increases during the twenty-first century. To build confidence in the prediction, models are selected for analysis based on their twentieth-century simulations, and their simulations of the future are diagnosed to ensure that the response is reasonable. Confidence in the model projections is also bolstered by agreement among models, in a so-called multimodel ensemble, and by analogy with present-day interannual variability.
The GCMs agree that the GPLLJ will be more intense in April, May, and June in the future. The selected models even agree on the reason for this intensification, namely, a westward extension and strengthening of the North Atlantic subtropical high (the Bermuda high) that occurs when greenhouse gas–induced warming over the continental United States exceeds that of the subtropical Atlantic in the spring. Accompanying the changes in the GPLLJ are springtime precipitation increases of 20%–40% in the upper Mississippi Valley, which are closely associated with intensified meridional moisture convergence by the jet, with decreases to the south, which results in reduced moist static stability in the region. The simulated differences in the Midwest circulation and hydrology in the spring for the twenty-first century are similar to the observed moisture balance and circulation anomalies for May and, especially, June of 1993, a year of devastating floods throughout the Mississippi Valley.
Synoptic Wave Perturbations and Convective Systems over Equatorial Africa
Authors: Nguyen Hanh , Duvel Jean-Philippe 
Published: June 2008

Abstract
Spectral analysis of the outgoing longwave radiation (OLR) time series over equatorial Africa reveals large oscillations of the convection with periods of between 3 and 6 days. In March and April, when the intertropical convergence zone (ITCZ) migrates northward and crosses equatorial Africa, this periodic behavior is most pronounced with a marked peak at 5–6 days. Robust horizontal and vertical patterns, consistent with a convectively coupled Kelvin wave, can be extracted by a simple composite technique based only on the phase of the convective oscillations over equatorial Africa. The composite reveals differences between continental and adjacent oceanic regions. Over the continent, the stronger oscillation of the convection is associated with larger temperature and moisture anomalies near the surface, suggesting an influence of diabatic processes on the amplitude of the perturbations. Some convective events over equatorial Africa are triggered by waves propagating eastward over the equatorial Atlantic. However, this cannot explain the robust periodic behavior observed over equatorial Africa because the convective variability over the Amazon basin and the equatorial Atlantic have different spectral characteristics with no marked peak at 5–6 days in March and April.
The mesoscale convective systems embedded in these synoptic disturbances are studied using satellite brightness temperature at higher spatial (0.5°) and temporal (3 h) resolution than the OLR (respectively, 2.5° and daily average). The diurnal and the wave modulations of occurrence, size, and life cycle of the mesoscale convective systems are inspected. These systems are generated preferentially over the western slopes of the Rift Valley highlands. They propagate west-southwestward over the Congo basin where they reach their maximum size. The 5–6-day perturbations do not modify the diurnal triggering of convective systems notably, but the perturbations do modify their development into larger organized convection, especially over the Congo basin. The implication of these results for understanding the physical source of these 5–6-day perturbations is discussed.
Residual Diagnosis of Diabatic Heating from ERA-40 and NCEP Reanalyses: Intercomparisons with TRMM
Authors: Chan Steven C. , Nigam Sumant 
Published: June 2008

Abstract
Diabatic heating is diagnosed from the 40-yr ECMWF Re-Analysis (ERA-40) circulation as a residue in the thermodynamic equation. The heating distribution is compared with the heating structure diagnosed from NCEP and 15-yr ECMWF Re-Analysis (ERA-15) circulation and latent heating generated from Tropical Rainfall Measuring Mission (TRMM) observations using the convective–stratiform heating (CSH) algorithm.
The ERA-40 residual heating in the tropics is found to be stronger than NCEP’s (and ERA-15), especially in July when its zonal–vertical average is twice as large. The bias is strongest over the Maritime Continent in January and over the eastern basins and Africa in July. Comparisons with precipitation indicate ERA-40 heating to be much more realistic over the eastern Pacific but excessive over the Maritime Continent, by at least 20% in January.
Intercomparison of precipitation estimates from heating-profile integrals and station and satellite analyses reveals the TRMM CSH latent heating to be chronically weak by as much as a factor of 2! It is the low-side outlier among nine precipitation estimates in three of the four analyzed regions. No less worrisome is the inconsistency between the integral of the CSH latent heating profile in the tropics and the TRMM precipitation retrievals constraining the CSH algorithm (e.g., the 3A25 analysis).
Confronting TRMM’s diagnosis of latent heating from local rainfall retrievals and local cumulus-model heating profiles with heating based on the large-scale assimilated circulation is a defining attribute of this study.
Control of Lower-Limb Overturning Circulation in the Southern Ocean by Diapycnal Mixing and Mesoscale Eddy Transfer
Authors: Ito Taka , Marshall John 
Published: June 2008

Abstract
A simple model is developed of the lower limb of the meridional overturning circulation in the Southern Ocean based on residual-mean theory. It is hypothesized that the strength of the lower-limb overturning (Ψ) is strongly controlled by the magnitude of abyssal diapycnal mixing (κ) and that of mesoscale eddy transfer (K). In particular, it is argued that Ψ ∝ κK. The scaling and associated theory find support in a suite of sensitivity experiments with an idealized ocean general circulation model. This study shows that intense diapycnal mixing is required to close the buoyancy budget of the lower-limb overturning circulation, in contrast to the upper limb, where air–sea buoyancy fluxes can provide the required diabatic forcing.
Ten Years of TRMM/VIRS On-Orbit Calibrations and Multiyear Comparisons of VIRS and MODIS
Authors: Lyu Cheng-Hsuan , Barnes William L. 
Published: June 2008

Abstract
After 10 years of successful operation of the Tropical Rainfall Measuring Mission (TRMM)/Visible Infrared Scanner (VIRS), based on sensor performance, the authors have reexamined the calibration algorithms and identified several ways to improve the current VIRS level-1B radiometric calibration software. This study examines the trends in VIRS on-orbit calibration results by using lunar measurements to enable separation of the solar diffuser degradation from that of the VIRS Earth-viewing sensor and by comparing the radiometric data with two nearly identical Moderate Resolution Imaging Spectroradiometer (MODIS) instruments on board the NASA Earth Observing System (EOS) Terra and Aqua satellites. For the VIRS, with spectral bands quite similar to several of the MODIS bands, the integrated lunar reflectance data were measured, from January 1998 to March 2007, at phase angles ranging from 0.94° to 121.8°. The authors present trending of the lunar data over periods of 4 yr (Aqua/MODIS), 6 yr (Terra/MODIS), and 10 yr (TRMM/VIRS) and use these observations to examine instrument radiometric stability. The VIRS-measured lunar irradiances are compared with the MODIS-measured lunar irradiances at phase angles around 54°–56°. With the upcoming modified VIRS level-1B version 7 calibration algorithm, the VIRS, along with MODIS, should provide better references for intercalibrating multiple Earth-observing sensors.
Reformulating the hazard ratio to enhance communication with clinical investigators
Authors: Moser Barry K , McCann Melinda H 
Published: June 2008

Background: Clinical trials with time to event outcomes are often designed utilizing the Cox [1] proportional hazard model with a hazard ratio parameter Δ. Purpose: The purpose of this article is to demonstrate that a Cox proportional hazard model with a hazard ratio parameter is equivalent to a Cox proportional hazard model with a parameter equal to the probability that a patient given one treatment will have an event earlier than if the same patient were given a different treatment. This probability will subsequently be referred to as θ. Clinically interesting differences between the treatment arms are easier for researchers to quantify in terms of θ in situations where they have a difficult time with the hazard ratio, allowing better communication between the statistician and the researcher. Methods: The problem and its solution are demonstrated mathematically. The utility of the Cox proportional hazard model in terms of θ is illustrated through a Lymphoma clinical trial example. Results: The Cox proportional hazard model with parameter θ is shown to be equivalent to the Cox proportional hazard model with a hazard ratio parameter Δ. A table of typical hazard ratios Δ is presented with their equivalent θ values. In the appendix the mathematical derivations are developed and an unbiased estimate of θ is provided using Gehan's [2] generalization of the Wilcoxon statistic. Limitations: The equivalence of the Cox proportional hazard model in terms of the probability θ and the hazard ratio Δ is established only for continuous failure times with a single binary covariate. Conditions under which approximate equivalence holds with multiple covariates are discussed in the Appendix. Conclusions: The probability θ provides a natural parameterization for the Cox proportional hazard model, affords a tool to conceptualize treatment differences, and provides a method to improve communication between statisticians and researchers. Clinical Trials 2008; 5: 248—252. http://ctj.sagepub.com
Overcoming challenges in designing and implementing a phase II randomized controlled trial using a presurgical model to test a dietary intervention in prostate cancer
Authors: Demark-Wahnefried Wendy , George Stephen L , Switzer Boyd R , Snyder Denise C , Madden John F , Polascik Thomas J , Ruffin Mack T , Vollmer Robin T 
Published: June 2008

Background: The time between the diagnosis of cancer and a planned definitive surgical procedure offers a strong and direct approach for assessing the impact of interventions (including lifestyle interventions) on the biology of the target tissue and the tumor. Despite the many strengths of presurgical models, there are practical issues and challenges that arise when using this approach. Purpose:/Methods We recently completed an NIH-funded phase II trial that utilized a presurgical model in testing the comparative effects of flaxseed supplementation and/or dietary fat restriction on the biology and biomarkers associated with prostatic carcinoma. Herein, we report the rationale for our original design, discuss modifications in strategy, and relay experiences in implementing this trial related to the following topics: (1) subject accrual; (2) subject retention; (3) intervention delivery; and (4) retrieval and completion rates regarding the collection of paraffin-embedded and fresh frozen prostate tissue, blood, urine, ejaculate, anthropometric measures and survey data. Results: This trial achieved its accrual target, i.e., a racially-representative (70% white, 30% minority) sample of 161 participants, low rates of attrition (7%); and collection rates that exceeded 90% for almost all biospecimens and survey data. While the experience gained from pilot studies was invaluable in designing this trial, the complexity introduced by the collection of several biospecimens, inclusion of a team of pathologists (to provide validated readings), and shifts in practice patterns related to prostatectomy, made it necessary to revise our protocol; lessons from our experiences are offered within this article. Conclusions: While our experience specifically relates to the implementation of a presurgical model-based trial in prostate cancer aimed at testing flaxseed-supplemented and fat-restricted diets, many of the lessons learned have broad application to trials that utilize a presurgical model or dietary modification within various cancer populations. Clinical Trials 2008; 5: 262—272. http://ctj.sagepub.com