bluuebunny/crossref_metadata_2025_split huggingface dataset:
Comparison of automated erythrocytapheresis versus manual exchange transfusion to treat cerebral macrovasculopathy in sickle cell anemia
Authors: Koehl Bérengère , Sommet Julie , Holvoet Laurent , Abdoul Hendy , Boizeau Priscilla , Ithier Ghislaine , Missud Florence , Couque Nathalie , Verlhac Suzanne , Voultoury Pauline , Sellami Fatiha , Baruchel André , Benkerrou Malika 
Published: March 2016

BACKGROUNDChronic exchange transfusion is effective for primary and secondary prevention of stroke in children with sickle cell anemia (SCA). Erythrocytapheresis is recognized to be the most efficient approach; however, it is not widely implemented and is not suitable for all patients. The aim of our study was to compare automated exchange transfusion (AET) with our manual method of exchange transfusion and, in particular, to evaluate the efficacy, safety, and cost of our manual method.STUDY DESIGN AND METHODSThirty‐nine SCA children with stroke and/or abnormal findings on transcranial Doppler were included in the study. We retrospectively analyzed 1353 exchange sessions, including 333 sessions of AET and 1020 sessions of manual exchange transfusion (MET).RESULTSBoth methods were well tolerated. The median decrease in hemoglobin (Hb)S per session was 21.5% with AET and 18.8% with our manual method (p < 0.0001) with no major increase in red blood cell consumption. Iron overload was well controlled, even with the manual method, with a median (interquartile range) ferritin level of 312 (152‐994) µg/L after 24 months of transfusions. The main differences in annual cost relate to equipment costs, which were 74 times higher with the automated method.CONCLUSIONOur study shows that continuous MET has comparable efficacy to the automated method in terms of stroke prevention, decrease in HbS, and iron overload prevention. It is feasible in all hospital settings and is often combined with AET successively over time.
Does Economic Diplomacy Work? A Meta‐analysis of Its Impact on Trade and Investment
Authors: Moons Selwyn J. V. , van Bergeijk Peter A. G. 
Published: March 2016

AbstractWe review the literature on economic diplomacy and provide a meta‐analysis of 32 empirical studies published in 1986–2011 that deal with the trade and investment impact of economic diplomacy (embassies, consulates, other diplomatic facilities, investment and export promotion offices, trade and state visits). Controlling for differences in research design, methodology, time frame and manner of data, we find a positive and significant effect of economic diplomacy on international economic flows with the exception of state visits and that this is true in a sample of 627 t‐statistics analysed with OLS and for a larger sample of 963 reported significance levels analysed with logit thus illustrating robustness with respect to sample and estimation technique. Our analyses show that reported effects of economic diplomacy on trade and investment in individual studies are sensitive to model specification. The primary studies that investigate only one source country are less likely to report significant positive effects. Compared to other sciences, economic studies are less likely to report significantly positive effects of economic diplomacy. Primary studies lump embassies and consulates (general) into one indicator miss that these instruments differ significantly. Embassies, consulates and agencies should thus be included as separate instruments in future research.
Defining a new diagnostic assessment parameter for wound care: Elevated protease activity, an indicator of nonhealing, for targeted protease‐modulating treatment
Authors: Serena Thomas E. , Cullen Breda M. , Bayliff Simon W. , Gibson Molly C. , Carter Marissa J. , Chen Lingyun , Yaakov Raphael A. , Samies John , Sabo Matthew , DeMarco Daniel , Le Namchi , Galbraith James 
Published: March 2016

ABSTRACTIt is widely accepted that elevated protease activity (EPA) in chronic wounds impedes healing. However, little progress has occurred in quantifying the level of protease activity that is detrimental for healing. The aim of this study was to determine the relationship between inflammatory protease activity and wound healing status, and to establish the level of EPA above which human neutrophil‐derived elastase (HNE) and matrix metalloproteases (MMP) activities correlate with nonhealing wounds. Chronic wound swab samples (n = 290) were collected from four wound centers across the USA to measure HNE and MMP activity. Healing status was determined according to percentage reduction in wound area over the previous 2–4 weeks; this was available for 211 wounds. Association between protease activity and nonhealing wounds was determined by receiver operating characteristic analysis (ROC), a statistical technique used for visualizing and analyzing the performance of diagnostic tests. ROC analysis showed that area under the curve (AUC) for HNE were 0.69 for all wounds and 0.78 for wounds with the most reliable wound trajectory information, respectively. For MMP, the corresponding AUC values were 0.70 and 0.82. Analysis suggested that chronic wounds having values of HNE >5 and/or MMP ≥13, should be considered wound healing impaired. EPA is indicative of nonhealing wounds. Use of a diagnostic test to detect EPA in clinical practice could enable clinicians to identify wounds that are nonhealing, thus enabling targeted treatment with protease modulating therapies.
Effects of ageing and physical activity on blood pressure and endothelial function during acute inflammation
Authors: Lane‐Cordova Abbi D. , Phillips Shane A. , Baynard Tracy , Woods Jeffrey A. , Motl Robert W. , Fernhall Bo 
Published: March 2016

New Findings

What is the central question of this study?
Do older and younger adults have similar vascular endothelial and blood pressure responses to acute inflammation? Does physical activity affect these responses?

What is the main finding and its importance?
Older adults reduce blood pressure whereas younger adults reduce endothelial function during acute inflammation. Physical activity does not provide protection against these inflammation‐induced changes. This is important because older adults regularly experience acute increases in systemic inflammation that may predispose older adults to cardiovascular events through dysregulation of blood pressure.

Ageing is characterized by chronic, low‐grade inflammation that is related to endothelial dysfunction and arterial stiffness. Physical activity can protect older adults (OAs) from cardiovascular dysfunction and increased inflammation. Acute inflammation causes transient endothelial dysfunction and arterial stiffening in younger adults (YAs), but may not have the same effect in OAs. We hypothesized that acute inflammation would increase blood pressure (BP) and endothelial impairment to a greater extent in OAs versus YAs, but that physical activity would be protective. We induced inflammation with an influenza vaccine in 22 OAs (55–75 years old) and 31 YAs (18–35 years old) and measured brachial flow‐mediated dilatation (FMD), BP and serum inflammatory markers before vaccination and at 24 and 48 h afterwards. Physical activity data were collected using accelerometry. During inflammation, only OAs reduced systolic BP (from 120 ± 3 to 115 ± 2 to 115 ± 3 mmHg, P < 0.05), but only YAs reduced FMD (from 11.3 ± 0.7 to 8.5 ± 0.6 to 8.9 ± 0.6% in YAs and from 6.7 ± 0.6 to 5.3 ± 0.7 to 6.0 ± 0.6% in OAs, P < 0.05 for time and interaction effects). The entire cohort increased C‐reactive protein (P < 0.05), but only YAs increased interleukin‐6 (P < 0.05 for time × age group interaction). Physical activity was related to the percentage change in inflammation in OAs (r = −0.50, P < 0.05) but not to the change in arterial function in either group (P > 0.05 for all). We conclude that acute inflammation reduced FMD only in YAs and reduced BP only in OAs. Physical activity did not affect arterial function during acute inflammation. Clinicians should be aware that all OAs are vulnerable to inflammation‐mediated reductions in BP and cardiovascular complications.
Murine startle mutantNmf11affects the structural stability of the glycine receptor and increases deactivation
Authors: Wilkins Megan E. , Caley Alex , Gielen Marc C. , Harvey Robert J. , Smart Trevor G. 
Published: March 2016

Key pointsHyperekplexia or startle disease is a serious neurological condition affecting newborn children and usually involves dysfunctional glycinergic neurotransmission.Glycine receptors (GlyRs) are major mediators of inhibition in the spinal cord and brainstem.A missense mutation, replacing asparagine (N) with lysine (K), at position 46 in the GlyR α1 subunit induced hyperekplexia following a reduction in the potency of the transmitter glycine; this resulted from a rapid deactivation of the agonist current at mutant GlyRs.These effects of N46K were rescued by mutating a juxtaposed residue, N61 on binding Loop D, suggesting these two asparagines may interact.Asparagine 46 is considered to be important for the structural stability of the subunit interface and glycine binding site, and its mutation represents a new mechanism by which GlyR dysfunction induces startle disease.AbstractDysfunctional glycinergic inhibitory transmission underlies the debilitating neurological condition, hyperekplexia, which is characterised by exaggerated startle reflexes, muscle hypertonia and apnoea. Here we investigated the N46K missense mutation in the GlyR α1 subunit gene found in the ethylnitrosourea (ENU) murine mutant,Nmf11, which causes reduced body size, evoked tremor, seizures, muscle stiffness, and morbidity by postnatal day 21. Introducing the N46K mutation into recombinant GlyR α1 homomeric receptors, expressed in HEK cells, reduced the potencies of glycine, β‐alanine and taurine by 9‐, 6‐ and 3‐fold respectively, and that of the competitive antagonist strychnine by 15‐fold. Replacing N46 with hydrophobic, charged or polar residues revealed that the amide moiety of asparagine was crucial for GlyR activation. Co‐mutating N61, located on a neighbouring β loop to N46, rescued the wild‐type phenotype depending on the amino acid charge. Single‐channel recording identified that burst length for the N46K mutant was reduced and fast agonist application revealed faster glycine deactivation times for the N46K mutant compared with the WT receptor. Overall, these data are consistent with N46 ensuring correct alignment of the α1 subunit interface by interaction with juxtaposed residues to preserve the structural integrity of the glycine binding site. This represents a new mechanism by which GlyR dysfunction induces startle disease.
Human Cytomegalovirus Infection Upregulates the Mitochondrial Transcription and Translation Machineries
Authors: Karniely S. , Weekes M. P. , Antrobus R. , Rorbach J. , van Haute L. , Umrania Y. , Smith D. L. , Stanton R. J. , Minczuk M. , Lehner P. J. , Sinclair J. H. 
Published: March 2016

ABSTRACT
Infection with human cytomegalovirus (HCMV) profoundly affects cellular metabolism. Like in tumor cells, HCMV infection increases glycolysis, and glucose carbon is shifted from the mitochondrial tricarboxylic acid cycle to the biosynthesis of fatty acids. However, unlike in many tumor cells, where aerobic glycolysis is accompanied by suppression of mitochondrial oxidative phosphorylation, HCMV induces mitochondrial biogenesis and respiration. Here, we affinity purified mitochondria and used quantitative mass spectrometry to determine how the mitochondrial proteome changes upon HCMV infection. We found that the mitochondrial transcription and translation systems are induced early during the viral replication cycle. Specifically, proteins involved in biogenesis of the mitochondrial ribosome were highly upregulated by HCMV infection. Inhibition of mitochondrial translation with chloramphenicol or knockdown of HCMV-induced ribosome biogenesis factor MRM3 abolished the HCMV-mediated increase in mitochondrially encoded proteins and significantly impaired viral growth under bioenergetically restricting conditions. Our findings demonstrate how HCMV manipulates mitochondrial biogenesis to support its replication.

IMPORTANCE
Human cytomegalovirus (HCMV), a betaherpesvirus, is a leading cause of morbidity and mortality during congenital infection and among immunosuppressed individuals. HCMV infection significantly changes cellular metabolism. Akin to tumor cells, in HCMV-infected cells, glycolysis is increased and glucose carbon is shifted from the tricarboxylic acid cycle to fatty acid biosynthesis. However, unlike in tumor cells, HCMV induces mitochondrial biogenesis even under aerobic glycolysis. Here, we have affinity purified mitochondria and used quantitative mass spectrometry to determine how the mitochondrial proteome changes upon HCMV infection. We find that the mitochondrial transcription and translation systems are induced early during the viral replication cycle. Specifically, proteins involved in biogenesis of the mitochondrial ribosome were highly upregulated by HCMV infection. Inhibition of mitochondrial translation with chloramphenicol or knockdown of HCMV-induced ribosome biogenesis factor MRM3 abolished the HCMV-mediated increase in mitochondrially encoded proteins and significantly impaired viral growth. Our findings demonstrate how HCMV manipulates mitochondrial biogenesis to support its replication.
Transfer of Viral Communities between Human Individuals during Fecal Microbiota Transplantation
Authors: Chehoud Christel , Dryga Anatoly , Hwang Young , Nagy-Szakal Dorottya , Hollister Emily B. , Luna Ruth Ann , Versalovic James , Kellermayer Richard , Bushman Frederic D. 
Published: March 2016

ABSTRACT

Fecal microbiota transplantation (FMT) is a highly effective treatment for refractory
Clostridium difficile
infections. However, concerns persist about unwanted cotransfer of pathogenic microbes such as viruses. Here we studed FMT from a single healthy human donor to three pediatric ulcerative colitis patients, each of whom received a course of 22 to 30 FMT treatments. Viral particles were purified from donor and recipient stool samples and sequenced; the reads were then assembled into contigs corresponding to viral genomes or partial genomes. Transfer of selected viruses was confirmed by quantitative PCR. Viral contigs present in the donor could be readily detected in recipients, with up to 32 different donor viral contigs appearing in a recipient sample. Reassuringly, none of these were viruses are known to replicate on human cells. Instead, viral contigs either scored as bacteriophage or could not be attributed taxonomically, suggestive of unstudied phage. The two most frequently transferred gene types were associated with temperate-phage replication. In addition, members of
Siphoviridae
, the group of typically temperate phages that includes phage lambda, were found to be transferred with significantly greater efficiency than other groups. On the basis of these findings, we propose that the temperate-phage replication style may promote efficient phage transfer between human individuals. In summary, we documented transfer of multiple viral lineages between human individuals through FMT, but in this case series, none were from viral groups known to infect human cells.

IMPORTANCE
Transfer of whole communities of viruses between humans has rarely been studied but is of likely medical importance. Here we studied fecal microbiota transplantation (FMT), a highly successful treatment for relapsing
Clostridium difficile
infection and, potentially, other gastrointestinal (GI) diseases. We investigated the transfer of viral communities during FMT and documented transfer of multiple viral lineages between humans. None of these were viruses that replicated on animal cells or that are known to be pathogenic. We found that temperate bacteriophage, which form stable associations with their hosts, were significantly more likely to be transferred during FMT. This supports a model in which the viral temperate replication style may have evolved in part to support efficient viral transmission between environments.
HIV-1 Gag Blocks Selenite-Induced Stress Granule Assembly by Altering the mRNA Cap-Binding Complex
Authors: Cinti Alessandro , Le Sage Valerie , Ghanem Marwan , Mouland Andrew J. 
Published: March 2016

ABSTRACT
Stress granules (SGs) are dynamic accumulations of stalled preinitiation complexes and translational machinery that assemble under stressful conditions. Sodium selenite (Se) induces the assembly of noncanonical type II SGs that differ in morphology, composition, and mechanism of assembly from canonical SGs. Se inhibits translation initiation by altering the cap-binding activity of eukaryotic translation initiation factor 4E (eIF4E)-binding protein 1 (4EBP1). In this work, we show that human immunodeficiency virus type 1 (HIV-1) Gag is able to block the assembly of type II noncanonical SGs to facilitate continued Gag protein synthesis. We demonstrate that expression of Gag reduces the amount of hypophosphorylated 4EBP1 associated with the 5′ cap potentially through an interaction with its target, eIF4E. These results suggest that the assembly of SGs is an important host antiviral defense that HIV-1 has evolved for inhibition through several distinct mechanisms.

IMPORTANCE
The antiviral stress response is an important host defense that many viruses, including HIV-1, have evolved to evade. Selenite induces a block in translation and leads to stress granule assembly through the sequestration of eIF4E by binding hypophosphorylated 4EBP1. In this work, we demonstrate that in the face of selenite-induced stress, HIV-1 is able to maintain Gag mRNA translation and to elicit a blockade to selenite-induced stress granule assembly by altering the amount of hypophosphorylated 4EBP1 on the 5′ cap.
Caspase-9b Interacts Directly with cIAP1 to Drive Agonist-Independent Activation of NF-κB and Lung Tumorigenesis
Authors: Vu Ngoc T. , Park Margaret A. , Shultz Michael D. , Bulut Gamze B. , Ladd Amy C. , Chalfant Charles E. 
Published: March 2016

Abstract
Alternate RNA processing of caspase-9 generates the splice variants caspase 9a (C9a) and caspase 9b (C9b). C9b lacks a domain present in C9a, revealing a tumorigenic function that drives the phenotype of non–small cell lung cancer (NSCLC) cells. In this study, we elucidated the mechanistic underpinnings of the malignant character of this splice isoform. In NSCLC cells, C9b expression correlated with activation of the canonical arm of the NF-κB pathway, a major pathway linked to the NSCLC tumorigenesis. Mechanistic investigations revealed that C9b activates this pathway via direct interaction with cellular inhibitor of apoptosis 1 (cIAP1) and subsequent induction of the E3 ligase activity of this IAP family member. The C9b:cIAP1 interaction occurred via the BIR3 domain of cIAP1 and the IAP-binding motif of C9b, but did not require proteolytic cleavage of C9b. This protein:protein interaction was essential for C9b to promote viability and malignant growth of NSCLC cells in vitro and in vivo, broadly translating to diverse NSCLC oncogenotypes. Overall, our findings identified a novel point for therapeutic invention in NSCLC that may be tractable to small-molecule inhibitors, as a new point to broadly address this widespread deadly disease. Cancer Res; 76(10); 2977–89. ©2016 AACR.
Genome-Wide Association Study of Bladder Cancer in a Chinese Cohort Reveals a New Susceptibility Locus at 5q12.3
Authors: Wang Meilin , Li Zhiqiang , Chu Haiyan , Lv Qiang , Ye Dingwei , Ding Qiang , Xu Chuanliang , Guo Jianming , Du Mulong , Chen Jianhua , Song Zhijian , Yin Changjun , Qin Chao , Gu Chengyuan , Zhu Yao , Xia Guowei , Liu Fang , Zhang Zhengsheng , Yuan Lin , Fu Guangbo , Hu Zhibin , Tong Na , Shen Jiawei , Liu Ke , Sun Jielin , Sun Yinghao , Li Jue , Li Xingwang , Shen Hongbing , Xu Jianfeng , Shi Yongyong , Zhang Zhengdong 
Published: March 2016

Abstract
Genome-wide association studies (GWAS) of bladder cancer have identified a number of susceptibility loci in European populations but have yet to uncover the genetic determinants underlying bladder cancer incidence among other ethnicities. Therefore, we performed the first GWAS in a Chinese cohort comprising 3,406 cases of bladder cancer and 4,645 controls. We identified a new susceptibility locus for bladder cancer at 5q12.3, located in the intron of CWC27 (rs2042329), that was significantly associated with disease risk (OR = 1.40; P = 4.61 × 10−11). However, rs2042329 was not associated with bladder cancer risk in patients of European descent. The rs2042329 risk allele was also related to significantly increased expression levels of CWC27 mRNA and protein in bladder cancer tissues from Chinese patients. Additional functional analyses suggested that CWC27 played an oncogenic role in bladder cancer by inducing cell proliferation and suppressing apoptosis. In conclusion, the identification of a risk-associated locus at 5q12.3 provides new insights into the inherited susceptibility to bladder cancer in Chinese populations and may help to identify high-risk individuals. Cancer Res; 76(11); 3277–84. ©2016 AACR.
Phase I Study of an AKT Inhibitor (MK-2206) Combined with Lapatinib in Adult Solid Tumors Followed by Dose Expansion in Advanced HER2+ Breast Cancer
Authors: Wisinski Kari B. , Tevaarwerk Amye J. , Burkard Mark E. , Rampurwala Murtuza , Eickhoff Jens , Bell Maria C. , Kolesar Jill M. , Flynn Christopher , Liu Glenn 
Published: March 2016

Abstract
Purpose: Preclinical data support combining AKT inhibitors with HER2-targeted therapies to overcome resistance to treatment. This phase I study combined the investigational AKT inhibitor, MK-2206, with lapatinib to determine the MTD.
Experimental Design: The dose escalation cohort enrolled adults with advanced solid tumors, who received MK-2206 dosed 30 to 60 mg every other day and lapatinib 1,000 to 1,500 mg daily continuously, escalated using a 3+3 design. Cycles were 28 days except cycle 1 (35 days, including an initial 8 days of MK-2206 alone to evaluate pharmacokinetic interactions). The dose expansion cohort enrolled adults with advanced HER2+ breast cancer.
Results: Twenty-three participants enrolled in the dose escalation cohort. Dose-limiting toxicities were hyponatremia, fatigue, rash, hypocalcemia, and mucositis. Common toxicities included diarrhea, nausea, and rash. The MTD was reached at MK-2206 45 mg orally every other day and lapatinib 1,500 mg orally daily. Two participants maintained stable disease for &gt;4 months, including a colorectal cancer participant with substantial carcinoembryonic antigen decrease. Of 5 participants in the dose expansion cohort, 2 maintained stable disease for &gt;6 months, including one with prior progression on single-agent lapatinib. Plasma MK-2206 concentrations decreased after addition of lapatinib, but in vitro studies indicate lapatinib increases the intracellular levels of MK-2206.
Conclusions: MK-2206 combined with lapatinib can be tolerated with both drugs above biologically active single-agent doses. Overlapping toxicities result in significant diarrhea and rash, which can be managed medically. Antitumor activity was promising and supports evaluation of AKT inhibitors combined with HER2-targeted therapies. Clin Cancer Res; 22(11); 2659–67. ©2016 AACR.