bluuebunny/crossref_metadata_2025 huggingface dataset:
B–B Coupling and B–B Catenation: Computational Study of the Structure and Reactions of Metal–Bis(borylene) Complexes
Authors: Ghorai Sagar , Jemmis Eluvathingal D.
Published: October 2018

A detailed molecular orbital analysis of the metal–bis(borylene) complex [Fe(CO)3{B(Dur)B(N(SiMe3)2)}] (Dur=2,3,5,6‐tetramethylphenyl) (1 a) serves as a focal point of recent developments in this area of chemistry, such as B–B coupling and B–B catenation reactions. There is strong a π delocalization between the Fe(CO)3 and (B‐Dur)(B‐N(SiMe3)2) units; the short B–B distance in 1 a is due to this π delocalization. The π‐donor ligand N(SiMe3)2 on the boron provides a decisive stability to the complex 1 a. The LUMO of 1 a has B–B σ‐bonding character. Hence B–B coupling is facilitated by filling the LUMO. Strong σ‐donating ligands, such as PMe3 or PCy3, induce B–B coupling. Expulsion of one CO from 1 a followed by dimerization leads to [Fe(CO)2{B(Dur)B(N(SiMe3)2)}]2 (3 a) with a short Fe−Fe distance of 2.355 Å. A detailed mechanism for the reaction of 3 a with CO to give the B–B catenation product 2 f is presented. The bonding of all intermediates is compared to their isolobal main‐group analogues.
5‐Oxyacetic Acid Modification Destabilizes Double Helical Stem Structures and Favors Anionic Watson–Crick like cmo5U‐G Base Pairs
Authors: Strebitzer Elisabeth , Rangadurai Atul , Plangger Raphael , Kremser Johannes , Juen Michael Andreas , Tollinger Martin , Al‐Hashimi Hashim M. , Kreutz Christoph
Published: October 2018

Watson–Crick like G‐U mismatches with tautomeric Genol or Uenol bases can evade fidelity checkpoints and thereby contribute to translational errors. The 5‐oxyacetic acid uridine (cmo5U) modification is a base modification at the wobble position on tRNAs and is presumed to expand the decoding capability of tRNA at this position by forming Watson–Crick like cmo5Uenol‐G mismatches. A detailed investigation on the influence of the cmo5U modification on structural and dynamic features of RNA was carried out by using solution NMR spectroscopy and UV melting curve analysis. The introduction of a stable isotope labeled variant of the cmo5U modifier allowed the application of relaxation dispersion NMR to probe the potentially formed Watson–Crick like cmo5Uenol‐G base pair. Surprisingly, we find that at neutral pH, the modification promotes transient formation of anionic Watson–Crick like cmo5U−‐G, and not enolic base pairs. Our results suggest that recoding is mediated by an anionic Watson–Crick like species, as well as bring an interesting aspect of naturally occurring RNA modifications into focus—the fine tuning of nucleobase properties leading to modulation of the RNA structural landscape by adoption of alternative base pairing patterns.
Effects of ultrasonic cavitation on neutralization process of low molecular weight polyethylene glycol
Authors: Azarpour Abbas , Zendehboudi Sohrab , Yusup Suzana , Khalid Athirah , Zhang Yahui
Published: October 2018

In recent decades, ultrasound has been broadly employed in different applications, particularly in the chemical industry. Ultrasound enhances chemical reactions in a solution via generation of cavitation microbubbles. It improves mass transfer rate and kinetic rate of targeted systems under various process conditions. In polyethylene glycol (PEG) production, the neutralization reaction is generally carried out by employing a mechanical stirring operation. However, this process produces a soluble salt containing potassium and acetate ions, which are known to appreciably manipulate/alter the properties of PEG. In this paper, ultrasound influence is initially analyzed through the neutralization of deionized water. This study then focuses on the neutralization of PEG using ultrasonic cavitation and its impact on the properties of PEG. The ultrasonic cavitation unit employed in this research is a COLE‐Parmer® 500 W & 20 kHz with an ultrasonic probe. To investigate the efficiency of the ultrasonic cavitation reactor and analyze the important aspects of the implemented method, the concentration of soluble salts and conductivity of PEG neutralized by the ultrasonic cavitation method are measured and compared with those of the commercial PEG prepared by the mechanical stirring methodology. The results reveal that the neutralization reaction via the ultrasonic cavitation lowers the conductivity and concentrations of potassium and acetate ions, compared to the traditional stirring methods. It is also concluded that the minimum conductivity and the minimum content of potassium and acetate ions are achieved at 30 % power and a reaction time of 5 min. This study promises the efficient utilization of the ultrasonic cavitation in the industrial sectors, particularly in pharmaceutical industries.
Treatment of childhood acute lymphoblastic leukemia with delayed first intrathecal therapy and omission of prophylactic cranial irradiation: Results of the TPOG‐ALL‐2002 study
Authors: Yeh Ting‐Chi , Liang Der‐Cherng , Hou Jen‐Yin , Jaing Tang‐Her , Lin Dong‐Tsamn , Yang Chao‐Ping , Peng Ching‐Tien , Hung Iou‐Jih , Lin Kai‐Hsin , Hsiao Chih‐Cheng , Jou Shiann‐Tarng , Chiou Shyh‐Shin , Chen Jiann‐Shiuh , Wang Shih‐Chung , Chang Te‐Kau , Wu Kang‐Hsi , Sheen Jiunn‐Ming , Yen Hsiu‐Ju , Chen Shih‐Hsiang , Lu Meng‐Yao , Li Meng‐Ju , Chang Tai‐Tsung , Huang Ting‐Huan , Chang Yu‐Hsiang , Chen Shu‐Huey , Yang Yung‐Li , Chang Hsiu‐Hao , Chen Bow‐Wen , Lin Pei‐Chin , Cheng Chao‐Neng , Chao Yu‐Hua , Yang Shang‐Hsien , Chao Yu‐Mei Y. , Liu Hsi‐Che
Published: October 2018

Background

To eliminate cranial irradiation (CrRT)–related sequelae and to minimize the adverse impact of traumatic lumbar puncture (TLP) with blasts, the Taiwan Pediatric Oncology Group (TPOG) introduced a modified central nervous system (CNS)–directed regimen characterized by delayed triple intrathecal therapy (TIT) and the omission of CrRT for all children with newly diagnosed acute lymphoblastic leukemia (ALL).

Methods

This study compared the treatment outcomes of patients overall and patients with a non–CNS‐1 status (CNS‐2, CNS‐3, or TLP with blasts) in 2 treatment eras, one before and another after the revision of the TPOG‐ALL‐2002 protocol by the introduction of the modification (era 1 [2002‐2008] with CrRT and era 2 [2009‐2012] with delayed first TIT and no CrRT).

Results

There were no statistically significant differences in major outcomes between the 903 patients treated in era 1 and the 444 patients treated in era 2: the 5‐year event‐free survival (EFS) rates were 75.7% ± 1.4% and 72.1% ± 2.4%, respectively (P = .260), and the cumulative risks of isolated CNS relapse were 4.0% ± 0.7% and 4.1% ± 1.0%, respectively (P = .960). There were also no differences between non–CNS‐1 patients treated in era 1 (n = 76) and era 2 (n =28): the 5‐year EFS rates were 52.3% ± 5.8% and 62.9% ± 9.4%, respectively (P = .199), and the cumulative risks of isolated CNS relapse were 6.3% ± 3.1% and 3.6% ± 3.5%, respectively (P = .639). Notably, TLP with blasts was completely eliminated after the first TIT was delayed in era 2.

Conclusions

The delay of the first TIT until the clearance of circulating blasts and the total omission of CrRT did not compromise survival or CNS control in patients with childhood ALL, including those with a non–CNS‐1 status.
The modular organization of the cerebral cortex: Evolutionary significance and possible links to neurodevelopmental conditions
Authors: Casanova Manuel F. , Casanova Emily L.
Published: October 2018

The recognition of discernible anatomical regularities that appear to self‐organize during development makes apparent the modular organization of the cerebral cortex. The metabolic cost engendered in sustaining interneuronal communications has emphasized the viability of short connections among neighboring neurons. This pattern of connectivity establishes a microcircuit which is repeated in parallel throughout the cerebral cortex. This canonical circuit is contained within the smallest module of information processing of the cerebral cortex; one which Vernon Mountcastle called the minicolumn. Plasticity within the brain is accounted, in part, by the presence of weak linkages that allow minicolumns to process information from a variety of sources and to quickly adapt to environmental exigencies without a need for genetic change. Recent research suggests that interlaminar correlated firing between minicolumns during the decision phase of target selection provides for the emergence of some executive functions. Bottlenecks of information processing within this modular minicolumnar organization may account for a variety of mental disorders observed in neurodevelopmental conditions.
Oncologist perspectives on chemotherapy‐induced nausea and vomiting (CINV) management and outcomes: A quantitative market research‐based survey
Authors: Aapro Matti , Ruffo Pierfrancesco , Panteri Roger , Costa Stefano , Piovesana Vittoria
Published: October 2018

Background

Chemotherapy‐induced nausea and vomiting (CINV) is a distressing side effect that can negatively impact patients' quality of life and could discourage completion of chemotherapy, thereby affecting overall treatment outcomes. Although adherence to antiemetic guidelines can reduce CINV incidence in patients receiving highly or moderately emetogenic chemotherapy, CINV control remains inadequate.

Aims

The objectives of this survey were to determine oncologists' practice patterns in CINV management, identify factors that contribute to antiemetic treatment failure, and determine the outcomes of uncontrolled CINV on health care resource utilisation and on patients' attitude towards chemotherapy.

Methods and results

Quantitative market research was performed using an online questionnaire. Responses from 300 European oncologists who prescribe antiemetics and see ≥50 patients/month were analysed. Results showed that the main reasons reported by oncologists for antiemetic treatment failure were underestimating the emetogenic potential of chemotherapy, utilising weaker antiemetic regimens than required, and patient non‐adherence because of administration mistakes or missed/delayed doses. Educational initiatives for the oncology multidisciplinary team may help improve guideline‐consistent prescribing. Also, the availability of simpler, more convenient antiemetic therapies may improve guideline adherence and patient compliance during home administration.

Conclusion

Achieving effective CINV control is a crucial goal to improve patients' quality of life, which should optimise chemotherapy outcomes, and would ultimately reduce health care costs.
Selective sharing: The impact of patterns of communication in young people experiencing maternal cancer
Authors: Rodriguez Leonor
Published: October 2018

Background

Adolescents that experience parental cancer can have significant difficulties and may be at a greater risk of emotional and behavioural problems; however, some studies have found that this experience can also be empowering and can promote positive growth. Open communication specifically has been associated with coping and less psychological distress in adolescents experiencing parental cancer.

Aims

The aim of this study is to identify communication patterns in adolescents that faced maternal cancer to provide recommendations for practice on how best to support adolescents at this challenging time.

Methods

Adolescents (n = 15) completed semistructured interviews with the main researcher to explore their experiences at the time of maternal cancer. Specifically, this study is a qualitative secondary thematic analysis.

Results

The term “selective sharing” was coined to characterise adolescent communication patterns, as they selected who they wished to talk to and how much information about maternal illness they shared. Barriers for adolescent open communication included perceived unavailability of their mothers to talk, fear, geographical separation from their families, previous family communication patterns, and the time since maternal diagnosis. Benefits of open communication included access to affection, support and information, as well as validation of their emotions and improved coping. Adolescents also provided recommendations to peers and practitioners based on their own experiences.

Conclusions

Adolescent communication patterns need to be evaluated as this can impact on their ability to cope with maternal cancer diagnosis. Practitioners can facilitate and encourage open communication, including both factual information about cancer and the emotions and thoughts adhered to this experience for adolescents, mothers, friends, and their families to support them at this challenging time.
Methods to Measure MDSC Immune Suppressive Activity In Vitro and In Vivo
Authors: Solito Samantha , Pinton Laura , De Sanctis Francesco , Ugel Stefano , Bronte Vincenzo , Mandruzzato Susanna , Marigo Ilaria
Published: October 2018

This unit presents methods to assess the immunosuppressive properties of immunoregulatory cells of myeloid origin, such as myeloid‐derived suppressor cells (MDSCs), both in vitro and in vivo in mice, as well as in biological samples from cancer patients. These methods could be adapted to test the impact of different suppressive populations on T cell activation, proliferation, and cytotoxic activity; moreover, they could be useful to assess the influence exerted by genetic modifications, chemical inhibitors, and drugs on immune suppressive pathways © 2018 by John Wiley & Sons, Inc.
Clients' experience of change: An exploration of the influence of reformulation tools in cognitive analytic therapy
Authors: Tyrer Rebecca , Masterson Ciara
Published: October 2018

Case formulation is considered important in both the development of the therapeutic relationship and in starting the process of therapeutic change. Cognitive analytic therapy (CAT) describes the developmental origins and maintenance of a client's problems in both written (reformulation letter) and diagrammatic form (sequential diagrammatic reformulation). This study aimed to investigate the effects of these reformulation tools on insight and symptom change. A small‐N repeated measures design was employed with quantitative and qualitative measures collected from six therapist/client dyads. Participating therapists kept a record of their delivery of CAT reformulation tools. Participating clients completed the insight subscale of the Self‐Reflection and Insight Scale every fourth session and the Clinical Outcomes in Routine Evaluation‐10 every session. Qualitative data from client change interviews regarding their experiences of CAT and attributions of change was explored using template analysis. Participants demonstrated improvements (symptom reduction and insight increases) over the course of the intervention. Administration of reformulation tools did not consistently result in significant changes on insight and symptom measures. However, the tools were identified by participants as leading to insight and emotional change within the context of a good therapeutic relationship. These findings suggest that a genuine therapeutic relationship is an important change mechanism operating through, and strengthened by, CAT‐specific tools.
Structural Design of Ionic Liquids for Optimizing Aromatic Dissolution
Authors: Jiang Haihui Joy , Imberti Silvia , Simmons Blake A. , Atkin Rob , Warr Gregory G.
Published: October 2018

Certain protic ionic liquids (PILs) are potentially low‐cost, high‐efficiency solvents for the extraction and processing of aromatic compounds. To understand the key design features of PILs that determine solubility selectivity at the atomic level, neutron diffraction was used to compare the bulk structure of two PILs with and without an aromatic solute, guaiacol (2‐methoxyphenol). Guaiacol is a common lignin residue in biomass processing, and a model compound for anisole‐ or phenol‐based food additives and drug precursors. Although the presence of amphiphilic nanostructure is important to facilitate the dissolution of solute nonpolar moieties, the local geometry and competitive interactions between the polar groups of the cation, anion, and solute are found to also strongly influence solvation. Based on these factors, a framework is presented for the design of PIL structure to minimize competition and to enhance driving forces for the dissolution of small aromatic species.
Application of Human‐Induced Pluripotent Stem Cells (hiPSCs) to Study Synaptopathy of Neurodevelopmental Disorders
Authors: Shen Xuting , Yeung Hoi Ting , Lai Kwok‐On
Published: October 2018

Synapses are the basic structural and functional units for information processing and storage in the brain. Their diverse properties and functions ultimately underlie the complexity of human behavior. Proper development and maintenance of synapses are essential for normal functioning of the nervous system. Disruption in synaptogenesis and the consequent alteration in synaptic function have been strongly implicated to cause neurodevelopmental disorders such as autism spectrum disorders (ASDs) and schizophrenia (SCZ). The introduction of human‐induced pluripotent stem cells (hiPSCs) provides a new path to elucidate disease mechanisms and potential therapies. In this review, we will discuss the advantages and limitations of using hiPSC‐derived neurons to study synaptic disorders. Many mutations in genes encoding for proteins that regulate synaptogenesis have been identified in patients with ASDs and SCZ. We use Methyl‐CpG binding protein 2 (MECP2), SH3 and multiple ankyrin repeat domains 3 (SHANK3) and Disrupted in schizophrenia 1 (DISC1) as examples to illustrate the promise of using hiPSCs as cellular models to elucidate the mechanisms underlying disease‐related synaptopathy.
Disruption of MET Receptor Tyrosine Kinase, an Autism Risk Factor, Impairs Developmental Synaptic Plasticity in the Hippocampus
Authors: Ma Xiaokuang , Chen Ke , Lu Zhongming , Piechowicz Mariel , Liu Qiang , Wu Jie , Qiu Shenfeng
Published: October 2018

As more genes conferring risks to neurodevelopmental disorders are identified, translating these genetic risk factors into biological mechanisms that impact the trajectory of the developing brain is a critical next step. Here, we report that disrupted signaling mediated MET receptor tyrosine kinase (RTK), an established risk factor for autism spectrum disorders, in the developing hippocampus glutamatergic circuit leads to profound deficits in neural development, synaptic transmission, and plasticity. In cultured hippocampus slices prepared from neonatal mice, pharmacological inhibition of MET kinase activity suppresses dendritic arborization and disrupts normal dendritic spine development. In addition, single‐neuron knockdown (RNAi) or overexpression of Met in the developing hippocampal CA1 neurons leads to alterations, opposite in nature, in basal synaptic transmission and long‐term plasticity. In forebrain‐specific Met conditional knockout mice (Metfx/fx;emx1cre), an enhanced long‐term potentiation (LTP) and long‐term depression (LTD) were observed at early developmental stages (P12–14) at the Schaffer collateral to CA1 synapses compared with wild‐type littermates. In contrast, LTP and LTD were markedly reduced at young adult stage (P56–70) during which wild‐type mice show robust LTP and LTD. The altered trajectory of synaptic plasticity revealed by this study indicate that temporally regulated MET signaling as an intrinsic, cell autonomous, and pleiotropic mechanism not only critical for neuronal growth and functional maturation, but also for the timing of synaptic plasticity during forebrain glutamatergic circuits development.
Epithelial‐mesenchymal Transition and Cancer Stem Cells: At the Crossroads of Differentiation and Dedifferentiation
Authors: Wang Hanmin , Unternaehrer Juli J.
Published: October 2018

In this review, we explore the connections between epithelial‐mesenchymal transition (EMT) and differentiation status. EMTs in development have been described as differentiation events, while in most cases EMTs in cancer have been depicted as dedifferentiation events. We will briefly summarize both embryo development and cancer progression with regard to the involvement of EMT and cell differentiation status. We further present the studies that provide evidence that EMT results in both differentiation and dedifferentiation. Finally, we present our resolution to this dilemma by suggesting that EMT brings about dedifferentiation that enables subsequent differentiation. In normal development, EMT events may cause a partial reversal of differentiation to overcome differentiation barriers. When EMT is aberrantly activated in cancer, cells gain attributes of stem cells that contribute to self‐renewal capabilities and are able to differentiate to all cell types represented in the tumor. The resulting cancer stem cells attain hallmarks of cancer, including replicative immortality, resistance to cell death, and invasiveness. Developmental Dynamics 248:10–20, 2019. © 2018 Wiley Periodicals, Inc.
English as a foreign language teacher training needs and perceived preparedness to include dyslexic learners: The case of Greece, Cyprus, and Poland
Authors: Nijakowska Joanna , Tsagari Dina , Spanoudis George
Published: October 2018

This study examines the effect of demographic variables on the beliefs of teachers of English as a foreign language (EFL) about their preparedness to include dyslexic learners in mainstream classrooms in Greece, Cyprus, and Poland and identifies their professional development needs. Statistically significant multivariate analysis effects were obtained for country, training, teaching experience with dyslexic learners, and school type. Unlike overall teaching experience and completed level of education (degree), the type of teaching experience with dyslexic EFL learners (direct contact and personal involvement in teaching) seems to shape the perception of teacher preparedness to successfully include these learners. Other interesting tendencies were identified such as between‐country differences concerning sources of prior professional knowledge on EFL and dyslexia as well as preferences for particular modes of training. The paper highlights the demand for professional training on EFL and dyslexia as this was confirmed across the three countries.
A Defect‐Free Naphthalene Diimide Bithiazole Copolymer via Regioselective Direct Arylation Polycondensation
Authors: Matsidik Rukiya , Giorgio Michele , Luzio Alessandro , Caironi Mario , Komber Hartmut , Sommer Michael
Published: October 2018

An optimized direct arylation polycondensation (DAP) protocol for the synthesis of a novel naphthalene diimide (NDI) 2,2′‐bithiazole (2‐BTz) copolymer (PNDI‐2‐BTz) is presented. The regioselective C–H activation of 2‐BTz at the 5‐positions allows for the synthesis of fully regioregular and homocoupling‐free PNDI‐2‐BTz of high molecular weight in less than 1 h in quantitative yield. Complete end group assignment shows functionalities according to monomer structures or to nucleophilic substitution, and allows for the reliable determination of absolute molecular weight. Compared to the well‐known bithiophene analog PNDIT2, an exceptionally high thermal stability, a hypsochromically shifted charge transfer absorption band and a lower‐lying LUMO energy level is found, making PNDI‐2‐BTz an interesting candidate for applications in organic electronic devices. In contrast to the selective and high yielding C–H activation of 2‐BTz at the 5‐position, the regioisomer 5,5′‐bithiazole is inactive under a variety of conditions.
The Multiple‐Streams Framework and Knowledge Utilization: Argumentative Couplings of Problem, Policy, and Politics Issues
Authors: Blum Sonja
Published: October 2018

Two problems are discussed in the—surprisingly unconnected—literatures on the multiple‐streams framework (MSF) and on knowledge utilization. In the MSF, the concept of coupling has been overlooked, namely the mechanisms of linking between the problem, policy, and politics streams. In the knowledge‐utilization literature, it is discussed whether political–strategic issues are the preserve of policy‐makers, or also considered by scientific experts. Through connecting both literatures, this article develops the concept of argumentative coupling, that is the linking of problem, policy, and politics issues through arguments. This follows the recently rising call of reading the MSF through an argumentative lens. Building on an ethnographic account of research–policy interactions, different types and three different logics of argumentative coupling are systematized: consequential, doctrinal, and political. Argumentative coupling illuminates how the ground for “final couplings” is prepared: by constructing canals between the streams, which entrepreneurs may sail when the wind is blowing.
Policy dynamics and types of agency: From individual to collective patterns of action
Authors: Capano Giliberto , Galanti Maria Tullia
Published: October 2018

Despite the relevance of structures and constraints to the outcomes of policy‐making, agency emerges as a key aspect in accounting for policy dynamics. Indeed, agency is a concept that may embrace different components according to their empirical reference and policy context.

In policy studies, different agents are conceptualized to be relevant in policy‐making, but they address the issues of similar individuals who randomly jump into the policy process to make a specific contribution. This paper proposes to de‐personalize agency in policy dynamics by arguing that the different types of agents can be attributed to specific patterns of action and that related tasks are a necessary element of stability and change in policy dynamics. Thus, we propose three types of patterns—entrepreneurship, brokerage, and leadership—and we show how the use of these concepts can help to better order, describe, and grasp agency in policy dynamics.
Authentication of the geographical origin of patchouli oil using front‐face fluorescence spectroscopy and chemometric analysis
Authors: Al Riza Dimas Firmanda , Widodo Slamet , Purwanto Y. Aris , Kondo Naoshi
Published: October 2018

Increasing consumer awareness of the authenticity of products has led to a demand for rapid measurement methods to support the traceability of high‐value commodities. In this research, a front‐face method was used to obtain fluorescence excitation–emission matrix fingerprints of patchouli oil samples from different geographical origins in Indonesia. Principal component analysis (PCA) was then used to explore the excitation–emission matrix (EEM) data structure of the samples, and 3D eigenvector value thresholding was used to discriminate important variables. It was found that there were five important EEM regions representing the sample variation. A decision‐tree model with a subset of two important regions, i.e. regions 1 and 3, was then developed for the classification of patchouli oils from different Indonesian islands. These results show that front‐face fluorescence spectroscopy has the potential to be used as a supporting tool for the discrimination of the geographical origin of patchouli oils.
PI3Kδ Is a Therapeutic Target in Hepatocellular Carcinoma
Authors: Ko Eunkyong , Seo Hyun‐Wook , Jung Eun Sun , Ju Soomi , Kim Baek‐hui , Cho Hyeki , Kim Yoon Jun , Park Young Min , Kim Jong‐Seo , Jung Guhung
Published: October 2018

Class I phosphoinositide 3‐kinase (PI3K) signaling is a major pathway in human cancer development and progression. Among the four PI3K isoforms, PI3Kα and PI3Kβ are ubiquitously expressed, whereas PI3Kγ and PI3Kδ are found primarily in leukocytes. Until now, PI3K targeting in solid tumors has focused on inhibiting PI3Kα‐mediated and PI3Kβ‐mediated cancer cell–intrinsic PI3K activity. The role of PI3Kδ in solid tumors is unknown. Here, we evaluated the effects of PI3Kδ using established hepatocellular carcinoma (HCC) cells, malignant hepatocytes derived from patients with advanced HCC, murine models, and HCC tissues using RNA sequencing, quantitative PCR, immunoblotting, immunofluorescence, microarray, liquid chromatography–tandem mass spectrometry, and kinase assay. We established a chemical carcinogenesis model of liver malignancy that reflects the malignant phenotype and the in vivo environment of advanced HCC. In this in vivo advanced HCC‐mimic system using HCC cells treated with hydrogen peroxide (H2O2), we showed that H2O2 selectively increases PI3Kδ activity while decreasing that of other class I PI3Ks. Blocking PI3Kδ activity with a PI3Kδ inhibitor or small interfering RNA–mediated PI3Kδ gene silencing inhibited HCC‐cell proliferation and dampened key features of malignant HCC, including the up‐regulation of telomerase reverse transcriptase (TERT). Mechanistically, H2O2 induced oxidative modification of the serpin peptidase inhibitor, serpin peptidase inhibitor (SERPINA3), blocking its ubiquitin‐dependent degradation and enhancing its activity as a transcriptional activator of PI3Kδ and TERT. High PI3Kδ levels in HCC were found to correlate with poor survival rates, with human advanced HCC showing positive correlations between the protein levels of oxidized SERPINA3, PI3Kδ, and TERT. Thus, PI3Kδ plays significant roles in malignant liver tumors. Conclusion: Our data identify PI3Kδ inhibition, recently approved for the treatment of human B‐cell malignancies, as a potential treatment for HCC.
Recognition of UK Insolvency Proceedings Post‐Brexit: The Impact of a ‘No Deal’ Scenario
Authors: Umfreville Chris , Omar Paul , Lücke Heike , Fannon Irene Lynch , Veder Michael , Carballo Piñeiro Laura
Published: October 2018

This paper examines the impact of a ‘no deal’ or ‘hard’ Brexit on the recognition of insolvency proceedings commenced in the UK by the remaining Member States of the European Union (EU) post‐Brexit. The paper considers the framework currently implemented by the Recast European Insolvency Regulation and the possible approaches when it will cease to apply to proceedings commenced post‐Brexit. The paper identifies that there will be no overarching framework in the event that ‘no deal’ is reached between the UK and the EU for post‐Brexit arrangements, resulting in reliance on individual Member States' domestic laws to determine recognition of insolvency proceedings commenced in the UK. The paper sets out the contrasting approaches of five of the UK's key trading partners in the EU: France, Germany, Ireland, the Netherlands and Spain. The paper concludes that UK insolvency proceedings will not be recognised in a consistent manner in these Member States, which will be detrimental to stakeholders in, and ultimately the economies of, the UK and these Member States. In doing so, the paper underlines the importance of an agreement being reached between the UK and the EU on the recognition of cross‐border insolvency proceedings for the benefit of all parties. Copyright © 2018 The Authors International Insolvency Review published by INSOL International and John Wiley & Sons Ltd.
ERBB2 and KRAS alterations mediate response to EGFR inhibitors in early stage gallbladder cancer
Authors: Iyer Prajish , Shrikhande Shailesh V. , Ranjan Malika , Joshi Asim , Gardi Nilesh , Prasad Ratnam , Dharavath Bhasker , Thorat Rahul , Salunkhe Sameer , Sahoo Bikram , Chandrani Pratik , Kore Hitesh , Mohanty Bhabani , Chaudhari Vikram , Choughule Anuradha , Kawle Dhananjay , Chaudhari Pradip , Ingle Arvind , Banavali Shripad , Gera Poonam , Ramadwar Mukta R. , Prabhash Kumar , Barreto Savio George , Dutt Shilpee , Dutt Amit
Published: October 2018

The uncommonness of gallbladder cancer in the developed world has contributed to the generally poor understanding of the disease. Our integrated analysis of whole exome sequencing, copy number alterations, immunohistochemical, and phospho‐proteome array profiling indicates ERBB2 alterations in 40% early‐stage rare gallbladder tumors, among an ethnically distinct population not studied before, that occurs through overexpression in 24% (n = 25) and recurrent mutations in 14% tumors (n = 44); along with co‐occurring KRAS mutation in 7% tumors (n = 44). We demonstrate that ERBB2 heterodimerizes with EGFR to constitutively activate the ErbB signaling pathway in gallbladder cells. Consistent with this, treatment with ERBB2‐specific, EGFR‐specific shRNA or with a covalent EGFR family inhibitor Afatinib inhibits tumor‐associated characteristics of the gallbladder cancer cells. Furthermore, we observe an in vivo reduction in tumor size of gallbladder xenografts in response to Afatinib is paralleled by a reduction in the amounts of phospho‐ERK, in tumors harboring KRAS (G13D) mutation but not in KRAS (G12V) mutation, supporting an essential role of the ErbB pathway. In overall, besides implicating ERBB2 as an important therapeutic target under neo‐adjuvant or adjuvant settings, we present the first evidence that the presence of KRAS mutations may preclude gallbladder cancer patients to respond to anti‐EGFR treatment, similar to a clinical algorithm commonly practiced to opt for anti‐EGFR treatment in colorectal cancer.
UCK2 upregulation might serve as an indicator of unfavorable prognosis of hepatocellular carcinoma
Authors: Yu Shuo , Li Xu , Guo Xingjun , Zhang Hang , Qin Renyi , Wang Ming
Published: October 2018

Uridine‐cytidine kinases (encoded by UCK1, UCKL1, and UCK2) catalyze the phosphorylation of uridine and cytidine to uridine monophosphate (UMP) and cytidine monophosphate (CMP). In this study, using data from the Cancer Genome Atlas (TCGA), we analyzed the expression profile of uridine‐cytidine kinase genes in hepatocellular carcinoma (HCC), their prognostic value, and the epigenetic alterations associated with their dysregulation. Results showed that UCKL1 and UCK2, but not UCK1 were significantly upregulated in HCC tissues than in adjacent normal tissues. Only UCK2 was significantly upregulated in the deceased group and the recurrence group, compared to the control groups. Multivariate analysis confirmed that increased UCK2 expression was an independent prognostic indicator of shorter overall survival (OS) (HR: 1.760, 95% CI: 1.398–2.216, P < 0.001) and recurrence‐free survival (RFS) (HR: 1.543, 95% CI: 1.232–1.933, P < 0.001). Two CpG sites (cg09277749 and cg21143899) were significantly hypomethylated in HCC tissues than in adjacent normal tissues and were negatively correlated with UCK2 expression. However, survival analysis showed that only high methylation of cg0927774 was associated with better OS and RFS of HCC patients. Based on the findings above, we infer that UCK2 upregulation might be a valuable prognostic marker in HCC. The methylation of status cg0927774 might play a critical role in its expression. © 2018 IUBMB Life, 71(1):105–112, 2019
Validation of delay‐multiply‐and‐standard‐deviation weighting factor for improved photoacoustic imaging of sentinel lymph node
Authors: Paridar Roya , Mozaffarzadeh Moein , Periyasamy Vijitha , Basij Maryam , Mehrmohammadi Mohammad , Pramanik Manojit , Orooji Mahdi
Published: October 2018

Delay‐and‐sum (DAS) is one of the most common algorithms used to construct the photoacoustic images due to its low complexity. However, it results in images with high sidelobes and low resolution. Delay‐and‐standard‐deviation (DASD) weighting factor can improve the contrast of the images compared to DAS. However, it still suffers from high sidelobes. In this work, a new weighting factor, named delay‐multiply‐and‐standard‐deviation (DMASD) is introduced to enhance the contrast of the reconstructed images compared to other mentioned methods. In the proposed method, the SD of the mutual multiplied delayed signals are calculated, normalized and multiplied to DAS beamformed data. The results show that DMASD improves the signal‐to‐noise‐ratio about 19.29 and 7.3 dB compared to DAS and DASD, respectively, for in vivo imaging of the sentinel lymph node. Moreover, the contrast ratio is improved by the DMASD about 23.61 and 10.81 dB compared to DAS and DASD, respectively.
Ex vivo induction of regulatory T cells from conventional CD4+ T cells is sensitive to substrate rigidity
Authors: Nataraj Neha M. , Dang Alex P. , Kam Lance C. , Lee Jounghyun H.
Published: October 2018

The immune system maintains a balance between protection and tolerance. Regulatory T cells (Tregs) function as a vital tolerance mechanism in the immune system to suppress effector immune cells. Additionally, Tregs can be utilized as a form of immunotherapy for autoimmune disorders. As T cells have previously been shown to exhibit sensitivity to the rigidity of an activating substrate upon activation via IL‐2 secretion, we herein explore the previously unknown effect of substrate rigidity on the induction of Tregs from conventional naïve mouse CD4+ T cells. Substrates with modulatable rigidities ranging from a hundred kilopascals to a few megapascals were fabricated via poly(dimethylsiloxane). We found that there was a significant increase in Treg induction at lower substrate rigidities (i.e., E ~ 100 kPa) compared to higher rigidity levels (i.e., E ~ 3 MPa). To confirm that this significant difference in induction rate was truly related to T‐cell mechanosensing, we administered compound Y‐27632 to inhibit myosin contractility. In the presence of Y‐27632, the myosin‐based contractility was disrupted and, as a result, the difference in Treg induction caused by the substrate rigidity was abrogated. This study demonstrates that mechanosensing is involved in Treg induction and raises questions about the underlying molecular mechanisms involved in this process. © 2018 Wiley Periodicals, Inc. J Biomed Mater Res Part A: 106A: 3001–3008, 2018.
Serum exosomal miR‐210 as a potential biomarker for clear cell renal cell carcinoma
Authors: Wang Xuegang , Wang Tao , Chen Chenxi , Wu Zhun , Bai Peide , Li Shouchun , Chen Bin , Liu Rongfu , Zhang Kaiyan , Li Wei , Chen Yuedong , Xing Jinchun
Published: October 2018

Exosomal microRNAs (miRNAs) are suggested to reflect molecular changes occurring in their cells of origin and are potential indicators in the early detection of cancers. This study aimed to determine whether certain exosomal miRNAs from tumor tissue can be used as noninvasive biomarkers for clear cell renal cell carcinoma (ccRCC). Based on ccRCC miRNA expression profiles and the literature, we selected six miRNAs (miR‐210, miR‐224, miR‐452, miR‐155, miR‐21, and miR‐34a) and analyzed their expression in tissues, sera, and serum exosomes through quantitative real‐time polymerase chain reaction in hypoxia‐induced (with CoCl2) renal cell lines. miR‐210, miR‐224, miR‐452, miR‐155, and miR‐21 were upregulated in tumor tissues compared with normal tissues. Serum miR‐210 and miR‐155 levels were higher in patients with ccRCC than in healthy controls (HCs). Furthermore, only exosomal miR‐210 was significantly upregulated in patients with ccRCC than in HCs. Moreover, receiver operating characteristic (ROC) curve analysis revealed an area under the ROC curve of 0.8779 (95% confidence interval, 0.7987‐0.9571) and a sensitivity and specificity of 82.5% and 80.0%, respectively. Moreover, exosomal miR‐210 was upregulated at an advanced stage, and Fuhrman grade and metastasis decreased significantly one month after surgery. Acute hypoxia exposure activates miR‐210 and release of exosomes with upregulated miR‐210 in both normal and tumor RCC cell lines and interferes with vacuole membrane protein 1 mRNA expression, especially in the metastatic ccRCC cell line. In conclusion, Serum exosomal miR‐210 originating from tumor tissue has potential as a novel noninvasive biomarker for the detection and prognosis of ccRCC.
Chemical inhibition of HSP90 inhibits TNF‐α mediated proliferation and induces apoptosis in human rheumatoid arthritis fibroblast‐like synoviocytes
Authors: Yang Bin , Liu Xiangru , Liang Yongqian , Li Yue
Published: October 2018

Rheumatoid arthritis fibroblast‐like synoviocytes (RAFLS) proliferate abnormally and resist apoptosis. Geldanamycin (GA) and other HSP90 inhibitors have emerged as promising therapeutic agents that inhibited cancer cell growth. In this study, we explored the effects of HSP90 inhibitor, GA, on tumor necrosis factor (TNF)‐α‐induced proliferation and apoptosis of RAFLS, and the underlying mechanism. Human RAFLS was isolated from the knee joints of patients with RA and subjected to TNF‐α treatment in combination of various concentration of GA. We found that GA dose‐dependently inhibited TNF‐α‐induced RAFLS proliferation as measured, but promoted RAFLS apoptosis. Further mechanistic study identified that GA dose‐dependently attenuated TNF‐α‐mediated activation of mitogen‐activated protein kinases (MAPKs) and nuclear factor‐kappa B (NF‐κB) pathways, both of which are involved in TNF‐α‐mediated RAFLS proliferation. Moreover, GA‐induced apoptosis and mitochondrial damage of RAFLS, as evidenced by increased Bax/Bcl‐2 ratio and mitochondrial cytochrome c release, and enhanced cleavages of caspase‐3, caspase‐9, and poly‐(ADP‐ribose) polymerase. Collectively, our results revealed that chemical inhibition of HSP90 by GA suppressed TNF‐α‐induced proliferation of RAFLSs through the MAPK and NF‐κB signaling pathways and induces RAFLS apoptosis via mitochondria‐dependent pathway. These findings demonstrated for the first time that HSP90 inhibition in RAFLS could be therapeutic beneficial for RA.
Identification of potential drugs targeting L,L‐diaminopimelate aminotransferase of Chlamydia trachomatis: An integrative pharmacoinformatics approach
Authors: Sadhasivam Anupriya , Vetrivel Umashankar
Published: October 2018

Chlamydia trachomatis (C.t) is a gram‐negative obligate intracellular bacteria, which is a major causative of infectious blindness and sexually transmitted diseases. A surge in multidrug resistance among chlamydial species has posed a challenge to adopt alternative drug targeting strategies. Recently, in C.t, L,L‐diaminopimelate aminotransferase (CtDAP‐AT) is proven to be a potential drug target due its essential role in cell survival and host nonspecificity. Hence, in this study, a multilevel precision‐based virtual screening of CtDAP‐AT was performed to identify potential inhibitors, wherein, an integrative stringent scoring and filtration were performed by coupling, glide docking score, binding free energy, ADMET (absorption, distribution, metabolism, and excretion, toxicity) prediction, density functional theory (quantum mechanics), and molecular dynamics simulation (molecular mechanics). On cumulative analysis, NSC_5485 (1,3‐bis((7‐chloro‐4‐quinolinyl)amino)‐2‐propanol) was found to be the most potential lead, as it showed higher order significance in terms of binding affinity, bonded interactions, favorable ADMET, chemical reactivity, and greater stabilization during complex formation. This is the first report on prioritization of small molecules from National Cancer Institute (NCI) and Maybridge data sets (341 519 compounds) towards targeting CtDAP‐AT. Thus, the proposed compound shall aid in effective combating of a broad spectrum of C.t infections as it surpassed all the levels of prioritization.
Retracted: Effects of microRNA‐494 on proliferation, migration, invasion, and apoptosis of medulloblastoma cells by mediating c‐myc through the p38 MAPK signaling pathway
Authors: Xu Xiao‐Heng , Zhang Si‐Jin , Hu Qi‐Bo , Song Xing‐Yu , Pan Wei
Published: October 2018

Medulloblastoma (MB) is the most prevalent brain tumor that occurs during childhood and originates from cerebellar granule cell precursors. Based on recent studies, the differential expression of several microRNAs is involved in MB, while the role of microRNA‐494 (miR‐494) in MB remains unclear. Therefore, we conducted this study to investigate the regulative role of miR‐494 in MB cells via the p38 mitogen‐activated protein kinase (MAPK) signaling pathway by mediating c‐myc. In the current study, MB cells were collected and transfected with miR‐494 mimic, miR‐494 inhibitor, siRNA‐
c‐myc, and miR‐494 inhibitor + siRNA‐c‐myc. The expressions of miR‐494, c‐myc, p38 MAPK, B‐cell lymphoma‐2 (Bcl‐2), Bcl‐2‐associated X protein (Bax), interleukin‐6 (IL‐6), metadherin (MTDH), phosphatase and tensin homolog (PTEN) and survivin were determined. Cell proliferation, cell‐cycle distribution, apoptosis, migration, and invasion were evaluated. The results revealed that there was a poor expression of miR‐494 and high expression of
c‐myc in MB tissues.
C‐myc was determined as the target gene of miR‐494. In response to miR‐494 mimic, MB cells were found to have increased Bax and PTEN expressions, as well as cell number in G1 phase and cell apoptosis and decreased
c‐myc, p38 MAPK, Bcl‐2, MTDH, IL‐6, and survivin expression and cell number count in the S phase, cell proliferation, migration, and invasion. In conclusion, the results demonstrated that the upregulation of miR‐494 results in the suppression of cell proliferation, migration, and invasion, while it promotes apoptosis of MB cells through the negative mediation of
c‐myc, which in turn inactivates the p38 MAPK pathway.
Stomatin‐like protein‐2 relieve myocardial ischemia/reperfusion injury by adenosine 5′‐monophosphate‐activated protein kinase signal pathway
Authors: Qiu Zhibing , Chen Xin , Yin Li , Chen Wen , Xu Yueyue , Jiang Ben
Published: October 2018

Previous studies have shown that stomatin‐like protein‐2 (SLP‐2) could regulate mitochondrial biogenesis and function. The study was designed to explore the contribution of SLP‐2 to the myocardial ischemia and reperfusion (I/R) injury. Anesthetized rats were treated with SLP‐2 and subjected to ischemia for 30 minutes before 3 hours of reperfusion. An oxygen‐glucose deprivation/reoxygenation model of I/R was established in H9C2 cells. In vivo, SLP‐2 significantly improved cardiac function recovery of myocardial I/R injury rats by increasing fractional shortening and ejection fraction. SLP‐2 pretreatment alleviated infarct area and myocardial apoptosis, which was paralleled by decreasing the level of cleaved caspase‐3 and the ratio of Bax/Bcl‐2, increasing the content of superoxide dismutase and reducing oxidative stress damage in serum. In addition, SLP‐2 increased the level of ATP and stabilized mitochondrial potential (Ψm). The present in vitro study revealed that overexpression with SLP‐2 reduced H9C2 cells apoptosis, accompanied by an increased level of ATP, the ratio of mitochondrial DNA/nuclear DNA, activities of complex II and V, and decreased the production of mitochondrial reactive oxygen species. Simultaneously, SLP‐2 activated the adenosine 5′‐monophosphate‐activated protein kinase (AMPK) signaling pathway in myocardial I/R injury rats and H9C2 cells. This study revealed that SLP‐2 mediates the cardioprotective effect against I/R injury by regulating AMPK signaling pathway.