bluuebunny/crossref_metadata_2025 huggingface dataset:
In vitro and in vivo anti‐tumour effects of MPT0B014, a novel derivative aroylquinoline, and in combination with erlotinib in human non‐small‐cell lung cancer cells
Authors: Tsai An‐Chi , Pai Hui‐Chen , Wang Chih‐Ya , Liou Jing‐Ping , Teng Che‐Ming , Wang Jing‐Chi , Pan Shiow‐Lin
Published: October 2013

Background and Purpose

The purpose of the current study was to assess a novel anti‐cancer drug, MPT0B014, which is not a substrate for the P‐glycoprotein (P‐gp) transporter, alone and in combination with erlotinib, against human non‐small cell lung cancer (NSCLC).

Experimental Approach

Cytotoxicity in human NSCLC cell lines was assessed by sulforhodamine B and 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide assays. Cell cycle phase distributions were estimated with FACScan flow cytometry. Protein expression was detected by Western blotting analysis. Efflux of rhodamine 123 or calcein‐acetoxymethylester was used to study the P‐gp profile. The A549 xenograft model in mice was used to assess in vivo anti‐tumour activity.

Key Results

MPT0B014 showed potent anti‐proliferative activity against A549, H1299 and H226 cells. It induced G2/M arrest with down‐regulation of Cdc (Tyr15) and Cdc25C, and up‐regulation of cyclin B1, phospho‐Cdc2 (Thr161) and Aurora A/B. P‐gp‐overexpressing National Cancer Institute/Adriamycin‐Resistant cells were also sensitive to B014. B014‐induced loss of Mcl‐1 was accompanied by activation of caspases‐3, ‐7, ‐8 and ‐9, and initiation of apoptosis. B014 in combination with erlotinib caused significant tumour inhibition in vitro and in vivo.

Conclusions and Implications

MPT0B014 exerted cytotoxicity against human NSCLC cell lines with little susceptibility to P‐gp. Combined with the EGF receptor inhibitor, erlotinib, MPT0B014 exerted significant growth inhibition of A549 cells both in vitro and in vivo. B014 could be useful as an anti‐cancer agent.
JNK signalling in cancer: in need of new, smarter therapeutic targets
Authors: Bubici Concetta , Papa Salvatore
Published: October 2013

The JNKs are master protein kinases that regulate many physiological processes, including inflammatory responses, morphogenesis, cell proliferation, differentiation, survival and death. It is increasingly apparent that persistent activation of JNKs is involved in cancer development and progression. Therefore, JNKs represent attractive targets for therapeutic intervention with small molecule kinase inhibitors. However, evidence supportive of a tumour suppressor role for the JNK proteins has also been documented. Recent studies showed that the two major JNK proteins, JNK1 and JNK2, have distinct or even opposing functions in different types of cancer. As such, close consideration of which JNK proteins are beneficial targets and, more importantly, what effect small molecule inhibitors of JNKs have on physiological processes, are essential. A number of ATP‐competitive and ATP‐non‐competitive JNK inhibitors have been developed, but have several limitations such as a lack of specificity and cellular toxicity. In this review, we summarize the accumulating evidence supporting a role for the JNK proteins in the pathogenesis of different solid and haematological malignancies, and discuss many challenges and scientific opportunities in the targeting of JNKs in cancer.
Loop diuretics are open‐channel blockers of the cystic fibrosis transmembrane conductance regulator with distinct kinetics
Authors: Ju Min , Scott‐Ward Toby S , Liu Jia , Khuituan Pissared , Li Hongyu , Cai Zhiwei , Husbands Stephen M , Sheppard David N
Published: October 2013

Background and Purpose

Loop diuretics are widely used to inhibit the Na+, K+, 2Cl− co‐transporter, but they also inhibit the cystic fibrosis transmembrane conductance regulator (CFTR) Cl− channel. Here, we investigated the mechanism of CFTR inhibition by loop diuretics and explored the effects of chemical structure on channel blockade.

Experimental Approach

Using the patch‐clamp technique, we tested the effects of bumetanide, furosemide, piretanide and xipamide on recombinant wild‐type human CFTR.

Key Results

When added to the intracellular solution, loop diuretics inhibited CFTR Cl− currents with potency approaching that of glibenclamide, a widely used CFTR blocker with some structural similarity to loop diuretics. To begin to study the kinetics of channel blockade, we examined the time dependence of macroscopic current inhibition following a hyperpolarizing voltage step. Like glibenclamide, piretanide blockade of CFTR was time and voltage dependent. By contrast, furosemide blockade was voltage dependent, but time independent. Consistent with these data, furosemide blocked individual CFTR Cl− channels with ‘very fast’ speed and drug‐induced blocking events overlapped brief channel closures, whereas piretanide inhibited individual channels with ‘intermediate’ speed and drug‐induced blocking events were distinct from channel closures.

Conclusions and Implications

Structure–activity analysis of the loop diuretics suggests that the phenoxy group present in bumetanide and piretanide, but absent in furosemide and xipamide, might account for the different kinetics of channel block by locking loop diuretics within the intracellular vestibule of the CFTR pore. We conclude that loop diuretics are open‐channel blockers of CFTR with distinct kinetics, affected by molecular dimensions and lipophilicity.
Bitter tasting compounds dilate airways by inhibiting airway smooth muscle calcium oscillations and calcium sensitivity
Authors: Tan Xiahui , Sanderson Michael J
Published: October 2013

Background and Purpose

While selective, bitter tasting, TAS2R agonists can relax agonist‐contracted airway smooth muscle (ASM), their mechanism of action is unclear. However, ASM contraction is regulated by Ca2+ signalling and Ca2+ sensitivity. We have therefore investigated how the TAS2R10 agonists chloroquine, quinine and denotonium regulate contractile agonist‐induced Ca2+ signalling and sensitivity.

Experimental Approach

Airways in mouse lung slices were contracted with either methacholine (MCh) or 5HT and bronchodilation assessed using phase‐contrast microscopy. Ca2+ signalling was measured with 2‐photon fluorescence microscopy of ASM cells loaded with Oregon Green, a Ca2+‐sensitive indicator (with or without caged‐IP3). Effects on Ca2+ sensitivity were assessed on lung slices treated with caffeine and ryanodine to permeabilize ASM cells to Ca2+.

Key Results

The TAS2R10 agonists dilated airways constricted by either MCh or 5HT, accompanied by inhibition of agonist‐induced Ca2+ oscillations. However, in non‐contracted airways, TAS2R10 agonists, at concentrations that maximally dilated constricted airways, did not evoke Ca2+ signals in ASM cells. Ca2+ increases mediated by the photolysis of caged‐IP3 were also attenuated by chloroquine, quinine and denotonium. In Ca2+‐permeabilized ASM cells, the TAS2R10 agonists dilated MCh‐ and 5HT‐constricted airways.

Conclusions and Implications

TAS2R10 agonists reversed bronchoconstriction by inhibiting agonist‐induced Ca2+ oscillations while simultaneously reducing the Ca2+ sensitivity of ASM cells. Reduction of Ca2+ oscillations may be due to inhibition of Ca2+ release through IP3 receptors. Further characterization of bronchodilatory TAS2R agonists may lead to the development of novel therapies for the treatment of bronchoconstrictive conditions.
Temperate mountain grasslands: a climate‐herbivore hypothesis for origins and persistence
Authors: Weigl Peter D. , Knowles Travis W.
Published: October 2013

Temperate montane grasslands and their unique biotas are declining worldwide as they are increasingly being invaded by forests. The origin and persistence of these landscapes have been the focus of such controversy that in many areas their conservation is in doubt. In the USA some biologists have largely dismissed the grass balds of the Southern Appalachians as human artifacts or anomalous and transitory elements of regional geography, worthy of only limited preservation efforts. On the basis of information from biogeography, community ecology, regional history and palaeontology and from consideration of two other montane grassland ecosystems—East Carpathian poloninas and Oregon Coast Range grass balds—we hypothesize that these landscapes are more widespread than was formerly recognized; they are, in many cases, natural and ancient and largely owe their origin and persistence to past climatic extremes and the activities of large mammalian herbivores.
Seed‐swallowing Toucans are Less Effective Dispersers of Guettarda viburnoides (Rubiaceae) than Pulp‐feeding Jays
Authors: Loayza Andrea P. , Rios Rodrigo S.
Published: October 2013

For many tropical plants, birds are the most important seed dispersers. Not all birds, however, will provide equally effective dispersal services. Behavioral differences, during and after feeding, can result in different establishment probabilities of new individuals. During 3 yr, we examined species‐specific quantitative and qualitative aspects of Guettarda viburnoides seed dispersal by avian frugivores, focusing on how these aspects modify seed dispersal effectiveness. Fruits of G. viburnoides were consumed by ten species of birds, two of which, Cyanocorax cyanomelas and Pteroglossus castanotis, removed 80 percent of the fruits. These two species differ in qualitative aspects of seed dispersal. First, they select for fruits of different sizes; C. cyanomelas feeds on larger fruits than P. castanotis, which results in the former dispersing larger endocarps than the latter. Second, they differ in their fruit handling treatment; C. cyanomelas are pulp consumers, whereas P. castanotis swallow the fruit whole, and are thus traditionally considered ‘legitimate’ dispersers. The probability of seedling emergence, the temporal pattern of emergence, the number of emerged seedlings per endocarp, and the probability of post‐dispersal seed predation differs between endocarps dispersed by C. cyanomelas and P. castanotis; endocarps dispersed by the former have higher emergence probabilities, higher number of seedlings, faster emergence times, and lower predation probabilities than those dispersed by the latter. Finally, these birds differ in their landscape patterns of endocarp deposition; C. cyanomelas disperses endocarps to habitats with higher recruitment probabilities. Ultimately, the pulp consumer C. cyanomelas is a more effective disperser of G. viburnoides than P. castanotis.
Apocynin, an NADPH oxidase inhibitor, suppresses rat prostate carcinogenesis
Authors: Suzuki Shugo , Shiraga Kazuhide , Sato Shinya , Punfa Wanisa , Naiki‐Ito Aya , Yamashita Yoriko , Shirai Tomoyuki , Takahashi Satoru
Published: October 2013

Recent evidence suggests that oxidative stress contributes to the pathogenesis of prostate cancer. The present study focused on the effect of apocynin, an inhibitor of NADPH oxidase, on prostate carcinogenesis using the transgenic rat for adenocarcinoma of prostate (TRAP) model. There were no toxic effects with apocynin treatment. The percentages and numbers of carcinomas in both the ventral and lateral prostate were significantly reduced by apocynin treatment, with dose dependence. Reduction of reactive oxygen species by apocynin was confirmed by immunohistochemistry of 8‐OHdG and dihydroethidium staining. Positivity of Ki67 was significantly reduced by apocynin treatment, and downregulation of clusterin expression, as well as inactivation of the MEK‐ERK1/2 pathway, was a feature of the apocynin treated groups. In human prostate cancer cell line LNCaP, apocynin also inhibited reactive oxygen species production and blocked cell growth by inducing G0/G1 arrest with downregulation of clusterin and cyclin D1. These data suggest that apocynin possesses chemopreventive potential against prostate cancer.
Therapeutic role of EF24 targeting glucose transporter 1‐mediated metabolism and metastasis in ovarian cancer cells
Authors: Zhang Dandan , Wang Yan , Dong Lina , Huang Yangang , Yuan Jing , Ben Wei , Yang Yang , Ning Ning , Lu Meisong , Guan Yongmei
Published: October 2013

Cancer cells require glucose to support their rapid growth through a process known as aerobic glycolysis, or the Warburg effect. As in ovarian cancer cells, increased metabolic activity and glucose concentration has been linked to aggressiveness of cancer. However, it is unclear as to whether targeting the glycolytic pathway may kill the malignant cells and likely have broad therapeutic implications against ovarian cancer metastasis. In the present research, we found that EF24, a HIF‐1α inhibitor, could significantly block glucose uptake, the rate of glycolysis, and lactate production compared with vehicle treatment in SKOV‐3, A2780 and OVCAR‐3 cells. These results might possibly contribute to the further observation that EF24 could inhibit ovarian cancer cell migration and invasion from wound healing and Transwell assays. Furthermore, as an important mediator of glucose metabolism, glucose transporter 1 (Glut1) was found to contribute to the function of EF24 in both energy metabolism and metastasis. To examine the effect of EF24 and the mediated role of Glut1 in vivo in a xenograph subcutaneous tumor model, intraperitoneal metastasis and lung metastasis model were introduced. Our results indicated that EF24 treatment could inhibit tumor growth, intraperitoneal metastasis and lung metastasis of SKOV‐3 cells, and Glut1 is a possible mediator for the role of EF24. In conclusion, our results highlight that an anti‐cancer reagent with an inhibiting effect on energy metabolism could inhibit metastasis, and EF24 is a possible candidate for anti‐metastasis therapeutic applications for ovarian cancer.
HOTAIR, a prognostic factor in esophageal squamous cell carcinoma, inhibits WIF‐1 expression and activates Wnt pathway
Authors: Ge Xiao‐Song , Ma Hua‐Juan , Zheng Xiao‐Hui , Ruan Hong‐Lian , Liao Xiao‐Yu , Xue Wen‐Qiong , Chen Yuan‐Bin , Zhang Ying , Jia Wei‐Hua
Published: October 2013

Long non‐coding RNAs (LncRNAs) have been recently found to be pervasively transcribed in the genome and critical regulators of the epigenome. HOTAIR, as a well‐known LncRNA, has been found to play important roles in several tumors. Herein, the clinical application value and biological functions of HOTAIR were focused and explored in esophageal squamous cell carcinoma (ESCC). It was found that there was a great upregulation of HOTAIR in ESCC compared to their adjacent normal esophageal tissues. Meanwhile, patients with high HOTAIR expression have a significantly poorer prognosis than those with low expression. Moreover, HOTAIR was further validated to promote migration and invasion of ESCC cells in vitro. Then some specific molecules with great significance were investigated after HOTAIR overexpression using microarray and quantitative real time‐polymerase chain reaction (qPCR). WIF‐1 playing an important role in Wnt/β‐catenin signaling pathway was selected and further tested by immunehistochemistry. Generally, inverse correlation between HOTAIR and WIF‐1 expression was demonstrated both in ESCC cells and tissues. Mechanistically, HOTAIR directly decreased WIF‐1 expression by promoting its histone H3K27 methylation in the promoter region and then activated the Wnt/β‐catenin signaling pathway. This newly identified HOTAIR/WIF‐1 axis clarified the molecular mechanism of ESCC cell metastasis and represented a novel therapeutic target in patients with ESCC.
Genome‐wide analysis of DNA methylation changes induced by gestational arsenic exposure in liver tumors
Authors: Suzuki Takehiro , Yamashita Satoshi , Ushijima Toshikazu , Takumi Shota , Sano Tomoharu , Michikawa Takehiro , Nohara Keiko
Published: October 2013

Inorganic arsenic is known to be a human carcinogen. Previous studies have reported that DNA methylation changes are involved in arsenic‐induced carcinogenesis, therefore, DNA methylation changes that are specific to arsenic‐induced tumors would be useful to distinguish tumors induced by arsenic from tumors caused by other factors and to dissect arsenic carcinogenesis. Previous studies have shown that gestational arsenic exposure of C3H mice, which tend to spontaneously develop liver tumors, increases the incidence of tumors in male offspring. In this study we used the same experimental protocol as in those previous studies and searched for DNA regions where methylation status was specifically altered in the liver tumors of arsenic‐exposed offspring by using methylated DNA immunoprecipitation–CpG island microarrays. The methylation levels of the DNA regions selected were measured by quantitative methylation‐specific PCR and bisulfite sequencing. The results of this study clarified a number of regions where DNA methylation status was altered in the liver tumors in the C3H mice compared to normal liver tissues. Among such regions, we showed that a gene body region of the oncogene Fosb underwent alteration in DNA methylation by gestational arsenic exposure. We also showed that Fosb expression significantly increased corresponding to the DNA methylation level of the gene body in the arsenic‐exposed group. These findings suggest that the DNA methylation status can be used to identify tumors increased by gestational arsenic exposure.
p53 accumulation is a strong predictor of recurrence in estrogen receptor‐positive breast cancer patients treated with aromatase inhibitors
Authors: Yamamoto Mitsugu , Hosoda Mitsuchika , Nakano Kiichiroh , Jia Shusheng , Hatanaka Kanako C. , Takakuwa Emi , Hatanaka Yutaka , Matsuno Yoshihiro , Yamashita Hiroko
Published: October 2013

Aromatase inhibitors have played a central role in endocrine therapy for estrogen receptor (ER)‐positive breast cancer in postmenopausal women. However, factors predictive of the efficacy of aromatase inhibitors, and prognostic factors, both for early and late recurrence in women treated with adjuvant aromatase inhibitors have not been identified. Whole genome analysis identified that a TP53 gene mutation exists in ER‐positive breast cancers, although the frequency of TP53 gene mutation in luminal tumors is lower compared with basal‐like or human epidermal growth factor receptor type 2 (HER2)‐positive breast cancers. We examined expression of p53, as well as ER, progesterone receptor, HER2 and Ki‐67 using immunohistochemistry in postmenopausal ER‐positive breast cancer patients who were treated with aromatase inhibitors as adjuvant endocrine therapy. There were 53 (21%) tumors that contained 10% or more p53‐positive cells. High p53 expression was positively correlated with tumor grade, HER2 score and Ki‐67 expression. Significant association was observed between disease‐free survival and high p53 expression in multivariate analysis (P < 0.0001). Compared with women without recurrence, women with early recurrence had significantly higher p53 expression (P < 0.0001), as did women with late recurrence (P = 0.037). The present study demonstrates that p53 accumulation is a strong predictor of both early and late recurrence in ER‐positive breast cancer patients treated with aromatase inhibitors as adjuvant endocrine therapy. TP53 gene alteration might be a key biological characteristic of ER‐positive breast cancer.
Mapping of Allosteric Druggable Sites in Activation‐Associated Conformers of the M2 Muscarinic Receptor
Authors: Miao Yinglong , Nichols Sara E. , McCammon J. Andrew
Published: October 2013

G‐protein‐coupled receptors (GPCRs) are key cellular signaling proteins and have been targeted by approximately 30–40% of marketed drugs for treating many human diseases including cancer and heart failure. Recently, we directly observed activation of the M2 muscarinic receptor through long‐timescale accelerated molecular dynamics (aMD) simulation, which revealed distinct inactive, intermediate and active conformers of the receptor. Here, FTMAP is applied to search for ‘hot spots’ in these activation‐associated conformers using a library of 16 organic probe molecules that represent fragments of potential drugs. Seven allosteric (non‐orthosteric) binding sites are identified in the M2 receptor through the FTMAP analysis. These sites are distributed in the solvent‐exposed extracellular and intracellular mouth regions, as well as the lipid‐exposed pockets formed by the transmembrane α helices TM3‐TM4, TM5‐TM6 and TM7‐TM1/TM2. They serve as promising target sites for designing novel allosteric modulators as receptor‐selective drugs.
Discovering Isozyme‐Selective Inhibitor Scaffolds of Human Carbonic Anhydrases Using Structural Alignment and De novo Drug Design Approaches
Authors: Xiang Fu , Xiang Jun , Fang Yuanping , Zhang Mingju , Li Maoteng
Published: October 2013

The development of isozyme‐selective carbonic anhydrase inhibitors is currently still a great challenge. In the present study, protein–ligand complex structures were obtained by AutoDock Vina with SBR ((R)‐N‐(3‐indol‐1‐yl‐2‐methyl‐propyl)‐4‐sulfamoyl‐benzamide) as the only inhibitor docked into the binding pockets of human isozymes CA I, II, IV, VI, IX, XII, and XIII. To make the spatial structures of complexes comparable, the co‐ordinates for CA domains were reassigned based on structural alignments. With preferred docking poses of SBR been reduced to seed structures, the LigBuilder was used to build up inhibitor molecules. The results suggested that sulfonamide derivatives with naphthalene, fluorene, and acridan as the scaffold structures can be the potential isozyme‐selective CAIs, especially for isozymes CA II, IV, and IX.
Potassium Channels: Structures, Diseases, and Modulators
Authors: Tian Chuan , Zhu Ruixin , Zhu Lixin , Qiu Tianyi , Cao Zhiwei , Kang Tingguo
Published: October 2013

Potassium channels participate in many critical biological functions and play important roles in a variety of diseases. In recent years, many significant discoveries have been made which motivate us to review these achievements. The focus of our review is mainly on three aspects. Firstly, we try to summarize the latest developments in structure determinants and regulation mechanism of all types of potassium channels. Secondly, we review some diseases induced by or related to these channels. Thirdly, both qualitative and quantitative approaches are utilized to analyze structural features of modulators of potassium channels. Our analyses further prove that modulators possess some certain natural‐product scaffolds. And pharmacokinetic parameters are important properties for organic molecules. Besides, with in silico methods, some features that can be used to differentiate modulators are derived. There is no doubt that all these studies on potassium channels as possible pharmaceutical targets will facilitate future translational research. All the strategies developed in this review could be extended to studies on other ion channels and proteins as well.
Characteristic Structural Features of Indolicidin: Effects of the cis‐trans Isomerism on its Conformation
Authors: Leitgeb Balázs
Published: October 2013

Indolicidin is an antimicrobial peptide showing a broad spectrum of antibacterial and antifungal activities, and according to the cis‐trans isomerism of three Xaa‐Pro peptide bonds, eight different stereoisomers could be distinguished for this peptide. As the cis‐trans isomerism about the Xaa‐Pro peptide bonds was not considered in previous studies, the structural features of distinct stereoisomeric forms were not characterized in detail, so far. In this theoretical study, the influences of cis‐trans isomerism on the conformation of indolicidin were investigated, as well as the typical structural properties of each stereoisomer were determined, focusing on the secondary structures and intramolecular interactions. Based on the results derived from the molecular dynamics simulations, it could be concluded that the eight different stereoisomeric forms of indolicidin adopted characteristic conformational features. Nevertheless, the appearance of various turn structures and intramolecular interactions proved to be dependent on the cis or trans nature of Xaa‐Pro peptide bonds, indicating the relevant role of Pro amino acids in determining the three‐dimensional structure of this peptide.
Ablation of Breast Cancer Cells Using Trastuzumab‐Functionalized Multi‐Walled Carbon Nanotubes and Trastuzumab‐Diphtheria Toxin Conjugate
Authors: Oraki Kohshour Mojtaba , Mirzaie Sako , Zeinali Majid , Amin Mansour , Said Hakhamaneshi Mohammad , Jalili Ali , Mosaveri Nader , Jamalan Mostafa
Published: October 2013

Trastuzumab (Herceptin®) is a monoclonal antibody (mAb) for specific ablation of HER2‐overexpressing malignant breast cancer cells. Intensification of antiproliferative activity of trastuzumab through construction of immunotoxins and nano‐immunoconjugates is a promising approach for treatment of cancer. In this study, trastuzumab was directly conjugated to diphtheria toxin (DT). Also, conjugates of trastuzumab and multiwalled carbon nanotubes (MWCNT) were constructed by covalent immobilization of trastuzumab onto MWCNTs. Then, antiproliferative activity of the fusion constructs against HER2‐overexpressing SK‐BR‐3 and also HER2‐negative MCF‐7 cancer cell lines were examined. Cells treated with trastuzumab‐MWCNT conjugates were irradiated with near‐infrared (NIR) light. Efficient absorption of NIR radiation and its conversion to heat by MWCNTs can be resulted to thermal ablation of cancerous cells. Our results strongly showed that both trastuzumab‐MWCNT and trastuzumab‐DT conjugates were significantly efficient in the specific killing of SK‐BR‐3 cells. Targeting of MWCNTs to cancerous cells using trastuzumab followed by exposure of cells to NIR radiation was more efficient in repression of cell proliferation than treatment for cancer cells with trastuzumab‐DT. Our results also showed that conjugation linkers can significantly affect the cytotoxicity of MWCNT‐immunoconjugates. In conclusion, our data demonstrated that trastuzumab‐MWCNT is a promising nano‐immunoconjugate for killing of HER2‐overexpressing cancerous cells.
Family environment and attention‐deficit/hyperactivity disorder in adopted children: associations with family cohesion and adaptability
Authors: Crea T. M. , Chan K. , Barth R. P.
Published: October 2013

Background

Positive family environments are crucial in promoting children's emotional and behavioural well‐being, and may also buffer development of attention‐deficit/hyperactivity disorder (ADHD). ADHD is highly heritable, but psychosocial factors in the family environment, particularly family cohesion and communication, may mediate genetic predispositions. The purpose of the current study is to examine the mediating influence of the adoptive family environment between pre‐adoptive risk factors and youths' ADHD symptomatology at 14 years post adoption.

Methods

The data used in this study were obtained from the fourth wave of the California Long‐Range Adoption Study (CLAS) (n = 449). Using structural equation modelling (SEM), family sense of coherence and family adaptability were tested as possible mediators between environmental and biological predictors and ADHD symptomatology. Predictors included birthweight, gender, age at adoption, adoption from foster care, transracial adoption status, ethnicity and having a previous diagnosis of ADHD.

Results

Results show that, while adoption from foster care is negatively associated with family functioning, higher family cohesion and adaptability mediate this influence on children's ADHD symptomatology. Older age of adoption directly predicts greater ADHD symptoms with no mediating influence of the family environment.

Conclusions

The mediating influence of the family environment between children's risk factors and ADHD symptoms suggests that family intervention strategies may be helpful in improving adopted children's outcomes. Once children are adopted, targeting family communication patterns and dynamics may be an additional part of developing an evidence‐based, post‐adoption services toolkit.
Pollution and Infant Health
Authors: Currie Janet
Published: October 2013

In this article, I review recent research showing that even relatively low levels of pollution can affect infants' health. This research attempts to go beyond documenting correlations by using sharp changes in pollution levels, carefully selecting control groups (including unexposed siblings as controls for exposed children), and considering behavioral responses to pollution such as maternal mobility. Poor and minority children are more likely to be affected, and differential exposure could be responsible for some of the observed group‐level differences in health at birth. Policy makers concerned about the roots of inequality should consider the role played by environmental exposures of pregnant mothers.
Toddlers Default to Canonical Surface‐to‐Meaning Mapping When Learning Verbs
Authors: Dautriche Isabelle , Cristia Alejandrina , Brusini Perrine , Yuan Sylvia , Fisher Cynthia , Christophe Anne
Published: October 2013

Previous work has shown that toddlers readily encode each noun in the sentence as a distinct argument of the verb. However, languages allow multiple mappings between form and meaning that do not fit this canonical format. Two experiments examined French 28‐month‐olds' interpretation of right‐dislocated sentences (nouni‐verb, nouni) where the presence of clear, language‐specific cues should block such a canonical mapping. Toddlers (N = 96) interpreted novel verbs embedded in these sentences as transitive, disregarding prosodic cues to dislocation (Experiment 1) but correctly interpreted right‐dislocated sentences containing well‐known verbs (Experiment 2). These results suggest that toddlers can integrate multiple cues in ideal conditions, but default to canonical surface‐to‐meaning mapping when extracting structural information about novel verbs in semantically impoverished conditions.
Parent–Child Discrepancies in Educational Expectations: Differential Effects of Actual Versus Perceived Discrepancies
Authors: Wang Yijie , Benner Aprile D.
Published: October 2013

This study explored how discrepancies between parents' and adolescents' educational expectations influenced adolescents' achievement using a nationally representative, longitudinal sample of 14,041 students (14 years old at baseline). Actual discrepancies (i.e., those between parents' and adolescents' actual educational expectations) and perceived discrepancies (i.e., those between adolescents' perceptions of their parents' educational expectations and adolescents' own) were examined. Achievement was higher when parents actually held higher expectations than adolescents held or when adolescents perceived that their parents' expectations were lower than their own. In contrast, achievement was lower when parents actually held lower expectations than adolescents held or when adolescents believed that their parents' expectations exceeded their own. Implications for identifying adolescents at risk and promoting adaptive parent–child educational expectations are discussed.
Highly expressed cytoplasmic FcεRIβ in human mast cells functions as a negative regulator of the FcRγ‐mediated cell activation signal
Authors: Okayama Y. , Matsuda A. , Kashiwakura J.‐I. , Sasaki‐Sakamoto T. , Nunomura S. , Shimokawa T. , Yamaguchi K. , Takahashi S. , Ra C.
Published: October 2013

Background

We recently reported that the interaction between Lyn and FcεRIβ is indispensable for FcεRI‐mediated human mast cell (MC) activation and that FcεRIβ functions as an amplifier of FcεRI‐mediated activation signal. Some of FcεRIβ in cytoplasm appeared not to be co‐localized with FcεRIα. The function of FcεRIβ in the cytoplasm remains unknown.

Methods

The localization of FcεRIβ and FcεRIα in giant papillae specimens from patients with allergic keratoconjunctivitis and of FcεRIβ, FcεRIα, and Lyn in cultured human MCs was examined using confocal microscopy. FcεRIβ was overexpressed using an adenovirus vector system. Mediators were measured by enzyme immunoassays or enzyme‐linked immunosorbent assays.

Results

In the subepithelial region, FcεRIβ was mainly localized in the cell membrane of MCs. In the perivascular region, FcεRIβ expression was scattered throughout the cytoplasm and in the cell membrane of MCs. Overexpression of FcεRIβ in MCs mainly increased its cytoplasmic expression and slightly up‐regulated cell surface FcεRI expression. However, overexpression of FcεRIβ in MCs resulted in down‐regulation of the tyrosine phosphorylation levels of FcεRIβ and Syk and down‐regulation of the Ca2+ influx soon after FcεRI aggregation and then resulted in down‐regulation of degranulation, PGD2 synthesis, and production of a set of cytokines. This negative regulatory effect may be due to inhibition of the redistribution of Lyn to small patches within the plasma membrane.

Conclusion

Cytoplasmic FcεRIβ, which is not co‐localized with FcεRIα, may function as a negative regulator, as it can capture important signalling molecules such as Lyn.
VB-201, an oxidized phospholipid small molecule, inhibits CD14- and Toll-like receptor-2-dependent innate cell activation and constrains atherosclerosis
Authors: Mendel I , Feige E , Yacov N , Salem Y , Levi I , Propheta-Meiran O , Shoham A , Ishai E , George J , Harats D , Breitbart E
Published: October 2013

Atherosclerosis is an inflammatory disease of the vascular wall. Activated monocytes and dendritic cells (DC) in the intima layer of the vasculature promote atherogenesis. Toll-like receptor (TLR)-2 and TLR-4, which are predominantly expressed on these cells and mediate their activation, are essential for atherosclerosis development. In this study we demonstrate that VB-201, an oxidized phospholipid (Ox-PL) small molecule, inhibits TLR signalling restricted to TLR-2 and TLR-4 in human and mouse monocytes and DC. Mechanistically, we show that VB-201 binds directly to TLR-2 and CD14, the TLR-4 co-receptor, to impair downstream cues and cytokine production. In a rabbit model, oral administration of VB-201 constrained atherosclerosis progression. This effect was not due to reduced cholesterol abundance, as hyperlipidaemia was sustained. We suggest that VB-201 may counter inflammation where TLR-2 and/or CD14 complicity is essential, and is therefore beneficial for the treatment of atherosclerosis.
Human T cell leukaemia virus type 2 tax protein mediates CC-chemokine expression in peripheral blood mononuclear cells via the nuclear factor kappa B canonical pathway
Authors: Barrios C S , Castillo L , Zhi H , Giam C-Z , Beilke M A
Published: October 2013

Retroviral co-infections with human immunodeficiency virus type-1 (HIV-1) and human T cell leukaemia virus type 1 (HTLV-1) or type 2 (HTLV-2) are prevalent in many areas worldwide. It has been observed that HIV-1/HTLV-2 co-infections are associated with slower rates of CD4+ T cell decline and delayed progression to AIDS. This immunological benefit has been linked to the ability of Tax2, the transcriptional activating protein of HTLV-2, to induce the expression of macrophage inflammatory protein (MIP)-1α/CCL3, MIP-1β/CCL4 and regulated upon activation normal T cell expressed and secreted (RANTES)/CCL5 and to down-regulate the expression of the CCR5 co-receptor in peripheral blood mononuclear cells (PBMCs). This study aimed to assess the role of Tax2-mediated activation of the nuclear factor kappa B (NF-κB) signalling pathway on the production of the anti-viral CC-chemokines MIP-1α, MIP-1β and RANTES. Recombinant Tax1 and Tax2 proteins, or proteins expressed via adenoviral vectors used to infect cells, were tested for their ability to activate the NF-κB pathway in cultured PBMCs in the presence or absence of NF-κB pathway inhibitors. Results showed a significant release of MIP-1α, MIP-1β and RANTES by PBMCs after the activation of p65/RelA and p50. The secretion of these CC-chemokines was significantly reduced (P < 0·05) by canonical NF-κB signalling inhibitors. In conclusion, Tax2 protein may promote innate anti-viral immune responses through the activation of the canonical NF-κB pathway.
Follicular bronchiolitis as phenotype associated with CD25 deficiency
Authors: Bezrodnik L , Caldirola M S , Seminario A G , Moreira I , Gaillard M I
Published: October 2013

Regulatory T cells [Tregs; CD4+CD25+ forkhead box protein 3 (FoxP3+)] are subsets of T cells involved in the maintenance of peripheral self-tolerance by actively suppressing the activation and expansion of autoreactive T cells. Signalling through the interleukin-2 receptor (IL-2R) contributes to T cell tolerance by controlling three important aspects of regulatory T cell (Treg) biology. CD25 is the α-chain of the IL-2R that, in concert with the β-chain and γ-chain, constitutes the complete IL-2R. CD25 contributes only to IL-2 binding affinity but not to the recruitment of signalling molecules. However, its importance in the development of a normal immune response is emphasized by the finding that a truncation mutant of CD25 results in an immunodeficiency in humans characterized by an increased susceptibility to viral, bacterial and fungal infections. In 1997, Sharfe et al. described an infant with severe bacterial, viral and fungal infections. Counts of autologous T lymphocytes were moderately low, T cells displayed a weak proliferative response to mitogens in vitro and the patient displayed no rejection of an allogeneic skin graft. However, unlike children with severe combined immunodeficiency (SCID), besides not having circulating T cells, the patient also developed peripheral lymphocytic proliferation and autoimmune primary biliary cirrhosis. We present the first female Argentine patient with mutation in CD25 associated with chronic and severe inflammatory lung disease (follicular bronchiolitis with lymphocyte hyperplasia), eczema and infections. She has no expression of CD25 on CD4+T cells and an extremely low amount of Tregs. The molecular study confirmed homozygous missense mutation in the alpha subunit of the IL-2 receptor (CD25αR) (c. 122 a > c; p. Y41S).
CD19 as a therapeutic target in a spontaneous autoimmune polyneuropathy
Authors: Abraham P M , Quan S H , Dukala D , Soliven B
Published: October 2013

Spontaneous autoimmune polyneuropathy (SAP) in B7-2 knock-out non-obese diabetic (NOD) mice is mediated by myelin protein zero (P0)-reactive T helper type 1 (Th1) cells. In this study, we investigated the role of B cells in SAP, focusing on CD19 as a potential therapeutic target. We found that P0-specific plasmablasts and B cells were increased in spleens of SAP mice compared to wild-type NOD mice. Depletion of B cells and plasmablasts with anti-CD19 monoclonal antibody (mAb) led to attenuation of disease severity when administered at 5 months of age. This was accompanied by decreased serum immunoglobulin (Ig)G and IgM levels, depletion of P0-specific plasmablasts and B cells, down-regulation/internalization of surface CD19 and increased frequency of CD4+ regulatory T cells in spleens. We conclude that B cells are crucial to the pathogenesis of SAP, and that CD19 is a promising B cell target for the development of disease-modifying agents in autoimmune neuropathies.
Myasthenia gravis: an update for the clinician
Authors: Sieb J P
Published: October 2013

This paper provides a thorough overview of the current advances in diagnosis and therapy of myasthenia gravis (MG). Nowadays the term ‘myasthenia gravis’ includes heterogeneous autoimmune diseases, with a postsynaptic defect of neuromuscular transmission as the common feature. Myasthenia gravis should be classified according to the antibody specificity [acetylcholine, muscle-specific receptor tyrosine kinase (MuSK), low-density lipoprotein receptor-related protein 4 (LRP4), seronegative], thymus histology (thymitis, thymoma, atrophy), age at onset (in children; aged less than or more than 50 years) and type of course (ocular or generalized). With optimal treatment, the prognosis is good in terms of daily functions, quality of life and survival. Symptomatic treatment with acetylcholine esterase inhibition is usually combined with immunosuppression. Azathioprine still remains the first choice for long-term immunosuppressive therapy. Alternative immunosuppressive options to azathioprine include cyclosporin, cyclophosphamide, methotrexate, mycophenolate mofetil and tacrolimus. Rituximab is a promising new drug for severe generalized MG. Emerging therapy options include belimumab, eculizumab and the granulocyte– macrophage colony-stimulating factor. One pilot study on etanercept has given disappointing results. For decades, thymectomy has been performed in younger adults to improve non-paraneoplastic MG. However, controlled prospective studies on the suspected benefit of this surgical procedure are still lacking. In acute exacerbations, including myasthenic crisis, intravenous immunoglobulin, plasmapheresis and immunoadsorption are similarly effective.
Neuroprotection effect of interleukin (IL)-17 secreted by reactive astrocytes is emerged from a high-level IL-17-containing environment during acute neuroinflammation
Authors: Hu M H , Zheng Q F , Jia X Z , Li Y , Dong Y C , Wang C Y , Lin Q Y , Zhang F Y , Zhao R B , Xu H W , Zhou J H , Yuan H P , Zhang W H , Ren H
Published: October 2013

An increase in interleukin (IL)-17A-producing cells, particularly at sites of tissue inflammation, is observed frequently, yet the mechanism is not fully understood. This study aims to dissect the role of IL-17 in autoimmunity-mediated neuroinflammation. The cytokine milieu containing elevated IL-17, which often appears in active states of autoimmunity, was mimicked in vitro by a supernatant obtained from rat peripheral blood monocytes stimulated with phorbol mystistate acetate (PMA)/ionomycin. The application of such inflammatory media on only primary cultured cerebellar granule neurones resulted in significant apoptosis, but the presence of astrocytes largely prevented the effect. The supernatants of the stimulated astrocytes, especially those that contained the highest level of IL-17, achieved the best protection, and this effect could be blocked by anti-IL-17 antibodies. Protein IL-17 inhibited intracellular calcium increase and protected the neurones under inflammatory attack from apoptosis. IL-17, but not interferon (IFN)-γ, in the inflammatory media contributed to astrocyte secretion of IL-17, which depended on the Janus kinase/signal transducers and activators of transcription (JAK/STAT) pathway activation. The astrocytes that were treated with IL-17 alone or with prolonged treatment of the inflammatory media failed to produce sufficient levels of IL-17. Moreover, confirmatory data were obtained in vivo in a monophasic experimental autoimmune uveitis (EAU) in Lewis rats; in this preparation, the high-level IL-17-containing the cytokine milieu was demonstrated, along with IL-17 secretion by the resident neural cells. The antagonism of IL-17 at a late stage disturbed the disease resolution and resulted in significant neural apoptosis. Our data show a dynamic role of IL-17 in the maintenance of homeostasis and neuroprotection in active neuroinflammation.
Effects of correction of vitamin D insufficiency on serum osteocalcin and glucose metabolism in obese children
Authors: Poomthavorn Preamrudee , Nantarakchaikul Palinee , Mahachoklertwattana Pat , Chailurkit La‐or , Khlairit Patcharin
Published: October 2013

Objectives

Osteocalcin (OCN) and vitamin D insufficiency (VDI) have been shown to be associated with abnormal glucose metabolism (GluMet). Whether correction of VDI affects serum OCN is unknown. This study evaluated the effects of correction of VDI on OCN and GluMet, and determined the associations of OCN with 25‐hydroxyvitamin D (25‐OHD) and GluMet.

Design, patients and measurements

This study involved 230 obese children in a cross‐sectional part and 72 participants in a prospective part in which children with VDI were treated with vitamin D2 at a dose of 20 000 IU daily for 28 days. All 230 children underwent an oral glucose tolerance test and had their serum total and undercarboxylated OCNs and 25‐OHD measured. Forty of 72 children were reassessed for the GluMet and serum total and undercarboxylated OCNs and 25‐OHD after the vitamin D2 treatment.

Results

In the prospective part, correction of VDI by raising mean (SD) 25‐OHD of 51·5 (12·3) to 141·8 (40·8) nmol/l resulted in an improvement of their GluMet and increase in their whole‐body insulin sensitivity index with no changes in their OCN measures. In the cross‐sectional part, after adjustments for age, sex and puberty, the total (β = 0·322) and undercarboxylated OCNs (β = 0·315) were positively associated with insulinogenic index, which is an index of insulin secretion (P = 0·034 and 0·037, respectively) in the group of prediabetic and diabetic children.

Conclusions

Correction of VDI increased insulin sensitivity and improved GluMet, but had no effect on serum OCN measures. OCN was associated with increased insulin secretion in children with abnormal GluMet.
131I‐MIBG therapy for malignant paraganglioma and phaeochromocytoma: systematic review and meta‐analysis
Authors: van Hulsteijn L. T. , Niemeijer N. D. , Dekkers O. M. , Corssmit E. P. M.
Published: October 2013

Background

131I‐MIBG therapy can be used for palliative treatment of malignant paraganglioma and phaeochromocytoma. The main objective of this study was to perform a systematic review and meta‐analysis assessing the effect of 131I‐MIBG therapy on tumour volume in patients with malignant paraganglioma/phaeochromocytoma.

Methods

A literature search was performed in December 2012 to identify potentially relevant studies. Main outcomes were the pooled proportions of complete response, partial response and stable disease after radionuclide therapy. A meta‐analysis was performed with an exact likelihood approach using a logistic regression with a random effect at the study level. Pooled proportions with 95% confidence intervals (CI) were reported.

Results

Seventeen studies concerning a total of 243 patients with malignant paraganglioma/phaeochromocytoma were treated with 131I‐MIBG therapy. The mean follow‐up ranged from 24 to 62 months. A meta‐analysis of the effect of 131I‐MIBG therapy on tumour volume showed pooled proportions of complete response, partial response and stable disease of, respectively, 0·03 (95% CI: 0·06–0·15), 0·27 (95% CI: 0·19–0·37) and 0·52 (95% CI: 0·41–0·62) and for hormonal response 0·11 (95% CI: 0·05–0·22), 0·40 (95% CI: 0·28–0·53) and 0·21 (95% CI: 0·10–0·40), respectively. Separate analyses resulted in better results in hormonal response for patients with paraganglioma than for patients with phaeochromocytoma.

Conclusions

Data on the effects of 131I‐MIBG therapy on malignant paraganglioma/phaeochromocytoma suggest that stable disease concerning tumour volume and a partial hormonal response can be achieved in over 50% and 40% of patients, respectively, treated with 131I‐MIBG therapy. It cannot be ruled out that stable disease reflects not only the effect of MIBG therapy, but also (partly) the natural course of the disease.
When would I use medical therapies for the treatment of primary hyperparathyroidism?
Authors: Crowley Rachel K. , Gittoes Neil J.
Published: October 2013

Although there may be controversy surrounding the indications for parathyroidectomy in primary hyperparathyroidism, it remains the only accepted definitive therapy. However, even if parathyroidectomy is indicated, some patients refuse surgery, are medically unfit or have residual or recurrent disease inaccessible to further surgery. Some of these patients may be suitable for long‐term observation but others require intervention for management of symptomatic or moderate to severe hypercalcaemia, loss of bone mineral density or renal calculi. The selection of a suitable therapy for each patient should be individualized.