bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Phase I, Dose-Escalation Study of the Multitargeted Receptor Tyrosine Kinase Inhibitor, Golvatinib, in Patients with Advanced Solid Tumors
Authors: Molife L. Rhoda , Dean Emma Jane , Blanco-Codesido Montserrat , Krebs Matthew G. , Brunetto Andre T. , Greystoke Alastair Peter , Daniele Gennaro , Lee Lucy , Kuznetsov Galina , Myint Khin Than , Wood Karen , de las Heras Begoña , Ranson Malcolm Richard 
Published: October 2014

Abstract
Purpose: Receptor tyrosine kinases c-Met and Ron transduce signals regulating cell migration and matrix invasion. This phase I dose-escalation trial tested golvatinib, a highly potent, small-molecule, ATP-competitive inhibitor of c-Met and multiple members of the Eph receptor family plus c-Kit and Ron.
Experimental Design: Patients with advanced solid tumors received golvatinib orally, once daily, continuously. Using a “3+3” design, dosing started at 100 mg once daily, escalating to the maximum tolerated dose (MTD) defined by dose-limiting toxicities. Pharmacokinetic, pharmacodynamic, and preliminary antitumor activity was assessed during dose escalation and in a MTD expansion cohort.
Results: Thirty-four patients were treated at six dose levels. The MTD was determined as 400 mg once daily. Three dose-limiting toxicities were observed: grade 3 increased γ-glutamyltransferase and alkaline phosphatase (200 mg), repeated grade 2 fatigue, and grade 3 fatigue (50.0%). Frequent treatment-related adverse events (with incidence &gt;10%) included diarrhea (58.8%), nausea (50%), vomiting (44.1%), fatigue (41.2%), decreased appetite (32.4%), elevated alanine aminotransferase (32.4%), elevated aspartate aminotransferase (20.6%), dry skin (11.8%), and dysgeusia (11.8%). Best overall response was stable disease (median duration 85 days, range 85–237). Pharmacokinetics demonstrated high variability, although maximum plasma concentration and area under the plasma concentration–time curve increased with dose. Soluble urokinase-type plasminogen activator receptor, VEGFR2, c-Met, and angiopoietin-2 levels increased after dose. Posttreatment decrease in either p-c-Met or p-ERK was observed in 3 of 4 paired biopsies at MTD.
Conclusions: Golvatinib at the MTD of 400 mg once daily was well tolerated with pharmacodynamic evidence of c-Met target modulation. Clin Cancer Res; 20(24); 6284–94. ©2014 AACR.
Doxycycline as an Inhibitor of the Epithelial-to-Mesenchymal Transition and Vasculogenic Mimicry in Hepatocellular Carcinoma
Authors: Meng Jie , Sun Baocun , Zhao Xiulan , Zhang Danfang , Zhao Xueming , Gu Qiang , Dong Xueyi , Zhao Nan , Liu Peimei , Liu Yanrong 
Published: October 2014

Abstract
This study was conducted to examine the effects of doxycycline on the survival time and proliferation of hepatocellular carcinoma (HCC) in vivo and on the biologic functions of HCC in vitro. This study was also designed to evaluate the effects of doxycycline on epithelial-to-mesenchymal transition (EMT)– and vasculogenic mimicry (VM)–related protein expression and on matrix metalloproteinase (MMP) and DNA methyltransferase (DNMT) activity in vitro. Human MHCC97H cells were injected into BALB/c mice, which were divided into treatment and control groups. Doxycycline treatment prolonged the mouse survival time and partly suppressed the growth of engrafted HCC tumor cells, with an inhibition rate of 43.39%. Higher amounts of VM and endothelium-dependent vessels were found in the control group than the treatment group. IHC indicated that epithelial (E)-cadherin expression was increased in the doxycycline-treated mice compared with the control group. In in vitro experiments, doxycycline promoted HCC cell adhesion but inhibited HCC cell viability, proliferation, migration, and invasion. Western blot analysis, semiquantitative RT-PCR, qRT-PCR, and immunofluorescence demonstrated that doxycycline inhibited the degradation of the epithelial marker E-cadherin and downregulated the expression levels of EMT promoters, the mesenchymal marker vimentin, and the VM-associated marker vascular endothelial (VE)-cadherin. Furthermore, the activities of MMPs and DNMTs were examined in different groups via gelatin zymography and a DNMT activity assay kit. A methylation-specific PCR was performed to assess the promoter methylation of CDH1 (the gene encoding E-cadherin). Doxycycline prolonged the mouse survival time by inhibiting EMT progression and VM formation. Mol Cancer Ther; 13(12); 3107–22. ©2014 AACR.
The Path to Reactivation of Antitumor Immunity and Checkpoint Immunotherapy
Authors: Kim Hye-Jung , Cantor Harvey 
Published: October 2014

AbstractCancer immunology has recently made major therapeutic inroads that represent clinical application of basic insights into mechanisms that govern immunity against tumors. Research into fundamental elements of T-cell and natural killer–cell biology, including the basis of antigen recognition, activation, proliferation, and survival, has informed the design of new therapeutic approaches to augment the body's natural anticancer immune response. Here, we describe some of the key steps that have provided the foundation for current strategies of immunotherapy. Cancer Immunol Res; 2(10); 926–36. ©2014 AACR.
Protein Biomarkers Identify Patients Unlikely to Benefit From Primary Prevention Implantable Cardioverter Defibrillators
Authors: Cheng Alan , Zhang Yiyi , Blasco-Colmenares Elena , Dalal Darshan , Butcher Barbara , Norgard Sanaz , Eldadah Zayd , Ellenbogen Kenneth A. , Dickfeld Timm , Spragg David D. , Marine Joseph E. , Guallar Eliseo , Tomaselli Gordon F. 
Published: October 2014

Background—
Primary prevention implantable cardioverter defibrillators (ICDs) reduce all-cause mortality, but the benefits are heterogeneous. Current risk stratification based on left ventricular ejection fraction has limited discrimination power. We hypothesize that biomarkers for inflammation, neurohumoral activation, and cardiac injury can predict appropriate shocks and all-cause mortality in patients with primary prevention ICDs.

Methods and Results—
The Prospective Observational Study of Implantable Cardioverter Defibrillators (PROSe-ICD) enrolled 1189 patients with systolic heart failure who underwent ICD implantation for primary prevention of sudden cardiac death. The primary end point was an ICD shock for adjudicated ventricular tachyarrhythmia. The secondary end point was all-cause mortality. After a median follow-up of 4.0 years, 137 subjects experienced an appropriate ICD shock and 343 participants died (incidence rates of 3.2 and 5.8 per 100 person-years, respectively). In multivariable-adjusted models, higher interleukin-6 levels increased the risk of appropriate ICD shocks. In contrast, C-reactive protein, interleukin-6, tumor necrosis factor-α receptor II, pro–brain natriuretic peptide (pro-BNP), and cardiac troponin T showed significant linear trends for increased risk of all-cause mortality across quartiles. A score combining these 5 biomarkers identified patients who were much more likely to die than to receive an appropriate shock from the ICD.

Conclusions—
An increase in serum biomarkers of inflammation, neurohumoral activation, and myocardial injury increased the risk for death but poorly predicted the likelihood of an ICD shock. These findings highlight the potential importance of serum-based biomarkers in identifying patients who are unlikely to benefit from primary prevention ICDs.

Clinical Trial Registration—

URL:
clinicaltrials.gov
; Unique Identifier: NCT00733590.
Transforming Growth Factor β–Activated Kinase 1 Signaling Pathway Critically Regulates Myocardial Survival and Remodeling
Authors: Li Lei , Chen Yi , Doan Jessica , Murray Jason , Molkentin Jeffery D. , Liu Qinghang 
Published: October 2014

Background—
Programmed necrosis (necroptosis) plays an important role in development, tissue homeostasis, and disease pathogenesis. The molecular mechanisms that regulate necroptosis in the heart and its physiological relevance in myocardial remodeling and heart failure remain largely unknown.

Methods and Results—

Here, we identified an obligate function for TAK1 (transforming growth factor β–activated kinase 1, gene name
Map3k7
) in regulating necroptotic myocyte death, myocardial remodeling, and heart failure propensity. Cardiac-specific ablation of
Map3k7
in mice induced spontaneous apoptosis and necroptosis that led to adverse remodeling and heart failure, and these effects were abolished by ablation of tumor necrosis factor receptor-1. Mechanistically, TAK1 functions as a molecular switch in tumor necrosis factor receptor-1 signaling by regulating the formation of 2 cell death complexes, RIP 1 (receptor-interacting protein 1)–FADD (Fas-associated protein with death domain)–caspase 8 and RIP1-RIP3, a process that is dependent on FADD and caspase 8 as scaffolding molecules. Importantly, inhibition of RIP1 or RIP3 largely blocked necroptotic cell death, adverse remodeling, and heart failure in TAK1-deficient mice.

Conclusions—
These results indicate that TAK1 functions as a key survival factor in the heart by directly antagonizing necroptosis, which is critical for the maintenance of myocardial homeostasis and the prevention of adverse myocardial remodeling.
Residential Proximity to Major Roadways and Prevalent Hypertension Among Postmenopausal Women: Results From the Women's Health Initiative San Diego Cohort
Authors: Kirwa Kipruto , Eliot Melissa N. , Wang Yi , Adams Marc A. , Morgan Cindy G. , Kerr Jacqueline , Norman Gregory J. , Eaton Charles B. , Allison Matthew A. , Wellenius Gregory A. 
Published: October 2014

Background
Living near major roadways has been linked with increased risk of cardiovascular events and worse prognosis. Residential proximity to major roadways may also be associated with increased risk of hypertension, but few studies have evaluated this hypothesis.

Methods and Results

We examined the cross‐sectional association between residential proximity to major roadways and prevalent hypertension among 5401 postmenopausal women enrolled into the San Diego cohort of the Women's Health Initiative. We used modified Poisson regression with robust error variance to estimate the association between prevalence of hypertension and residential distance to nearest major roadway, adjusting for participant demographics, medical history, indicators of individual and neighborhood socioeconomic status, and for local supermarket/grocery and fast food/convenience store density. The adjusted prevalence ratios for hypertension were 1.22 (95%
CI
: 1.07, 1.39), 1.13 (1.00, 1.27), and 1.05 (0.99, 1.12) for women living ≤100, >100 to 200, and >200 to 1000 versus >1000 m from a major roadway (
P
for trend=0.006). In a model treating the natural log of distance to major roadway as a continuous variable, a shift in distance from 1000 to 100 m from a major roadway was associated with a 9% (3%, 16%) higher prevalence of hypertension.

Conclusions
In this cohort of postmenopausal women, residential proximity to major roadways was positively associated with the prevalence of hypertension. If causal, these results suggest that living close to major roadways may be an important novel risk factor for hypertension.
Bursaphelenchus osumiana n. sp. (Tylenchomorpha: Aphelenchoididae) isolated from dead Pinus armandii var. amamiana in Osumi Islands in Japan
Authors: Kanzaki Natsumi , Akiba Mitsuteru , Kanetani Seiichi , Tetsuka Kenshi , Ikegame Hiroharu 
Published: October 2014

An undescribed Bursaphelenchus species was isolated and cultured from materials collected during a field survey of a declining endemic pine species. Two nematode isolates were obtained from dead Pinus armandii var. amamiana on two islands (Yakushima and Tanegashima) in Kagoshima, Japan. The new nematode is described and illustrated herein as B. osumiana n. sp. Typologically, B. osumiana n. sp. is similar to B. parvispicularis and B. paraparvispicularis, i.e., males of these species have a short, stout spicule. The new species is distinguished from the other two by the shape of the male bursal flap (very small and triangular) and female tail morphology (weakly ventrally arcuate with narrow rounded or weakly pointed terminus), which are unique to this species. Near full-length molecular sequences of the small subunit (18S), internal transcribed spacer region, and D2D3 expansion segments of the large subunit of ribosomal RNA and a partial sequence of the mitochondrial cytochrome oxidase subunit I (mtCOI) were obtained to molecularly profile the new species. The sequence profiles were identical for the two isolates of B. osumiana n. sp., and were close to those of B. parvispicularis and B. paraparvispicularis. The new species was clearly distinguished molecularly from both of its close relatives and its molecular phylogenetic status and typological characters were in accordance. Other biological characters, e.g., carrier insect species and pathogenicity with regard to pine tree species, have not been clarified and should be examined in future studies.
Life history trait analysis of the entomopathogenic nematode Steinernema riobrave
Authors: Addis Temesgen , Teshome Asmamaw , Strauch Olaf , Ehlers Ralf-Udo 
Published: October 2014

Life history traits (LHT) of Steinernema riobrave strain Sr 7-12 and Sr HYB19 were assessed at 25°C in monoxenic culture using a hanging drop technique. The LHT were studied with 5 × 109, 10 × 109 and 20 × 109 cells ml−1 of Xenorhabdus cabanillasii in semi-solid Nematode Growth Gelrite. Increased X. cabanillasii densities had a significant positive influence on offspring production on both Sr 7-12 and the hybrid Sr HYB19. At the higher bacterial food density, the total fertility rate (TFR) per female of Sr 7-12 was 2022 offspring and the net reproductive rate () reached 1904 offspring. Similarly, for Sr HYB19, the TFR per female was 2434 and was 1903. The percentage offspring produced via intra-uterine development (endotokia matricida) was relatively higher at 5 × 109 bacterial cells ml−1 than at higher bacterial density, with 64% and 66% of the total offspring produced by Sr 7-12 and Sr HYB19, respectively. A positive correlation () was recorded for offspring production and bacterial food density and for female body volume with bacterial density (). Female nematodes survived longer at higher bacterial food density; however, females of both strains could not survive longer than 7.8 days, beginning from hatching and always ending 1 day after initiation of endotokia matricida. Based on LHT results, there is a potential to maximise yield of dauer juveniles in liquid culture through increasing bacterial food density.
Yeatesinia barbata gen. n., sp. n. (Nematoda: Plectida: Plectidae), a most remarkable nematode from New Zealand
Authors: Holovachov Oleksandr , Boström Sven 
Published: October 2014

The new genus and speciesYeatesinia barbatagen. n., sp. n. is described from a sand dune habitat in New Zealand. The new genus is characterised by a body length of 299-357 μm in females and 304-361 μm in males, lip region rounded dorso-ventrally, broad laterally, dorsally inclined, lateral sides of lip region with two large, horn-like, projections, each bearing one seta at its base, each amphid surrounded by three setiform sensilla, oral opening a broad transverse slit located on the dorsal body surface, and different structure of cuticle in the dorsal and ventral body sectors. This combination of unique morphological characters clearly separates the new genus from all other members of the Plectidae. The phylogenetic affinities ofYeatesiniagen. n. and its relationships to other genera of the family Plectidae are discussed.
Host status and phenotypic diversity of rice cultivars resistant to Meloidogyne species under glasshouse conditions
Authors: Machado Andressa C.Z. , de Araújo Filho Jerônimo V. 
Published: October 2014

Five pot trials were carried out under glasshouse conditions to assess the host response of some selected rice cultivars to Meloidogyne javanica, M. paranaensis and M. enterolobii, based on nematode reproductive factor (RF) and number of nematodes (g root)−1. We also determined the broad-sense heritability and variance component estimations associated with M. paranaensis and M. incognita resistance. In addition, cluster analysis of cultivars was conducted. All cultivars were rated as susceptible or highly susceptible to M. javanica and highly resistant to M. enterolobii. To M. paranaensis, only cvs IAPAR 177 and BRS Caravela were resistant. From the principal component analysis and Ward’s cluster analysis, we obtained four conspicuous clusters of cultivars according to Meloidogyne species resistance, which demonstrates the variability of the genetic material studied. Higher broad-sense heritability values for RF and nematodes (g root)−1 were obtained. Taken together, our findings suggest that improvement of resistance of rice to Meloidogyne species resistance is possible. The implications for management programmes are also discussed.
Word Order, Information Structure and Intonation of Discontinuous Nominal Constructions in Cantonese / Ordre des mots, structure de l’information et intonation des phrases nominales discontinues en Cantonais
Authors: Ding Picus Sizhi , Féry Caroline 
Published: October 2014

This paper examines the syntactic, intonational and information structural properties of discontinuous nominal constructions in Cantonese. Four different syntactic constructions are identified which are used to indicate different information status of elements in a noun phrase, all involving two full NPs with either overt or covert heads. Discourse particles play a crucial role, not only for the interpretation of information structure, but also as anchoring points for boundary tones. Otherwise, intonation and prosody are not affected by word order changes, with the exception of optional pauses after or before dislocated constituents. Cet article examine la structure de l’information des syntagmes nominaux discontinus en Cantonais, ainsi que leurs propriétés syntaxiques et intonatives. Quatre constructions syntaxiques distinctes ont été identifiées qui servent à exprimer des rôles spécifiques de structure de l’information sur des parties de syntagmes nominaux. Ces rôles impliquent deux syntagmes nominaux complets et indépendants l’un de l’autre, avec des têtes prononcées ou non. Les particules discursives jouent un rôle essentiel, non seulement pour l’interprétation de la structure de l’information, mais aussi pour l’ancrage des tons de frontière. L’intonation et la prosodie ne jouent aucun rôle en dehors des pauses facultatives avant ou après les syntagmes discontinus. L’intonation n’est pas affectée par les changements d’ordre des mots.
Statistical Characteristics of Unsteady Storms in Radar Observations for the Beijing–Tianjin Region
Authors: Wang Yu , Wang Hong-Qing , Han Lei , Lin Yin-Jing , Zhang Yan 
Published: October 2014

AbstractThis study was designed to provide basic information for the improvement of storm nowcasting. According to the mean direction deviation of storm movement, storms were classified into three types: 1) steady storms (S storms, extrapolated efficiently), 2) unsteady storms (U storms, extrapolated poorly), and 3) transitional storms (T storms). The U storms do not fit the linear extrapolation processes because of their unsteady movements. A 6-yr warm-season radar observation dataset was used to highlight and analyze the differences between U storms and S storms. The analysis included geometric features, dynamic factors, and environmental parameters. The results showed that storms with the following characteristics changed movement direction most easily in the Beijing–Tianjin region: 1) smaller storm area, 2) lower thickness (echo-top height minus base height), 3) lower movement speed, 4) weaker updrafts and the maximum value located in the mid- and upper troposphere, 5) storm-relative vertical wind profiles dominated by directional shear instead of speed shear, 6) lower relative humidity in the mid- and upper troposphere, and 7) higher surface evaporation and ground roughness.
Morphology, Intensity, and Rainfall Production of MJO Convection: Observations from DYNAMO Shipborne Radar and TRMM
Authors: Xu Weixin , Rutledge Steven A. 
Published: October 2014

Abstract
This study uses Dynamics of the Madden–Julian Oscillation (DYNAMO) shipborne [Research Vessel (R/V) Roger Revelle] radar and Tropical Rainfall Measuring Mission (TRMM) Precipitation Radar (PR) datasets to investigate MJO-associated convective systems in specific organizational modes [mesoscale convective system (MCS) versus sub-MCS and linear versus nonlinear]. The Revelle radar sampled many “climatological” aspects of MJO convection as indicated by comparison with the long-term TRMM PR statistics, including areal-mean rainfall (6–7 mm day−1), convective intensity, rainfall contributions from different morphologies, and their variations with MJO phase. Nonlinear sub-MCSs were present 70% of the time but contributed just around 20% of the total rainfall. In contrast, linear and nonlinear MCSs were present 10% of the time but contributed 20% and 50%, respectively. These distributions vary with MJO phase, with the largest sub-MCS rainfall fraction in suppressed phases (phases 5–7) and maximum MCS precipitation in active phases (phases 2 and 3). Similarly, convective–stratiform rainfall fractions also varied significantly with MJO phase, with the highest convective fractions (70%–80%) in suppressed phases and the largest stratiform fraction (40%–50%) in active phases. However, there are also discrepancies between the Revelle radar and TRMM PR. Revelle radar data indicated a mean convective rain fraction of 70% compared to 55% for TRMM PR. This difference is mainly due to the reduced resolution of the TRMM PR compared to the ship radar. There are also notable differences in the rainfall contributions as a function of convective intensity between the Revelle radar and TRMM PR. In addition, TRMM PR composites indicate linear MCS rainfall increases after MJO onset and produce similar rainfall contributions to nonlinear MCSs; however, the Revelle radar statistics show the clear dominance of nonlinear MCS rainfall.
Sounding-Based Thermodynamic Budgets for DYNAMO
Authors: Johnson Richard H. , Ciesielski Paul E. , Ruppert James H. , Katsumata Masaki 
Published: October 2014

Abstract
The Dynamics of the Madden–Julian Oscillation (DYNAMO) field campaign, conducted over the Indian Ocean from October 2011 to March 2012, was designed to study the initiation of the Madden–Julian oscillation (MJO). Two prominent MJOs occurred in the experimental domain during the special observing period in October and November. Data from a northern and a southern sounding array (NSA and SSA, respectively) have been used to investigate the apparent heat sources and sinks (Q1 and Q2) and radiative heating rates QR throughout the life cycles of the two MJO events. The MJO signal was far stronger in the NSA than the SSA. Time series of Q1, Q2, and the vertical eddy flux of moist static energy reveal an evolution of cloud systems for both MJOs consistent with prior studies: shallow, nonprecipitating cumulus during the suppressed phase, followed by cumulus congestus, then deep convection during the active phase, and finally stratiform precipitation. However, the duration of these phases was shorter for the November MJO than for the October event. The profiles of Q1 and Q2 for the two arrays indicate a greater stratiform rain fraction for the NSA than the SSA—a finding supported by TRMM measurements. Surface rainfall rates and net tropospheric QR determined as residuals from the budgets show good agreement with satellite-based estimates. The cloud radiative forcing was approximately 20% of the column-integrated convective heating and of the same amplitude as the normalized gross moist stability, leaving open the possibility of radiative–convective instability for the two MJOs.