bluuebunny/crossref_metadata_2025 huggingface dataset:
Analysis of structural trends of sub-sea-floor strata in the Isfjorden area of the West Spitsbergen Fold-and-Thrust Belt based on multichannel seismic data
Authors: Blinova Maria , Faleide Jan Inge , Gabrielsen Roy H. , Mjelde Rolf
Published: May 2013

A dense grid of 2D multichannel seismic data was used for the interpretation of sub-sea-floor structures in the area of Isfjorden in western Spitsbergen. West Spitsbergen underwent Eocene transpressional deformation that resulted in formation of the West Spitsbergen Fold-and-Thrust Belt. Three horizons were defined for the seismic interpretation as well-expressed and continuous reflections: (1) the top of the metamorphic basement; (2) the base of the upper Carboniferous Nordenskiöldbreen Formation; (3) the base of the Lower Cretaceous Helvetiafjellet Formation. Time–structure maps and analysis of the sub-bottom structural trends were generated for each horizon. The top of the metamorphic basement displays north–south-trending graben structures, apparently representing continuation of the Devonian grabens from northern Spitsbergen. The tectonostratigraphic unit bounded by the base of the upper Carboniferous Nordenskiöldbreen Formation and base of the Helvetiafjellet Formation encloses the fold-and-thrust belt and is affiliated with WSW–ENE shortening involving three décollement levels. Within this unit the strata between the middle (Triassic shales) and upper (Upper Jurassic shales) décollements have undergone the most intense strain, whereas sediments situated between the basal (lower Permian evaporites) and middle décollements underwent a relatively mild deformation. The strata above the base of the Helvetiafjellet Formation are characterized by minor Tertiary deformation only.
Caldera events in a rift depocentre: an example from the Jurassic Neuquén basin, Argentina
Authors: D’Elia Leandro , Martí Joan
Published: May 2013

We analyse the volcanic stratigraphy of the Lower Jurassic synrift sequence of the Sañicó depocentre, which is a sub-basin of one of the most important hydrocarbon basins in South America, the Neuquén rift basin. The Sañicó depocentre comprises a complex multicyclic volcano-sedimentary succession. The oldest part of the succession preserves a volcano-sedimentary sequence interpreted as the record of a stratovolcano. The middle part of the succession is characterized by the emplacement of two thick ignimbrites that completely filled the depocentre. Finally, the uppermost part of the succession records subordinate volcanism characterized by andesitic lavas associated with epiclastic sediments. The Sañicó depocentre shows a complex subsidence history that involves an interplay between tectonics and volcanism. During the early and late synrift phases, subsidence was relatively slow and permitted the accumulation of thick sequences of volcanic and sedimentary deposits throughout a long period of time. During the middle synrift phase, subsidence was very rapid and allowed the accumulation of a thick ignimbrite sequence in a very short time interval. In this study, this middle episode is interpreted as corresponding to a caldera-like event in which rapid subsidence occurred along the same normal faults that controlled tectonic subsidence during the previous and subsequent episodes.
Sub-aqueous sand extrusion dynamics
Authors: Ross Jessica A. , Peakall Jeff , Keevil Gareth M.
Published: May 2013

Extruded sandstone mounds and sandstone sheets are increasingly recognized in the geological record and seismic data, yet the underlying mechanisms that control these features, and determine whether deposits form discrete accumulations or areally extensive sheets, remain poorly understood. Here we address these issues through study of a well-exposed ancient sand sheet in the Shannon Basin, Ireland. Sand volcanoes are shown to have erupted contemporaneously following liquefaction and fluidization of delta-front mouth-bar sands and silts, the expelled sediment forming an extruded sheet of sand. The sand sheet formed during a single prolonged eruption event with the interaction of radial gravity currents from the hundreds of vents exerting control on the internal architecture of the extrudite. Based on our observations, here we develop a process-based model that demonstrates that sand extrusions can form sheets only if (1) multiple vents are extruding coevally, causing gravity currents to interact, or (2) topographic forcing, such as channelling, redirects the otherwise radial gravity currents, resulting in sheet-like deposition of extruded material away from the vent site. This study provides a new model of sand extrudite formation, and examines the potential for identifying extrudites from core and bed-scale studies and differentiating them from liquefied beds.
Dietary Fat in Breast Cancer Survival
Authors: Makarem Nour , Chandran Urmila , Bandera Elisa V. , Parekh Niyati
Published: May 2013

Laboratory evidence suggests a plausible role for dietary fat in breast cancer pathophysiology. We conducted a systematic literature review to assess the epidemiological evidence on the impact of total dietary fat and fat subtypes, measured pre- and/or postcancer diagnosis, in relation to breast cancer–specific and all-cause mortality among breast cancer survivors. Studies were included if they were in English, had a sample size ≥200, and presented the hazard ratio/rate ratio for recurrence, disease-specific mortality, or all-cause mortality (n = 18). Although the results are mixed, most studies suggested that higher saturated fat intake prediagnosis was associated with increased risk of breast cancer–specific and all-cause mortality. Postdiagnostic trans fat intake was associated with a 45% and 78% increased risk of all-cause mortality. Higher monounsaturated fat intake before and after diagnosis was generally associated with increased risk of all-cause and breast cancer–specific mortality, albeit the majority of the studies were statistically nonsignificant. Two studies evaluating omega-3 fat intake suggested an inverse association with all-cause mortality. Although there were too few studies on fat subtypes to draw definitive conclusions, high consumption of saturated fat may exert a detrimental effect on breast cancer–specific and all-cause mortality, whereas omega-3 fat may be beneficial. The inconsistent and limited evidence warrants research to assess the impact of consumption of fat subtypes on breast cancer recurrence and mortality.
Demographic Change and Parent-Child Relationships in Adulthood
Authors: Seltzer Judith A. , Bianchi Suzanne M.
Published: May 2013

Demographic changes in who becomes a parent, how many children parents have, and the marital statuses of parents and children affect the extent to which parents and adult children provide for each other later in life. We describe these demographic changes and their implications for the help parents and children give each other throughout their adult years. The changing demography of US families has increased both generations' need for family assistance among those already disadvantaged and has exacerbated differences between the socioeconomically advantaged and disadvantaged in the availability of kin support. Variations in the marital histories of parents and children also contribute to a divergence between mother-child and father-child relationships in later life. The churning of couple relationships in both generations blurs the boundaries between who is in the family and who is not, threatening the effectiveness of the family safety net among those who may need it the most.
International Migration and Familial Change in Communities of Origin: Transformation and Resistance
Authors: Arias Patricia
Published: May 2013

This article reviews recent anthropological and sociological findings and discussions surrounding the possible impacts of international migration on family dynamics in the home—both for rural and indigenous people—in Mexico. Because one of the major changes has to do with the escalation of female migration, as well as the circumstances facing those women who stay behind, this article emphasizes the position of women in the realm of international migration from a gendered perspective.
Neuregulin-1/ErbB4 signaling regulates Kv4.2-mediated transient outward K+ current through the Akt/mTOR pathway
Authors: Yao Jin-Jing , Sun Ji , Zhao Qian-Ru , Wang Chang-Ying , Mei Yan-Ai
Published: May 2013

Neuregulin-1 (NRG-1) is a member of a family of neurotrophic factors that is required for the differentiation, migration, and development of neurons. NRG-1 signaling is thought to contribute to both neuronal development and the neuropathology of schizophrenia, which is believed to be a neurodevelopmental disorder. However, few studies have investigated the role of NRG-1 on voltage-gated ion channels. In this study, we report that NRG-1 specifically increases the density of transient outward K+ currents ( IA) in rat cerebellar granule neurons (CGNs) in a time-dependent manner without modifying the activation or inactivation properties of IA channels. The increase in IA density is mediated by increased protein expression of Kv4.2, the main α-subunit of the IA channel, most likely by upregulation of translation. The effect of NRG-1 on IA density and Kv4.2 expression was only significant in immature neurons. Mechanistically, both Akt and mammalian target of rapamycin (mTOR) signaling pathways are required for the increased NRG-1-induced IA density and expression of Kv4.2. Moreover, pharmacological blockade of the ErbB4 receptor reduced the effect of NRG-1 on IA density and Kv4.2 induction. Our data reveal, for the first time, that stimulation of ErbB4 signaling by NRG-1 upregulates the expression of K+ channel proteins via activation of the Akt/mTOR signaling pathway and plays an important role in neuronal development and maturation. NRG1 does not acutely change IA and delayed-rectifier outward ( IK) of rat CGNs, suggesting that it may not alter excitability of immature neurons by altering potassium channel property.
Distinct and additive effects of sodium bicarbonate and continuous mild heat stress on fiber type shift via calcineurin/NFAT pathway in human skeletal myoblasts
Authors: Yamaguchi Tetsuo , Omori Maiko , Tanaka Nobuho , Fukui Naoshi
Published: May 2013

Ingestion of sodium bicarbonate (NaHCO3) is known to enhance athletic performance, probably via increased extracellular buffering capacity. At present, little is known about the direct effects of NaHCO3 on myogenesis, especially in vitro. Here, we examined the effects of NaHCO3 and the combined effects of NaHCO3 and continuous mild heat stress (CMHS) at 39°C on the differentiation of human skeletal muscle myoblasts (HSMMs). Levels of myosin heavy chain (MyHC) type I mRNA increased with increasing NaHCO3 concentrations; in contrast, those of MyHC IIx decreased. The NaHCO3-induced fast-to-slow shift was additively enhanced by CMHS. Likewise, intracellular calcium levels and expression of three factors, nuclear factor of activated T cells c2 (NFATc2), NFATc4, and peroxisome-proliferator-activated receptor-γ coactivator-1α, were upregulated with increasing NaHCO3 concentrations; moreover, these effects of NaHCO3 were additively enhanced by CMHS. Overexpression experiments and small interfering RNA-mediated knockdown experiments confirmed that NFATc2 and NFATc4 were involved in MyHC I regulation. The present study provided evidence that NaHCO3 and CMHS distinctly and additively induced a fast-to-slow fiber type shift through changes in intracellular calcium levels and the modulation of calcium signaling.
Roles for cytosolic NADPH redox in regulating pulmonary artery relaxation by thiol oxidation-elicited subunit dimerization of protein kinase G1α
Authors: Neo Boon Hwa , Patel Dhara , Kandhi Sharath , Wolin Michael S.
Published: May 2013

The activity of glucose-6-phosphate dehydrogenase (G6PD) appears to control a vascular smooth muscle relaxing mechanism regulated through cytosolic NADPH oxidation. Since our recent studies suggest that thiol oxidation-elicited dimerization of the 1α form of protein kinase G (PKG1α) contributes to the relaxation of isolated endothelium-removed bovine pulmonary arteries (BPA) to peroxide and responses to hypoxia, we investigated whether cytosolic NADPH oxidation promoted relaxation by PKG1α dimerization. Relaxation of BPA to G6PD inhibitors 6-aminonicotinamide (6-AN) and epiandrosterone (studied under hypoxia to minimize basal levels of NADPH oxidation and PKG1α dimerization) was associated with increased PKG1α dimerization and PKG-mediated vasodilator-stimulated phosphoprotein (VASP) phosphorylation. Depletion of PKG1α by small inhibitory RNA (siRNA) inhibited relaxation of BPA to 6-AN and attenuated the increase in VASP phosphorylation. Relaxation to 6-AN did not appear to be altered by depletion of soluble guanylate cyclase (sGC). Depletion of G6PD, thioredoxin-1 (Trx-1), and Trx reductase-1 (TrxR-1) in BPA with siRNA increased PKG1α dimerization and VASP phosphorylation and inhibited force generation under aerobic and hypoxic conditions. Depletion of TrxR-1 with siRNA inhibited the effects of 6-AN and enhanced similar responses to peroxide. Peroxiredoxin-1 depletion by siRNA inhibited PKG dimerization to peroxide, but it did not alter PKG dimerization under hypoxia or the stimulation of dimerization by 6-AN. Thus regulation of cytosolic NADPH redox by G6PD appears to control PKG1α dimerization in BPA through its influence on Trx-1 redox regulation by the NADPH dependence of TrxR-1. NADPH regulation of PKG dimerization may contribute to vascular responses to hypoxia that are associated with changes in NADPH redox.
Protein composition of bronchoalveolar lavage fluid and airway surface liquid from newborn pigs
Authors: Bartlett Jennifer A. , Albertolle Matthew E. , Wohlford-Lenane Christine , Pezzulo Alejandro A. , Zabner Joseph , Niles Richard K. , Fisher Susan J. , McCray Paul B. , Williams Katherine E.
Published: May 2013

The airway mucosa and the alveolar surface form dynamic interfaces between the lung and the external environment. The epithelial cells lining these barriers elaborate a thin liquid layer containing secreted peptides and proteins that contribute to host defense and other functions. The goal of this study was to develop and apply methods to define the proteome of porcine lung lining liquid, in part, by leveraging the wealth of information in the Sus scrofa database of Ensembl gene, transcript, and protein model predictions. We developed an optimized workflow for detection of secreted proteins in porcine bronchoalveolar lavage (BAL) fluid and in methacholine-induced tracheal secretions [airway surface liquid (ASL)]. We detected 674 and 3,858 unique porcine-specific proteins in BAL and ASL, respectively. This proteome was composed of proteins representing a diverse range of molecular classes and biological processes, including host defense, molecular transport, cell communication, cytoskeletal, and metabolic functions. Specifically, we detected a significant number of secreted proteins with known or predicted roles in innate and adaptive immunity, microbial killing, or other aspects of host defense. In greatly expanding the known proteome of the lung lining fluid in the pig, this study provides a valuable resource for future studies using this important animal model of pulmonary physiology and disease.
Adapting global influenza management strategies to address emerging viruses
Authors: Noah Diana L. , Noah James W.
Published: May 2013

Death by respiratory complications from influenza infections continues to be a major global health concern. Antiviral drugs are widely available for therapy and prophylaxis, but viral mutations have resulted in resistance that threatens to reduce the long-term utility of approved antivirals. Vaccination is the best method for controlling influenza, but vaccine strategies are blunted by virus antigenic drift and shift. Genetic shift in particular has led to four pandemics in the last century, which have prompted the development of efficient global surveillance and vaccination programs. Although the influenza pandemic of 2009 emphasized the need for the rapid standardization of global surveillance methods and the preparation and dissemination of global assay standards for improved reporting and diagnostic tools, outbreaks of novel influenza strains continue to occur, and current efforts must be enhanced by aggressive public education programs to promote increased vaccination rates in the global population. Recently, a novel H7N9 avian influenza virus with potential to become a pandemic strain emerged in China and was transmitted from animals to humans with a demonstrated >20% mortality rate. Sporadic outbreaks of highly lethal avian virus strains have already increased public awareness and altered annual vaccine production strategies to prevent the natural adaption of this virus to human-to-human transmission. Additional strategies for combating influenza include advancement of new antivirals for unexploited viral or host cellular targets; novel adjuvants and alternate vaccine delivery systems; and development of universal protein, DNA, or multivalent vaccines designed to increase immune responsiveness and enhance public health response times.
Quantitative microscopy of the lung: a problem-based approach. Part 2: stereological parameters and study designs in various diseases of the respiratory tract
Authors: Mühlfeld Christian , Ochs Matthias
Published: May 2013

Design-based stereology provides efficient methods to obtain valuable quantitative information of the respiratory tract in various diseases. However, the choice of the most relevant parameters in a specific disease setting has to be deduced from the present pathobiological knowledge. Often it is difficult to express the pathological alterations by interpretable parameters in terms of volume, surface area, length, or number. In the second part of this companion review article, we analyze the present pathophysiological knowledge about acute lung injury, diffuse parenchymal lung diseases, emphysema, pulmonary hypertension, and asthma to come up with recommendations for the disease-specific application of stereological principles for obtaining relevant parameters. Worked examples with illustrative images are used to demonstrate the work flow, estimation procedure, and calculation and to facilitate the practical performance of equivalent analyses.
Doxorubicin-induced markers of myocardial autophagic signaling in sedentary and exercise trained animals
Authors: Smuder Ashley J. , Kavazis Andreas N. , Min Kisuk , Powers Scott K.
Published: May 2013

Doxorubicin (DOX) is an effective antitumor agent used in cancer treatment. However, its clinical use is limited due to cardiotoxicity. Indeed, the side effects of DOX are irreversible and include the development of cardiomyopathy and ultimately congestive heart failure. Although many studies have investigated the events leading to DOX-induced cardiotoxicity, the mechanisms responsible for DOX-induced cardiotoxicity remain unknown. In general, evidence suggests that DOX-induced cardiotoxicity is associated with an increased generation of reactive oxygen species and oxidative damage, leading to the activation of cellular proteolytic systems. In this regard, the autophagy/lysosomal proteolytic system is a constitutively active catabolic process that is responsible for the degradation of both organelles and cytosolic proteins. We tested the hypothesis that systemic DOX administration results in altered cardiac gene and protein expression of mediators of the autophagy/lysosomal system. Our results support this hypothesis, as DOX treatment increased both the mRNA and protein levels of numerous key autophagy genes. Because exercise training has been shown to be cardioprotective against DOX-induced damage, we also determined whether exercise training before DOX administration alters the expression of important components of the autophagy/lysosomal system in cardiac muscle. Our findings show that exercise training inhibits DOX-induced cardiac increases in autophagy signaling. Collectively, our results reveal that DOX administration promotes activation of the autophagy/lysosomal system pathway in the heart, and that endurance exercise training can be a cardioprotective intervention against myocardial DOX-induced toxicity.
Endocardial endothelium is a key determinant of force-frequency relationship in rat ventricular myocardium
Authors: Shen Xiaoxu , Tan Zhen , Zhong Xin , Tian Ye , Wang Xian , Yu Bo , Ramirez-Correa Genaro , Murphy Anne , Gabrielson Kathleen , Paolocci Nazareno , Gao Wei Dong
Published: May 2013

We tested the hypothesis that removing endocardial endothelium (EE) negatively impacts the force-frequency relationship (FFR) of ventricular myocardium and dissected the signaling that underlies this phenomenon. EE of rat trabeculae was selectively damaged by brief (<1 s) exposure to 0.1% Triton X-100. Force, intracellular Ca2+transient (iCa2+), and activity of protein kinase A (PKA) and protein kinase C (PKC) were determined. In control muscles, force and iCa2+increased as the stimulation frequency increased in steps of 0.5 Hz up to 3.0 Hz. However, EE-denuded (EED) muscles exhibited a markedly blunted FFR. Neither isoproterenol (ISO; 0.1–5 nmol/l) nor endothelin-1 (ET-1; 10–100 nmol/l) alone restored the slope of FFR in EED muscles. Intriguingly, however, a positive FFR was restored in EED preparations by combining low concentrations of ISO (0.1 nmol/l) and ET-1 (20 nmol/l). In intact muscles, PKA and PKC activity increased proportionally with the increase in frequency. This effect was completely lost in EED muscles. Again, combining ISO and ET-1 fully restored the frequency-dependent rise in PKA and PKC activity in EED muscles. In conclusion, selective damage of EE leads to significantly blunted FFR. A combination of low concentrations of ISO and ET-1 successfully restores FFR in EED muscles. The interdependence of ISO and ET-1 in this process indicates cross-talk between the β1-PKA and ET-1-PKC pathways for a normal (positive) FFR. The results also imply that dysfunction of EE and/or EE-myocyte coupling may contribute to flat (or even negative) FFR in heart failure.
First‐Principles Study on Stability and Magnetism of NimAln (m = 1–3, n = 1–9) Clusters
Authors: Zhang Xiao , Li Bao-Xing , Ma Zhi-wei , Gu Jiao-jiao
Published: May 2013

The investigation on the structures, stabilities, and magnetism of NimAln (m = 1–3, n = 1–9) clusters has been made by using first principles. We found some new ground‐state structures which had not been found before. These mixed species prefer to adopt three‐dimensional (3D) structures starting from four atoms. All the ground‐state structures for the Ni‐Al clusters are different from those of the corresponding pure Al clusters with the same number of atoms except for three atoms. The Mulliken population analysis shows that some charges transfer from the Al atoms to the Ni atoms. NiAln (n = odd number) cations, Ni2Al6 neutral, Ni2Al1 and Ni3Al cations and anions, and Ni3Al5 anion have the magnetic moments of 2 μB. The magnetic moments of NiAl4 and NiAl6 cluster neutrals and cations are 2 μB and 3 μB, respectively. All the other cluster neutrals and ions do not have any nontrivial magnetic moments. The 3d electrons in Ni atoms are mainly responsible for the magnetism of the mixed Ni‐Al clusters.
A Scientific Assessment of Sociodemographic Factors, Physical Activity Level, and Nutritional Knowledge as Determinants of Dietary Quality among Indo-Mauritian Women
Authors: Dunneram Yashvee , Jeewon Rajesh
Published: May 2013

A healthy diet is of particular concern throughout the life of women to avoid many chronic illnesses especially during their 30s to 50s. There are published data on dietary quality and its determinants among women, but there is a lack of similar data regarding women in Mauritius. This study aimed to investigate the association between age and dietary quality in relation to sociodemographic factors, physical activity level (PAL) and nutritional knowledge (NK). A survey-based study was conducted in 2012 among Indo-Mauritian women including 117 young (21.35±1.98), 160 reaching middle age (34.02±5.09) and 50 middle-aged (37.85±8.32). Validated questionnaires were used to elicit information on the determinants. A food frequency table consisting of 18 food items was used to assess dietary quality. Univariate and multivariate analyses were used to determine the association between various factors and dietary quality. The mean dietary score of middle-aged women (18.70±2.67) was closer to recommended dietary guidelines compared to young women (17.22±3.40), and women reaching middle age (17.55±3.29). Educational level, PAL, NK, and age were main determinants of dietary quality among Indo-Mauritian women (P<0.05). Younger women with low educational level, PAL, and NK are at risk of poor dietary quality.
The Fractional Carleson Measures on the Unit Ball ofℝn+1
Authors: Wang Dongfang , Ma Bolin
Published: May 2013

We construct a quantity in terms ofLpintegral of the Jacobian of a conformal self-map on the unit ball ofℝn+1. Then, we characterize the fractional Carleson measures on the unit ball by the quantity.
Some Results on Fuzzy Soft Topological Spaces
Authors: Gunduz (Aras) Cigdem , Bayramov Sadi
Published: May 2013

We introduce some important properties of fuzzy soft topological spaces. Furthermore, fuzzy soft continuous mapping, fuzzy soft open and fuzzy soft closed mappings, and fuzzy soft homeomorphism for fuzzy soft topological spaces are given and structural characteristics are discussed and studied.
Avirulent Toxoplasma gondii Generates Therapeutic Antitumor Immunity by Reversing Immunosuppression in the Ovarian Cancer Microenvironment
Authors: Baird Jason R. , Fox Barbara A. , Sanders Kiah L. , Lizotte Patrick H. , Cubillos-Ruiz Juan R. , Scarlett Uciane K. , Rutkowski Melanie R. , Conejo-Garcia Jose R. , Fiering Steven , Bzik David J.
Published: May 2013

Reversing tumor-associated immunosuppression seems necessary to stimulate effective therapeutic immunity against lethal epithelial tumors. Here, we show this goal can be addressed using cps, an avirulent, nonreplicating uracil auxotroph strain of the parasite Toxoplasma gondii (T. gondii), which preferentially invades immunosuppressive CD11c+ antigen-presenting cells in the ovarian carcinoma microenvironment. Tumor-associated CD11c+ cells invaded by cps were converted to immunostimulatory phenotypes, which expressed increased levels of the T-cell receptor costimulatory molecules CD80 and CD86. In response to cps treatment of the immunosuppressive ovarian tumor environment, CD11c+ cells regained the ability to efficiently cross-present antigen and prime CD8+ T-cell responses. Correspondingly, cps treatment markedly increased tumor antigen-specific responses by CD8+ T cells. Adoptive transfer experiments showed that these antitumor T-cell responses were effective in suppressing solid tumor development. Indeed, intraperitoneal cps treatment triggered rejection of established ID8-VegfA tumors, an aggressive xenograft model of ovarian carcinoma, also conferring a survival benefit in a related aggressive model (ID8-Defb29/Vegf-A). The therapeutic benefit of cps treatment relied on expression of IL-12, but it was unexpectedly independent of MyD88 signaling as well as immune experience with T. gondii. Taken together, our results establish that cps preferentially invades tumor-associated antigen-presenting cells and restores their ability to trigger potent antitumor CD8+ T-cell responses. Immunochemotherapeutic applications of cps might be broadly useful to reawaken natural immunity in the highly immunosuppressive microenvironment of most solid tumors. Cancer Res; 73(13); 3842–51. ©2013 AACR.
Genomic Profiling Defines Subtypes of Prostate Cancer with the Potential for Therapeutic Stratification
Authors: Schoenborn Jamie R. , Nelson Pete , Fang Min
Published: May 2013

The remarkable variation in prostate cancer clinical behavior represents an opportunity to identify and understand molecular features that can be used to stratify patients into clinical subgroups for more precise outcome prediction and treatment selection. Significant progress has been made in recent years in establishing the composition of genomic and epigenetic alterations in localized and advanced prostate cancers using array-based technologies and next-generation sequencing approaches. The results of these efforts shed new light on our understanding of this disease and point to subclasses of prostate cancer that exhibit distinct vulnerabilities to therapeutics. The goal of this review is to categorize the genomic data and, where available, corresponding expression, functional, or related therapeutic information, from recent large-scale and in-depth studies that show a new appreciation for the molecular complexity of this disease. We focus on how these results inform our growing understanding of the mechanisms that promote genetic instability, as well as routes by which specific genes and biologic pathways may serve as biomarkers or potential targets for new therapies. We summarize data that indicate the presence of genetic subgroups of prostate cancers and show the high level of intra- and intertumoral heterogeneity, as well as updated information on disseminated and circulating tumor cells. The integrated analysis of all types of genetic alterations that culminate in altering critical biologic pathways may serve as the impetus for developing new therapeutics, repurposing agents used currently for treating other malignancies, and stratifying early and advanced prostate cancers for appropriate interventions. Clin Cancer Res; 19(15); 4058–66. ©2013 AACR.
Stearoyl Co-A Desaturase 1 as a ccRCC Therapeutic Target: Death by Stress
Authors: Leung Janet Y. , Kim William Y.
Published: May 2013

There is a need for the discovery of novel therapeutic strategies to effectively treat advanced clear cell renal cell carcinoma (ccRCC). Inhibition of stearoyl-coA desaturase 1 (SCD1) in ccRCC reveals antitumor activity, independently and in synergy with mTOR inhibition. SCD1 may be a potential novel therapeutic target in treating ccRCC. Clin Cancer Res; 19(12); 3111–3. ©2013 AACR.
Novel Curcumin-Loaded Magnetic Nanoparticles for Pancreatic Cancer Treatment
Authors: Yallapu Murali M. , Ebeling Mara C. , Khan Sheema , Sundram Vasudha , Chauhan Neeraj , Gupta Brij K. , Puumala Susan E. , Jaggi Meena , Chauhan Subhash C.
Published: May 2013

Curcumin (CUR), a naturally occurring polyphenol derived from the root of Curcuma longa, has showed potent anticancer and cancer prevention activity in a variety of cancers. However, the clinical translation of CUR has been significantly hampered due to its extensive degradation, suboptimal pharmacokinetics, and poor bioavailability. To address these clinically relevant issues, we have developed a novel CUR-loaded magnetic nanoparticle (MNP-CUR) formulation. Herein, we have evaluated the in vitro and in vivo therapeutic efficacy of this novel MNP-CUR formulation in pancreatic cancer. Human pancreatic cancer cells (HPAF-II and Panc-1) exhibited efficient internalization of the MNP-CUR formulation in a dose-dependent manner. As a result, the MNP-CUR formulation effectively inhibited growth of HPAF-II and Panc-1 cells in cell proliferation and colony formation assays. The MNP-CUR formulation suppressed pancreatic tumor growth in an HPAF-II xenograft mouse model and improved the survival of mice by delaying tumor growth. The growth-inhibitory effect of MNP-CUR formulation correlated with the suppression of proliferating cell nuclear antigen (PCNA), B-cell lymphoma-extra large (Bcl-xL), induced myeloid leukemia cell differentiation protein (Mcl-1), cell surface–associated Mucin 1 (MUC1), collagen I, and enhanced membrane β-catenin expression. MNP-CUR formulation did not show any sign of hemotoxicity and was stable after incubation with human serum proteins. In addition, the MNP-CUR formulation improved serum bioavailability of CUR in mice up to 2.5-fold as compared with free CUR. Biodistribution studies show that a significant amount of MNP-CUR formulation was able to reach the pancreatic xenograft tumor(s), which suggests its clinical translational potential. In conclusion, this study suggests that our novel MNP-CUR formulation can be valuable for the treatment of pancreatic cancer. Mol Cancer Ther; 12(8); 1471–80. ©2013 AACR.
Dose-Response Association between Smoking and Atopic Eczema: Results from a Large Cross- Sectional Study in Adolescents
Authors: Graif Yael , German Larissa , Ifrah Anneke , Livne Irit , Shohat Tamy
Published: May 2013

Background: Tobacco smoking and exposure to environmental tobacco smoke (ETS) are known risk factors for asthma, but their association with atopic eczema is unclear. Objective: To investigate the association of smoking and exposure to ETS with prevalence of atopic eczema in a national sample of 13- to 14-year-olds in Israel. Methods: Cross-sectional study within the framework of the International Study on Asthma and Allergies in Childhood. Results: Complete data were available for 10,298 schoolchildren. Atopic eczema as well as asthma and allergic rhinitis were significantly more prevalent in smokers than nonsmokers. Multiple regression analysis revealed a dose-response association between smoking and atopic eczema compared to not smoking: occasional smokers, odds ratio (OR) = 1.6 (95% confidence interval (CI) = 1.2-2.3); daily smokers, OR = 2.2 (95% CI = 1.4-3.6). Exposure to ETS at home was significantly associated with asthma (OR = 1.25; 95% CI = 1.1-1.5) but not atopic eczema. Conclusions: The dose-response association between active smoking and atopic eczema in adolescents is a novel observation which deserves further consideration.
Diffusion Tensor Imaging in Idiopathic Parkinson's Disease and Multisystem Atrophy (Parkinsonian Type)
Authors: Cnyrim Christian Daniel , Kupsch Andreas , Ebersbach Georg , Hoffmann Karl-Titus
Published: May 2013

Background: Differentiation between Parkinson's disease (PD) and atypical Parkinson syndromes (AP) is usually based on clinical examination, but can be challenging especially at early stages of the diseases. Diffusion tensor imaging (DTI) allows for differentiation between PD and AP with good specificity. It is a promising tool for clinical application, but has not been elaborated completely with respect to methodology and validity. Objective: In this study we evaluated differences of the apparent diffusion coefficient (ADC) and fractional anisotropy (FA) within white brain matter between patients with PD and multisystem atrophy of the parkinsonian type (MSAp). Materials and Methods: DTI data of 9 PD and 9 MSAp patients were compared by means of a hypothesis-free whole-brain analysis algorithm (TBSS) focusing on changes within white matter. Results: We found significantly higher values of the ADC in the MSAp group in the anterior limb of the inner capsule, superior parts of the corona radiata, and lateral periputaminal white matter. Group differences in FA values were not significant. Conclusion: Changes of the ADC close to the putamen proved most consistent and seem to be promising for the ongoing clinical implementation of DTI for the differentiation of hypokinetic-rigid movement disorders.
Differential Effects of Central and Peripheral Fat Tissues on the Delayed Rectifier K+ Outward Currents in Cardiac Myocytes
Authors: Lee Kun-Tai , Tang Paul Wei-Hua , Tsai Wei-Chung , Liu I-Hsin , Yen Hsueh-Wei , Voon Wen-Chol , Wu Bin-Nan , Sheu Sheng-Hsiung , Lai Wen-Ter
Published: May 2013

Objectives: The amount of fat tissue is associated with an increasing incidence of cardiac arrhythmias. The purpose of this study was to investigate effects of adipocytokines from different body fat on delayed rectifier K+ outward currents (IK). Methods: H9c2 cells were treated with adipocytokine-free medium (the Adipo-free group) and with adipocytokines from epicardial (central fat group) and limb (peripheral fat group) rat fat tissues. IK, as well as expressions of Kv2.1 and Kv2.1 mRNA in H9c2 cells, were measured and compared between different groups. Results: IK measured in H9c2 cells immediately after treatment with adipocytokines were not significantly different from those treated with adipocytokine-free medium. After H9c2 cells were treated with adipocytokines for 18 h, IK were significantly decreased in the peripheral and central fat groups in comparison with the Adipo-free group. Compared with the peripheral fat group, IK were more significantly decreased in the central fat group. Expressions of Kv2.1 and Kv2.1 mRNA in H9c2 cells were not significantly different among the three groups. Conclusions: Adipocytokines significantly decreased IK in H9c2 cells, and IK was more prominently decreased by adipocytokines from epicardial fat than from limb fat tissues. The decrease in IK by adipocytokines may partially contribute to the mechanisms of arrhythmogenesis by fat tissues.
A Pharmacokinetic Study and Correlation with Clinical Response of Rufinamide in Infants with Epileptic Encephalopathies
Authors: la Marca Giancarlo , Rosati Anna , Falchi Melania , Malvagia Sabrina , Della Bona Maria Luisa , Pellacani Simona , Guerrini Renzo
Published: May 2013

Aim: To evaluate the relationship between the pharmacokinetic (PK) parameters and therapeutic and adverse effects of rufinamide (RUF) in children with epileptic encephalopathies (EE) aged <4 years. Methods: PK analysis was conducted at the steady state using a previously validated liquid chromatography tandem-mass spectrometric method in 15 children aged 6-42 months treated with RUF in add-on. Responders were defined as patients who achieved >50% decrease of seizures. Tolerability was evaluated by analysis of a parental report of adverse effects, a clinical examination and laboratory tests. Results: Maximum plasma concentration (47.40 ± 35.36 mg/l), average plasma concentration (39.94 ± 24.53 mg/l) and half-life (13.66 ± 4.43 h) were extremely variable and considerably higher than those reported in older children treated with the same dose regimen. At the last evaluation, 9 patients (60%) were responders. Conclusion: RUF is efficacious and is well tolerated in children with EE. Nonetheless, a correlation between dose, serum concentration and efficacy could not be demonstrated. The variability in measured concentrations may be related to polytherapy that is necessary for controlling seizures in this very severe form of epilepsy, in which the off-label use of RUF is justified.
Low Urine Vascular Endothelial Growth Factor Levels Are Associated with Mechanical Ventilation, Bronchopulmonary Dysplasia and Retinopathy of Prematurity
Authors: Levesque Bernadette M. , Kalish Leslie A. , Winston Abigail B. , Parad Richard B. , Hernandez-Diaz Sonia , Phillips Michele , Zolit Amy , Morey JoAnn , Gupta Munish , Mammoto Akiko , Ingber Donald E. , Van Marter Linda J.
Published: May 2013

Background: Organ-specific vascular endothelial growth factor (VEGF) expression is decreased during the pathogenesis of bronchopulmonary dysplasia (BPD) and retinopathy of prematurity (ROP) several weeks before either disease can be diagnosed. Early measurement of organ-specific tissue VEGF levels might allow identification of infants at high risk for these diseases, but is not clinically feasible. Urine VEGF is easily measured and useful in early diagnosis of several diseases. Objectives: Our aims were to assess the correlation of urine VEGF levels measured in the first postnatal month with subsequent BPD or ROP diagnosis and to determine whether various infant characteristics influence urine VEGF levels. Methods: 106 subjects born at <29 weeks' gestation and surviving to 36 weeks' postmenstrual age were selected from an existing database and biorepository. Urine VEGF and total protein were measured in 2-3 samples per subject. Results: Urine VEGF/protein levels increased by 72% per week (p < 0.0001) during the first postnatal month. In multivariable analysis controlling for postnatal age, lower VEGF/protein was associated with higher levels of mechanical respiratory support (p = 0.006), male gender (p = 0.001) and early sepsis (p = 0.003) but not with fraction of inspired oxygen. Lower urine VEGF/protein and mechanical ventilation were each associated with BPD and ROP. In analyses adjusted for respiratory support, lower urine VEGF/protein and ROP remained associated but urine VEGF/protein and BPD did not. Conclusions: Low urine VEGF/protein levels in the first postnatal month are associated with mechanical ventilation, BPD, and ROP.
Peritoneal Dialysis in Patients with Refractory Congestive Heart Failure: Potential Prognostic Factors
Authors: Kunin Margarita , Arad Michael , Dinour Dganit , Freimark Dov , Holtzman Eli J.
Published: May 2013

Background: Peritoneal dialysis (PD) is increasingly used for long-term management of refractory congestive heart failure (CHF). In this study, we investigated the outcome of patients with refractory CHF treated with PD, aiming to identify potential prognostic factors for long term-survival. Methods: This was a prospective observational study over a period of 42 months which included 37 refractory CHF patients. Results: Median survival on PD was 14 months (1-41 months). Long survivors had serum sodium >132 mEq/l (p < 0.001), serum albumin >3.2 g/dl (p < 0.001) and hospitalization rate <2 days per month a year before starting the treatment (p = 0.008). Patients in the lowest survival quartile had lower serum albumin (2.8 vs. 3.5 g/dl in longer survivors, p = 0.003) and serum sodium (126 vs. 137 mEq/l, p < 0.0001), higher serum leukocyte count (7,500 vs. 6,800/μl in long survivors, p = 0.033), higher glomerular filtration rate (39.4 vs. 29.9 ml/min/1.73 m2, p = 0.035), had more hospitalization before starting the treatment (3.4 vs. 1.9 days per month, p = 0.003) and lower estimated left ventricular mass index (113 vs. 137 g/m2, p = 0.035). Long-term survivors demonstrated significant improvement in the New York Heart Association functional class by a median of one class, reduced hospitalization rate by 55% and decrease in dependence on intravenous diuretics and vasoactive medications (73% drop in CHF day care visits during the first year of treatment). Conclusions: Survival of patients with refractory CHF treated with PD is highly variable. Serum sodium, serum albumin and hospitalization rate are important prognostic factors for long-term survival. Long survivors demonstrated improved functional status, reduced hospitalization and mortality rates.
A Simple Device Prevents Hysterotomy Extensions during Cesarean Delivery for Failed Second Stage of Labor
Authors: Barrier Breton F. , Allison Jana L. , Andelin Clark O. , Drobnis Erma Z.
Published: May 2013

Background/ Aims: During arrest of descent, maternal tissues conform to the fetal head, resulting in a suction-cup like effect during cesarean delivery. We hypothesize that breaking this suction might ease delivery. A novel device was designed for this purpose and tested in this series of 23 patients. Methods: University-based retrospective cohort feasibility study. Term pregnant women with second-stage labor arrest (n = 23) provided written consent for use of the experimental device, inserted vaginally prior to cesarean delivery. Delivering obstetricians rated device effectiveness. Following case collection, the presence of hysterotomy extensions in study patients was retrospectively compared with controls (n = 49) from the same study period. Results: On a 7-point Likert scale, consultant obstetricians rated overall device effectiveness as 6.0, and resident obstetricians rated it 6.3, consistent with a moderate improvement in ease of delivery. The device performed optimally at mid-pelvic stations (0 to +1), with no hysterotomy extensions (n = 0/17), which was significantly better than controls (n = 14/41, 34%, p < 0.01). Conclusion: A simple device prevented hysterotomy extension during second-stage cesarean delivery at 0 and +1 station. Obstetricians perceived that the device afforded a moderate improvement in delivery compared with previous deliveries in which the device was not used.
In vivo platelet activation and platelet hyperreactivity in abacavir-treated HIV-infected patients
Authors: Belfiori Barbara , Petito Eleonora , Guglielmini Giuseppe , Malincarne Lisa , Mezzasoma AnnaMaria , Sebastiano Manuela , Conti Valentina , Giannini Silvia , Bonora Stefano , Baldelli Franco , Falcinelli Emanuela , Francisci Daniela , Gresele Paolo
Published: May 2013

Abacavir (ABC) has been associated with ischaemic cardiovascular events in HIV-infected patients, but the pathogenic mechanisms are unknown. Aim of our study was to assess whether ABC induces in vivo platelet activation and ex vivo platelet hyper-reactivity. In a retrospective, case-control study, in vivo platelet activation markers were measured in 69 HIV-infected patients, before starting therapy and after 6–12 months of either ABC (n=35) or tenofovir (TDF) (n=34), and compared with those from 20 untreated HIV-infected patients. A subgroup of patients was restudied after 28–34 months for ex vivo platelet reactivity. In vivo platelet activation markers were assessed by ELISA or flow cytometry, ex vivo platelet reactivity by light transmission aggregometry (LTA) and PFA-100®. The in vitro effects of the ABC metabolite, carbovir triphosphate, on aggregation and intra-platelet cGMP were also studied. sPLA2, sPsel and sGPV increased significantly 6–12 months after the beginning of ABC, but not of TDF or of no treatment. Ex vivo platelet function studies showed enhanced LTA, shorter PFA-100® C/ADP closure time and enhanced platelet expression of P-sel and CD40L in the ABC group. The intake of ABC blunted the increase of intraplatelet cGMP induced by nitric oxide (NO) and acutely enhanced collagen-induced aggregation. Preincubation of control platelets with carbovir triphosphate in vitro enhanced platelet aggregation and blunted NO-induced cGMP elevation. In conclusion, treatment with ABC enhances in vivo platelet activation and induces platelet hyperreactivity by blunting the inhibitory effects of NO on platelets. These effects may lead to an increase of ischaemic cardiovascular events.
Identification and characterisation of mutations associated with von Willebrand disease in a Turkish patient cohort
Authors: Abuzenadah Adel , Cartwright Ashley , Al-Shammari Nawal , Coyle Rachael , Eckert Michaela , Al-Buhairan Ahlam , Messenger Sarah , Budde Ulrich , Gürsel Türkiz , Ingerslev Jørgen , Peake Ian , Goodeve Anne , Hampshire Daniel
Published: May 2013

Several cohort studies have investigated the molecular basis of von Willebrand disease (VWD); however, these have mostly focused on European and North American populations. This study aimed to investigate mutation spectrum in 26 index cases (IC) from Turkey diagnosed with all three VWD types, the majority (73%) with parents who were knowingly related. IC were screened for mutations using multiplex ligation-dependent probe amplification and analysis of all von Willebrand factor gene (VWF) exons and exon/intron boundaries. Selected missense mutations were expressed in vitro. Candidate VWF mutations were identified in 25 of 26 IC and included propeptide missense mutations in four IC (two resulting in type 1 and two in recessive 2A), all influencing VWF expression in vitro. Four missense mutations, a nonsense mutation and a small in-frame insertion resulting in type 2A were also identified. Of 15 type 3 VWD IC, 13 were homozygous and two compound heterozygous for 14 candidate mutations predicted to result in lack of expression and two propeptide missense changes. Identification of intronic breakpoints of an exon 17–18 deletion suggested that the mutation resulted from non-homologous end joining. This study provides further insight into the pathogenesis of VWD in a population with a high degree of consanguineous partnerships.