bluuebunny/crossref_metadata_2025 huggingface dataset:
Social Exclusion and Economic Growth: An Empirical Investigation in European Economies
Authors: Dell'Anno Roberto , Amendola Adalgiso
Published: December 2013

The aims of this article are to propose an overall index of social exclusion and to analyze its relationship with economic growth in European countries. We approach social exclusion as a multidimensional phenomenon by a three‐mode principal components analysis (Tucker3 model). This method is applied to estimate an indicator of social exclusion for 28 European countries between 1995 and 2010. The empirical evidence shows that in the short run: (1) Granger causality runs one way from social exclusion to economic growth and not the other way; (2) countries with a higher level of social exclusion have higher growth rates of realGDPper capita; and (3) social exclusion has a larger effect than income inequality on economic growth. The policy implication of our analysis is that social inclusion is not a source of economic growth in the short term.
Design and Control of an Magnetic Resonance Compatible Precision Pneumatic Active Cannula Robot
Authors: Comber David B. , Barth Eric J. , Webster Robert J.
Published: December 2013

The versatile uses and excellent soft tissue distinction afforded by magnetic resonance imaging (MRI) has led to the development of many MR-compatible devices for MRI-guided interventions. This paper presents a fully pneumatic MR-compatible robotic platform designed for neurosurgical interventions. Actuated by nonmagnetic pneumatic piston-cylinders, the robotic platform manipulates a five degree-of-freedom active cannula designed for deep brain interventions. Long lines of tubing connect the cylinders to remotely located pressure sensors and valves, and MRI-compatible optical sensors mounted on the robot provide the robot joint positions. A robust, nonlinear, model-based controller precisely translates and rotates the robot joints, with mean steady-state errors of 0.032 mm and 0.447 deg, respectively. MRI-compatibility testing in a 3-Tesla closed-bore scanner has shown that the robot has no impact on the signal-to-noise ratio, and that geometric distortion remains within recommended calibration limits for the scanner. These results demonstrate that pneumatic actuation is a promising solution for neurosurgical interventions that either require or can benefit from submillimeter precision. Additionally, this paper provides a detailed solution to the control problems imposed by severe nonlinearities in the pneumatic system, which has not previously been discussed in the context of MR-compatible devices.
Synthesis and Characterization of Nafion-ZrOH-CaO Hybrid Membrane for Proton Exchange Membrane Fuel Cell
Authors: Mazinani Vahid , Tabaian SeyedHadi , Rezaei Milad , Mallahi Mahdiyeh , Mohammadijoo Mohsen , Omidvar Hamid
Published: December 2013

Nafion-CaO, Nafion-ZrOH, and Nafion-CaO-ZrOH membranes are fabricated in order to improve proton conductivity, thermal stability, and mechanical properties as well as decrease methanol crossover in direct methanol fuel cells. The ion exchange method is utilized to incorporate Ca and Zr into Nafion membranes. Prepared membranes are characterized by using absorption transmission reflectance (ATR) and energy dispersive X-ray spectroscopy (EDS) techniques. Methanol crossover decreases significantly for all fabricated membranes. Nafion-CaO and Nafion-CaO-ZrOH membranes exhibit a 10 and 6 time increase in proton conductivity compared to Nafion (0.08 Scm–1), while the proton conductivity of Nafion-ZrOH decreases. The elastic modulus enhance from 48 MPa for Nafion to 60, 78, and 90 MPa for Nafion-CaO, Nafion-ZrOH, and Nafion-CaO-ZrOH membranes. In addition, the thermal stability of Nafion (360 °C) increases to 407, 457, and 470 °C for fabricated membranes.
DragonFlex Smart Steerable Laparoscopic Instrument
Authors: Jelínek Filip , Pessers Rob , Breedveld Paul
Published: December 2013

Despite its success, e.g., in prostatectomy, da Vinci's steerable grasper EndoWrist from Intuitive Surgical has a complex design prone to steel cable fatigue, potential sterilization issues and high associated costs, all of which insinuate a need for an alternative. The aim of this paper is to demonstrate a design of a structurally simple handheld steerable laparoscopic grasping forceps free from cable fatigue, while attaining sufficient bending stiffness for surgery and improving on EndoWrist's maneuverability and dimensions. Having equal joint functionality to EndoWrist, DragonFlex's instrument tip contains only four parts, driven and bound by two cables mechanically fixed in the handle. Two orthogonal planar joints feature an innovative rolling link mechanism allowing the cables to follow circular arc profiles of a diameter 1.5 times larger than the width of the instrument shaft. Besides maximizing the cable lifespan, the rolling link was designed to equalize the force requirements on both cables throughout joint rotation, making the handling fluid and effortless. The smart joint design and stacked instrument construction enable control of seven degrees of freedom by only two cables and seven instrument components in tip, shaft and handgrip altogether. Two DragonFlex prototypes were developed by means of additive manufacturing technology, allowing grasping and omnidirectional steering over ±90 deg, exhibiting promisingly high bending stiffness and featuring extreme simplicity at 5 mm dimensions. DragonFlex concept sheds new light on the possibilities of additive manufacturing of surgical instruments, allowing for a feature-packed design, simple assembly, suitability for disposable use and potential MRI compatibility.
Draft Genome Sequences of Elizabethkingia anophelis Strains R26
T
and Ag1 from the Midgut of the Malaria Mosquito Anopheles gambiae
Authors: Kukutla Phanidhar , Lindberg Bo G. , Pei Dong , Rayl Melanie , Yu Wanqin , Steritz Matthew , Faye Ingrid , Xu Jiannong
Published: December 2013

Elizabethkingia anophelis
is a species in the family
Flavobacteriaceae
. It is a dominant resident in the mosquito gut and also a human pathogen. We present the draft genome sequences of two strains of
E. anophelis
, R26
T
and Ag1, which were isolated from the midgut of the malaria mosquito
Anopheles gambiae
.
Detection of angiographically occult, ruptured cerebral aneurysms: case series and literature review
Authors: Chen Michael
Published: December 2013

Background

Ruptured and thrombosed cerebral aneurysms pose a risk for rebleeding that may go undetected because they are angiographically occult. The presence of multiple aneurysms may further complicate efforts in accurately identifying the true source because their treatment may circumvent further necessary investigations.

Methods

This case series and literature review illustrates the background and clinical features of ruptured thrombosed cerebral aneurysms.

Results

Thrombosed ruptured cerebral aneurysms have several common anatomic and physiologic mechanisms for their occurrence. They may evade detection if not considered part of a diligent thorough approach that includes careful analysis of the pattern of initial bleeding on non-contrast head CT scan.

Conclusions

Despite negative angiographic studies, and even when multiple cerebral aneurysms are present, diffuse subrachnoid hemorrhage may still warrant further investigation.
Nonrelativistic and relativistic bound state solutions of the molecular Tietz potential via the improved asymptotic iteration method
Authors: Yahya W.A. , Issa K. , Falaye B.J. , Oyewumi K.J.
Published: December 2013

We have obtained the approximate analytical solutions of the relativistic and nonrelativistic molecular Tietz potential using the improved asymptotic iteration method. By approximating the centrifugal term through the Greene–Aldrich approximation scheme, we have obtained the energy eigenvalues and wave functions for all orbital quantum numbers [Formula: see text]. Where necessary, we made comparison with the result obtained previously in the literature. The relative closeness of the two results reveal the accuracy of the method presented in this study. We proceed further to obtain the rotational-vibrational energy spectrum for some diatomic molecules. These molecules are CO, HCl, H2, and LiH. We have also obtained the relativistic bound state solution of the Klein−Gordon equation with this potential. In the nonrelativistic limits, our result converges to that of the Schrödinger system.
PREDICTIONS FOR $B \to \tau \bar{\mu} + \mu \bar{\tau}$
Authors: BOUBAA DRIS , DATTA ALAKABHA , DURAISAMY MURUGESWARAN , KHALIL SHAABAN
Published: December 2013

The observation of [Formula: see text] at present experiments would be a clear sign of new physics. In this paper, we calculate this process in an extended Higgs sector framework where the decay is mediated by the exchange of spin zero particle with flavor changing neutral current couplings. If we identify the scalar with the newly discovered state at LHC with a mass ~125 GeV then we find that, after imposing all experimental constraints, the [Formula: see text] can be as high as ~10-6 and [Formula: see text] can be as high as ~10-7. We also calculate this process in the minimal supersymmetric standard model and find the [Formula: see text] is typically of the order ~10-8.
PHASE TRANSITION AND THERMODYNAMIC PROPERTIES OF MAGNESIUM FLUORIDE BY FIRST PRINCIPLES
Authors: ZHANG TIAN , CHENG YAN , LV ZHEN-LONG , JI GUANG-FU , GONG MIN
Published: December 2013

The structural stabilities, phase transitions and thermodynamic properties of MgF 2 under high pressure and temperature are investigated by first-principles calculations based on plane-wave pseudopotential density functional theory method within the local density approximation. The calculated lattice parameters of MgF 2 in all four phases under zero pressure and zero temperature are in good agreement with the existing experimental data and other theoretical results. Our results demonstrate that MgF 2 undergoes a series of structural phase transitions from rutile (P42/mnm)→ CaCl 2-type (Pnnm)→ modified fluorite (Pa-3)→ cotunnite (Pnam) under high pressure and the obtained transition pressures are in fairly good agreement with the experimental results. The temperature-dependent volume and thermodynamic properties of MgF 2 in the rutile phase at 0 GPa are presented and the thermodynamic properties of MgF 2 in the rutile, CaCl 2-type, modified fluorite and cotunnite phases at 300 K are also predicted using the quasi-harmonic approximation model (QHA) and the quasi-harmonic Debye model (QHD), respectively. Moreover, the partial density of states and the electronic density of the four phases under the phase transition are also investigated.
BEFORE THE BANG
Authors: BISWAS TIRTHABIR
Published: December 2013

While inflation has been an extremely successful cosmological paradigm, almost certainly something have had to have happened before it began. Can the pre-inflationary phase be of any theoretical or phenomenological significance? Could Quantum Gravity have played any interesting role in this story? These are some of the questions we want to explore in this essay written for the Gravity Research Foundation 2013 "Awards for Essays on Gravitation" competition.
Alignment of Carbon Nanotubes: An Approach to Modulate Cell Orientation and Asymmetry
Authors: Cheng Qingsu , Harris Greg M. , Blais Marc-Olivier , Rutledge Katy , Jabbarzadeh Ehsan
Published: December 2013

Stem cells offer a promising tool in tissue engineering strategies, as their differentiated derivatives can be used to reconstruct most biological tissues. These approaches rely on controlling the biophysical cues that tune the ultimate fate of cells. In this context, significant effort has gone to parse out the role of conflicting matrix-elicited signals (e.g., topography and elasticity) in regulation of macroscopic characteristics of cells (e.g., shape and polarity). A critical hurdle, however, lies in our inability to recapitulate the nanoscale spatiotemporal pattern of these signals. The study presented in this manuscript took an initial step to overcome this challenge by developing a carbon nanotube (CNT)-based substrate for nanoresolution control of focal adhesion formation and cell alignment. The utility of this system was studied using human umbilical vascular endothelial cells (HUVECs) and human embryonic stem cells (hESCs) at a single cell level. Our results demonstrated the ability to control cell orientation by merely controlling the alignment of focal adhesions at a nanoscale size. Our long-term vision is to use these nanoengineered substrates to mimic cell orientation in earlier development and explore the role of polarity in asymmetric division and lineage specification of dividing cells.
Polaronic behavior of La0.8Te0.2MnO3
Authors: Filipič Cene , Levstik Adrijan
Published: December 2013

We have analyzed recently published data of the ac electrical conductivity and dielectric constant in La 0.8 Te 0.2 MnO 3 (LTMO), and at temperatures below 500 K both quantities follow the universal dielectric response (UDR) typical of hopping or tunneling of localized charge carriers. A detailed analysis of the temperature dependence of the UDR parameter s in terms of the theoretical model for tunneling of small polarons revealed that below 500 K, this mechanism governs the charge transport in LTMO system.
Effects of zinc substitution on the dielectric properties ofCa5Nb4TiO17microwave ceramics
Authors: Li Chunchun , Wei Xiaoyong , Yan Haixue , Reece Michael J.
Published: December 2013

Ca5-xZnxNb4TiO17ceramics with 0 ≤ x ≤ 0.4 were prepared through a solid-state reaction method. Effects of zinc substitution on sintering behavior and microwave dielectric properties of Ca5Nb4TiO17ceramics were investigated. The sintering temperature was significantly lowered from 1480°C for pure Ca5Nb4TiO17to 1260°C for x = 0.4. The microwave dielectric properties are strongly correlated with the composition. It is worth noting that the temperature coefficient of resonant frequency (τf) displays a tendency toward positive value, ranging from −126.4 ppm/°C to −8.6 ppm/°C. A temperature stable microwave ceramic with dielectric constant of 52 and Q × f value of 9937 GHz is achieved at x = 0.4 and is a potential candidate for application as cores in dielectrically loaded antennas.
Applied Animal Genomics: Results from the Field
Authors: Van Eenennaam Alison L. , Weigel Kent A. , Young Amy E. , Cleveland Matthew A. , Dekkers Jack C.M.
Published: December 2013

Genomic selection (GS) is the use of statistical methods to estimate the genetic merit of a genotyped animal based on prediction equations derived from large ancestral populations with both phenotypes and genotypes. It has revolutionized the dairy cattle breeding industry and has been implemented with varying degrees of success in other animal breeding programs, including swine, poultry, and beef cattle. The findings of empirical field studies applying GS to the breeding sectors of these main animal protein industries are reviewed. Several translational considerations must be addressed before implementing GS in genetic improvement programs. These include determining and obtaining economically relevant phenotypes and determining the optimal size of the training population, cost-effective genotyping strategies, the practicality of field implementation, and the relative costs versus the benefits of the realized rate of genetic gain. GS may additionally change the optimal breeding scheme design, and studies that address this consideration are also reviewed briefly.
Antidepressant Use in Pregnant and Postpartum Women
Authors: Yonkers Kimberly A. , Blackwell Katherine A. , Glover Janis , Forray Ariadna
Published: December 2013

Women in their reproductive years are at risk of experiencing depressive and anxiety disorders. As such, it is likely that pregnant women will undergo treatment with antidepressants. We review the risk of adverse birth outcomes and neonatal complications subsequent to antidepressant use in pregnancy. An inconsistent literature shows that antidepressant exposure is associated with shortened gestations and diminished fetal growth; these effects are small. Transitory neonatal signs are seen in some neonates after exposure to antidepressants in utero. No specific pattern of malformations has been consistently associated with antidepressants, with the possible exception of paroxetine and cardiac malformations. There is inconclusive evidence of a link between antidepressants in late pregnancy and persistent pulmonary hypertension in the newborn. Extensive study finds that antidepressants cannot be considered major teratogens. It is likely that confounding factors contribute to a number of the adverse effects found to be associated with antidepressant use in pregnancy.
c-Fos mediates repression of the apical sodium-dependent bile acid transporter by fibroblast growth factor-19 in mice
Authors: Ghosh Ayantika , Chen Frank , Banerjee Swati , Xu Ming , Shneider Benjamin L.
Published: December 2013

Fibroblast growth factor-19 (FGF-19), a bile acid-responsive enterokine, is secreted by the ileum and regulates a variety of metabolic processes. These studies examined the signal transduction pathways operant in FGF-19-mediated repression of the apical sodium-dependent bile acid transporter (ASBT). Responses to FGF-19 were assessed in Caco-2 and CT-26 cells and in mice where c- fos was conditionally silenced in the intestine by a cre-lox strategy. FGF-19 treatment of Caco-2 cells or wild-type mice led to a significant reduction in ASBT protein expression and enhanced phosphorylation of extracellular signaling kinase 1/2 (ERK1/2), c-Fos, and c-Jun. FGF-19 treatment of Caco-2 cells led to a reduction in activity of the human ASBT promoter and this repression could be blocked by treatment with a mitogen-activated protein kinase/ERK kinase (MEK1/2) inhibitor or by silencing jun kinase 1, jun kinase 2, c- fos, or c- jun. Site directed mutagenesis of a c- fos binding element in the ASBT promoter blocked FGF-19-mediated repression in luciferase reporter constructs. ASBT promoter activity was repressed by FGF-19 in CT-26 cells and this repression could be reduced by MEK1/2 inhibition or silencing c- fos. FGF-19-mediated repression of ASBT protein expression was abrogated in mice where c- fos was conditionally silenced in the intestine. In contrast, ASBT was repressed in the c-Fos expressing gallbladders of the same mice. The studies demonstrate that FGF-19 represses the expression of ASBT in the ileum and gallbladder via a signal transduction pathway involving MEK1/2, ERK1/2, JNK1, JNK2, and c-Fos.
Quantification of regional fractional ventilation in human subjects by measurement of hyperpolarized3He washout with 2D and 3D MRI
Authors: Horn Felix C. , Deppe Martin H. , Marshall Helen , Parra-Robles Juan , Wild Jim M.
Published: December 2013

Multiple-breath washout hyperpolarized3He MRI was used to calculate regional parametric images of fractional ventilation ( r) as the ratio of fresh gas entering a volume unit to the total end inspiratory volume of the unit. Using a single dose of inhaled hyperpolarized gas and a total acquisition time of under 1 min, gas washout was measured by dynamic acquisitions during successive breaths with a fixed delay. A two-dimensional (2D) imaging protocol was investigated in four healthy subjects in the supine position, and in a second protocol the capability of extending the washout imaging to a three-dimensional (3D) acquisition covering the whole lungs was tested. During both protocols, subjects were breathing comfortably, only restricted by synchronization of breathing to the sequence timings. The 3D protocol was also successfully tested on one patient with cystic fibrosis. Mean r values from each volunteer were compared with global gas volume turnover, as calculated from flow measurement at the mouth divided by total lung volume (from MRI images), and a significant correlation ( r = 0.74, P < 0.05) was found. The effects of gravity on R were investigated, and an average decrease in r of 5.5%/cm (Δ r = 0.016 ± 0.006 cm−1) from posterior to anterior was found in the right lung. Intersubject reproducibility of r imaging with the 2D and 3D protocol was tested, and a significant correlation between repeated experiments was found in a pixel-by-pixel comparison. The proposed methods can be used to measure r on a regional basis.
Intravenous phentolamine abolishes coronary vasoconstriction in response to mild central hypovolemia
Authors: Gao Zhaohui , Muller Matthew D. , Sinoway Lawrence I. , Leuenberger Urs A.
Published: December 2013

Animal studies indicate alpha-adrenergic coronary vasoconstriction helps maintain left ventricular function during physiological stress. Whether this process occurs in humans is unknown. In the current study, we used transthoracic Doppler echocardiography to test the effect of lower body negative pressure (LBNP) on coronary blood flow velocity (CBV, left anterior descending coronary artery) and myocardial function in eight young healthy subjects before and after systemic infusion of phentolamine, a nonselective alpha blocker. Heart rate (HR) and blood pressure (BP) were monitored on a beat-by-beat basis. Peak diastolic CBV and myocardial systolic and diastolic tissue velocities (Sm and Em), were quantified at baseline, and at −5 mmHg, −10 mmHg, and −15 mmHg LBNP. Coronary vascular resistance index (CVRI) was calculated as the quotient of diastolic BP and CBV. Phentolamine reduced baseline diastolic BP and increased HR but did not affect the reflex adjustments to LBNP. The reduction in CBV due to LBNP was blunted by phentolamine at −10 mmHg and −15 mmHg. Importantly, the increase in CVRI (i.e., coronary vasoconstriction) was abolished by phentolamine at −5 mmHg (0.21 ± 0.06 vs. 0.83 ± 0.13), −10 mmHg (0.24 ± 0.03 vs. 1.68 ± 0.31), and −15 mmHg (0.27 ± 0.10 vs. 2.34 ± 0.43). These data indicate that alpha-adrenergic coronary vasoconstriction is present during low levels of LBNP. With alpha blockade, more coronary flow is needed to maintain cardiac function. Our data suggest that alpha-adrenergic tone enhances coronary flow efficiency, presumably by redistributing flow from the epicardium to the endocardium.
Deletion of Cysteine-Cysteine Receptor 7 Promotes Fibrotic Injury in Experimental Post-Thrombotic Vein Wall Remodeling
Authors: Laser Adriana , Elfline Megan , Luke Cathy , Slack Dallas , Shah Anuj , Sood Vikram , Deatrick Barry , McEvoy Brendan , Ostra Carson , Comerota Anthony , Kunkel Steven , Hogaboam Cory , Henke Peter K.
Published: December 2013

Objective—

Deep vein thrombosis (VT) can result in vein wall injury, which clinically manifests as post-thrombotic syndrome. Postinjury fibrosis may be modulated in part through cellular cysteine-cysteine receptor 7 (CCR7)–mediated events. We tested the hypothesis that late vein wall fibrotic remodeling is dependent on CCR7.

Approach and Results—

CCR7
−/−
and C57BL/6 wild-type mice had inferior vena cava VT induced by nonstasis or stasis mechanisms. In both models, VT size was largest at day 1 and trended down by day 21, and CCR7
+
cells peaked at day 8 in wild-type mice. No significant differences in VT resolution were found in CCR7
−/−
as compared with wild type in either model. In the nonstasis VT model, vein wall changes consistent with fibrotic injury were evidenced by significant increases in collagen I, III, matrix metalloproteinase 2, and transforming growth factor-β gene expression, increases in α-smooth muscle actin and fibroblast specific protein-1 antigen, and total collagen at 8 days. Correspondingly, SM22α and fibroblast specific protein-1, but not DDR2
+
cells, were increased at 8 days. Early wild-type thrombus exposure inhibited profibrotic gene expression in CCR7
−/−
in ex vivo vein wall culture. Bone marrow chimera experiments further showed that circulating CCR7
+
leukocytes partially rescued midterm profibrotic changes in CCR7
−/−
mice. In human histological sections of chronic thrombosed femoral veins, CCR7
+
cells were present in the fibrotic areas.

Conclusions—

Post-thrombotic vein wall remodeling is impaired in CCR7
−/−
mice, with a profibrotic phenotype, is dependent on the thrombotic mechanism, and is mediated by circulating CCR7
+
cells. Unlike other postinjury fibrotic responses, CCR7
+
signaling may be important for positive vein wall remodeling after VT.
Macro-evolutionary trade-offs as the basis for the distribution of European bats
Authors: Haarsma Anne-Jifke , Siepel Henk
Published: December 2013

Bats have a high species diversity and show unique ecological traits. The distribution patterns of European bat species differ between species. In this paper we seek to explain which life history traits, or interrelations between traits, can best explain observed differences in the distribution patterns of bats. Traits are interrelated and sometimes involve trade-offs, implying that a change in one trait may have positive or negative consequences for other traits. We describe the main morphological, physiological and ecological adaptations of insectivorous European bat species. We make pair-wise relations between traits, indicating the interrelations between traits, in terms of possible trade-offs. We relate the consequences of these trade-offs to the distribution maps of the species, focusing on the traits relevant for southern and northern distribution limits. We found coarse patterns that might indicate the distribution of related species are a consequence of their physiological, morphological and ecological adaptations and the interrelations between these adaptations. Hence, we think life-history strategies can be used to explain differences in species distribution. The method presented in this paper might also be useful for other mammal groups with a high species diversity, such as Rodentia and Soricidae.
Postprocessing of Ensemble Weather Forecasts Using a Stochastic Weather Generator
Authors: Chen Jie , Brissette François P. , Li Zhi
Published: December 2013

This study proposes a new statistical method for postprocessing ensemble weather forecasts using a stochastic weather generator. Key parameters of the weather generator were linked to the ensemble forecast means for both precipitation and temperature, allowing the generation of an infinite number of daily times series that are fully coherent with the ensemble weather forecast. This method was verified through postprocessing reforecast datasets derived from the Global Forecast System (GFS) for forecast leads ranging between 1 and 7 days over two Canadian watersheds in the Province of Quebec. The calibration of the ensemble weather forecasts was based on a cross-validation approach that leaves one year out for validation and uses the remaining years for training the model. The proposed method was compared with a simple bias correction method for ensemble precipitation and temperature forecasts using a set of deterministic and probabilistic metrics. The results show underdispersion and biases for the raw GFS ensemble weather forecasts, which indicated that they were poorly calibrated. The proposed method significantly increased the predictive power of ensemble weather forecasts for forecast leads ranging between 1 and 7 days, and was consistently better than the bias correction method. The ability to generate discrete, autocorrelated daily time series leads to ensemble weather forecasts’ straightforward use in forecasting models commonly used in the fields of hydrology or agriculture. This study further indicates that the calibration of ensemble forecasts for a period up to one week is reasonable for precipitation, and for temperature it could be reasonable for another week.
Iron and hepcidin: a story of recycling and balance
Authors: Camaschella Clara
Published: December 2013

To avoid iron deficiency and overload, iron availability is tightly regulated at both the cellular and systemic levels. The liver peptide hepcidin controls iron flux to plasma from enterocytes and macrophages through degradation of the cellular iron exporter ferroportin. The hepcidin-ferroportin axis is essential to maintaining iron homeostasis. Genetic inactivation of proteins of the hepcidin-activating pathway causes iron overload of varying severity in human and mice. Hepcidin insufficiency and increased iron absorption are also characteristic of anemia due to ineffective erythropoiesis in which, despite high total body iron, hepcidin is suppressed by the high erythropoietic activity, worsening both iron overload and anemia in a vicious cycle. Hepcidin excess resulting from genetic inactivation of a hepcidin inhibitor, the transmembrane protease serine 6 (TMPRSS6) leads to a form of iron deficiency refractory to oral iron. Increased hepcidin explains the iron sequestration and iron-restricted erythropoiesis of anemia associated with chronic inflammatory diseases. In mice, deletion of TMPRSS6 in vivo has profound effects on the iron phenotype of hemochromatosis and beta-thalassemia. Hepcidin manipulation to restrict iron is a successful strategy to improve erythropoiesis in thalassemia, as shown clearly in preclinical studies targeting TMPRSS6; attempts to control anemia of chronic diseases by antagonizing the hepcidin effect are ongoing. Finally, the metabolic pathways identified from iron disorders are now being explored in other human pathologic conditions, including cancer.
New immune strategies for the treatment of acute lymphoblastic leukemia: antibodies and chimeric antigen receptors
Authors: Advani Anjali S.
Published: December 2013

The prognosis of adult acute lymphoblastic leukemia (ALL) remains poor and novel treatment strategies are needed. Antibody-based therapies represent such an approach. ALL cells express various surface antigens that are targets for monoclonal antibodies. This review focuses on 4 major classes of antibody therapy: (1) naked antibodies, (2) T-cell-engaging bispecific single-chain antibodies, (3) immunoconjugates/immunotoxins, and (4) chimeric antigen receptors. Preclinical and clinical data are reviewed. This area of research represents an exciting new approach to help improve the outcome of this disease. Several clinical trials are currently incorporating this therapy in the treatment of newly diagnosed and relapsed adult ALL patients.
Signaling the end of chronic lymphocytic leukemia: new frontline treatment strategies
Authors: Hallek Michael
Published: December 2013

The management of chronic lymphocytic leukemia (CLL) is undergoing profound changes. Several new drugs have been approved for CLL treatment (fludarabine, bendamustine, and the monoclonal antibodies alemtuzumab, rituximab, and ofatumumab) and many more drugs are in advanced clinical development to be approved for this disease. In addition, the extreme heterogeneity of the clinical course and our improved ability to foresee the prognosis of this leukemia by the use of clinical, biological, and genetic parameters now allow us to characterize patients with a very mild onset and course, an intermediate prognosis, or a very aggressive course with high-risk leukemia. Therefore, it becomes increasingly challenging to select the right treatment strategy for each condition. This article summarizes the currently available diagnostic and therapeutic tools and gives an integrated recommendation of how to manage CLL in 2013. Moreover, I propose a strategy how we might integrate the novel agents for CLL therapy into sequential treatment approaches in the near future.
Immunotherapeutic strategies including transplantation: eradication of disease
Authors: Gribben John G. , Riches John C.
Published: December 2013

Although there have been recent advances with targeted therapies in chronic lymphocytic leukemia (CLL), chemoimmunotherapy remains the treatment of choice; however, this approach is not curative. A key feature of CLL is that it induces a state of immunosuppression, causing increased susceptibility to infections and failure of an antitumor immune response, often worsened by the immunosuppressive effect of treatment. Because of its improved specificity, immunotherapy potentially offers a way out of this dilemma. Allogeneic stem cell transplantation remains the only curative option, but is hampered by the toxicity of GVHD. After many years of promise but little reward, many other immunotherapeutic approaches are now in transition to the clinical setting. Clinical trials including CLL vaccines, CXCR4 antagonists, and adoptive cellular immunotherapies such as chimeric antigen receptor–modified T cells, CD40 ligand gene therapy, and the immunomodulatory drug lenalidomide are ongoing. Results to date suggest that immunotherapeutic approaches for the treatment of CLL might finally be fulfilling their promise.
Update on current monitoring recommendations in chronic myeloid leukemia: practical points for clinical practice
Authors: Oehler Vivian G.
Published: December 2013

Excellent therapeutic options exist for the treatment of chronic-phase chronic myeloid leukemia (CML) patients. Therefore, managing CML patients has become a more common practice for many physicians. Most chronic-phase CML patients achieve durable cytogenetic and molecular responses on first-line tyrosine kinase inhibitor therapy. However, careful monitoring and assessment of adherence are essential for successful outcomes and to identify patients at risk for failing therapy. The European LeukemiaNet and National Comprehensive Cancer Network provide guidance and strategies for monitoring and managing patients treated with TKIs. These recommendations continue to evolve as approved treatment options expand to include second- and third-generation tyrosine kinase inhibitors. How measurements of response are defined and data supporting recent recommended changes to monitoring are reviewed here. These changes include increasing recognition of the importance of early response. The relevance of achieving deep molecular responses will also be addressed.
Drug discovery in rare indications: opportunities and challenges
Authors: Richon Victoria M.
Published: December 2013

Over the past decade, the number of new therapies developed for the treatment of rare diseases continues to increase. The most rapid growth has been in the development of new drugs for oncology indications. One focus in drug discovery for oncology indications is the development of targeted therapies for select patient subgroups characterized by genetic alterations. The identification of these patient subgroups has increased in the past decade and has resulted in a corresponding increase in the development of new drugs for genetically defined patient subgroups. As an example of the development of new therapeutics for rare indications, I describe here the drug discovery efforts leading to the development of DOT1L inhibitors for the treatment of MLL-rearranged leukemia.
Core-binding factor acute myeloid leukemia: can we improve on HiDAC consolidation?
Authors: Paschka Peter , Döhner Konstanze
Published: December 2013

Acute myeloid leukemia (AML) with t(8;21) or inv(16) is commonly referred to as core-binding factor AML (CBF-AML). The incorporation of high-dose cytarabine for postremission therapy has substantially improved the outcome of CBF-AML patients, especially when administered in the setting of repetitive cycles. For many years, high-dose cytarabine was the standard treatment in CBF-AML resulting in favorable long-term outcome in approximately half of the patients. Therefore, CBF-AML patients are generally considered to be a favorable AML group. However, a substantial proportion of patients cannot be cured by the current treatment. Additional genetic alterations discovered in CBF-AML help in our understanding of the process of leukemogenesis and some of them may refine the risk assessment in CBF-AML and, importantly, also serve as targets for novel therapeutic approaches. We discuss the clinical and genetic heterogeneity of CBF-AML, with a particular focus on the role of KIT mutations as a prognosticator, and also discuss recent efforts to target the KIT kinase in the context of existing therapeutic regimens.
T-cell therapy for viral infections
Authors: Heslop Helen E. , Leen Ann M.
Published: December 2013

Viral infections remain a major cause of morbidity in patients with immunodeficiency, such as recipients of hemopoietic stem cell transplantation. Adoptive transfer of donor-derived virus-specific cytotoxic T lymphocytes is a strategy to restore virus-specific immunity to prevent or treat viral diseases and has been tested in the clinical setting for more than 20 years. Several different groups have used expanded virus-specific T-cell products specific for one or multiple viruses to both reconstitute antiviral immunity after transplantation and to treat active viral infections. Response rates are encouraging, although resistance has been seen when the infused cell population has had restricted specificity or has targeted antigens expressed in donor-infected but not virally infected recipient cells. The goal of current trials is to make this approach more broadly applicable using more rapidly available products from the donor, such as directly selected or briefly expanded cells or closely matched banked cells.
T-cell adoptive immunotherapy for acute lymphoblastic leukemia
Authors: Fry Terry J. , Mackall Crystal L.
Published: December 2013

Substantial progress has been made in the treatment of precursor B-cell acute lymphoblastic leukemia (B-ALL), but recurrent disease remains a leading cause of death in children due to cancer and outcomes for adults with B-ALL remain poor. Recently, complete clinical responses have been observed in small numbers of patients with B-ALL treated with adoptive immunotherapy using T cells genetically engineered to express chimeric antigen receptors (CARs) targeting CD19, a cell surface molecule present in essentially all cases of B-ALL. Preclinical data suggest that CARs targeting CD22, another antigen present in the majority of B-ALL cases, are similarly potent. Several clinical studies already under way will soon more clearly define the rate of response to this novel therapy in B-ALL. Further work is needed to identify optimal platforms for CAR-based adoptive immunotherapy for leukemia, to establish guidelines for managing toxicity, and to determine whether the remissions induced by this approach can be rendered durable.
Vaso-occlusion in sickle cell disease: pathophysiology and novel targeted therapies
Authors: Manwani Deepa , Frenette Paul S.
Published: December 2013

Recurrent and unpredictable episodes of vaso-occlusion are the hallmark of sickle cell disease. Symptomatic management and prevention of these events using the fetal hemoglobin–reactivating agent hydroxyurea are currently the mainstay of treatment. Discoveries over the past 2 decades have highlighted the important contributions of various cellular and soluble participants in the vaso-occlusive cascade. The role of these elements and the opportunities for therapeutic intervention are summarized in this review.
Long-lasting recombinant factor VIII proteins for hemophilia A
Authors: Shapiro Amy D.
Published: December 2013

In the past 50 years, the lifespan of an individual affected with severe hemophilia A has increased from a mere 20 years to near that of the general unaffected population. These advances are the result of and parallel advances in the development and manufacture of replacement therapies. We are now poised to witness further technologic leaps with the development of longer-lasting replacement therapies, some of which are likely to be approved for market shortly. Prophylactic therapy is currently the standard of care for young children with severe hemophilia A, yet requires frequent infusion to achieve optimal results. Longer-lasting products will transform our ability to deliver prophylaxis, especially in very young children. Longer-lasting replacement therapies will require changes to our current treatment plans including those for acute bleeding, prophylaxis, surgical interventions, and even perhaps immunotolerance induction. Ongoing observation will be required to determine the full clinical impact of this new class of products.
Management of early-stage Hodgkin lymphoma: is there still a role for radiation?
Authors: Johnson Peter W. M.
Published: December 2013

Although radiotherapy is highly effective for the treatment of Hodgkin lymphoma, the realization of its potential long-term toxicity and the demonstration of excellent results from combination chemotherapy have led to a retreat from its use in early-stage disease. Recent trials using functional imaging may allow better identification of those patients for whom radiotherapy may be safely omitted without compromising cure rates and this review examines the evidence for this.
Treatment of fungal disease in the setting of neutropenia
Authors: Walsh Thomas J. , Gamaletsou Maria N.
Published: December 2013

Invasive fungal infections are important causes of morbidity and attributable mortality in neutropenic patients with hematological malignancies, myelodysplasia, and aplastic anemia. Successful risk-based strategies can be implemented for prophylaxis, empirical therapy, and preemptive therapy for the prevention and early treatment of invasive fungal infections in neutropenic hosts. The use of echinocandins for invasive candidiasis and voriconazole for invasive aspergillosis has significantly improved outcome. Recent studies demonstrate, however, that resistant fungal pathogens may emerge during the course of these antifungal interventions. Although triazole-resistant Candida spp. have been well described as causes of breakthrough candidemia, other organisms now pose a similar threat. Such organisms include echinocandin-resistant Candida glabrata and Candida parapsilosis species complex. The Mucorales, Fusarium spp., and Scedosporium spp. may emerge in the setting of voriconazole prophylaxis. The challenges of these emerging pathogens underscore the need for the development of new antifungal agents and strategies.
Understanding MYC-driven aggressive B-cell lymphomas: pathogenesis and classification
Authors: Ott German , Rosenwald Andreas , Campo Elias
Published: December 2013

MYC is a potent oncogene initially identified as the target of the t(8;14)(q24;q32) chromosome translocation in Burkitt lymphoma. MYC gene alterations have been identified in other mature B-cell neoplasms that are usually associated with an aggressive clinical behavior. Most of these tumors originate in cells that do not normally express MYC protein. The oncogenic events leading to MYC up-regulation seem to overcome the inhibitory effect of physiological repressors such as BCL6 or BLIMP1. Aggressive lymphomas frequently carry additional oncogenic alterations that cooperate with MYC dysregulation, likely counteracting its proapoptotic function. The development of FISH probes and new reliable antibodies have facilitated the study of MYC gene alterations and protein expression in large series of patients, providing new clinical and biological perspectives regarding MYC dysregulation in aggressive lymphomas. MYC gene alterations in large B-cell lymphomas are frequently associated with BCL2 or BCL6 translocations conferring a very aggressive behavior. Conversely, MYC protein up-regulation may occur in tumors without apparent gene alterations, and its association with BCL2 overexpression also confers a poor prognosis. In this review, we integrate all of this new information and discuss perspectives, challenges, and open questions for the diagnosis and management of patients with MYC-driven aggressive B-cell lymphomas.
Blood manipulation: current challenges from an anti-doping perspective
Authors: Mørkeberg Jakob
Published: December 2013

The delivery of oxygen is the limiting factor during whole-body endurance exercise in well-trained individuals, so manipulating the amount of hemoglobin in the blood results in changes in endurance exercise capacity. Athletes began using novel erythropoiesis-stimulating agents well before they were approved for medical use. Older manipulation practices, such as autologous blood transfusions or the administration of first-generation recombinant human erythropoietins, are still widely abused due to challenges in their detection. More recent performance enhancement maneuvers include efforts to mask doping and to induce increased endogenous erythropoietin expression. Confessions by athletes have revealed an ongoing yet extremely sophisticated modus operandi when manipulating the blood. In this review, weaknesses in detection methods and sample collection procedures are scrutinized and strategies developed to circumvent the test system discussed.
Transfusion guidelines: when to transfuse
Authors: Szczepiorkowski Zbigniew M. , Dunbar Nancy M.
Published: December 2013

Transfusion of blood and blood components has been a routine practice for more than half a century. The rationale supporting this practice is that replacement of blood loss should be beneficial for the patient. This assumption has constituted the underpinning of transfusion medicine for many decades. Only over the past 20 years, we have seen a more concerted effort to answer very basic questions regarding the value of transfusion therapy. An assessment of the value of transfusion based on well-designed and appropriately powered randomized, controlled trials is the first step in optimizing transfusion practices. Systematic reviews provide the second step by building the knowledge base necessary to assess the impact of transfusion practice on patient outcomes. The third step is the development of clinical practice guidelines, and this occurs when systematic reviews are interpreted by individuals with expertise in transfusion medicine. Such guidelines are typically supported by professional organizations and/or health authorities. Implementation of clinical practice guidelines can be challenging, especially in an area as heterogeneous as transfusion medicine. However, clinical practice guidelines are necessary for the practice of evidence-based medicine, which optimizes patient care and improves patient outcomes. This review focuses on clinical practice guidelines for transfusion of three blood components: RBCs, platelets and plasma. In addition, we provide the approach used to implement clinical practice guidelines at our own institution.
Mechanisms of trauma-induced coagulopathy
Authors: White Nathan J.
Published: December 2013

The identification and management of coagulopathy is a critical component of caring for the severely injured patient. Notions of the mechanisms of coagulopathy in trauma patients have been supplanted by new insights resulting from close examination of the biochemical and cellular changes associated with acute tissue injury and hemorrhagic shock. Acute intrinsic coagulopathy arising in severely injured trauma patients is now termed trauma-induced coagulopathy (TIC) and is an emergent property of tissue injury combined with hypoperfusion. Mechanisms contributing to TIC include anticoagulation, consumption, platelet dysfunction, and hyperfibrinolysis. This review discusses current understanding of TIC mechanisms and their relative contributions to coagulopathy in the face of increasingly severe injury and highlights how they interact to produce coagulation system dysfunction.