bluuebunny/crossref_metadata_2025 huggingface dataset:
An ecopreneur’s growing resilience after a series of earthquakes
Authors: Kirkwood Jodyanne , Dwyer Kirsty , Walton Sara
Published: June 2017

Purpose

This paper aims to examine the experiences of an ecopreneurial venture that was operating before, during and after the 2010-2011 series of earthquakes in Christchurch, New Zealand. The aim is to elucidate on the tension existing between an ecopreneur’s personal green values/ethics and his need to be resilient and do what was necessary to ensure his business’s survival, which was operating before, during and after an extreme event – the 2010-2011 series of earthquakes in Christchurch, New Zealand.

Design/methodology/approach

The data are gathered from a longitudinal case study of Just Organic Ltd (an organic fruit and vegetable delivery service) over a five-year period which covers time before and after the earthquakes. Data were gathered via two in-depth face-to-face interviews with the ecopreneur, along with a number of email and telephone follow-ups.

Findings

Findings indicate that an extreme event such as an earthquake will inhibit the green values of an ecopreneur as the ecopreneur works to ensure business survival. To continue to operate successfully, the ecopreneur developed a resilient and hardy nature and adapted operational processes to run in a more entrepreneurial fashion. It would seem that holding firmly to green values irrespective of a changed business environment is detrimental to business viability and survivability. The ecopreneur bounced forward, rather than bouncing back from the disaster.

Research limitations/implications

The implications for research, policy makers and ecopreneurs and entrepreneurs in general are discussed. There are lessons to be learned from the experiences of the ecopreneur who is operating Just Organic Limited.

Originality/value

This paper is one of the few that has examined the impact the Christchurch earthquakes had on an existing eco-business. The longitudinal data enable a unique insight into the operational aspects of an eco-business before and after a series of earthquakes.
Status and international alliance formation
Authors: Powell K. Skylar , Takahashi Hidenori , Roehl Tom
Published: June 2017

Purpose

Evidence suggests that “single-market” alliances are more likely to form between firms in similar socially determined status positions. However, in international alliances, firms come from different status interfaces and foreign partners may become status competitors. Hence, the preference for partners with similar socially derived status positions in their respective markets, or status homophily, is unclear in ‘international’ partner selections. This analysis aims to better understand this issue.

Design/methodology/approach

This research explores status homophily in international alliance formation using a database of hand-collected tombstone announcements for US initial public offering syndicates involving Japanese securities firms from 1975 through 1984.

Findings

Results suggest that firms are attracted to partners who occupy similar socially derived status positions in their own home markets. Additionally, high-status host-country firms may signal status differences within alliances to reduce status competition from high-status foreign partners.

Originality/value

This research indicates that “international” alliance research needs to consider socially derived status positions. Additionally, academics and practitioners alike can benefit from the knowledge that status signaling within alliances can be a type of competitive behavior between cooperating firms.
Productive researchers in countries with limited research capacity
Authors: Kuzhabekova Aliya , Mukhamejanova Dinara
Published: June 2017

Purpose

This study aims to explore how some researchers become successful in the research context of a transitional country despite the resource- and training-related limitations imposed by an immature research system.

Design/methodology/approach

The research uses Unger’s ideas within agency theory, specifically, his concepts of “negative capability” and “formative context” as its framework. The study adopts a descriptive qualitative approach, whereby the data collected from 19 in-depth interviews with successful researchers from various universities of Kazakhstan is analyzed using emergent thematic coding.

Findings

The study findings are consistent with Unger’s agency theory. The theory predicts that researchers can achieve their goals by adapting to the constrained context and can take steps to transform the context in desirable ways. Specifically, the Kazakhstani researchers have successfully adapted the Soviet mechanism of research schools to the new realities by “exploiting” a recently introduced government-funded mobility program for doctoral students for their own purposes. This mechanism is conductive to junior researchers’ capacity building, as well as to increasing the productivity of the leading researchers and their research teams.

Originality/value

The contribution of the study consists in the fact that it explores the process of researcher development, more specifically, individual level research capacity building in the context of a transitional post-Soviet country. The study pays special attention to the role of international mobility and research schools in the development of research skills. The conclusions of the paper are of interest to the scholars of researcher development in general and to the specialists in individual research capacity building in Eurasia in particular.
Exclusion and Counter‐exclusion: The Struggle over Shrimp Farming in a Coastal Village in Bangladesh
Authors: Afroz Sharmin , Cramb Rob , Grünbühel Clemens
Published: June 2017

This article explores the processes whereby control over land and water is exercised in the context of commercial shrimp cultivation in coastal Bangladesh. The authors draw on the insight that the exercise of control over resources implies both inclusion for some and exclusion for others, and that shifting the boundary between the two involves the deployment of four interacting ‘powers of exclusion’ — regulation, the market, force and legitimation — the effectiveness of which depends on specific historical conjunctures. The article uses a case study of a village in Khulna District to explore: (a) the processes by which poor farmers were excluded from their land by large shrimp farmers; (b) the ways in which villagers experienced the changes in land use and social relations associated with the shrimp boom; and (c) the conjunction of internal and external factors that enabled smallholders to collectively mobilize to reverse their exclusion from the land. Understanding these messy and contingent processes of exclusion and counter‐exclusion helps to inform strategies aimed at securing the property rights and livelihoods of the rural poor.
Ancient oncogenesis, infection and human evolution
Authors: Rifkin Riaan F. , Potgieter Marnie , Ramond Jean‐Baptiste , Cowan Don A.
Published: June 2017

The recent discovery that malignant neoplastic lesions date back nearly 2 million years ago not only highlights the antiquity of cancer in the human lineage, but also provides remarkable insight into ancestral hominin disease pathology. Using these Early Pleistocene examples as a point of departure, we emphasize the prominent role of viral and bacterial pathogens in oncogenesis and evaluate the impact of pathogens on human evolutionary processes in Africa. In the Shakespearean vernacular “what's past is prologue,” we highlight the significance of novel information derived from ancient pathogenic DNA. In particular, and given the temporal depth of human occupation in sub‐Saharan Africa, it is emphasized that the region is ideally positioned to play a strategic role in the discovery of ancient pathogenic drivers of not only human mortality, but also human evolution. Ancient African pathogen genome data can provide novel revelations concerning human‐pathogen coevolutionary processes, and such knowledge is essential for forecasting the ways in which emerging zoonotic and increasingly transmissible diseases might influence human demography and longevity in the future.
Evaluating Statistical Targets for Assembling Parallel Mixed‐Format Test Forms
Authors: Debeer Dries , Ali Usama S. , van Rijn Peter W.
Published: June 2017

Test assembly is the process of selecting items from an item pool to form one or more new test forms. Often new test forms are constructed to be parallel with an existing (or an ideal) test. Within the context of item response theory, the test information function (TIF) or the test characteristic curve (TCC) are commonly used as statistical targets to obtain this parallelism. In a recent study, Ali and van Rijn proposed combining the TIF and TCC as statistical targets, rather than using only a single statistical target. In this article, we propose two new methods using this combined approach, and compare these methods with single statistical targets for the assembly of mixed‐format tests. In addition, we introduce new criteria to evaluate the parallelism of multiple forms. The results show that single statistical targets can be problematic, while the combined targets perform better, especially in situations with increasing numbers of polytomous items. Implications of using the combined target are discussed.
Race and Gender Recidivism Differences Among Juvenile Mental Health Court Graduates
Authors: Behnken Monic P. , Bort Alison , Borbon Megan
Published: June 2017

Grounded in the theory of therapeutic jurisprudence, this research explores whether recidivism differs by race, ethnicity, or gender among juvenile mental health court graduates (N = 63). Mean number of pre‐program offenses were compared to the mean number of offenses committed by program completion. Results showed statistically significant reductions in recidivism by both males (p < .001) and females (p < .003). Racial and ethnic minorities demonstrated larger reductions when compared to Whites (p < .001 for Hispanics and p < .01 for combined ethnicities). These results contribute to the literature on effective intervention models for diverse juvenile offender populations.
INSTITUTIONAL OWNERSHIP AND EARNING MANAGEMENT BY BANK HOLDING COMPANIES
Authors: Elyasiani Elyas , Wen Yuan , Zhang Rongrong
Published: June 2017

We explore the role of institutional investors as a source of market discipline in mitigating earning management (EMGT) by bank holding companies (BHCs). We propose that ownership by monitoring institutions (institutional investors with large and long‐term stakes and independence from managers) is associated with less EMGT because they have greater incentives/skills for monitoring their investees than other shareholders. We find that EMGT by BHCs is negatively associated with ownership by monitoring institutions for larger and riskier banks and for the post‐SunTrust decision period. Nonmonitoring institutional ownership is unassociated or in some cases weakly or even positively associated with EMGT. Our findings suggest that regulators should facilitate ownership by monitoring institutions as a complement to regulation.
Keeping women off the jury in 1920s England and Wales
Authors: Crosby K.
Published: June 2017

The Sex Disqualification (Removal) Act 1919 ended the prohibition on female jurors. This did not mean that English and Welsh juries became representative institutions overnight, however: the property qualifications ensured that juries were still drawn from the top few per cent of the local population; and the 1919 Act expressly permitted trial judges to order single-sex juries where the nature of the evidence required it. The continued existence of peremptory challenges allowed defendants in felony trials to exclude women from their juries whenever they preferred to be tried only by men. Finally, some judges permitted female jurors to excuse themselves from particular trials if they so desired. This paper explores the effects these factors had on the practical enjoyment of the female jury franchise after the passing of the 1919 Act. It finds that the picture is remarkably localised: rates of women serving on juries were very different for the five assize circuits for which adequate records exist (Midland, Oxford, South Eastern, South Wales and Western). By exploring these issues, this paper reveals how flexible the female jury franchise was in its early years, and shows how important local differences were in keeping women off the jury.
Alternative Resilience Indices for City Ecosystems Subjected to Natural Hazards
Authors: Bozza Anna , Asprone Domenico , Parisi Fulvio , Manfredi Gaetano
Published: June 2017

Prompt and efficient responses against natural hazards are needed to build cities capable of withstanding disasters, namely resilient cities. This study aims at presenting and testing synthetic resilience indices over a real urban center threatened by multiple hazards, for which a global overview of city performance is requested. An integrated framework is proposed for quantitative resilience assessment by way of time‐independent synthetic indices. The approach proposed is in accordance to the complex network theory and uses a global indicator of the system connectivity to assess the city functioning also in case of network disruption. Resilience is evaluated as a proxy for systemic urban damage by modeling a city ecosystem as a hybrid social–physical network. Seismic and landslide scenario analyses are performed for the city of Sarno, Italy. A probability‐based approach is used to compute urban vulnerability. Subsequently, to highlight changes in results according to the type of disaster, a recovery strategy is simulated to assess efficiency and damage states in each recovery stage, and urban resilience.
Poly(ethylene) glycol hydrogel based on oxa-Michael reaction: Precursor synthesis and hydrogel formation
Authors: Wang Hanqi , Cheng Fang , He Wei , Zhu Jiaohui , Cheng Gang , Qu Jingping
Published: June 2017

This paper reported a facile strategy for the one-pot synthesis of vinyl sulfone (VS) group terminated hydrogel precursors [poly(ethylene) glycol (PEG)-VS] and PEG hydrogels via catalytic oxa-Michael reaction. Nine potential catalysts were investigated for the reaction between PEG and divinyl sulfone, among which 4-dimethylaminopyridine (DMAP) prevailed for its high catalytic activity. DMAP produced PEG-VS with a conversion of more than 90% in 2 h under a solvent-free condition at room temperature, which significantly simplifies the synthesis of PEG-VS. The preparation of PEG hydrogels was realized by adding glycerol as a crosslinker, and the physical and the mechanical properties were easily controlled by changing the crosslinker concentration as well as the PEG chain length. This strategy can also be applied to other polyhydroxy compounds as crosslinkers, and thus, a library of hydrogels with designed structures and desired properties could be prepared. The PEG hydrogels showed good antifouling properties, low cytotoxicity, and ability to release drugs at a tunable rate, indicating versatile potential bioapplications.
Discovery and Mechanistic Study of Benzamide Derivatives That Modulate Hepatitis B Virus Capsid Assembly
Authors: Wu Shuo , Zhao Qiong , Zhang Pinghu , Kulp John , Hu Lydia , Hwang Nicky , Zhang Jiming , Block Timothy M. , Xu Xiaodong , Du Yanming , Chang Jinhong , Guo Ju-Tao
Published: June 2017

Chronic hepatitis B virus (HBV) infection is a global public health problem. Although the currently approved medications can reliably reduce the viral load and prevent the progression of liver diseases, they fail to cure the viral infection. In an effort toward discovery of novel antiviral agents against HBV, a group of benzamide (BA) derivatives that significantly reduced the amount of cytoplasmic HBV DNA were discovered. The initial lead optimization efforts identified two BA derivatives with improved antiviral activity for further mechanistic studies. Interestingly, similar to our previously reported sulfamoylbenzamides (SBAs), the BAs promote the formation of empty capsids through specific interaction with HBV core protein but not other viral and host cellular components. Genetic evidence suggested that both SBAs and BAs inhibited HBV nucleocapsid assembly by binding to the heteroaryldihydropyrimidine (HAP) pocket between core protein dimer-dimer interfaces. However, unlike SBAs, BA compounds uniquely induced the formation of empty capsids that migrated more slowly in native agarose gel electrophoresis from A36V mutant than from the wild-type core protein. Moreover, we showed that the assembly of chimeric capsids from wild-type and drug-resistant core proteins was susceptible to multiple capsid assembly modulators. Hence, HBV core protein is a dominant antiviral target that may suppress the selection of drug-resistant viruses during core protein-targeting antiviral therapy. Our studies thus indicate that BAs are a chemically and mechanistically unique type of HBV capsid assembly modulators and warranted for further development as antiviral agents against HBV.

IMPORTANCE
HBV core protein plays essential roles in many steps of the viral replication cycle. In addition to packaging viral pregenomic RNA (pgRNA) and DNA polymerase complex into nucleocapsids for reverse transcriptional DNA replication to take place, the core protein dimers, existing in several different quaternary structures in infected hepatocytes, participate in and regulate HBV virion assembly, capsid uncoating, and covalently closed circular DNA (cccDNA) formation. It is anticipated that small molecular core protein assembly modulators may disrupt one or multiple steps of HBV replication, depending on their interaction with the distinct quaternary structures of core protein. The discovery of novel core protein-targeting antivirals, such as benzamide derivatives reported here, and investigation of their antiviral mechanism may lead to the identification of antiviral therapeutics for the cure of chronic hepatitis B.
Drug Modulators of B Cell Signaling Pathways and Epstein-Barr Virus Lytic Activation
Authors: Kosowicz John G. , Lee Jaeyeun , Peiffer Brandon , Guo Zufeng , Chen Jianmeng , Liao Gangling , Hayward S. Diane , Liu Jun O. , Ambinder Richard F.
Published: June 2017

Epstein-Barr virus (EBV) is a ubiquitous human gammaherpesvirus that establishes a latency reservoir in B cells. In this work, we show that ibrutinib, idelalisib, and dasatinib, drugs that block B cell receptor (BCR) signaling and are used in the treatment of hematologic malignancies, block BCR-mediated lytic induction at clinically relevant doses. We confirm that the immunosuppressive drugs cyclosporine and tacrolimus also inhibit BCR-mediated lytic induction but find that rapamycin does not inhibit BCR-mediated lytic induction. Further investigation shows that mammalian target of rapamycin complex 2 (mTORC2) contributes to BCR-mediated lytic induction and that FK506-binding protein 12 (FKBP12) binding alone is not adequate to block activation. Finally, we show that BCR signaling can activate EBV lytic induction in freshly isolated B cells from peripheral blood mononuclear cells (PBMCs) and that activation can be inhibited by ibrutinib or idelalisib.

IMPORTANCE
EBV establishes viral latency in B cells. Activation of the B cell receptor pathway activates lytic viral expression in cell lines. Here we show that drugs that inhibit important kinases in the BCR signaling pathway inhibit activation of lytic viral expression but do not inhibit several other lytic activation pathways. Immunosuppressant drugs such as cyclosporine and tacrolimus but not rapamycin also inhibit BCR-mediated EBV activation. Finally, we show that BCR activation of lytic infection occurs not only in tumor cell lines but also in freshly isolated B cells from patients and that this activation can be blocked by BCR inhibitors.
Fine-Scale Structure Analysis Shows Epidemic Patterns of Clonal Complex 95, a Cosmopolitan Escherichia coli Lineage Responsible for Extraintestinal Infection
Authors: Gordon David M. , Geyik Sarah , Clermont Olivier , O’Brien Claire L. , Huang Shiwei , Abayasekara Charmalie , Rajesh Ashwin , Kennedy Karina , Collignon Peter , Pavli Paul , Rodriguez Christophe , Johnston Brian D. , Johnson James R. , Decousser Jean-Winoc , Denamur Erick
Published: June 2017

Escherichia coli
clonal complex 95 represents a cosmopolitan, genetically diverse lineage, and the extensive substructure observed in this lineage is epidemiologically and clinically relevant. The frequency with which CC95 strains are responsible for extraintestinal infection appears to have been stable over the past 15 years. However, the different subgroups identified within this lineage have an epidemic structure depending on the host, sample, continent, and time. Thus, the evolution and spread of strains belonging to CC95 are very different from those of another cosmopolitan human-associated clonal complex, CC131, which has increased significantly in frequency as a cause of extraintestinal infection over the past 15 years due to the evolution and spread of two very closely related, nearly monomorphic lineages.
Effectiveness of α2agonists for sedation in paediatric critical care: study protocol for a retrospective cohort observational study
Authors: Hayden John C , Dawkins Ian , Breatnach Cormac , Leacy Finbarr P , Foxton June , Healy Martina , Cousins Gráinne , Gallagher Paul J , Doherty Dermot R
Published: June 2017

Introduction

Mechanically ventilated children in paediatric intensive care units are commonly administered analgesics and sedative agents to minimise pain and distress and facilitate cooperation with medical interventions. Opioids and benzodiazepines are the most common analgesic and sedative agents but have safety concerns. The α2agonists clonidine and dexmedetomidine are alternative sedatives in use despite neither having robust evidence to support their use. Studies evaluating effectiveness of α2agonists to date have not focused on sedation-based outcomes instead focusing on opioid-sparing properties and ventilation outcomes. The aim of this study is to evaluate if an opioid-based sedation regimen, with an α2agonist adjunct (clonidine or dexmedetomidine), produces a non-inferior proportion of time adequately sedated compared with a control group without an α2agonist adjunct, while conferring potential additional benefits such as reduced opioid administration and less exposure to potential additional agents such as benzodiazepines.

Methods and analysis

We will conduct a retrospective cohort study in two Irish paediatric intensive care units using clinical information on patient characteristics, sedation scores and drug use. Eligible children admitted between January 2014 and June 2016 who were mechanically ventilated and received an opioid infusion will be included. Patients will be categorised into two exposure categories (received an α2agonist or did not receive an α2agonist) and the time adequately sedated (measured using the COMFORT Behaviour Score) will be calculated using interpolation of nursing sedation scores at each recorded time point. At least 150 per group is planned for inclusion to ensure adequate study power. Propensity score matching will be used in analysis to account for potential confounding by indication.

Ethics and dissemination

The study has been approved by the ethics committees of both hospitals. Dissemination will occur via local, national and international presentations for academic and healthcare audiences as well as through peer reviewed publications.
Sex differences in the oxygen delivery, extraction, and uptake during moderate-walking exercise transition
Authors: Beltrame Thomas , Villar Rodrigo , Hughson Richard L.
Published: June 2017

Previous studies in children and older adults demonstrated faster oxygen uptake (V̇O2) kinetics in males compared with females, but young healthy adults have not been studied. We hypothesized that young men would have faster aerobic system dynamics in response to the onset of exercise than women. Interactions between oxygen supply and utilization were characterized by the dynamics of V̇O2, deoxyhemoglobin (HHb), tissue saturation index (TSI), cardiac output (Q̇), and calculated arteriovenous O2 difference (a–vO2diff) in women and men. Eighteen healthy active young women and men (9 of each sex) with similar aerobic fitness levels volunteered for this study. Participants performed an incremental cardiopulmonary treadmill exercise test and 3 moderate-intensity treadmill exercise tests (at 80% V̇O2 of gas exchange threshold). Data related to the moderate exercise were submitted to exponential data modelling to obtain parameters related to the aerobic system dynamics. The time constants of V̇O2, a–vO2diff, HHb, and TSI (30 ± 6, 29 ± 1, 16 ± 1, and 15 ± 2 s, respectively) in women were statistically (p < 0.05) faster than the time constants in men (42 ± 10, 49 ± 21, 19 ± 3, and 20 ± 4 s, respectively). Although Q̇ dynamics were not statistically different (p = 0.06) between groups, there was a trend to slower Q̇ dynamics in men corresponding with the slower V̇O2 kinetics. These results indicated that the peripheral and pulmonary oxygen extraction dynamics were remarkably faster in women. Thus, contrary to the hypothesis, V̇O2 dynamics measured at the mouth at the onset of submaximal treadmill walking were faster in women compared with men.
Brownian motion of classical spins: Anomalous dissipation and generalized Langevin equation
Authors: Bandyopadhyay Malay , Jayannavar A. M.
Published: June 2017

In this work, we derive the Langevin equation (LE) of a classical spin interacting with a heat bath through momentum variables, starting from the fully dynamical Hamiltonian description. The derived LE with anomalous dissipation is analyzed in detail. The obtained LE is non-Markovian with multiplicative noise terms. The concomitant dissipative terms obey the fluctuation–dissipation theorem. The Markovian limit correctly produces the Kubo and Hashitsume equation. The perturbative treatment of our equations produces the Landau–Lifshitz equation and the Seshadri–Lindenberg equation. Then we derive the Fokker–Planck equation corresponding to LE and the concept of equilibrium probability distribution is analyzed.
Preliminary CFD Assessment of an Experimental Test Facility Operating with Heavy Liquid Metals
Authors: Lizzoli Matteo , Borreani Walter , Devia Francesco , Lomonaco Guglielmo , Tarantino Mariano
Published: June 2017

The CFD analysis of a Venturi nozzle operating in LBE (key component of the CIRCE facility, owned by ENEA) is presented in this paper. CIRCE is a facility developed to investigate in detail the fluid-dynamic behavior of ADS and/or LFR reactor plants. The initial CFD simulations have been developed hand in hand with the comparison with experimental data: the test results were used to confirm the reliability of the CFD model, which, in turn, was used to improve the interpretation of the experimental data. The Venturi nozzle is modeled with a 3D CFD code (STAR-CCM+). Later on, the CFD model has been used to assess the performance of the component in conditions different from the ones tested in CIRCE: the performance of the Venturi is presented, in terms of pressure drops, for various operating conditions. Finally, the CFD analysis has been focused on the evaluation of the effects of the injection of an inert gas in the flow of the liquid coolant on the performance of the Venturi nozzle.
Pediatric Ovarian Growing Teratoma Syndrome
Authors: Rentea Rebecca M. , Varghese Aaron , Ahmed Atif , Kats Alexander , Manalang Michelle , Dowlut-McElroy Tazim , Hendrickson Richard J.
Published: June 2017

Ovarian immature teratoma is a germ cell tumor that comprises less than 1% of ovarian cancers and is treated with surgical debulking and chemotherapy depending on stage. Growing teratoma syndrome (GTS) is the phenomenon of the growth of mature teratoma elements with normal tumor markers during or following chemotherapy for treatment of a malignant germ cell tumor. These tumors are associated with significant morbidity and mortality due to invasive and compressive growth as well as potential for malignant transformation. Current treatment modality is surgical resection. We discuss a 12-year-old female who presented following resection of a pure ovarian immature teratoma (grade 3, FIGO stage IIIC). Following chemotherapy and resection of a pelvic/liver recurrence demonstrating mature teratoma, she underwent molecular genetics based chemotherapeutic treatment. No standardized management protocol has been established for the treatment of GTS. The effect of chemotherapeutic agents for decreasing the volume of and prevention of expansion is unknown. We review in detail the history, diagnostic algorithm, and previous reported pediatric cases as well as treatment options for pediatric patients with GTS.
Reduction of Interhemispheric Functional Brain Connectivity in Early Blindness: A Resting-State fMRI Study
Authors: Hou Fen , Liu Xia , Zhou Zhifeng , Zhou Jingyi , Li Hengguo
Published: June 2017

Objective. The purpose of this study was to investigate the resting-state interhemispheric functional connectivity in early blindness by using voxel-mirrored homotopic connectivity (VMHC). Materials and Methods. Sixteen early blind patients (EB group) and sixteen age- and gender-matched sighted control volunteers (SC group) were recruited in this study. We used VMHC to identify brain areas with significant differences in functional connectivity between different groups and used voxel-based morphometry (VBM) to calculate the individual gray matter volume (GMV). Results. VMHC analysis showed a significantly lower connectivity in primary visual cortex, visual association cortex, and somatosensory association cortex in EB group compared to sighted controls. Additionally, VBM analysis revealed that GMV was reduced in the left lateral calcarine cortices in EB group compared to sighted controls, while it was increased in the left lateral middle occipital gyri. Statistical analysis showed the duration of blindness negatively correlated with VMHC in the bilateral middle frontal gyri, middle temporal gyri, and inferior temporal gyri. Conclusions. Our findings help elucidate the pathophysiological mechanisms of EB. The interhemispheric functional connectivity was impaired in EB patients. Additionally, the middle frontal gyri, middle temporal gyri, and inferior temporal gyri may be potential target regions for rehabilitation.
Nicotinamide Administration Improves Remyelination after Stroke
Authors: Wang Congxiao , Zhang Yi , Ding Jie , Zhao Zhen , Qian Cheng , Luan Ying , Teng Gao-Jun
Published: June 2017

Aims. Stroke is a leading cause of morbidity and mortality. This study aimed to determine whether nicotinamide administration could improve remyelination after stroke and reveal the underlying mechanism. Methods. Adult male C57BL/6J mice were intraperitoneally (i.p.) administered with nicotinamide (200 mg/kg, daily) or saline after stroke induced by photothrombotic occlusion of the middle cerebral artery. FK866 (3 mg/kg, daily, bis in die), an inhibitor of NAMPT, and ANA-12 (0.5 mg/kg, daily), an antagonist of tropomyosin-related kinase B (TrkB), were administered intraperitoneally 1 h before nicotinamide administration. Functional recovery, MRI, and histological assessment were performed after stroke at different time points. Results. The nicotinamide-treated mice showed significantly lower infarct area 7 d after stroke induction and significantly higher fractional anisotropy (FA) in the ipsilesional internal capsule (IC) 14 d after stroke induction than the other groups. Higher levels of NAD+, BDNF, and remyelination markers were observed in the nicotinamide-treated group. FK866 administration reduced NAD+ and BDNF levels in the nicotinamide-treated group. ANA-12 administration impaired the recovery from stroke with no effect on NAD+ and BDNF levels. Furthermore, lesser functional deficits were observed in the nicotinamide-treated group than in the control group. Conclusions. Nicotinamide administration improves remyelination after stroke via the NAD+/BDNF/TrkB pathway.
Association of Poor Differentiation or Positive Vertical Margin with Residual Disease in Patients with Subsequent Colectomy after Complete Macroscopic Endoscopic Resection of Early Colorectal Cancer
Authors: Kim Ki Ju , Lee Hyun Seok , Jeon Seong Woo , Jin Sun , Lee Sang Won
Published: June 2017

In the presence of unfavorable pathologic results after endoscopic resection of colorectal cancer, colectomy is routinely performed. We determined the risk factors for residual diseases in patients with colectomy after complete macroscopic endoscopic resection of early colorectal cancer. We identified consecutive patients who underwent endoscopic resection of early colorectal cancer and subsequently underwent colectomy, from January 2011 to December 2014. Clinicopathologic risk factors related to the residual disease were analyzed. In total, 148 patients underwent endoscopic resection and subsequent colectomy. Residual disease on colectomy was noted in 16 (10.9%) patients. The rates of poorly differentiated/mucinous histology (p=0.028) and of positive or unknown vertical resection margin (p=0.047) were higher in patients with residual disease than in those without. In multivariate analysis, a poorly differentiated/mucinous histology and positive or unknown vertical resection margin were significantly associated with residual disease (odds ratio = 7.508 and 2.048,p=0.015and 0.049, resp.). After complete macroscopic endoscopic resection of early colorectal cancer, there is a greater need for additional colectomy in cases with a positive or unknown vertical resection margin or a poorly differentiated/mucinous histology, because of their higher risk of residual cancer and lymph node metastasis.
Antidiabetic Drugs in Alzheimer’s Disease: Mechanisms of Action and Future Perspectives
Authors: Femminella Grazia Daniela , Bencivenga Leonardo , Petraglia Laura , Visaggi Lucia , Gioia Lucia , Grieco Fabrizio Vincenzo , de Lucia Claudio , Komici Klara , Corbi Graziamaria , Edison Paul , Rengo Giuseppe , Ferrara Nicola
Published: June 2017

Diabetes mellitus (DM) and Alzheimer’s disease (AD) are two highly prevalent conditions in the elderly population and major public health burden. In the past decades, a pathophysiological link between DM and AD has emerged and central nervous system insulin resistance might play a significant role as a common mechanism; however, other factors such as inflammation and oxidative stress seem to contribute to the shared pathophysiological link. Both preclinical and clinical studies have evaluated the possible neuroprotective mechanisms of different classes of antidiabetic medications in AD, with some promising results. Here, we review the evidence on the mechanisms of action of antidiabetic drugs and their potential use in AD.
Obsessive-Compulsive Disorder Associated with Posterior Cranial Fossa Meningioma
Authors: Takeuchi Nobuyuki , Kato Etushi , Kanemoto Kousuke
Published: June 2017

We report here a patient in whom the effects of a cerebellum mass may have led to development of obsessive-compulsive disorder (OCD). A 33-year-old woman showed symptoms of OCD, including obsessive worry about infection from tainted blood and repetitive confirmation, which worsened during pregnancy. She had comprehension in regard to her illness and no evidence of cognitive dysfunction and did not meet other DSM-5 criteria such as depression. One month after giving childbirth, the symptoms worsened, while headache and dizziness also developed. The Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) score was 34. The patient was examined for a headache and a posterior cranial fossa meningioma was found. Following resection of the meningioma, the OCD symptoms were remarkably reduced (Y-BOCS score 10). There is only one previous report of pure OCD associated with a cerebellar mass and the present findings should help to elucidate the mechanism.
Microarray Analysis of Circular RNA Expression Profile Associated with 5-Fluorouracil-Based Chemoradiation Resistance in Colorectal Cancer Cells
Authors: Xiong Wei , Ai Yi-Qin , Li Yun-Fen , Ye Qing , Chen Zheng-Ting , Qin Ji-Yong , Liu Qiu-Yan , Wang Hong , Ju Yun-He , Li Wen-Hui , Li Yun-Feng
Published: June 2017

Preoperative 5-fluorouracil- (5-FU-) based chemoradiotherapy is a standard treatment for locally advanced colorectal cancer (CRC). However, the effect of 5-FU-based chemoradiotherapy on CRC is limited due to the development of chemoradiation resistance (CRR), and the molecular mechanisms underlying this resistance are yet to be investigated. Recently, circular RNAs (circRNAs), which can function as microRNA sponges, were found to be involved in the development of several cancers. In this study, we focused on clarifying the modulation of the expression profiles of circRNAs in CRR. Microarray analysis identified 71 circRNAs differentially expressed in chemoradiation-resistant CRC cells. Among them, 47 were upregulated and 24 were downregulated by more than twofold. Furthermore, expression modulation of five representative circRNAs was validated by quantitative reverse transcription PCR (qRT-PCR). Moreover, these modulated circRNAs were predicted to interact with 355 miRNAs. Furthermore, Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis showed that the most modulated circRNAs regulate several cancers and cancer-related pathways, and the possible mechanism underlying CRR was discussed. This is the first report revealing the circRNA modulations in 5-FU chemoradiation-resistant CRC cells by microarray. The study provided a useful database for further understanding CRR and presents potential targets to overcome CRR in CRC.
Pharmacokinetics and Drug Interactions Determine Optimum Combination Strategies in Computational Models of Cancer Evolution
Authors: Chakrabarti Shaon , Michor Franziska
Published: June 2017

The identification of optimal drug administration schedules to battle the emergence of resistance is a major challenge in cancer research. The existence of a multitude of resistance mechanisms necessitates administering drugs in combination, significantly complicating the endeavor of predicting the evolutionary dynamics of cancers and optimal intervention strategies. A thorough understanding of the important determinants of cancer evolution under combination therapies is therefore crucial for correctly predicting treatment outcomes. Here we developed the first computational strategy to explore pharmacokinetic and drug interaction effects in evolutionary models of cancer progression, a crucial step towards making clinically relevant predictions. We found that incorporating these phenomena into our multiscale stochastic modeling framework significantly changes the optimum drug administration schedules identified, often predicting nonintuitive strategies for combination therapies. We applied our approach to an ongoing phase Ib clinical trial (TATTON) administering AZD9291 and selumetinib to EGFR-mutant lung cancer patients. Our results suggest that the schedules used in the three trial arms have almost identical efficacies, but slight modifications in the dosing frequencies of the two drugs can significantly increase tumor cell eradication. Interestingly, we also predict that drug concentrations lower than the MTD are as efficacious, suggesting that lowering the total amount of drug administered could lower toxicities while not compromising on the effectiveness of the drugs. Our approach highlights the fact that quantitative knowledge of pharmacokinetic, drug interaction, and evolutionary processes is essential for identifying best intervention strategies. Our method is applicable to diverse cancer and treatment types and allows for a rational design of clinical trials. Cancer Res; 77(14); 3908–21. ©2017 AACR.
Recommendations for Surveillance for Children with Leukemia-Predisposing Conditions
Authors: Porter Christopher C. , Druley Todd E. , Erez Ayelet , Kuiper Roland P. , Onel Kenan , Schiffman Joshua D. , Wolfe Schneider Kami , Scollon Sarah R. , Scott Hamish S. , Strong Louise C. , Walsh Michael F. , Nichols Kim E.
Published: June 2017

Leukemia, the most common childhood cancer, has long been recognized to occasionally run in families. The first clues about the genetic mechanisms underlying familial leukemia emerged in 1990 when Li-Fraumeni syndrome was linked to TP53 mutations. Since this discovery, many other genes associated with hereditary predisposition to leukemia have been identified. Although several of these disorders also predispose individuals to solid tumors, certain conditions exist in which individuals are specifically at increased risk to develop myelodysplastic syndrome (MDS) and/or acute leukemia. The increasing identification of affected individuals and families has raised questions around the efficacy, timing, and optimal methods of surveillance. As part of the AACR Childhood Cancer Predisposition Workshop, an expert panel met to review the spectrum of leukemia-predisposing conditions, with the aim to develop consensus recommendations for surveillance for pediatric patients. The panel recognized that for several conditions, routine monitoring with complete blood counts and bone marrow evaluations is essential to identify disease evolution and enable early intervention with allogeneic hematopoietic stem cell transplantation. However, for others, less intensive surveillance may be considered. Because few reports describing the efficacy of surveillance exist, the recommendations derived by this panel are based on opinion, and local experience and will need to be revised over time. The development of registries and clinical trials is urgently needed to enhance understanding of the natural history of the leukemia-predisposing conditions, such that these surveillance recommendations can be optimized to further enhance long-term outcomes. Clin Cancer Res; 23(11); e14–e22. ©2017 AACR.

See all articles in the online-only CCR Pediatric Oncology Series.
Reactivation of the p90RSK–CDC25C Pathway Leads to Bypass of the Ganetespib-Induced G2–M Arrest and Mediates Acquired Resistance to Ganetespib inKRAS-Mutant NSCLC
Authors: Chatterjee Suman , Huang Eric H.-B. , Christie Ian , Burns Timothy F.
Published: June 2017

A subset of non–small cell lung cancers (NSCLC) are dependent upon oncogenic driver mutations, including the most frequently observed driver mutant KRAS, which is associated with a poor prognosis. As direct RAS targeting in the clinic has been unsuccessful to date, use of Hsp90 inhibitors appeared to be a promising therapy for KRAS-mutant NSCLC; however, limited clinical efficacy was observed due to rapid resistance. Furthermore, the combination of the Hsp90 inhibitor (Hsp90i), ganetespib, and docetaxel was tested in a phase III clinical trial and failed to demonstrate benefit. Here, we investigated the mechanism(s) of resistance to ganetespib and explored why the combination with docetaxel failed in the clinic. We have not only identified a critical role for the bypass of the G2–M cell-cycle checkpoint as a mechanism of ganetespib resistance (GR) but have also found that GR leads to cross-resistance to docetaxel. Reactivation of p90RSK and its downstream target, CDC25C, was critical for GR and mediated the bypass of a G2–M arrest. Overexpression of either p90RSK or CDC25C lead to bypass of G2–M arrest and induced ganetespib resistance in vitro and in vivo. Moreover, resistance was dependent on p90RSK/CDC25C signaling, as synthetic lethality to ERK1/2, p90RSK, or CDC25C inhibitors was observed. Importantly, the combination of ganetespib and p90RSK or CDC25C inhibitors was highly efficacious in parental cells. These studies provide a way forward for Hsp90 inhibitors through the development of novel rationally designed Hsp90 inhibitor combinations that may prevent or overcome resistance to Hsp90i. Mol Cancer Ther; 16(8); 1658–68. ©2017 AACR.
Optimising Intravenous Volume Resuscitation of the Newborn in the Delivery Room: Practical Considerations and Gaps in Knowledge
Authors: Finn Daragh , Roehr Charles C. , Ryan C. Anthony , Dempsey Eugene M.
Published: June 2017

Volume resuscitation (VR) for the treatment of newborn shock is a rare but potentially lifesaving intervention. Conducting clinical studies to assess the effectiveness of VR in the delivery room during newborn stabilization is challenging. We review the available literature and current management guidelines to determine which infants will benefit from VR, the frequency of VR, and the choice of agents used. In addition, the potential role for placental transfusion in the prevention of newborn shock is explored.
Importance of Light Filters in Modern Vitreoretinal Surgery: An Update of the Literature
Authors: Coppola Michele , Cicinelli Maria Vittoria , Rabiolo Alessandro , Querques Giuseppe , Bandello Francesco
Published: June 2017

Purpose: Direct endobulbar illumination during vitreoretinal surgery causes light-induced retinal damage known as phototoxicity. Spectral filters have been proposed to eliminate hazardous wavelengths from the emission spectrum before entering the eye. The purpose of our paper is to review advances in vitreoretinal surgery, focusing on intraoperative light filters. Methods: A PubMed and Medline database search was carried out using the terms “spectral filters” associated with “vitreoretinal surgery,” “phototoxicity,” and “vitrectomy.” Original articles, reviews, and book chapters up to March 2017 were reviewed; a few select articles published before 2000 are included for historical purposes. Material from recent meeting presentations was also added. The preferred language for the reviewed literature was English. Results: Spectral filters significantly reduce the risk of phototoxicity associated with endoillumination in vitreoretinal surgery, allowing higher exposure times than with optic light fibers alone. Spectral filters may affect intraoperative luminance, but do not alter color contrast. Amber filters showed superiority over green and yellow filters. Conclusion: The choice of light sources coupled to spectral filters is strongly suggested, especially in dye-assisted chromovitrectomy. Histological donor eye studies and large multicenter trials are needed to validate the amount of photoprotection provided by spectral filters before a general recommendation can be made.
Microvesicles in vascular homeostasis and diseases
Authors: Ridger Victoria C. , Boulanger Chantal M. , Angelillo-Scherrer Anne , Badimon Lina , Blanc-Brude Olivier , Bochaton-Piallat Marie-Luce , Boilard Eric , Buzas Edit I. , Caporali Andreas , Dignat-George Francoise , Evans Paul C. , Lacroix Romaric , Lutgens Esther , Ketelhuth Daniel F. J. , Nieuwland Rienk , Toti Florence , Tuñon Jose , Weber Christian , Hoefer Imo E. , Lip Gregory Y. H. , Werner Nikos , Shantsila Eduard , ten Cate Hugo , Thomas Mark , Harrison Paul
Published: June 2017

Microvesicles are members of the family of extracellular vesicles shed from the plasma membrane of activated or apoptotic cells. Microvesicles were initially characterised by their pro-coagulant activity and described as “microparticles”. There is mounting evidence revealing a role for microvesicles in intercellular communication, with particular relevance to hemostasis and vascular biology. Coupled with this, the potential of microvesicles as meaningful biomarkers is under intense investigation. This Position Paper will summarise the current knowledge on the mechanisms of formation and composition of microvesicles of endothelial, platelet, red blood cell and leukocyte origin. This paper will also review and discuss the different methods used for their analysis and quantification, will underline the potential biological roles of these vesicles with respect to vascular homeostasis and thrombosis and define important themes for future research.