bluuebunny/crossref_metadata_2025_split huggingface dataset:
Preoperative criterion identifying a low‐risk group for lymph node metastasis in intrahepatic cholangiocarcinoma
Authors: Yoh Tomoaki , Hatano Etsuro , Seo Satoru , Terajima Hiroaki , Uchida Yoichiro , Taura Kojiro , Yasuchika Kentaro , Uemoto Shinji 
Published: April 2018

AbstractBackgroundImaging study cannot identify patients with potential low‐risk for lymph node (LN) metastasis in intrahepatic cholangiocarcinoma (ICC). The purpose of this study was to identify a low‐risk group for LN metastasis in ICC using preoperatively available factors.MethodsData from 127 consecutive patients, who underwent curative intent surgery for ICC at Kyoto University Hospital and Kitano Hospital between 2002 and 2016, were retrospectively analyzed. By using only preoperative data, multiple linear regression model for predicting LN metastasis was developed.ResultsForty‐three patients exhibited LN metastasis (33.9%). Serum CA19‐9 levels ≥37 IU/ml, ICC with hilar invasion, and LN swelling were identified as independent preoperative predictors of LN metastasis. The prediction model for LN metastasis using these three factors revealed good discrimination (area under the receiver operating characteristics curve 0.874, P < 0.001). Negative for all three factors (i.e. CA19‐9 levels <37 IU/ml, peripheral ICC and no LN swelling) identified 35 patients (27.6%) as a low‐risk group, with the false negative rate of 2.3%.ConclusionsWe proposed a preoperative criterion for predicting LN metastasis, giving rise to the identification of ICC patients who showed a low‐risk of LN metastasis.
Molecular Substantiation and Drug Efficacy of Relatively High Molecular Weight S‐BINOLs; Appraised as Breast Cancer Medication and PI3Kinase Inhibitors
Authors: Muralidharan Vivek Panyam , Alagumuthu Manikandan , Arumugam Sivakumar , Iyer Sathiyanarayanan Kulathu 
Published: April 2018

Relatively high molecular weight S‐BINOLs with substituted functional groups were synthesized, and structures were elucidated by FTIR, 1H nuclear magnetic resonance, 13C nuclear magnetic resonance, and HRMS. As a preliminary step, the compounds were docked into the active site of phosphoinositide3‐kinase (PI3Kinase) (Protein Data Bank ID: 2IUG) that is a crucial regulator of apoptosis or programmed cell death. To ensure the PI3Kinase inhibition, because it was predicted as the most suitable bioactivity of these compounds, a competitive ELISA PI3Kinase inhibition study was carried out. Compounds 3, 4a, 4b, and 6 were assessed for cytotoxicity/antiproliferative effects on MCF‐7 (breast cancer) and HCT116 (colon cancer) cell lines. In the docking studies, excellent binding affinities of 3, 4a, 4b, and 6 (−11.36, −14.52, −14.86, and −21.76 kcal/mol, respectively) and the inhibitory constants (ki) (4.75 nM, 81.64 pM, 78.23 pM, and 14.24 pM, respectively) encouraged us to carry out anticancer studies further. Excellent inhibitory values were obtained in the range of 82–90% relative activity and IC50 range of 5–12 nM. In the cytotoxicity, the relative inhibition activity was remarkably found high in MCF‐7 cell lines as 89.14% (6), 82.18% (4b), 80.46% (3), and 74.78% (4a) with the IC50 range of 0.02–0.18 μM. No compounds were found inactive for the proposed activity in this study. The Structure Activity Relationship studies prove that compounds 3, 4a, 4b, and 6 are specific PI3Kinase inhibitors with the competence to cure breast cancers.
Shaping eosinophil identity in the tissue contexts of development, homeostasis, and disease
Authors: Abdala-Valencia Hiam , Coden Mackenzie E , Chiarella Sergio E , Jacobsen Elizabeth A , Bochner Bruce S , Lee James J , Berdnikovs Sergejs 
Published: April 2018

AbstractEosinophils play homeostatic roles in different tissues and are found in several organs at a homeostatic baseline, though their tissue numbers increase significantly in development and disease. The morphological, phenotypical, and functional plasticity of recruited eosinophils are influenced by the dynamic tissue microenvironment changes between homeostatic, morphogenetic, and disease states. Activity of the epithelial-mesenchymal interface, extracellular matrix, hormonal inputs, metabolic state of the environment, as well as epithelial and mesenchymal-derived innate cytokines and growth factors all have the potential to regulate the attraction, retention, in situ hematopoiesis, phenotype, and function of eosinophils. This review examines the reciprocal relationship between eosinophils and such tissue factors, specifically addressing: (1) tissue microenvironments associated with the presence and activity of eosinophils; (2) non-immune tissue ligands regulatory for eosinophil accumulation, hematopoiesis, phenotype, and function (with an emphasis on the extracellular matrix and epithelial–mesenchymal interface); (3) the contribution of eosinophils to regulating tissue biology; (4) eosinophil phenotypic heterogeneity in different tissue microenvironments, classifying eosinophils as progenitors, steady state eosinophils, and Type 1 and 2 activated phenotypes. An appreciation of eosinophil regulation by non-immune tissue factors is necessary for completing the picture of eosinophil immune activation and understanding the functional contribution of these cells to development, homeostasis, and disease.Review on the two-way communication between tissue and eosinophils, discussing eosinophil heterogeneity in the framework of biological processes occurring in different tissue states.
Oxidized LDL phagocytosis during foam cell formation in atherosclerotic plaques relies on a PLD2–CD36 functional interdependence
Authors: Ganesan Ramya , Henkels Karen M , Wrenshall Lucile E , Kanaho Yasunori , Di Paolo Gilbert , Frohman Michael A , Gomez-Cambronero Julian 
Published: April 2018

AbstractThe uptake of cholesterol carried by low-density lipoprotein (LDL) is tightly controlled in the body. Macrophages are not well suited to counteract the cellular consequences of excess cholesterol leading to their transformation into “foam cells,” an early step in vascular plaque formation. We have uncovered and characterized a novel mechanism involving phospholipase D (PLD) in foam cell formation. Utilizing bone marrow-derived macrophages from genetically PLD deficient mice, we demonstrate that PLD2 (but not PLD1)-null macrophages cannot fully phagocytose aggregated oxidized LDL (Agg-Ox-LDL), which was phenocopied with a PLD2-selective inhibitor. We also report a role for PLD2 in coupling Agg-oxLDL phagocytosis with WASP, Grb2, and Actin. Further, the clearance of LDL particles is mediated by both CD36 and PLD2, via mutual dependence on each other. In the absence of PLD2, CD36 does not engage in Agg-Ox-LDL removal and when CD36 is blocked, PLD2 cannot form protein–protein heterocomplexes with WASP or Actin. These results translated into humans using a GEO database of microarray expression data from atheroma plaques versus normal adjacent carotid tissue and observed higher values for NFkB, PLD2 (but not PLD1), WASP, and Grb2 in the atheroma plaques. Human atherectomy specimens confirmed high presence of PLD2 (mRNA and protein) as well as phospho-WASP in diseased arteries. Thus, PLD2 interacts in macrophages with Actin, Grb2, and WASP during phagocytosis of Agg-Ox-LDL in the presence of CD36 during their transformation into “foam cells.” Thus, this study provides new molecular targets to counteract vascular plaque formation and atherogenesis.
Kindlin-3 negatively regulates the release of neutrophil extracellular traps
Authors: Xu Zhen , Ni Beiwen , Cao Zhongyuan , Zielonka Jacek , Gao Juan , Chen Fangyuan , Kalyanaraman Balaraman , White Gilbert C , Ma Yan-Qing 
Published: April 2018

Abstract
Neutrophils fight infections by generating reactive oxygen species (ROS) and extracellular traps (NETs). However, how neutrophils modulate ROS/NET generation is mechanistically unclear. Kindlin-3, an essential integrin activator expressed in hematopoietic cells, is required to support integrin-mediated neutrophil recruitment during inflammation. Here, we report a novel role of kindlin-3 in regulating ROS/NET generation in neutrophils. When overexpressing kindlin-3 in neutrophil-like differentiated HL-60 cells (HL-60N), ROS/NET generation from these cells were significantly suppressed. Interestingly, overexpression of a kindlin-3 mutant that is defective for interacting with integrins in HL-60N cells still inhibited ROS/NET generation, suggesting that the role of kindlin-3 in inhibiting ROS/NET signaling may be independent of its binding to integrins. Consistently, knockdown of kindlin-3 in HL-60N cells led to enhanced ROS/NET generation. In addition, bone marrow neutrophils isolated from kindlin-3-deficient mice showed elevated ROS/NET generation when compared with WT counterparts. As expected, overexpression of exogenous kindlin-3 in mouse neutrophils could suppress NET release ex vivo and in vivo. Collectively, these results demonstrate that kindlin-3 in neutrophils is involved in modulating the ROS/NET signaling, providing a novel mechanism for fine-tuning neutrophil behaviors during inflammation.
Kindlin-3 is a novel regulator for fine-tuning the generation of ROS/NETs in neutrophils during inflammation.
miRNA regulation of innate immunity
Authors: Momen-Heravi Fatemeh , Bala Shashi 
Published: April 2018

Abstract
MicroRNAs (miRNAs) are small noncoding RNA and are pivotal posttranscriptional regulators of both innate and adaptive immunity. They act by regulating the expression of multiple immune genes, thus, are the important elements to the complex immune regulatory network. Deregulated expression of specific miRNAs can lead to potential autoimmunity, immune tolerance, hyper-inflammatory phenotype, and cancer initiation and progression. In this review, we discuss the contributory pathways and mechanisms by which several miRNAs influence the development of innate immunity and fine-tune immune response. Moreover, we discuss the consequence of deregulated miRNAs and their pathogenic implications.
PKD regulates actin polymerization, neutrophil deformability, and transendothelial migration in response to fMLP and trauma
Authors: Wille Christoph , Eiseler Tim , Langenberger Sven-Thorben , Richter Julia , Mizuno Kensaku , Radermacher Peter , Knippschild Uwe , Huber-Lang Markus , Seufferlein Thomas , Paschke Stephan 
Published: April 2018

AbstractNeutrophils are important mediators of the innate immune defense and of the host response to a physical trauma. Because aberrant infiltration of injured sites by neutrophils was shown to cause adverse effects after trauma, we investigated how neutrophil infiltration could be modulated at the cellular level. Our data indicate that protein kinase D (PKD) is a vital regulator of neutrophil transmigration. PKD phosphorylates the Cofilin-phosphatase Slingshot-2L (SSH-2L). SSH-2L in turn dynamically regulates Cofilin activity and actin polymerization in response to a chemotactic stimulus for neutrophils, for example, fMLP. Here, we show that inhibition of PKD by two specific small molecule inhibitors results in broad, unrestricted activation of Cofilin and strongly increases the F-actin content of neutrophils even under basal conditions. This phenotype correlates with a significantly impaired neutrophil deformability as determined by optical stretcher analysis. Consequently, inhibition of PKD impaired chemotaxis as shown by reduced extravasation of neutrophils. Consequently, we demonstrate that transendothelial passage of both, neutrophil-like NB4 cells and primary PMNs recovered from a hemorrhagic shock trauma model was significantly reduced. Thus, inhibition of PKD may represent a promising modulator of the neutrophil response to trauma.Protein Kinase D coordinates actin polymerization, neutrophil deformability and transendothelial migration via its substrate Slingshot2 and Cofilin.
Monocyte function in patients with myelodysplastic syndrome
Authors: Pollyea Daniel A , Hedin Brenna R , O’Connor Brian P , Alper Scott 
Published: April 2018

AbstractMyelodysplastic syndrome (MDS) is a malignant hematopoietic stem cell disorder that frequently evolves into acute myeloid leukemia (AML). Patients with MDS are prone to infectious complications, in part due to the presence of severe neutropenia and/or neutrophil dysfunction. However, not all patients with neutropenia become infected, suggesting that other immune cells may compensate in these patients. Monocytes are also integral to immunologic defense; however, much less is known about monocyte function in patients with MDS. In the current study, we monitor the composition of peripheral blood monocytes and several aspects of monocyte function in MDS patients, including HLA-DR expression, LPS-induced inflammatory cytokine production, and phagocytosis. We find that monocytes from MDS patients exhibit relatively normal innate immune functions compared to monocytes from healthy control subjects. We also find that HLA-DR expression is moderately increased in monocytes from MDS patients. These results suggest that monocytes could compensate for other immune deficits in MDS patients to help fight infection. We also find that the range of immune functions in monocytes from MDS patients correlates with several key clinical parameters, including blast cell count, monocyte count, and revised International Prognostic Scoring System score, suggesting that disease severity impacts monocyte function in MDS patients.Monocytes from patients with Myelodysplastic Syndrome exhibit relatively normal immune function and could contribute to infection control in these patients.
Fipronil recognition by the FA1 site of human serum albumin
Authors: Ascenzi Paolo , Leboffe Loris , Toti Daniele , Polticelli Fabio , Trezza Viviana 
Published: April 2018

AbstractFipronil is a broad‐spectrum pesticide widely used in agriculture, horticulture, and forestry. Because fipronil can cause a variety of toxic effects in animals and humans, its use is authorized as a pesticide in veterinary medicinal products for pets, but not for the treatment of livestock animals whose products are intended for consumption. Recently, however, the presence of fipronil residues has been detected in the eggs and meat of layer hens from farms located in different European countries. Given the relevance of fipronil toxicity for human health, it is important to gain information concerning its fate in the human body, including its binding mode to human serum albumin (HSA), the most abundant protein in plasma. Here, the inhibition of heme‐Fe(III) binding to the fatty acid site 1 (FA1) of HSA by fipronil is reported. Docking simulations support functional data, indicating that the FA1 site is the preferential cleft for fipronil recognition by HSA. The affinity of fipronil for HSA (Kf = 1.9 × 10−6 M, at pH 7.3, and 20.0°C) may be relevant in vivo. Indeed, HSA could play a pivotal role in fipronil transport and scavenging, thus reducing the pesticide‐free plasmatic levels, with consequent reduced systemic toxicity. In turn, fipronil binding to the FA1 site of HSA could impair the recognition of endogenous and exogenous molecules.
Study on a 65‐mer peptide mimetic enzyme with GPx and SOD dual function
Authors: Yin Juxin , Zhuang Jianjian , Lv Shaowu , Mu Ying 
Published: April 2018

AbstractExcessive reactive oxygen species (ROS) levels are harmful to the body. The peroxidase, GPx, and the superoxide dismutase, SOD, are important antioxidant enzymes for preventing ROS‐induced damage. Se‐CuZn‐65P is an enzyme mimetic with dual GPx and SOD antioxidant function. However, currently, its production is mainly based on the cysteine auxotrophic expression technique, which is inefficient, expensive, and time consuming. In this study, we combined protein engineering and the chemical mutation method to synthesize Se‐CuZn‐65P. The DNA sequence encoding the 65 amino acid peptide with the desired sequence transformations to incorporate the SOD and the GPx catalytic sites was cloned and expressed in a soluble protein expression vector. The protein yield increased up to 152 mg/L, which is 10 times higher than in previous studies. The SOD and GPx activity of Se‐CuZn‐65P was high (1181 U/mg and 753 U/μmol, respectively). The binding constant of glutathione was 5.6 × 104 L·mol−1, which shows that Se‐CuZn‐65P efficiently catalyzed hydrogen peroxide reduction by glutathione. Mitochondrial damage experiments confirmed the double protective role of the Se‐CuZn‐65P peptide and demonstrated functional synergy between the SOD and the GPx domains, which indicates its potential to be used in the treatment of ROS‐related diseases. Our research may give a new thought to increase the yield of mimic.
Improving lymph node characterization in staging malignant lymphoma using first‐order ADC texture analysis from whole‐body diffusion‐weighted MRI
Authors: De Paepe Katja N. , De Keyzer Frederik , Wolter Pascal , Bechter Oliver , Dierickx Daan , Janssens Ann , Verhoef Gregor , Oyen Raymond , Vandecaveye Vincent 
Published: April 2018

BackgroundCorrect staging and treatment initiation in malignant lymphoma depends on accurate lymph node characterization. However, nodal assessment based on conventional and diffusion‐weighted (DWI) MRI remains challenging, particularly in smaller nodes.PurposeTo evaluate first‐order apparent diffusion coefficient (ADC) texture parameters compared to mean ADC for lymph node characterization in non‐Hodgkin lymphoma (NHL) using whole‐body DWI (WB‐DWI).Study TypeRetrospective.PopulationTwenty‐eight patients with NHL.Field Strength/Sequence3T whole‐body DWI using two b‐values (0–1000 s/mm2).AssessmentRegions of interest were drawn on the three most hyperintense lymph nodes on b1000‐images, irrespective of size, in all nodal body regions. Diagnostic performance of mean ADC (ADCmean) was compared with first‐order ADC texture parameters: standard deviation (ADCstdev), kurtosis (ADCkurt), and skewness (ADCskew). Additional subanalyses focused on the accuracy of ADCmean and ADC texture parameters in different lymph node volumes and nodal regions.Statistical TestsBenign and malignant nodes were compared using Mann–Whitney U‐tests with 18‐Fluoro‐deoxyglucose positron emission tomography computed tomography and bone marrow biopsy as reference standard. Receiver operating characteristic analyses were performed to determine cutoff values and calculate sensitivity, specificity, accuracy, and positive and negative predictive value (PPV, NPV).ResultsADCmean (P = 0.008), ADCskew and ADCkurt differed significantly between benign and malignant nodes (P < 0.001), while ADCstdev didn't (P = 0.21). ADCskew was the best discriminating parameter, with 79% sensitivity, 86% specificity, 83% accuracy, 85% PPV, and 81% NPV. In every volume category, ADCskew yielded the highest accuracy (88% in 0–25th percentile volume, 75% in 25th–75th percentile, 93% in 75–100th percentile). On a per‐region basis, ADCskew accuracy varied 13.6% between nodal regions, while ADCmean, ADCkurt, and ADCstdev showed interregional variation of 17.4%, 20.3%, and 14.9%, respectively.Data ConclusionFirst‐order ADC texture analysis with WB‐DWI improved lymph node characterization compared to ADCmean. ADCskew was the most accurate and robust discriminatory parameter over all lymph node volumes and nodal body regions.Level of Evidence: 3Technical Efficacy: Stage 2J. Magn. Reson. Imaging 2018;48:897–906.
Modified breath‐hold compressed‐sensing 3D MR cholangiopancreatography with a small field‐of‐view and high resolution acquisition: Clinical feasibility in biliary and pancreatic disorders
Authors: Zhu Liang , Xue Huadan , Sun Zhaoyong , Qian Tianyi , Weiland Elisabeth , Kuehn Bernd , Asbach Patrick , Hamm Bernd , Jin Zhengyu 
Published: April 2018

BackgroundCompressed‐sensing (CS) accelerated 3D MR cholangiopancreatography (MRCP) could be acquired in both navigator‐triggered (NT) and breath‐hold (BH) mode, but the latter has been considered inferior in depicting pancreatic duct and diagnosing pancreatic duct‐related diseases.PurposeTo prospectively evaluate the clinical feasibility of a modified 3D BH‐CS‐MRCP prototype protocol with small field‐of‐view (FOV) and higher spatial resolution, and to compare its performance to the original BH‐CS‐MRCP and NT‐CS‐MRCP.Study TypeProspective cohort study.PopulationEighty‐two patients with suspected pancreaticobiliary diseases (46 male, median age, 55 years, range, 16–79 years), including seven noncooperative patients.Field Strength/Sequence3T, CS‐MRCP.AssessmentThree protocols were performed in random order in each patient. Acquisition time of each protocol was recorded. Image quality, background suppression, duct visibility, and diagnostic confidence with duct anatomic variations and duct‐related pathologies were rated on a 5‐point scale by two blinded radiologists independently.Statistical TestsThe Wilcoxon signed‐rank test was used to compare the intraindividual difference. Interobserver agreement was determined using kappa coefficients. The diagnostic performance was calculated using receiver operating characteristic curves.ResultsAcquisition time was 17 seconds for both BH‐CS‐MRCP protocols, and 127.5 ± 36.9 seconds for NT‐CS‐MRCP. In 75 cooperative patients, the incidence of major artifacts was low for all protocols (5.3–8.0%). Background suppression was similar with the two BH‐CS‐MRCP protocols (3.67 ± 0.77 for original BH‐CS‐MRCP and 3.70 ± 0. 57 for modified BH‐CS‐MRCP, respectively), both inferior to the NT‐CS‐MRCP protocol (4.41 ± 0.68, P < 0.001 for both). Modified BH‐CS‐MRCP and NT‐CS‐MRCP depicted pancreatic duct and second‐level branches of biliary duct better than original BH‐CS‐MRCP (all P < 0.01). The diagnostic performance for detecting bile duct abnormalities was similar for all protocols (P = 0.53–0.87), whereas for detecting pancreatic duct abnormalities, modified BH‐CS‐MRCP and NT‐CS‐MRCP had significantly better performance compared to original BH‐CS‐MRCP (both P < 0.01). In seven noncooperative patients, NT‐CS‐MRCP had superior image quality than both BH protocols (both P < 0.01).Data ConclusionModified BH‐CS‐MRCP is feasible for pancreatic and biliary disorders. NT‐CS‐MRCP might be more useful in noncooperative patients.Level of Evidence: 2Technical Efficacy: Stage 2J. Magn. Reson. Imaging 2018;47:1389–1399.
Citalopram attenuated neurobehavioral, biochemical, and metabolic alterations in transient middle cerebral artery occlusion model of stroke in male Wistar rats
Authors: Gupta Sangeetha , Upadhayay Deepti , Sharma Uma , Jagannathan Naranamangalam R. , Gupta Yogendra Kumar 
Published: April 2018

AbstractOxidative stress and inflammation are implicated as cardinal mechanisms of neuronal death following stroke. In the present study citalopram (Cit) was investigated in a 2 h middle cerebral artery occlusion (MCAo) model of stroke in male Wistar rats. Pretreatment, posttreatment (Post Cit) and pre plus posttreatment (Pre + Post Cit) with Cit were evaluated for its neuroprotective effect. In pretreatment protocol, effect of Cit at three doses (2, 4, and 8 mg/kg) administered i.p., 1 h prior to MCAo was evaluated using neurological deficit score (NDS), motor deficit paradigms, and cerebral infarction 24 h post‐MCAo. In posttreatment and pre plus posttreatment protocol, the effective dose of Cit (4 mg/kg) was administered i.p., 0.5 h post‐reperfusion (Post Cit) only, and 1 h prior to MCAo and again at 0.5 h post‐reperfusion (Pre + Post Cit), respectively. These two groups were assessed for NDS and cerebral infarction. Though NDS was significantly reduced in both Post Cit and Pre + Post Cit groups, significant reduction in cerebral infarction was evident only in Pre + Post Cit group. Infarct volume assessed by magnetic resonance imaging was significantly attenuated in Pre + Post Cit group (10.6 ± 1.1%) compared to MCAo control group (18.5 ± 3.0%). Further, Pre + Post Cit treatment significantly altered 17 metabolites along with attenuation of malondialdehyde, reduced glutathione, matrix metalloproteinases, and apoptotic markers as compared to MCAo control. These results support the neuroprotective effect of Cit, mediated through amelioration of oxidative stress, inflammation, apoptosis, and altered metabolic profile.