bluuebunny/crossref_metadata_2025_split huggingface dataset:
Assessment of airway response distribution and paradoxical airway dilation in mice during methacholine challenge
Authors: Dubsky S. , Zosky G. R. , Perks K. , Samarage C. R. , Henon Y. , Hooper S. B. , Fouras A. 
Published: December 2016

Detailed information on the distribution of airway diameters during bronchoconstriction in situ is required to understand the regional response of the lungs. Imaging studies using computed tomography (CT) have previously measured airway diameters and changes in response to bronchoconstricting agents, but the manual measurements used have severely limited the number of airways measured per subject. Hence, the detailed distribution and heterogeneity of airway responses are unknown. We have developed and applied dynamic imaging and advanced image-processing methods to quantify and compare hundreds of airways in vivo. The method, based on CT, was applied to house dust-mite-sensitized and control mice during intravenous methacholine (MCh) infusion. Airway diameters were measured pre- and post-MCh challenge, and the results compared demonstrate the distribution of airway response throughout the lungs during mechanical ventilation. Forced oscillation testing was used to measure the global response in lung mechanics. We found marked heterogeneity in the response, with paradoxical dilation of airways present at all airway sizes. The probability of paradoxical dilation decreased with decreasing baseline airway diameter and was not affected by pre-existing inflammation. The results confirm the importance of considering the lung as an entire interconnected system rather than a collection of independent units. It is hoped that the response distribution measurements can help to elucidate the mechanisms that lead to heterogeneous airway response in vivo. NEW & NOTEWORTHY Information on the distribution of airway diameters during bronchoconstriction in situ is critical for understanding the regional response of the lungs. We have developed an imaging method to quantify and compare the size of hundreds of airways in vivo during bronchoconstriction in mice. The results demonstrate large heterogeneity with both constriction and paradoxical dilation of airways, confirming the importance of considering the lung as an interconnected system rather than a collection of independent units.
Approach for Classification and Severity Grading of Long-term and Late-Onset Health Events among Childhood Cancer Survivors in the St. Jude Lifetime Cohort
Authors: Hudson Melissa M. , Ehrhardt Matthew J. , Bhakta Nickhill , Baassiri Malek , Eissa Hesham , Chemaitilly Wassim , Green Daniel M. , Mulrooney Daniel A. , Armstrong Gregory T. , Brinkman Tara M. , Klosky James L. , Krull Kevin R. , Sabin Noah D. , Wilson Carmen L. , Huang I-Chan , Bass Johnnie K. , Hale Karen , Kaste Sue , Khan Raja B. , Srivastava Deo Kumar , Yasui Yutaka , Joshi Vijaya M. , Srinivasan Saumini , Stokes Dennis , Hoehn Mary Ellen , Wilson Matthew , Ness Kirsten K. , Robison Leslie L. 
Published: December 2016

Abstract
Characterization of toxicity associated with cancer and its treatment is essential to quantify risk, inform optimization of therapeutic approaches for newly diagnosed patients, and guide health surveillance recommendations for long-term survivors. The NCI Common Terminology Criteria for Adverse Events (CTCAE) provides a common rubric for grading severity of adverse outcomes in cancer patients that is widely used in clinical trials. The CTCAE has also been used to assess late cancer treatment-related morbidity but is not fully representative of the spectrum of events experienced by pediatric and aging adult survivors of childhood cancer. Also, CTCAE characterization does not routinely integrate detailed patient-reported and medical outcomes data available from clinically assessed cohorts. To address these deficiencies, we standardized the severity grading of long-term and late-onset health events applicable to childhood cancer survivors across their lifespan by modifying the existing CTCAE v4.03 criteria and aligning grading rubrics from other sources for chronic conditions not included or optimally addressed in the CTCAE v4.03. This article describes the methods of late toxicity assessment used in the St. Jude Lifetime Cohort Study, a clinically assessed cohort in which data from multiple diagnostic modalities and patient-reported outcomes are ascertained. Cancer Epidemiol Biomarkers Prev; 26(5); 666–74. ©2016 AACR.
Comparison of Acalabrutinib, A Selective Bruton Tyrosine Kinase Inhibitor, with Ibrutinib in Chronic Lymphocytic Leukemia Cells
Authors: Patel Viralkumar , Balakrishnan Kumudha , Bibikova Elena , Ayres Mary , Keating Michael J. , Wierda William G. , Gandhi Varsha 
Published: December 2016

Abstract
Purpose: Ibrutinib inhibits Bruton tyrosine kinase (BTK) by irreversibly binding to the Cys-481 residue in the enzyme. However, ibrutinib also inhibits several other enzymes that contain cysteine residues homologous to Cys-481 in BTK. Patients with relapsed/refractory or previously untreated chronic lymphocytic leukemia (CLL) demonstrate a high overall response rate to ibrutinib with prolonged survival. Acalabrutinib, a selective BTK inhibitor developed to minimize off-target activity, has shown promising overall response rates in patients with relapsed/refractory CLL. A head-to-head comparison of ibrutinib and acalabrutinib in CLL cell cultures and healthy T cells is needed to understand preclinical biologic and molecular effects.
Experimental Design: Using samples from patients with CLL, we compared the effects of both BTK inhibitors on biologic activity, chemokine production, cell migration, BTK phosphorylation, and downstream signaling in primary CLL lymphocytes and on normal T-cell signaling to determine the effects on other kinases.
Results: Both BTK inhibitors induced modest cell death accompanied by cleavage of PARP and caspase-3. Production of CCL3 and CCL4 chemokines and pseudoemperipolesis were inhibited by both drugs to a similar degree. These drugs also showed similar inhibitory effects on the phosphorylation of BTK and downstream S6 and ERK kinases. In contrast, off-target effects on SRC-family kinases were more pronounced with ibrutinib than acalabrutinib in healthy T lymphocytes.
Conclusions: Both BTK inhibitors show similar biological and molecular profile in primary CLL cells but appear different on their effect on normal T cells. Clin Cancer Res; 23(14); 3734–43. ©2016 AACR.
Targeting Elastase for Molecular Imaging of Early Atherosclerotic Lesions
Authors: Glinzer Almut , Ma Xiaopeng , Prakash Jaya , Kimm Melanie A. , Lohöfer Fabian , Kosanke Katja , Pelisek Jaroslav , Thon Moritz P. , Vorlova Sandra , Heinze Katrin G. , Eckstein Hans-Henning , Gee Michael W. , Ntziachristos Vasilis , Zernecke Alma , Wildgruber Moritz 
Published: December 2016

Objective—
Neutrophils accumulate in early atherosclerotic lesions and promote lesion growth. In this study, we evaluated an elastase-specific near-infrared imaging agent for molecular imaging using hybrid fluorescence molecular tomography/x-ray computed tomography.

Approach and Results—
Murine neutrophils were isolated from bone marrow and incubated with the neutrophil-targeted near-infrared imaging agent Neutrophil Elastase 680 FAST for proof of principle experiments, verifying that the elastase-targeted fluorescent agent is specifically cleaved and activated by neutrophil content after lysis or cell stimulation. For in vivo experiments, low-density lipoprotein receptor–deficient mice were placed on a Western-type diet and imaged after 4, 8, and 12 weeks by fluorescence molecular tomography/x-ray computed tomography. Although this agent remains silent on injection, it produces fluorescent signal after cleavage by neutrophil elastase. After hybrid fluorescence molecular tomography/x-ray computed tomography imaging, mice were euthanized for whole-body cryosectioning and histological analyses. The in vivo fluorescent signal in the area of the aortic arch was highest after 4 weeks of high-fat diet feeding and decreased at 8 and 12 weeks. Ex vivo whole-body cryoslicing confirmed the fluorescent signal to locate to the aortic arch and to originate from the atherosclerotic arterial wall. Histological analysis demonstrated the presence of neutrophils in atherosclerotic lesions.

Conclusions—
This study provides evidence that elastase-targeted imaging can be used for in vivo detection of early atherosclerosis. This imaging approach may harbor potential in the clinical setting for earlier diagnosis and treatment of atherosclerosis.
Adipocyte-Specific Deficiency of NADPH Oxidase 4 Delays the Onset of Insulin Resistance and Attenuates Adipose Tissue Inflammation in Obesity
Authors: Den Hartigh Laura J. , Omer Mohamed , Goodspeed Leela , Wang Shari , Wietecha Tomasz , O’Brien Kevin D. , Han Chang Yeop 
Published: December 2016

Objective—
Obesity is associated with insulin resistance and adipose tissue inflammation. Reactive oxygen species (ROS) increase in adipose tissue during the development of obesity. We previously showed that in response to excess nutrients like glucose and palmitate, adipocytes generated ROS via NADPH oxidase (NOX) 4, the major adipocyte isoform, instead of using mitochondrial oxidation. However, the role of NOX4-derived ROS in the development of whole body insulin resistance, adipocyte inflammation, and recruitment of macrophages to adipose tissue during the development of obesity is unknown.

Approach and Results—
In this study, control C57BL/6 mice and mice in which NOX4 has been deleted specifically in adipocytes were fed a high-fat, high-sucrose diet. During the development of obesity in control mice, adipocyte NOX4 and pentose phosphate pathway activity were transiently increased. Primary adipocytes differentiated from mice with adipocytes deficient in NOX4 showed resistance against high glucose or palmitate-induced adipocyte inflammation. Mice with adipocytes deficient in NOX4 showed a delayed onset of insulin resistance during the development of obesity, with an initial reduction in adipose tissue inflammation that normalized with prolonged high-fat, high-sucrose feeding.

Conclusions—
These findings imply that NOX4-derived ROS may play a role in the onset of insulin resistance and adipose tissue inflammation. As such, therapeutics targeting NOX4-mediated ROS production could be effective in preventing obesity-associated conditions, such as insulin resistance.
Body Mass Index and Mortality Among Adults Undergoing Cardiac Surgery
Authors: Mariscalco Giovanni , Wozniak Marcin J. , Dawson Alan G. , Serraino Giuseppe F. , Porter Richard , Nath Mintu , Klersy Catherine , Kumar Tracy , Murphy Gavin J. 
Published: December 2016

Background:
In an apparent paradox, morbidity and mortality are lower in obese patients undergoing cardiac surgery, although the nature of this association is unclear. We sought to determine whether the obesity paradox observed in cardiac surgery is attributable to reverse epidemiology, bias, or confounding.

Methods:
Data from the National Adult Cardiac Surgery registry for all cardiac surgical procedures performed between April 2002 and March 2013 were extracted. A parallel systematic review and meta-analysis (MEDLINE, Embase, SCOPUS, Cochrane Library) through June 2015 were also accomplished. Exposure of interest was body mass index categorized into 6 groups according to the World Health Organization classification.

Results:
A total of 401 227 adult patients in the cohort study and 557 720 patients in the systematic review were included. A U-shaped association between mortality and body mass index classes was observed in both studies, with lower mortality in overweight (adjusted odds ratio, 0.79; 95% confidence interval, 0.76–0.83) and obese class I and II (odds ratio, 0.81; 95% confidence interval, 0.76–0.86; and odds ratio, 0.83; 95% confidence interval, 0.74–0.94) patients relative to normal-weight patients and increased mortality in underweight individuals (odds ratio, 1.51; 95% confidence interval, 1.41–1.62). In the cohort study, a U-shaped relationship was observed for stroke and low cardiac output syndrome but not for renal replacement therapy or deep sternal wound infection. Counter to the reverse epidemiology hypotheses, the protective effects of obesity were less in patients with severe chronic renal, lung, or cardiac disease and greater in older patients and in those with complications of obesity, including the metabolic syndrome and atherosclerosis. Adjustments for important confounders did not alter our results.

Conclusions:
Obesity is associated with lower risks after cardiac surgery, with consistent effects noted in multiple analyses attempting to address residual confounding and reverse causation.
Renal Dysfunction Is Associated With Poststroke Discharge Disposition and In-Hospital Mortality
Authors: El Husseini Nada , Fonarow Gregg C. , Smith Eric E. , Ju Christine , Schwamm Lee H. , Hernandez Adrian F. , Schulte Phillip J. , Xian Ying , Goldstein Larry B. 
Published: December 2016

Background and Purpose—
Kidney disease is a frequent comorbidity in patients presenting with acute ischemic stroke. We evaluated whether the estimated glomerular filtration rate (eGFR) on admission is associated with poststroke in-hospital mortality or discharge disposition.

Methods—

In this cohort study, data from ischemic stroke patients in Get With The Guidelines–Stroke linked to fee-for-service Medicare data were analyzed. The Modification of Diet in Renal Disease study equation was used to calculate the eGFR (mL/min/1.73 m
2
). Dialysis was identified by
International Classification of Diseases, Ninth Revision
codes. Adjusted multivariable Cox proportional hazards models were used to determine the independent associations of eGFR with discharge disposition and in-hospital mortality. Adjusted individual models also examined whether the association of clinical and demographic factors with outcomes varied by eGFR level.

Results—
Of 232 236 patients, 47.3% had an eGFR ≥60, 26.6% an eGFR 45 to 59, 16.8% an eGFR 30 to 44, 5.6% an eGFR 15 to 29, 0.7% an eGFR<15 without dialysis, and 2.8% were receiving dialysis. Of the total cohort, 11.8% died during the hospitalization or were discharged to hospice, and 38.6% were discharged home. After adjusting for other relevant variables, renal dysfunction was independently associated with an increased risk of in-hospital mortality that was highest among those with eGFR <15 without dialysis (odds ratio, 2.52; 95% confidence interval, 2.07–3.07). An eGFR 15 to 29 (odds ratio, 0.82; 95% confidence interval, 0.78–0.87), eGFR <15 (odds ratio, 0.72; 95% confidence interval, 0.61–0.86), and dialysis (odds ratio, 0.86; 95% confidence interval, 0.79–0.94) remained associated with lower odds of being discharged home. In addition, the associations of several clinical and demographic factors with outcomes varied by eGFR level.

Conclusions—
eGFR on admission is an important predictor of poststroke short-term outcomes.
Predictors and Clinical Impact of Incident Lacunes in Cerebral Autosomal Dominant Arteriopathy With Subcortical Infarcts and Leukoencephalopathy
Authors: Ling Yifeng , De Guio François , Duering Marco , Jouvent Eric , Hervé Dominique , Godin Ophélia , Dichgans Martin , Chabriat Hugues 
Published: December 2016

Background and Purpose—
Previous studies in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy showed that accumulation of lacunes strongly relate to clinical severity. However, the potential predictors of incident lacunes and their clinical consequences over a short time frame have not been investigated. This study aimed to determine the predictors and clinical impact of such lesions in a large cohort of patients.

Methods—
Two hundred and six NOTCH3 mutation carriers (mean age, 49.5±10.6 years) were followed up over 3 years. Incident lacunes were identified using difference imaging from 3-dimensional T1 images. Clinical events and change in different clinical scores such as the Mattis Dementia Rating Scale, Modified Rankin Scale, Barthel index, and time to complete part A and part B of Trail Making Test were recorded. Associations were analyzed with multivariable logistic regression analysis and ANCOVA.

Results—

Over a mean period of 3.4±0.7 years, incident lacunes occurred in 51 of 206 patients. Both the number of lacunes (
P
<0.0001) and systolic blood pressure at baseline (
P
<0.01) were independent predictors of incident lacunes during follow-up. The results were still significant after excluding patients with systolic blood pressure >140 mm Hg. Incident lacunes were also associated with incident stroke and with change in time to complete Trail Making Test part B, initiation/perseveration subscale of the Mattis Dementia Rating Scale and Barthel Index over the study period.

Conclusions—
Systolic blood pressure and the number of prevalent lacunes are independent predictors of incident lacunes in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. These lesions mainly impact executive performances and functional independence over 3 years.
A novel mechanism regulating human platelet activation by MMP-2–mediated PAR1 biased signaling
Authors: Sebastiano Manuela , Momi Stefania , Falcinelli Emanuela , Bury Loredana , Hoylaerts Marc F. , Gresele Paolo 
Published: December 2016

Key PointsActive MMP-2 enhances platelet activation by cleaving PAR1 at an extracellular site different from the thrombin cleavage site. The novel PAR1-tethered ligand exposed by MMP-2 selectively stimulates PAR1-dependent Gq and G12/13 pathway activation.
How I treat anemia in pregnancy: iron, cobalamin, and folate
Authors: Achebe Maureen M. , Gafter-Gvili Anat 
Published: December 2016

AbstractAnemia of pregnancy, an important risk factor for fetal and maternal morbidity, is considered a global health problem, affecting almost 50% of pregnant women. In this article, diagnosis and management of iron, cobalamin, and folate deficiencies, the most frequent causes of anemia in pregnancy, are discussed. Three clinical cases are considered. Iron deficiency is the most common cause. Laboratory tests defining iron deficiency, the recognition of developmental delays and cognitive abnormalities in iron-deficient neonates, and literature addressing the efficacy and safety of IV iron in pregnancy are reviewed. An algorithm is proposed to help clinicians diagnose and treat iron deficiency, recommending oral iron in the first trimester and IV iron later. Association of folate deficiency with neural tube defects and impact of fortification programs are discussed. With increased obesity and bariatric surgery rates, prevalence of cobalamin deficiency in pregnancy is rising. Low maternal cobalamin may be associated with fetal growth retardation, fetal insulin resistance, and excess adiposity. The importance of treating cobalamin deficiency in pregnancy is considered. A case of malarial anemia emphasizes the complex relationship between iron deficiency, iron treatment, and malaria infection in endemic areas; the heightened impact of combined etiologies on anemia severity is highlighted.
Abnormal joint and bone wound healing in hemophilia mice is improved by extending factor IX activity after hemarthrosis
Authors: Sun Junjiang , Hua Baolai , Livingston Eric W. , Taves Sarah , Johansen Peter B. , Hoffman Maureane , Ezban Mirella , Monroe Dougald M. , Bateman Ted A. , Monahan Paul E. 
Published: December 2016

Key Points
Joint and bone healing abnormalities are demonstrated in hemophilic mice that are not solely because of the amount of blood in their joints. Following initial hemostasis, extended FIX activity is needed in the week after hemarthrosis to normalize osteochondral healing.
Comparison of a teratogenic transcriptome-based predictive test based on human embryonic versus inducible pluripotent stem cells
Authors: Shinde Vaibhav , Perumal Srinivasan Sureshkumar , Henry Margit , Rotshteyn Tamara , Hescheler Jürgen , Rahnenführer Jörg , Grinberg Marianna , Meisig Johannes , Blüthgen Nils , Waldmann Tanja , Leist Marcel , Hengstler Jan Georg , Sachinidis Agapios 
Published: December 2016

Abstract
Background
Human embryonic stem cells (hESCs) partially recapitulate early embryonic three germ layer development, allowing testing of potential teratogenic hazards. Because use of hESCs is ethically debated, we investigated the potential for human induced pluripotent stem cells (hiPSCs) to replace hESCs in such tests.

Methods
Three cell lines, comprising hiPSCs (foreskin and IMR90) and hESCs (H9) were differentiated for 14 days. Their transcriptome profiles were obtained on day 0 and day 14 and analyzed by comprehensive bioinformatics tools.

Results
The transcriptomes on day 14 showed that more than 70% of the “developmental genes” (regulated genes with > 2-fold change on day 14 compared to day 0) exhibited variability among cell lines. The developmental genes belonging to all three cell lines captured biological processes and KEGG pathways related to all three germ layer embryonic development. In addition, transcriptome profiles were obtained after 14 days of exposure to teratogenic valproic acid (VPA) during differentiation. Although the differentially regulated genes between treated and untreated samples showed more than 90% variability among cell lines, VPA clearly antagonized the expression of developmental genes in all cell lines: suppressing upregulated developmental genes, while inducing downregulated ones. To quantify VPA-disturbed development based on developmental genes, we estimated the “developmental potency” (D
p
) and “developmental index” (D
i
).

Conclusions
Despite differences in genes deregulated by VPA, uniform D
i
values were obtained for all three cell lines. Given that the D
i
values for VPA were similar for hESCs and hiPSCs, D
i
can be used for robust hazard identification, irrespective of whether hESCs or hiPSCs are used in the test systems.
IL-10 distinguishes a unique population of activated, effector-like CD8+ T cells in murine acute liver inflammation
Authors: Rood Julia E , Canna Scott W , Weaver Lehn K , Tobias John W , Behrens Edward M 
Published: December 2016

Abstract
Immune-mediated liver injury is a central feature of hyperinflammatory diseases, such as hemophagocytic syndromes, yet the immunologic mechanisms underlying those processes are incompletely understood. In this study, we used the toll-like receptor 9 (TLR9)–mediated model of a hemophagocytic syndrome known as macrophage activation syndrome (MAS) to dissect the predominant immune cell populations infiltrating the liver during inflammation. We identified CD8+ T cells that unexpectedly produce interleukin-10 (IL-10) in addition to interferon-γ (IFN-γ) as a major hepatic population induced by TLR9 stimulation. Despite their ability to produce this anti-inflammatory cytokine, IL-10+ hepatic CD8+ T cells in TLR9–MAS mice did not resemble CD8+ T suppressor cells. Instead, the induction of these cells occurred independently of antigen stimulation and was partially dependent on IFN-γ. IL-10+ hepatic CD8+ T cells demonstrated an activated phenotype and high turnover rate, consistent with an effector-like identity. Transcriptional analysis of this population confirmed a gene signature of effector CD8+ T cells yet suggested responsiveness to liver injury–associated growth factors. Together, these findings suggest that IL-10+ CD8+ T cells induced by systemic inflammation to infiltrate the liver have initiated an inflammatory, rather than regulatory, program and may thus have a pathogenic role in severe, acute hepatitis.