bluuebunny/crossref_metadata_2025 huggingface dataset:
Substituent effects on chiral resolutions of derivatized 1‐phenylalkylamines by heptakis(2,3‐di‐O‐methyl‐6‐O‐tert‐butyldimethylsilyl)‐β‐cyclodextrin GC stationary phase
Authors: Issaraseriruk Natthapol , Sritana‐anant Yongsak , Shitangkoon Aroonsiri
Published: April 2018

Chiral resolutions of trifluoroacetyl‐derivatized 1‐phenylalkylamines with different type and position of substituent were investigated by capillary gas chromatography by using heptakis(2,3‐di‐O‐methyl‐6‐O‐tert‐butyldimethylsilyl)‐β‐cyclodextrin diluted in OV‐1701 as a chiral stationary phase. The influence of column temperature on retention and enantioselectivity was examined. All enantiomers of meta‐substituted analytes as well as fluoro‐substituted analytes could be resolved. Temperature had a favorable influence on enantioselectivity for small amines with substituents at the ortho‐position. The type of substituent at the stereogenic center of amines also had a crucial effect as the ethyl group led to poor enantioseparation. Among all analytes studied, trifluoroacetyl‐derivatized 1‐(2′‐fluorophenyl)ethylamine exhibited baseline resolution with the shortest analysis time.
Robust precision matrix estimation via weighted median regression with regularization
Authors: Chun Hyonho , Lee Myung Hee , Kim Sung‐Ho , Oh Jihwan
Published: April 2018

A precision matrix is an important parameter of interests because its elements describe useful association information among multiple variables, which has a wide variety of applications. For example, it is used for inferring gene regulation networks in genomic studies and stock association networks in financial studies. However, in many cases, the precision matrix needs to be robustly estimated due to the presence of outliers. We propose estimating a sparse scaled precision matrix via weighted median regression with regularization. Our weighted median regression approach is consistent under various distributional assumptions including multivariate t‐ or contaminated Gaussian distributions. This fact is illustrated with simulation studies and a real data analysis with monthly stock return data.The Canadian Journal of Statistics 46: 265–278; 2018 © 2018 Statistical Society of Canada
Identification of Potentially Potent Heme Oxygenase 1 Inhibitors through 3D‐QSAR Coupled to Scaffold‐Hopping Analysis
Authors: Floresta Giuseppe , Amata Emanuele , Dichiara Maria , Marrazzo Agostino , Salerno Loredana , Romeo Giuseppe , Prezzavento Orazio , Pittalà Valeria , Rescifina Antonio
Published: April 2018

A 3D quantitative structure–activity relationship (3D‐QSAR) model for predicting the activity of heme oxygenase 1 (HO‐1) inhibitors was constructed with the aim of providing a useful tool for the identification, design, and optimization of novel HO‐1 inhibitors. The model was built using a set of 222 HO‐1 inhibitors recovered from the Heme Oxygenase Database (HemeOxDB) and developed with the software Forge. The present model showed high statistical quality, as confirmed by its robust predictive potential and satisfactory descriptive capability. The drawn‐up 3D map enables prompt visual comprehension of the electrostatic, hydrophobic, and shaping features underlying the interactions with HO‐1 inhibitors. A theoretical approach for the generation of new lead compounds was performed by means of scaffold‐hopping analysis. For the first time, a 3D‐QSAR model is reported for this target, and was built with a number of chemically diverse HO‐1 inhibitors; the model also accounts well for individual ligand affinities. The new model contains all of the inhibitors published to date with high potency toward the selected target and contains a complete pharmacophore description of the binding cavity of HO‐1. These features will ensure application in accelerating the identification of new potent and selective HO‐1 inhibitors.
The impact of BCR‐ABL1 transcript type on tyrosine kinase inhibitor responses and outcomes in patients with chronic myeloid leukemia
Authors: Ercaliskan Abdulkadir , Eskazan A. Emre
Published: April 2018

Although the majority of patients with chronic myeloid leukemia do well with treatment with tyrosine kinase inhibitors (TKIs), some patients still have inferior outcomes. There are many factors that might play a part, including the different BCR‐ABL1 transcript types at baseline. The current study was performed to determine the possible impact of different transcripts on the treatment responses and outcomes of patients with chronic myeloid leukemia who are receiving TKI therapy. The authors performed a systematic literature search by using the terms “b2a2/b3a2,” “e13a2/e14a2,” or “transcript type.” e14a2 was the more common transcript type. The majority of the studies demonstrated no significant difference regarding age, sex, leukocyte counts, and hemoglobin levels between patients with the e13a2 and e14a2 transcripts. However, in approximately one‐half of the studies, the e14a2 transcript was associated with higher platelet counts. Almost no studies demonstrated a significant association between disease risk scores and transcript types. In the majority of studies, having the e14a2 transcript was associated with earlier, deeper, and higher molecular response rates. Although better event‐free survival was observed in patients with the e14a2 transcript in some of the studies, the majority demonstrated that transcript type did not have an impact on progression‐free and overall survival. Treatment‐free remission currently is a topic of much interest, and to the authors' knowledge there are limited data with conflicting results regarding the possible effects of transcript types on the outcomes of patients after discontinuation of TKIs. Because having the e14a2 transcript appears to be related to a favorable outcome, choosing second‐generation TKIs for frontline therapy might be a convenient approach in patients with chronic myeloid leukemia with the e13a2 transcript. The authors believe this finding warrants further investigation.
Pharmacokinetic Interaction Between Fingolimod and Carbamazepine in Healthy Subjects
Authors: David Olivier J. , Behrje Rhett , Pal Parasar , Hara Hisanori , Lates Christian D. , Schmouder Robert
Published: April 2018

This open‐label, single‐sequence study in healthy subjects investigated the effects of steady‐state carbamazepine on the pharmacokinetic (PK) profile of a single 2‐mg dose of fingolimod. In period 1, a single oral dose of fingolimod 2 mg (day 1) was followed by PK and safety assessments up to 36 days. In period 2, carbamazepine was administered in flexible, up‐titrated doses (600 mg twice daily maximum) for 49 days. Fingolimod was administered on day 35, followed by a study completion evaluation (day 71). The PK analysis included 23 of 26 of the enrolled subjects (88.5%). Coadministration of fingolimod at steady‐state carbamazepine concentrations resulted in increased fingolimod CL/F by 67% through the induction of CYP3A4, a cytochrome with negligible involvement in fingolimod clearance in an uninduced state. Fingolimod Cmax was reduced by 18% and AUCinf by 40%, as was T1/2 (106 vs 163 hours). A similar trend was observed for fingolimod‐P. Models linking fingolimod‐P blood concentrations to lymphocyte count or annual relapse rate suggest that such a decrease would have a low impact on the treatment effect. However, in the absence of efficacy data of fingolimod at doses lower than the therapeutic dose, their coadministration should be used with caution.
Quantifying shorebird habitat in managed wetlands by modeling shallow water depth dynamics
Authors: Schaffer‐Smith Danica , Swenson Jennifer J. , Reiter Matthew E. , Isola Jennifer E.
Published: April 2018

Over 50% of Western Hemisphere shorebird species are in decline due to ongoing habitat loss and degradation. In some regions of high wetland loss, shorebirds are heavily reliant on a core network of remaining human‐managed wetlands during migration journeys in the spring and fall. While most refuges have been designed and managed to match the habitat needs of waterfowl, shorebirds typically require much shallower water (<10 cm deep). Traditional static habitat modeling approaches at relatively coarse spatial and temporal resolution are insufficient to capture dynamic changes within this narrow water depth range. Our objectives were to (1) develop a method to quantify shallow water habitat distributions in inland non‐tidal wetlands, and (2) to assess how water management practices affect the amount of shorebird habitat in Sacramento National Wildlife Refuge Complex. We produced water depth distributions and modeled optimal habitat (<10 cm deep) within 23 managed wetlands using high‐resolution topography and fixed‐point water depth records. We also demonstrated that habitat availability, specifically suitable water depth ranges, can be tracked from satellite imagery and high‐resolution topography. We found that wetlands with lower topographic roughness may have a higher potential to provide shorebird habitat and that strategically reducing water levels could increase habitat extent. Over 50% of the wetlands measured provided optimal habitat across <10% of their area at the peak of migration in early April, and most provided a brief duration of shallow water habitat. Reducing water volumes could increase the proportion of optimal habitat by 1–1,678% (mean = 294%) compared to actual volumes measured at peak spring migration in 2016. For wetlands with a high habitat potential, beginning wetland drawdown earlier and extending drawdown time could dramatically improve habitat conditions at the peak of shorebird migration. Our approach can be adapted to track dynamic hydrologic changes at broader spatial scales as additional high‐resolution topographic (e.g., lidar, drone imagery photogrammetry) and optical remote sensing data (e.g., planet imagery, drone photography) become available.
Using imaging spectroscopy to detect variation in terrestrial ecosystem productivity across a water‐stressed landscape
Authors: DuBois Sean , Desai Ankur R. , Singh Aditya , Serbin Shawn P. , Goulden Michael L. , Baldocchi Dennis D. , Ma Siyan , Oechel Walter C. , Wharton Sonia , Kruger Eric L. , Townsend Philip A.
Published: April 2018

A central challenge to understanding how climate anomalies, such as drought and heatwaves, impact the terrestrial carbon cycle, is quantification and scaling of spatial and temporal variation in ecosystem gross primary productivity (GPP). Existing empirical and model‐based satellite broadband spectra‐based products have been shown to miss critical variation in GPP. Here, we evaluate the potential of high spectral resolution (10 nm) shortwave (400–2,500 nm) imagery to better detect spatial and temporal variations in GPP across a range of ecosystems, including forests, grassland‐savannas, wetlands, and shrublands in a water‐stressed region. Estimates of GPP from eddy covariance observations were compared against airborne hyperspectral imagery, collected across California during the 2013–2014 HyspIRI airborne preparatory campaign. Observations from 19 flux towers across 23 flight campaigns (102 total image‐flux tower pairs) showed GPP to be strongly correlated to a suite of spectral wavelengths and band ratios associated with foliar physiology and chemistry. A partial least squares regression (PLSR) modeling approach was then used to predict GPP with higher validation accuracy (adjusted R2 = 0.71) and low bias (0.04) compared to existing broadband approaches (e.g., adjusted R2 = 0.68 and bias = −5.71 with the Sims et al. model). Significant wavelengths contributing to the PLSR include those previously shown to coincide with Rubisco (wavelengths 1,680, 1,740, and 2,290 nm) and Vcmax (wavelengths 1,680, 1,722, 1,732, 1,760, and 2,300 nm). These results provide strong evidence that advances in satellite spectral resolution offer significant promise for improved satellite‐based monitoring of GPP variability across a diverse range of terrestrial ecosystems.
The impact of environmental factors in birdsong acquisition using automated recorders
Authors: Priyadarshani Nirosha , Castro Isabel , Marsland Stephen
Published: April 2018

The use of automatic acoustic recorders is becoming a principal method to survey birds in their natural habitats, as it is relatively noninvasive while still being informative. As with any other sound, birdsong degrades in amplitude, frequency, and temporal structure as it propagates to the recorder through the environment. Knowing how different birdsongs attenuate under different conditions is useful to, for example, develop protocols for deploying acoustic recorders and improve automated detection methods, an essential part of the research field that is becoming known as ecoacoustics. This article presents playback and recapture (record) experiments carried out under different environmental conditions using twenty bird calls from eleven New Zealand bird species in a native forest and an open area, answering five research questions: (1) How does birdsong attenuation differ between forest and open space? (2) What is the relationship between transmission height and birdsong attenuation? (3) How does frequency of birdsong impact the degradation of sound with distance? (4) Is birdsong attenuation different during the night compared to the day? and (5) what is the impact of wind on attenuation? Bird calls are complex sounds; therefore, we have chosen to use them rather than simple tones to ensure that this complexity is not missed in the analysis. The results demonstrate that birdsong transmission was significantly better in the forest than in the open site. During the night, the attenuation was at a minimum in both experimental sites. Transmission height affected the propagation of the songs of many species, particularly the flightless ones. The effect of wind was severe in the open site and attenuated lower frequencies. The reverberations due to reflective surfaces masked higher frequencies (8 kHz) in the forest even at moderate distances. The findings presented here can be applied to develop protocols for passive acoustic monitoring. Even though the attenuation can be generalized to frequency bands, the structure of the birdsong is also important. Selecting a reasonable sampling frequency avoids unnecessary data accumulation because higher frequencies attenuate more in the forest. Even at moderate distances, recorders capture significantly attenuated birdsong, and hence, automated analysis methods for field recordings need to be able to detect and recognize faint birdsong.
Understanding the Reactivity of Group 6 Metal (M = Cr, W) Alkynyl Fischer Carbene Complexes with Multi‐Reactive Masked Dienes
Authors: Collado Alba , Gómez‐Gallego Mar , Santiago Alicia , Sierra Miguel A.
Published: April 2018

Group 6 alkynyl Fischer carbene complexes behave as electrophiles with highly reactive masked dienes such as anthrone and 3‐hydroxy‐2‐pyrone, which also can react as bidentate nucleophiles. Both Cr0 and W0 alkynyl carbene complexes require tertiary amines to promote the formation of 1,4‐C‐addition products, but a marked dependence of the reactivity on the metal was observed. Although W0 complexes form exclusively the 1,4‐C‐adducts in the presence of a catalytic amount of base, Cr0 complexes lead to new anthrone‐derived bis‐carbene complexes, obtained by a sequential 1,4‐C‐ and 1,4‐O‐addition process with high diastereoselectivity and only in the presence of an excess of base. DFT computational studies show that the gap between the LUMO of the complex and the HOMO of the anthrone determines the differences in reactivity and that the stability of the intermediate metal allenyls formed after the initial 1,4‐addition is decisive for the outcome of the reaction.
Selective Determination of Verapamil in Pharmaceutics and Urine Using a Boron‐doped Diamond Electrode Coupled to Flow Injection Analysis with Multiple‐pulse Amperometric Detection
Authors: Barbosa Lima Amanda , Ferreira Lucas Franco , Barbosa Sandro Luiz , de Souza Gil Eric , Amorim Bezerra da Silva Rodrigo , Pio dos Santos Wallans Torres
Published: April 2018

This work presents a simple and low‐cost method for fast and selective determination of Verapamil (VP) in tablets and human urine samples using a boron‐doped diamond working electrode (BDD) coupled to a flow injection analysis system with multiple pulse amperometric detection (FIA‐MPA). The electrochemical behaviour of VP in 0.1 mol L−1 sulfuric acid showed three merged oxidation peaks at around +1.4 V and upon reverse scan, one reduction peak at 0.0 V (vs. Ag/AgCl). The MPA detection was performed applying a sequence of three potential pulses on BDD electrode: (1) at +1.6 V for VP oxidation, (2) at +0.2 V for reduction of the oxidized product and (3) at +0.1 V for cleaning of the working electrode surface. The FIA system was optimized with injection volume of 150 μL and flow rate of 3.5 mL min−1. The method showed a linear range from 0.8 to 40.0 μmol L−1 (R>0.99) with a low limit of detection of 0.16 μmol L−1, good repeatability (RSD<2.2 %; n=10) and sample throughput (45 h−1). Selective determination of VP in urine was performed at+0.2 V due to absence of interference from ascorbic and uric acids in this potential. The addition‐recovery tests in both samples were close to 100 % and the results were similar to an official method.
Electrocatalytic Activity of Nanohybrids Based on Carbon Nanomaterials and MFe2O4 (M=Co, Mn) towards the Reduction of Hydrogen Peroxide
Authors: Gutierrez Fabiana A. , Mazario Eva , Menéndez Nieves , Herrasti Pilar , Rubianes María D. , Zagal José H. , Yañez C. , Rivas Gustavo A. , Bollo Soledad , Recio F. Javier
Published: April 2018

We report the advantages of hybrid nanomaterials prepared with electrogenerated ferrites (MFe2O4; M: Co, Mn) and multi‐walled carbon nanotubes (MWCNTs) or thermally reduced graphene oxide (TRGO) on the electro‐reduction of hydrogen peroxide. Glassy carbon electrodes (GCE) modified with these hybrid nanomaterials dispersed in Nafion/isopropanol demonstrated a clear synergism on the catalytic reduction of reduction of hydrogen peroxide at pH 13.00. The intimate interaction between MFe2O4 and carbon nanomaterials allowed a better electronic transfer and a facilitated regeneration of M2+ at the carbon nanomaterials, reducing the charge transfer resistances for hydrogen peroxide reduction and increasing the sensitivities of the amperometric response.
Recombinant interleukin‐4 alleviates mechanical allodynia via injury‐induced interleukin‐4 receptor alpha in spinal microglia in a rat model of neuropathic pain
Authors: Okutani Hiroai , Yamanaka Hiroki , Kobayashi Kimiko , Okubo Masamichi , Noguchi Koichi
Published: April 2018

Glial cells play important roles in the development and maintenance of neuropathic pain. In particular, activated microglia in the spinal cord facilitate the hyper‐excitability of dorsal horn neurons after peripheral nerve injury via pro‐inflammatory molecules. In this study, we investigated the possible involvement of the anti‐inflammatory cytokine, interleukin‐4 (IL‐4), in neuropathic pain. We did not detect the expression of IL‐4 mRNA in the rat dorsal root ganglion or spinal cord; however, peripheral nerve injury induced the expression of IL‐4 receptor (IL‐4R) alpha mRNA in the spinal cord. A histological analysis revealed that nerve injury induced IL‐4R alpha mRNA in activated spinal microglia ipsilateral to the injury site. Additionally, the increases in IL‐4R alpha were coincident with the increased expression of phosphorylated signal transducer and activator of transcription 6 (pSTAT6) in spinal microglia. Intrathecal administration of recombinant IL‐4 suppressed mechanical hypersensitivity in neuropathic rats, and the analgesic effect of IL‐4 was accompanied by further enhancement of pSTAT6 expression in spinal microglia. Taken together, these results suggest that the adaptive responses of microglia to nerve injury involve both inflammatory and anti‐inflammatory signaling, including IL‐4R alpha and pSTAT6. These findings support that utilizing the endogenous anti‐nociceptive activity of IL‐4R alpha may modify the cell lineage of pro‐nociceptive microglia, thus providing a novel therapeutic strategy for neuropathic pain.
Genetic deletion of xCT attenuates peripheral and central inflammation and mitigates LPS‐induced sickness and depressive‐like behavior in mice
Authors: Albertini Giulia , Deneyer Lauren , Ottestad‐Hansen Sigrid , Zhou Yun , Ates Gamze , Walrave Laura , Demuyser Thomas , Bentea Eduard , Sato Hideyo , De Bundel Dimitri , Danbolt Niels C. , Massie Ann , Smolders Ilse
Published: April 2018

The communication between the immune and central nervous system (CNS) is affected in many neurological disorders. Peripheral injections of the endotoxin lipopolysaccharide (LPS) are widely used to study this communication: an LPS challenge leads to a biphasic syndrome that starts with acute sickness and is followed by persistent brain inflammation and chronic behavioral alterations such as depressive‐like symptoms. In vitro, the response to LPS treatment has been shown to involve enhanced expression of system
. This cystine‐glutamate antiporter, with xCT as specific subunit, represents the main glial provider of extracellular glutamate in mouse hippocampus. Here we injected male xCT knockout and wildtype mice with a single intraperitoneal dose of 5 mg/kg LPS. LPS‐injection increased hippocampal xCT expression but did not alter the mainly astroglial localization of the xCT protein. Peripheral and central inflammation (as defined by cytokine levels and morphological activation of microglia) as well as LPS‐induced sickness and depressive‐like behavior were significantly attenuated in xCT‐deficient mice compared with wildtype mice. Our study is the first to demonstrate the involvement of system
in peripheral and central inflammation in vivo and the potential therapeutic relevance of its inhibition in brain disorders characterized by peripheral and central inflammation, such as depression.
Distinguishable brain networks relate disease susceptibility to symptom expression in schizophrenia
Authors: Liu Zhaowen , Zhang Jie , Zhang Kai , Zhang Junying , Li Xiaojing , Cheng Wei , Li Mingli , Zhao Liansheng , Deng Wei , Guo Wanjun , Ma Xiaohong , Wang Qiang , Matthews Paul M. , Feng Jianfeng , Li Tao
Published: April 2018

Disease association studies have characterized altered resting‐state functional connectivities describing schizophrenia, but failed to model symptom expression well. We developed a model that could account for symptom severity and meanwhile relate this to disease‐related functional pathology. We correlated BOLD signal across brain regions and tested separately for associations with disease (disease edges) and with symptom severity (symptom edges) in a prediction‐based scheme. We then integrated them in an “edge bi‐color” graph, and adopted mediation analysis to test for causality between the disease and symptom networks and symptom scores. For first‐episode schizophrenics (FES, 161 drug‐naïve patients and 150 controls), the disease network (with inferior frontal gyrus being the hub) and the symptom‐network (posterior occipital‐parietal cortex being the hub) were found to overlap in the temporal lobe. For chronic schizophrenis (CS, 69 medicated patients and 62 controls), disease network was dominated by thalamocortical connectivities, and overlapped with symptom network in the middle frontal gyrus. We found that symptom network mediates the relationship between disease network and symptom scores in FEP, but was unable to define a relationship between them for the smaller CS population. Our results suggest that the disease network distinguishing core functional pathology in resting‐state brain may be responsible for symptom expression in FES through a wider brain network associated with core symptoms. We hypothesize that top–down control from heteromodal prefrontal cortex to posterior transmodal cortex contributes to positive symptoms of schizophrenia. Our work also suggests differences in mechanisms of symptom expression between FES and CS, highlighting a need to distinguish between these groups.
Functional connections between activated and deactivated brain regions mediate emotional interference during externally directed cognition
Authors: Di Plinio Simone , Ferri Francesca , Marzetti Laura , Romani Gian Luca , Northoff Georg , Pizzella Vittorio
Published: April 2018

Recent evidence shows that task‐deactivations are functionally relevant for cognitive performance. Indeed, higher cognitive engagement has been associated with higher suppression of activity in task‐deactivated brain regions ‐ usually ascribed to the Default Mode Network (DMN). Moreover, a negative correlation between these regions and areas actively engaged by the task is associated with better performance. DMN regions show positive modulation during autobiographical, social, and emotional tasks. However, it is not clear how processing of emotional stimuli affects the interplay between the DMN and executive brain regions. We studied this interplay in an fMRI experiment using emotional negative stimuli as distractors. Activity modulations induced by the emotional interference of negative stimuli were found in frontal, parietal, and visual areas, and were associated with modulations of functional connectivity between these task‐activated areas and DMN regions. A worse performance was predicted both by lower activity in the superior parietal cortex and higher connectivity between visual areas and frontal DMN regions. Connectivity between right inferior frontal gyrus and several DMN regions in the left hemisphere was related to the behavioral performance. This relation was weaker in the negative than in the neutral condition, likely suggesting less functional inhibitions of DMN regions during emotional processing. These results show that both executive and DMN regions are crucial for the emotional interference process and suggest that DMN connections are related to the interplay between externally‐directed and internally‐focused processes. Among DMN regions, superior frontal gyrus may be a key node in regulating the interference triggered by emotional stimuli.
Targeting the MET oncogene by concomitant inhibition of receptor and ligand via an antibody‐“decoy” strategy
Authors: Basilico Cristina , Modica Chiara , Maione Federica , Vigna Elisa , Comoglio Paolo M.
Published: April 2018

MET, a master gene sustaining “invasive growth,” is a relevant target for cancer precision therapy. In the vast majority of tumors, wild‐type MET behaves as a “stress‐response” gene and relies on the ligand (HGF) to sustain cell “scattering,” invasive growth and apoptosis protection (oncogene “expedience”). In this context, concomitant targeting of MET and HGF could be crucial to reach effective inhibition. To test this hypothesis, we combined an anti‐MET antibody (MvDN30) inducing “shedding” (i.e., removal of MET from the cell surface), with a “decoy” (i.e., the soluble extracellular domain of the MET receptor) endowed with HGF‐sequestering ability. To avoid antibody/decoy interaction—and subsequent neutralization—we identified a single aminoacid in the extracellular domain of MET—lysine 842—that is critical for MvDN30 binding and engineered the corresponding recombinant decoyMET (K842E). DecoyMETK842E retains the ability to bind HGF with high affinity and inhibits HGF‐induced MET phosphorylation. In HGF‐dependent cellular models, MvDN30 antibody and decoyMETK842E used in combination cooperate in restraining invasive growth, and synergize in blocking cancer cell “scattering.” The antibody and the decoy unbridle apoptosis of colon cancer stem cells grown in vitro as spheroids. In a preclinical model, built by orthotopic transplantation of a human pancreatic carcinoma in SCID mice engineered to express human HGF, concomitant treatment with antibody and decoy significantly reduces metastatic spread. The data reported indicate that vertical targeting of the MET/HGF axis results in powerful inhibition of ligand‐dependent MET activation, providing proof of concept in favor of combined target therapy of MET “expedience.”
Developing anti‐HER2 vaccines: Breast cancer experience
Authors: Al‐Awadhi Aydah , Lee Murray James , Ibrahim Nuhad K.
Published: April 2018

Breast cancer accounts for more than one million new cases annually and is the leading cause of death in women globally. HER2 overexpression induces cellular and humoral immune responses against the HER2 protein and is associated with higher tumor proliferation rates. Trastuzumab‐based therapies are effectively and widely used as standard of care in HER2‐amplified/overexpressed breast cancer patients; one cited mechanism of action is the induction of passive immunity and antibody‐dependent cellular cytotoxicity against malignant breast cancer cells. These findings drove the efforts to generate antigen‐specific immunotherapy to trigger the patient's immune system to target HER2‐overexpressing tumor cells, which led to the development of various vaccines against the HER2 antigen. This article discusses the various anti‐HER2 vaccine formulations and strategies and their potential role in the metastatic and adjuvant settings.
Digital Resources for Social Studies
Authors: Kenna Joshua L. , Pellegrino Anthony M.
Published: April 2018

This forum highlights and evaluates apps, computer programs, and websites that teachers, students, and other interested parties can use to explore, research, and engage in content learning and literacy practices.
Comparative proteomic analyses of human adipose extracellular matrices decellularized using alternative procedures
Authors: Thomas‐Porch Caasy , Li Jie , Zanata Fabiana , Martin Elizabeth C. , Pashos Nicholas , Genemaras Kaylynn , Poche J. Nicholas , Totaro Nicholas P. , Bratton Melyssa R. , Gaupp Dina , Frazier Trivia , Wu Xiying , Ferreira Lydia Masako , Tian Weidong , Wang Guangdi , Bunnell Bruce A. , Flynn Lauren , Hayes Daniel , Gimble Jeffrey M.
Published: April 2018

Decellularized human adipose tissue has potential clinical utility as a processed biological scaffold for soft tissue cosmesis, grafting, and reconstruction. Adipose tissue decellularization has been accomplished using enzymatic‐, detergent‐, and/or solvent‐based methods. To examine the hypothesis that distinct decellularization processes may yield scaffolds with differing compositions, the current study employed mass spectrometry to compare the proteomes of human adipose‐derived matrices generated through three independent methods combining enzymatic‐, detergent‐, and/or solvent‐based steps. In addition to protein content, bioscaffolds were evaluated for deoxyribose nucleic acid depletion, extracellular matrix composition, and physical structure using optical density, histochemical staining, and scanning electron microscopy. Mass spectrometry based proteomic analyses identified 25 proteins (having at least two peptide sequences detected) in the scaffolds generated with an enzymatic approach, 143 with the detergent approach, and 102 with the solvent approach, as compared to 155 detected in unprocessed native human fat. Immunohistochemical detection confirmed the presence of the structural proteins actin, collagen type VI, fibrillin, laminin, and vimentin. Subsequent in vivo analysis of the predominantly enzymatic‐ and detergent‐based decellularized scaffolds following subcutaneous implantation in GFP+ transgenic mice demonstrated that the matrices generated with both approaches supported the ingrowth of host‐derived adipocyte progenitors and vasculature in a time dependent manner. Together, these results determine that decellularization methods influence the protein composition of adipose tissue‐derived bioscaffolds. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A:2481–2493, 2018.
Effects of 24 Months of Treatment With Romosozumab Followed by 12 Months of Denosumab or Placebo in Postmenopausal Women With Low Bone Mineral Density: A Randomized, Double-Blind, Phase 2, Parallel Group Study
Authors: McClung Michael R , Brown Jacques P , Diez-Perez Adolfo , Resch Heinrich , Caminis John , Meisner Paul , Bolognese Michael A , Goemaere Stefan , Bone Henry G , Zanchetta Jose R , Maddox Judy , Bray Sarah , Grauer Andreas
Published: April 2018

Over 12 months, romosozumab increased bone formation and decreased bone resorption, resulting in increased bone mineral density (BMD) in postmenopausal women with low BMD (NCT00896532). Herein, we report the study extension evaluating 24 months of treatment with romosozumab, discontinuation of romosozumab, alendronate followed by romosozumab, and romosozumab followed by denosumab. Postmenopausal women aged 55 to 85 years with a lumbar spine (LS), total hip (TH), or femoral neck T-score ≤–2.0 and ≥–3.5 were enrolled and randomly assigned to placebo, one of five romosozumab regimens (70 mg, 140 mg, 210 mg monthly [QM]; 140 mg Q3M; 210 mg Q3M) for 24 months, or open-label alendronate for 12 months followed by romosozumab 140 mg QM for 12 months. Eligible participants were then rerandomized 1:1 within original treatment groups to placebo or denosumab 60 mg Q6M for an additional 12 months. Percentage change from baseline in BMD and bone turnover markers (BTMs) at months 24 and 36 and safety were evaluated. Of 364 participants initially randomized to romosozumab, placebo, or alendronate, 315 completed 24 months of treatment and 248 completed the extension. Romosozumab markedly increased LS and TH BMD through month 24, with largest gains observed with romosozumab 210 mg QM (LS = 15.1%; TH = 5.4%). Women receiving romosozumab who transitioned to denosumab continued to accrue BMD, whereas BMD returned toward pretreatment levels with placebo. With romosozumab 210 mg QM, bone formation marker P1NP initially increased after treatment initiation and gradually decreased to below baseline by month 12, remaining below baseline through month 24; bone resorption marker β-CTX rapidly decreased after treatment, remaining below baseline through month 24. Transition to denosumab further decreased both BTMs, whereas after transition to placebo, P1NP returned to baseline and β-CTX increased above baseline. Adverse events were balanced between treatment groups through month 36. These data suggest that treatment effects of romosozumab are reversible upon discontinuation and further augmented by denosumab. © 2018 The Authors Journal of Bone and Mineral Research published by Wiley Periodicals, Inc.
Evaluation of 4‐bp insertion/deletion polymorphism within the 3′UTR of SGSM3 in bladder cancer using mismatch PCR‐RFLP method: A preliminary report
Authors: Hashemi Mohammad , Bahari Gholamreza , Bizhani Fatemeh , Danesh Hiva , Sarhadi Shamim , Ziaee Seyed Amir Mohsen , Basiri Abbas , Narouie Behzad , Taheri Mohsen , Ghavami Saeid
Published: April 2018

The small G protein signaling modulator 3 (SGSM3) has been shown to be associated with small G‐protein‐coupled receptor signaling. There is little data regarding the impact of SGSM3 polymorphisms on cancer risk. In the present study, we aimed to evaluate the impact of 4‐bp insertion/deletion (rs56228771) polymorphism in the 3′UTR of SGSM3 and susceptibility to bladder cancer in a sample of the Iranian population. This case‐control study included 143 pathologically confirmed bladder cancer patients and 144 healthy subjects. The SGSM3 4‐bp ins/del (rs56228771) variant was determined by mismatch PCR‐RFLP. The findings showed that ins/del genotype and ins allele of SGSM3 4‐bp ins/del polymorphism significantly increased the risk of bladder cancer (OR = 3.11, 95%CI = 1.70‐5.71, P < 0.0001 and OR = 2.11, 95%CI = 1.27‐3.52, P = 0.004, respectively). Our findings support an association between 4‐bp ins/del polymorphism in the 3′UTR of SGSM3 and the risk of bladder cancer in an Iranian population. Additional studies with larger sample sizes and diverse ethnicities are warranted to establish if such an association exists in general.
Protein phosphatase 2A mediates JS‐K‐induced apoptosis by affecting Bcl‐2 family proteins in human hepatocellular carcinoma HepG2 cells
Authors: Liu Ling , Huang Zile , Chen Jingjing , Wang Jiangang , Wang Shuying
Published: April 2018

Protein phosphatase 2A (PP2A) is an important enzyme within various signal transduction pathways. The present study was investigated PP2A mediates JS‐K‐induced apoptosis by affecting Bcl‐2 family protein. JS‐K showed diverse inhibitory effects in five HCC cell lines, especially HepG2 cells. JS‐K caused a dose‐ and time‐dependent reduction in cell viability and increased in levels of LDH release. Meanwhile, JS‐K‐ induced apoptosis was characterized by mitochondrial membrane potential reduction, Hoechst 33342+/PI+ dual staining, release of cytochrome c (Cyt c), and activation of cleaved caspase‐9/3. Moreover, JS‐K‐treatment could lead to the activation of protein phosphatase 2A‐C (PP2A‐C), decrease of anti‐apoptotic Bcl‐2 family‐protein expression including p‐Bcl‐2 (Ser70), Bcl‐2, Bcl‐xL, and Mcl‐1 as well as the increase of pro‐apoptosis Bcl‐2 family‐protein including Bim, Bad, Bax, and Bak. Furthermore, JS‐K caused a marked increase of intracellular NO levels while pre‐treatment with Carboxy‐PTIO (a NO scavenger) reduced the cytotoxicity effects and the apoptosis rate. Meanwhile, pre‐treatment with Carboxy‐PTIO attenuated the JS‐K‐induced up‐regulation of PP2A, Cyt c, and cleaved‐caspase‐9/3 activation. The silencing PP2A‐C by siRNA could abolish the activation of PP2A‐C, down‐regulation of anti‐apoptotic Bcl‐2 family‐protein (p‐Bcl‐2, Bcl‐2, Bcl‐xL, and Mcl‐1), increase of pro‐apoptosis Bcl‐2 family‐protein (Bim, Bad, Bax, and Bak) and apoptotic‐related protein (Cyt c, cleaved caspase‐9/3) that were caused by JS‐K in HepG2 cells. In addition, pre‐treatment with OA (a PP2A inhibitor) also attenuated the above effects induced by JS‐K. In summary, NO release from JS‐K induces apoptosis through PP2A activation, which contributed to the regulation of Bcl‐2 family proteins.
Human APOBEC3B interacts with the heterogenous nuclear ribonucleoprotein A3 in cancer cells
Authors: Mishra Nawneet , Reddy K Sony , Timilsina Uddhav , Gaur Deepak , Gaur Ritu
Published: April 2018

Human APOBEC3B (A3B), like other APOBEC3 members, is a cytosine deaminase which causes hypermutation of single stranded genome. Recent studies have shown that A3B is predominantly elevated in multiple cancer tissues and cell lines such as the bladder, cervix, lung, head and neck, and breast. Upregulation and activation of A3B in developing tumors can cause an unexpected cluster of mutations which promote cancer development and progression. The cellular proteins which facilitate A3B function through direct or indirect interactions remain largely unknown. In this study, we performed LC‐MS‐based proteomics to identify cellular proteins which coimmunoprecipitated with A3B. Our results indicated a specific interaction of A3B with hnRNP A3 (heterogeneous nuclear ribonucleoprotein). This interaction was verified by co‐immunoprecipitation and was found to be RNA‐dependent. Furthermore, A3B and hnRNP A3 colocalized as evident from immunofluorescence analysis.
Retracted: MicroRNA‐339‐3p alleviates inflammation and edema and suppresses pulmonary microvascular endothelial cell apoptosis in mice with severe acute pancreatitis‐associated acute lung injury by regulating Anxa3 via the Akt/mTOR signaling pathway
Authors: Wu Xing‐Mao , Ji Kai‐Qiang , Wang Hai‐Yuan , Zhao Yang , Jia Jia , Gao Xiao‐Peng , Zang Bin
Published: April 2018

Severe acute pancreatitis (SAP) is a disease with a high mortality. Patients with SAP may also be complicated with acute lung injury (ALI). So far the therapy for SAP‐ALI is still limited. Emerging evidences demonstrate that microRNAs (miRs) could play a role in SAP‐ALI. This study aims to define the role of miR‐339‐3p in SAP‐ALI via Anxa3 through the Akt/mTOR signaling pathway. Ten mice were selected as sham group and 36 mice as model group which further assigned into different groups. Relationship between miR‐339‐3p and Anxa3 was detected by dual luciferase reporter gene assay. Levels of TNF‐α, IL‐6, and serum amylase (AMS) and myeloperoxidase (MPO) in lung tissues were determined by ELISA. Expression of related genes in pulmonary vascular endothelial cells (PMVECs) and lungs tissues was determined by Western blot analysis and RT‐qPCR. Cell apoptosis was detected by flow cytometry and TUNEL. SAP‐ALI mice had decreased survival rate, increased levels of TNF‐α, IL‐6, AMS, MPO, and Schmidt scores. miR‐339‐3p was poorly expressed in lung tissue of SAP‐ALI mice while Anxa3 was reciprocal. Anxa3 was targeted by miR‐339‐3p. miR‐339‐3p inhibited the relative expression of the Akt/mTOR signaling pathway‐related proteins, alleviated inflammation and edema of SAP‐ALI mice, and suppressed apoptosis of PMVECs; Anxa3 exhibited opposite trends. In conclusion, overexpressed miR‐339‐3p could suppress Anxa3 to inhibit the Akt/mTOR signaling pathway, so as to decrease tissue edema, inflammation, and PMVEC apoptosis in SAP‐ALI mice.
Tctex‐1, a novel interaction partner of Kidney Injury Molecule‐1, is required for efferocytosis
Authors: Ismail Ola Z. , Sriranganathan Saranga , Zhang Xizhong , Bonventre Joseph V. , Zervos Antonis S. , Gunaratnam Lakshman
Published: April 2018

Kidney injury molecule‐1 (KIM‐1) is a phosphatidylserine receptor that is specifically upregulated on proximal tubular epithelial cells (PTECs) during acute kidney injury and mitigates tissue damage by mediating efferocytosis (the phagocytic clearance of apoptotic cells). The signaling molecules that regulate efferocytosis in TECs are not well understood. Using a yeast two‐hybrid screen, we identified the dynein light chain protein, Tctex‐1, as a novel KIM‐1‐interacting protein. Immunoprecipitation and confocal imaging studies suggested that Tctex‐1 associates with KIM‐1 in cells at baseline, but, dissociates from KIM‐1 within 90 min of initiation of efferocytosis. Interfering with actin or microtubule polymerization interestingly prevented the dissociation of KIM‐1 from Tctex‐1. Moreover, the subcellular localization of Tctex‐1 changed from being microtubule‐associated to mainly cytosolic upon expression of KIM‐1. Short hairpin RNA‐mediated silencing of endogenous Tctex‐1 in cells significantly inhibited efferocytosis to levels comparable to that of knock down of KIM‐1 in the same cells. Importantly, Tctex‐1 was not involved in the delivery of KIM‐1 to the cell‐surface. On the other hand, KIM‐1 expression significantly inhibited the phosphorylation of Tctex‐1 at threonine 94 (T94), a post‐translational modification which is known to disrupt the binding of Tctex‐1 to dynein on microtubules. In keeping with this, we found that KIM‐1 bound less efficiently to the phosphomimic (T94E) mutant of Tctex‐1 compared to wild type Tctex‐1. Surprisingly, expression of Tctex‐1 T94E did not influence KIM‐1‐mediated efferocytosis. Our studies uncover a previously unknown role for Tctex‐1 in KIM‐1‐dependent efferocytosis in epithelial cells.
MicroRNA‐224 suppresses osteoblast differentiation by inhibiting SMAD4
Authors: Luo Yuan , Cao Xiaodong , Chen Junfeng , Gu Jianwei , Zhao Jitong , Sun Junying
Published: April 2018

Osteoblast differentiation was found to be regulated by a variety of cell signaling and intracellular regulatory factors. In this study, we aimed at investigating the regulatory effect of microRNA‐224 on osteoblast differentiation and its molecular mechanism. Expression of miR‐224 in the osteoblasts, adipose‐derived mesenchymal stem cells (MSC‐A), bone marrow‐derived mesenchymal stem cells (MSC‐B) and mbilical cord‐derived mesenchymal stem cells (MSC‐U) were detected using RT‐PCR. Expression of miR‐224 was lower in osteoblast than in the three mesenchymal stem cells and it revealed a decreasing time‐dependent trend from 0 day to 28 days during osteoblast differentiation. By using alkaline phosphatase (ALP) activity assay and alizarin red S (ARS) staining, we found that the mineralization nodules decreased in miR‐224‐mimics group and increased in miR‐224‐inhibitor group. The Western blot detection of osteoblast markers, such as osteocalcin (OCN), osteopontin (OPN), bone sialoprotein (BSP), and runt related transcription factor 2 (RUNX2), also verified that overexpression of miR‐224 inhibited osteoblast differentiation, while its inhibition promoted osteoblast differentiation. Luciferase reporter assay was performed in our study, which illustrated that miR‐224 regulated SMAD4 directly by targeting SMAD4 3′UTR. Then after the inhibition of SMAD4, we found that lower expression of SMAD4 suppressed the osteoblast differentiation and the related signaling pathway using RT‐PCR and Western blot. Our results revealed a new mechanism of osteoblast differentiation, and provided a new therapeutic agent to promote bone anabolism by targeting miR‐224.
NOTCH4 regulates colorectal cancer proliferation, invasiveness, and determines clinical outcome of patients
Authors: Zhang Zixi , Bu Xin , Yang Jingyi , Zhu Shaojun , He Shuixiang , Zheng Jianyong , Wang Weizhong , Chu Dake
Published: April 2018

Notch signal has complex roles in human malignancies, which might be attributed to the diversity of Notch receptors. Here, we set out to identify the association of NOTCH4 with colorectal cancer (CRC). In the hospital‐based study cohort, we investigated NOTCH4 mRNA levels in primary CRC, as well as its association with clinicopathologic characteristics. Besides, NOTCH4 cDNA and siRNA was transfected into colorectal cancer cell line to elucidate its impact on tumor cell proliferation and migration. Results revealed a statistically significant lower expression of NOTCH4 mRNA in tumor specimens compared with that in control. NOTCH4 level in CRC was found to be related to tumor differentiation, invasion, and node metastasis. Moreover, it was demonstrated that NOTCH4 mRNA level could be an independent prognostic factor for both disease‐free and overall survival of CRC patients. Overexpression of NOTCH4 in CRC cell lines suppressed tumor cell proliferation, migration, and invasion, while induced apoptosis. In the opposite, the malignant behavior of CRC cells was enhanced by NOTCH4 knockdown. These results demonstrated for the first time that NOTCH4 expression was decreased in CRC, which could determine tumor proliferation, relapse, and prognosis.
Interleukin‐6 induced overexpression of valosin‐containing protein (VCP)/p97 is associated with androgen‐independent prostate cancer (AIPC) progression
Authors: Duscharla Divya , Reddy Kami Reddy Karthik , Dasari Chandrashekhar , Bhukya Supriya , Ummanni Ramesh
Published: April 2018

Though Androgen deprivation therapy (ADT) is effective initially, numerous patients become resistant to it and develop castration resistant PCa (CRPC). Cytokines promotes ligand independent activation of AR. Interleukin‐6 (IL‐6) levels are elevated in CRPC patients and regulate AR activity. However, progression to CRPC is not fully understood. In this study, we analyzed differential protein expression in LNCaP cells treated with IL‐6 using proteomics. Results revealed altered expression of 27 proteins and Valosin‐containing protein (VCP)/p97 plays a predominant role in co‐regulation of altered proteins. Interestingly, IL‐6 induced VCP expression through Pim‐1 via STAT3 is AR independent there by suggesting a role for VCP in CRPC. Transfection of LNCaP cells for VCP overexpression showed an increased cell proliferation, migration, and invasion where as its inhibition by NMS‐873 showed the reverse effect causing cell death. Mechanistic studies demonstrate that cell death occurs due to apoptosis by endoplasmic reticulum (ER) stress, elevated cell cycle inhibitors p21, p27kip1, and active PARP and reduced Bcl‐2. VCP promotes cell invasion and migration by altering E‐cadherin and Vimentin levels inversely triggering EMT of PCa cells. VCP immunostaining revealed no staining in BPH but strong staining in PCa. This study determines VCP may play an important role in progression to CRPC and it can be a favorable target with to develop new therapies to treat ADT resistant prostate cancer.