bluuebunny/crossref_metadata_2025_split huggingface dataset:
Preventive zinc supplementation for children, and the effect of additional iron: a systematic review and meta-analysis
Authors: Mayo-Wilson Evan , Imdad Aamer , Junior Jean , Dean Sohni , Bhutta Zulfiqar A 
Published: June 2014

ObjectiveZinc deficiency is widespread, and preventive supplementation may have benefits in young children. Effects for children over 5 years of age, and effects when coadministered with other micronutrients are uncertain. These are obstacles to scale-up. This review seeks to determine if preventive supplementation reduces mortality and morbidity for children aged 6 months to 12 years.DesignSystematic review conducted with the Cochrane Developmental, Psychosocial and Learning Problems Group. Two reviewers independently assessed studies. Meta-analyses were performed for mortality, illness and side effects.Data sourcesWe searched multiple databases, including CENTRAL and MEDLINE in January 2013. Authors were contacted for missing information.Eligibility criteria for selecting studiesRandomised trials of preventive zinc supplementation. Hospitalised children and children with chronic diseases were excluded.Results80 randomised trials with 205 401 participants were included. There was a small but non-significant effect on all-cause mortality (risk ratio (RR) 0.95 (95% CI 0.86 to 1.05)). Supplementation may reduce incidence of all-cause diarrhoea (RR 0.87 (0.85 to 0.89)), but there was evidence of reporting bias. There was no evidence of an effect of incidence or prevalence of respiratory infections or malaria. There was moderate quality evidence of a very small effect on linear growth (standardised mean difference 0.09 (0.06 to 0.13)) and an increase in vomiting (RR 1.29 (1.14 to 1.46)). There was no evidence of an effect on iron status. Comparing zinc with and without iron cosupplementation and direct comparisons of zinc plus iron versus zinc administered alone favoured cointervention for some outcomes and zinc alone for other outcomes. Effects may be larger for children over 1 year of age, but most differences were not significant.ConclusionsBenefits of preventive zinc supplementation may outweigh any potentially adverse effects in areas where risk of zinc deficiency is high. Further research should determine optimal intervention characteristics and delivery strategies.
Microbiota Modulate Tumoral Immune Surveillance in Lung through a γδT17 Immune Cell-Dependent Mechanism
Authors: Cheng Min , Qian Liting , Shen Guodong , Bian Geng , Xu Tingjuan , Xu Weiping , Shen Gan , Hu Shilian 
Published: June 2014

Abstract
Commensal bacteria are crucial to maintain immune homeostasis in mucosal tissues and disturbances in their ecology can affect disease susceptibility. Here, we report evidence that commensal bacteria shape the efficiency of immune surveillance in mucosal tissues. Antibiotic-treated (Abt) mice were more susceptible to development of engrafted B16/F10 melanoma and Lewis lung carcinoma, exhibiting a shortened mean survival time with more numerous and larger tumor foci in the lungs. The defective antitumor response of Abt mice was independent of dehydration caused by antibiotics. Host defenses relied upon intact commensal bacteria with no class specificity. Mechanistic investigations revealed a defective induction of the γδT17 cell response in lungs of Abt mice; here, more aggressive tumor development was observed, possibly related to a reduction in IL6 and IL23 expression there. Adding normal γδT cells or supplementing IL17 restored the impaired immune surveillance phenotype in Abt mice. Overall, our results demonstrated the importance of commensal bacteria in supporting the host immune response against cancer, defined an important role for γδT17 responses in the mechanism, and suggested deleterious effects of antibiotic treatment on cancer susceptibility and progression. Cancer Res; 74(15); 4030–41. ©2014 AACR.
Human Brat Ortholog TRIM3 Is a Tumor Suppressor That Regulates Asymmetric Cell Division in Glioblastoma
Authors: Chen Gang , Kong Jun , Tucker-Burden Carol , Anand Monika , Rong Yuan , Rahman Fahmia , Moreno Carlos S. , Van Meir Erwin G. , Hadjipanayis Constantinos G. , Brat Daniel J. 
Published: June 2014

Abstract
Cancer stem cells, capable of self-renewal and multipotent differentiation, influence tumor behavior through a complex balance of symmetric and asymmetric cell divisions. Mechanisms regulating the dynamics of stem cells and their progeny in human cancer are poorly understood. In Drosophila, mutation of brain tumor (brat) leads to loss of normal asymmetric cell division by developing neural cells and results in a massively enlarged brain composed of neuroblasts with neoplastic properties. Brat promotes asymmetric cell division and directs neural differentiation at least partially through its suppression on Myc. We identified TRIM3 (11p15.5) as a human ortholog of Drosophila brat and demonstrate its regulation of asymmetric cell division and stem cell properties of glioblastoma (GBM), a highly malignant human brain tumor. TRIM3 gene expression is markedly reduced in human GBM samples, neurosphere cultures, and cell lines and its reconstitution impairs growth properties in vitro and in vivo. TRIM3 expression attenuates stem-like qualities of primary GBM cultures, including neurosphere formation and the expression of stem cell markers CD133, Nestin, and Nanog. In GBM stem cells, TRIM3 expression leads to a greater percentage dividing asymmetrically rather than symmetrically. As with Brat in Drosophila, TRIM3 suppresses c-Myc expression and activity in human glioma cell lines. We also demonstrate a strong regulation of Musashi–Notch signaling by TRIM3 in GBM neurospheres and neural stem cells that may better explain its effect on stem cell dynamics. We conclude that TRIM3 acts as a tumor suppressor in GBM by restoring asymmetric cell division. Cancer Res; 74(16); 4536–48. ©2014 AACR.
Acquired Resistance to Endocrine Treatments Is Associated with Tumor-Specific Molecular Changes in Patient-Derived Luminal Breast Cancer Xenografts
Authors: Cottu Paul , Bièche Ivan , Assayag Franck , El Botty Rania , Chateau-Joubert Sophie , Thuleau Aurélie , Bagarre Thomas , Albaud Benoit , Rapinat Audrey , Gentien David , de la Grange Pierre , Sibut Vonick , Vacher Sophie , Hatem Rana , Servely Jean-Luc , Fontaine Jean-Jacques , Decaudin Didier , Pierga Jean-Yves , Roman-Roman Sergio , Marangoni Elisabetta 
Published: June 2014

Abstract
Purpose: Patients with luminal breast cancer (LBC) often become endocrine resistant over time. We investigated the molecular changes associated with acquired hormonoresistances in patient-derived xenografts of LBC.
Experimental Design: Two LBC xenografts (HBCx22 and HBCx34) were treated with different endocrine treatments (ET) to obtain xenografts with acquired resistances to tamoxifen (TamR) and ovariectomy (OvaR). PI3K pathway activation was analyzed by Western blot analysis and IHC and responses to ET combined to everolimus were investigated in vivo. Gene expression analyses were performed by RT-PCR and Affymetrix arrays.
Results: HBCx22 TamR xenograft was cross-resistant to several hormonotherapies, whereas HBCx22 OvaR and HBCx34 TamR exhibited a treatment-specific resistance profile. PI3K pathway was similarly activated in parental and resistant xenografts but the addition of everolimus did not restore the response to tamoxifen in TamR xenografts. In contrast, the combination of fulvestrant and everolimus induced tumor regression in vivo in HBCx34 TamR, where we found a cross-talk between the estrogen receptor (ER) and PI3K pathways. Expression of several ER-controlled genes and ER coregulators was significantly changed in both TamR and OvaR tumors, indicating impaired ER transcriptional activity. Expression changes associated with hormonoresistance were both tumor and treatment specific and were enriched for genes involved in cell growth, cell death, and cell survival.
Conclusions: PDX models of LBC with acquired resistance to endocrine therapies show a great diversity of resistance phenotype, associated with specific deregulations of ER-mediated gene transcription. These models offer a tool for developing anticancer therapies and to investigate the dynamics of resistance emerging during pharmacologic interventions. Clin Cancer Res; 20(16); 4314–25. ©2014 AACR.
Complex Disease–, Gene–, and Drug–Drug Interactions: Impacts of Renal Function, CYP2D6 Phenotype, and OCT2 Activity on Veliparib Pharmacokinetics
Authors: Li Jing , Kim Seongho , Sha Xianyi , Wiegand Richard , Wu Jianmei , LoRusso Patricia 
Published: June 2014

Abstract
Purpose: Veliparib, a poly (ADP-ribose) polymerase (PARP) inhibitor, undergoes renal excretion and liver metabolism. This study quantitatively assessed the interactions of veliparib with metabolizing enzyme (CYP2D6) and transporter (OCT2) in disease settings (renal impairment).
Experimental Design: Veliparib in vitro metabolism was examined in human liver microsomes and recombinant enzymes carrying wild-type CYP2D6 or functional defect variants (CYP2D6*10 and *4). Plasma pharmacokinetics were evaluated in 27 patients with cancer. A parent–metabolite joint population model was developed to characterize veliparib and metabolite (M8) pharmacokinetics and to identify patient factors influencing veliparib disposition. A physiologically based pharmacokinetic model integrated with a mechanistic kidney module was developed to quantitatively predict the individual and combined effects of renal function, CYP2D6 phenotype, and OCT2 activity on veliparib pharmacokinetics.
Results: In vitro intrinsic clearance of CYP2D6.1 and CYP2D6.10 for veliparib metabolism were 0.055 and 0.017 μL/min/pmol CYP, respectively. Population mean values for veliparib oral clearance and M8 clearance were 13.3 and 8.6 L/h, respectively. Creatinine clearance was identified as the significant covariate on veliparib oral clearance. Moderate renal impairment, CYP2D6 poor metabolizer, and co-administration of OCT2 inhibitor (cimetidine) increased veliparib steady-state exposure by 80%, 20%, and 30%, respectively. These factors collectively led to &gt;2-fold increase in veliparib exposure.
Conclusions: Renal function (creatinine clearance) is a significant predictor for veliparib exposure in patients with cancer. Although a single factor (i.e., renal impairment, CYP2D6 deficiency, and reduced OCT2 activity) shows a moderate impact, they collectively could result in a significant and potentially clinically relevant increase in veliparib exposure. Clin Cancer Res; 20(15); 3931–44. ©2014 AACR.
Factor XI Regulates Pathological Thrombus Formation on Acutely Ruptured Atherosclerotic Plaques
Authors: van Montfoort Maurits L. , Kuijpers Marijke J.E. , Knaup Véronique L. , Bhanot Sanjay , Monia Brett P. , Roelofs Joris J.T.H. , Heemskerk Johan W.M. , Meijers Joost C.M. 
Published: June 2014

Objective—
Coagulation factor XI is proposed as therapeutic target for anticoagulation. However, it is still unclear whether the antithrombotic properties of factor XI inhibitors influence atherosclerotic disease and atherothrombosis. Our aim is to investigate whether factor XI antisense oligonucleotides could prevent thrombus formation on acutely ruptured atherosclerotic plaques.

Approach and Results—

Atherosclerotic plaques in the carotid arteries of
Apoe
−/−
mice were acutely ruptured using ultrasound. The subsequent thrombus formation was visualized and quantified by intravital microscopy and immunohistochemistry. Mice were pretreated with either factor XI antisense or nonsense oligonucleotides (50 mg/kg) to lower factor XI plasma levels. A tail bleeding assay was used to determine the safety. On plaque rupture, initial platelet adhesion and platelet plug formation were not impaired in animals treated with factor XI antisense oligonucleotides. However, the ensuing thrombus formation and fibrin deposition were significantly lower after 5 to 10 minutes (
P
<0.05) in factor XI antisense oligonucleotide–treated animals without inducing a bleeding tendency. Furthermore, thrombi from antisense-treated animals were less stable than thrombi from placebo-treated animals. Moreover, macrophage infiltration and collagen deposition were lower in the carotid arteries of factor XI antisense–treated animals. No neutrophils were present.

Conclusions—
Factor XI antisense oligonucleotides safely prevent thrombus formation on acutely ruptured atherosclerotic plaques in mice. Furthermore, perturbed carotid arteries from factor XI antisense–treated animals show a less severe inflammatory response.
Macrophage-Independent Regulation of Reverse Cholesterol Transport by Liver X Receptors
Authors: Breevoort Sarah R. , Angdisen Jerry , Schulman Ira G. 
Published: June 2014

Objective—
The ability of high-density lipoprotein (HDL) particles to accept cholesterol from peripheral cells, such as lipid-laden macrophages, and to transport cholesterol to the liver for catabolism and excretion in a process termed reverse cholesterol transport (RCT) is thought to underlie the beneficial cardiovascular effects of elevated HDL. The liver X receptors (LXRs; LXRα and LXRβ) regulate RCT by controlling the efflux of cholesterol from macrophages to HDL and the excretion, catabolism, and absorption of cholesterol in the liver and intestine. Importantly, treatment with LXR agonists increases RCT and decreases atherosclerosis in animal models. Nevertheless, LXRs are expressed in multiple tissues involved in RCT, and their tissue-specific contributions to RCT are still not well defined.

Approach and Results—
Using tissue-specific LXR deletions together with in vitro and in vivo assays of cholesterol efflux and fecal cholesterol excretion, we demonstrate that macrophage LXR activity is neither necessary nor sufficient for LXR agonist–stimulated RCT. In contrast, the ability of LXR agonists primarily acting in the intestine to increase HDL mass and HDL function seems to underlie the ability of LXR agonists to stimulate RCT in vivo.

Conclusions—
We demonstrate that activation of LXR in macrophages makes little or no contribution to LXR agonist–stimulated RCT. Unexpectedly, our studies suggest that the ability of macrophages to efflux cholesterol to HDL in vivo is not regulated by macrophage activity but is primarily determined by the quantity and functional activity of HDL.
Strategies to Design and Analyze Targeted Sequencing Data
Authors: Lin Honghuang , Wang Min , Brody Jennifer A. , Bis Joshua C. , Dupuis Josée , Lumley Thomas , McKnight Barbara , Rice Kenneth M. , Sitlani Colleen M. , Reid Jeffrey G. , Bressler Jan , Liu Xiaoming , Davis Brian C. , Johnson Andrew D. , O’Donnell Christopher J. , Kovar Christie L. , Dinh Huyen , Wu Yuanqing , Newsham Irene , Chen Han , Broka Andi , DeStefano Anita L. , Gupta Mayetri , Lunetta Kathryn L. , Liu Ching-Ti , White Charles C. , Xing Chuanhua , Zhou Yanhua , Benjamin Emelia J. , Schnabel Renate B. , Heckbert Susan R. , Psaty Bruce M. , Muzny Donna M. , Cupples L. Adrienne , Morrison Alanna C. , Boerwinkle Eric 
Published: June 2014

Background—
Genome-wide association studies have identified thousands of genetic variants that influence a variety of diseases and health-related quantitative traits. However, the causal variants underlying the majority of genetic associations remain unknown. Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) Consortium Targeted Sequencing Study aims to follow up genome-wide association study signals and identify novel associations of the allelic spectrum of identified variants with cardiovascular-related traits.

Methods and Results—

The study included 4231 participants from 3 CHARGE cohorts: the Atherosclerosis Risk in Communities Study, the Cardiovascular Health Study, and the Framingham Heart Study. We used a case–cohort design in which we selected both a random sample of participants and participants with extreme phenotypes for each of 14 traits. We sequenced and analyzed 77 genomic loci, which had previously been associated with ≥1 of 14 phenotypes. A total of 52 736 variants were characterized by sequencing and passed our stringent quality control criteria. For common variants (minor allele frequency ≥1%), we performed unweighted regression analyses to obtain
P
values for associations and weighted regression analyses to obtain effect estimates that accounted for the sampling design. For rare variants, we applied 2 approaches: collapsed aggregate statistics and joint analysis of variants using the sequence kernel association test.

Conclusions—
We sequenced 77 genomic loci in participants from 3 cohorts. We established a set of filters to identify high-quality variants and implemented statistical and bioinformatics strategies to analyze the sequence data and identify potentially functional variants within genome-wide association study loci.
Persistent Racial Disparity in Stroke Hospitalization and Economic Impact in Young Adults in the Buckle of Stroke Belt
Authors: Boan Andrea D. , Feng Wuwei (Wayne) , Ovbiagele Bruce , Bachman David L. , Ellis Charles , Adams Robert J. , Kautz Steven A. , Lackland Daniel T. 
Published: June 2014

Background and Purpose—
Mounting evidence points to a decline in stroke incidence. However, little is known about recent patterns of stroke hospitalization within the buckle of the stroke belt. This study aims to investigate the age- and race-specific secular trends in stroke hospitalization rates, inpatient stroke mortality rates, and related hospitalization charges during the past decade in South Carolina.

Methods—

Patients from 2001 to 2010 were identified from the State Inpatient Hospital Discharge Database with a primary discharge diagnosis of stroke (
International Classification of Diseases, Ninth Revision
codes: 430–434, 436, 437.1). Age- and race-stroke–specific hospitalization rates, hospital charges, charges associated with racial disparity, and 30-day stroke mortality rates were compared between blacks and whites.

Results—

Of the 84 179 stroke hospitalizations, 31 137 (37.0%) were from patients aged <65 years and 29 846 (35.5%) were blacks. Stroke hospitalization rates decreased in the older population (aged ≥65 years) for both blacks and whites (
P
<0.001) but increased among the younger group (aged <65 years;
P
=0.004); however, this increase was mainly driven by a 17.3% rise among blacks (
P
=0.001), with no difference seen among whites (
P
=0.84). Of hospital charges totaling $2.77 billion, $453.2 million (16.4%) are associated with racial disparity (79.6% from patients aged <65 years). Thirty-day stroke mortality rates decreased in all age-race-stroke–specific groups (
P
<0.001).

Conclusions—
The stroke hospitalization rate increased in the young blacks only, which results in a severe and persistent racial disparity. It highlights the urgent need for a racial disparity reduction in the younger population to alleviate the healthcare burden.
Acute and Delayed Deferoxamine Treatment Attenuates Long-Term Sequelae After Germinal Matrix Hemorrhage in Neonatal Rats
Authors: Klebe Damon , Krafft Paul R. , Hoffmann Clotilde , Lekic Tim , Flores Jerry J. , Rolland William , Zhang John H. 
Published: June 2014

Background and Purpose—
This study investigated if acute and delayed deferoxamine treatment attenuates long-term sequelae after germinal matrix hemorrhage (GMH).

Methods—
Bacterial collagenase (0.3 U) was infused intraparenchymally into the right hemispheric ganglionic eminence in P7 rat pups to induce GMH. GMH animals received either deferoxamine or vehicle twice a day for 7 consecutive days. Deferoxamine administration was initiated at either 1 hour or 72 hours post-GMH. Long-term neurocognitive deficits and motor coordination were assessed using Morris water maze, rotarod, and foot fault tests between day 21 to 28 post-GMH. At 28 days post-GMH, brain morphology was assessed and extracellular matrix protein (fibronectin and vitronectin) expression was determined.

Results—
Acute and delayed deferoxamine treatment improved long-term motor and cognitive function at 21 to 28 days post-GMH. Attenuated neurofunction was paralleled with improved overall brain morphology at 28 days post-GMH, reducing white matter loss, basal ganglia loss, posthemorrhagic ventricular dilation, and cortical loss. GMH resulted in significantly increased expression of fibronectin and vitronectin, which was reversed by acute and delayed deferoxamine treatment.

Conclusions—
Acute and delayed deferoxamine administration ameliorated long-term sequelae after GMH.
‘Nose’ in Armenian
Authors: Asatrian Garnik 
Published: June 2014

Armenian has two main signifiers for ‘nose’, k‘it‘ and pinc‘, both remaining obscure. Presumably, they have no Indo-European origin. Body-part names usually are not borrowed. They present predominantly genuine (or substrate) forms, including ideophones, based on internal resources of the language, or terms, shaped through semantic shift of metaphors. Incidentally, the essential part of the Armenian body-part names includes lexemes of the clear IE provenance.
The paper attempts to summarise the relevant material on and trace the possible background of the above terms.
The Role of Nonconvective Condensation Processes in Response of Surface Shortwave Cloud Radiative Forcing to El Niño Warming
Authors: Li Lijuan , Wang Bin , Zhang Guang J. 
Published: June 2014

Abstract
The weak response of surface shortwave cloud radiative forcing (SWCF) to El Niño over the equatorial Pacific remains a common problem in many contemporary climate models. This study shows that two versions of the Grid-Point Atmospheric Model of the Institute of Atmospheric Physics (IAP)/State Key Laboratory of Numerical Modeling for Atmospheric Sciences and Geophysical Fluid Dynamics (LASG) (GAMIL) produce distinctly different surface SWCF response to El Niño. The earlier version, GAMIL1, underestimates this response, whereas the latest version, GAMIL2, simulates it well. To understand the causes for the different SWCF responses between the two simulations, the authors analyze the underlying physical mechanisms. Results indicate the enhanced stratiform condensation and evaporation in GAMIL2 play a key role in improving the simulations of multiyear annual mean water vapor (or relative humidity), cloud fraction, and in-cloud liquid water path (ICLWP) and hence in reducing the biases of SWCF and rainfall responses to El Niño due to all of the improved dynamical (vertical velocity at 500 hPa), cloud amount, and liquid water path (LWP) responses. The largest contribution to the SWCF response improvement in GAMIL2 is from LWP in the Niño-4 region and from low-cloud cover and LWP in the Niño-3 region. Furthermore, as a crucial factor in the low-cloud response, the atmospheric stability change in the lower layers is significantly influenced by the nonconvective heating variation during La Niña.
Clinical applications of herbal medicines for anxiety and insomnia; targeting patients with bipolar disorder
Authors: Baek Ji Hyun , Nierenberg Andrew A , Kinrys Gustavo 
Published: June 2014

Objectives: Patients with bipolar disorder frequently continue to experience residual anxiety and insomnia between mood episodes. In real-world practice, patients increasingly self-prescribe alternative medicines. Methods: We reviewed case reports, open-label, and placebo-controlled trials investigating the use of herbal medicines to treat anxiety and insomnia, and discussed their potential applications for bipolar disorder. Results: Eleven herbal medicines that have been studied in human subjects are included in this review. Mechanisms of action, efficacy, side effects, and drug-drug interactions are discussed. Based on currently available evidence, valerian seems to be the most promising candidate for insomnia and anxiety in bipolar disorder. Conclusions: Adjunctive herbal medicines may have the potential to alleviate these symptoms and improve the outcomes of standard treatment, despite limited evidence. Physicians need to have a more in-depth understanding of the evidence of benefits, risks, and drug interactions of alternative treatments.