Search

This article uses the organisational trust repair model developed by Gillespie and Dietz to examine how the Royal Bank of Liverpool, which suspended payments during the commercial crisis in 1847, escaped liquidation and resumed business. This case study uses newspaper reports and selected corporate records to explore narratives of trust between bank management and different interest groups over the course of resuscitating the establishment. The case affords three distinct but interlaced conduits enabling analysis of the dynamics of trust repair: reassertion of credibility through appealing to its reputational past; reconciliation of competing expectations from different parties, and renegotiation of boundaries between directors’ powers and stakeholders’ rights. Exploring the professional standpoint, local attributes and moral discourses within which restoration of the bank was situated enables evaluation of the bank’s strategies for rebuilding trust and redeeming corporate legitimacy through a contemporary theoretical perspective, offering lessons for corporate trust repair in the twenty-first century.

Purpose: Neuroblastoma is a childhood tumor of the peripheral sympathetic nervous system with an often lethal outcome due to metastatic disease. Migration and epithelial–mesenchymal transitions have been implicated in metastasis but they are hardly investigated in neuroblastoma.Experimental Design: Cell migration of 16 neuroblastoma cell lines was quantified in Transwell migration assays. Gene expression profiling was used to derive a migration signature, which was applied to classify samples in a neuroblastoma tumor series. Differential expression of transcription factors was analyzed in the subsets. NOTCH3 was prioritized, and inducible transgene expression studies in cell lines were used to establish whether it functions as a master switch for motility.Results: We identified a 36-gene expression signature that predicts cell migration. This signature was used to analyse expression profiles of 88 neuroblastoma tumors and identified a group with distant metastases and a poor prognosis. This group also expressed a known mesenchymal gene signature established in glioblastoma. Neuroblastomas recognized by the motility and mesenchymal signatures strongly expressed genes of the NOTCH pathway. Inducible expression of a NOTCH intracellular (NOTCH3-IC) transgene conferred a highly motile phenotype to neuroblastoma cells. NOTCH3-IC strongly induced expression of motility- and mesenchymal marker genes. Many of these genes were significantly coexpressed with NOTCH3 in neuroblastoma, as well as colon, kidney, ovary, and breast tumor series.Conclusion: The NOTCH3 transcription factor is a master regulator of motility in neuroblastoma. A subset of neuroblastoma with high expression of NOTCH3 and its downstream-regulated genes has mesenchymal characteristics, increased incidence of metastases, and a poor prognosis. Clin Cancer Res; 19(13); 3485–94. ©2013 AACR.

Supplementary Data from Mesenchymal-Type Neuroblastoma Cells Escape ALK Inhibitors

Supplementary Legends - PDF file 80K, This file contains the legends to supplementary figures, supplementary movies and supplementary tables

Supplementary Tables - XLS file 163K. This file contains 6 supplementary tables

Cancer therapy frequently fails due to the emergence of resistance. Many tumors include phenotypically immature tumor cells, which have been implicated in therapy resistance. Neuroblastoma cells can adopt a lineage-committed adrenergic (ADRN) or an immature mesenchymal (MES) state. They differ in epigenetic landscape and transcription factors, and MES cells are more resistant to chemotherapy. Here we analyzed the response of MES cells to targeted drugs. Activating anaplastic lymphoma kinase (ALK) mutations are frequently found in neuroblastoma and ALK inhibitors (ALKi) are in clinical trials. ALKi treatment of ADRN neuroblastoma cells with a tumor-driving ALK mutation induced cell death. Conversely, MES cells did not express either mutant or wild-type ALK and were resistant to ALKi, and MES cells formed tumors that progressed under ALKi therapy. In assessing the role of MES cells in relapse development, TRAIL was identified to specifically induce apoptosis in MES cells and to suppress MES tumor growth. Addition of TRAIL to ALKi treatment of neuroblastoma xenografts delayed relapses in a subset of the animals, suggesting a role for MES cells in relapse formation. While ADRN cells resembled normal embryonal neuroblasts, MES cells resembled immature precursor cells, which also lacked ALK expression. Resistance to targeted drugs can therefore be an intrinsic property of immature cancer cells based on their resemblance to developmental precursors.Significance:In neuroblastoma, mesenchymal tumor cells lack expression of the tumor-driving ALK oncogene and are resistant to ALKi, but dual treatment with ALKi and mesenchymal cell–targeting TRAIL delays tumor relapse.

Supporting video 2 - MOV file 1047K, IMR32-NOTCH3IC cells cultured with doxycycline. Note the fast-moving presence of different cells.

Supplementary Figures - PDF file 2758K, This file contains supplementary figure 1-7

Cancer therapy frequently fails due to the emergence of resistance. Many tumors include phenotypically immature tumor cells, which have been implicated in therapy resistance. Neuroblastoma cells can adopt a lineage-committed adrenergic (ADRN) or an immature mesenchymal (MES) state. They differ in epigenetic landscape and transcription factors, and MES cells are more resistant to chemotherapy. Here we analyzed the response of MES cells to targeted drugs. Activating anaplastic lymphoma kinase (ALK) mutations are frequently found in neuroblastoma and ALK inhibitors (ALKi) are in clinical trials. ALKi treatment of ADRN neuroblastoma cells with a tumor-driving ALK mutation induced cell death. Conversely, MES cells did not express either mutant or wild-type ALK and were resistant to ALKi, and MES cells formed tumors that progressed under ALKi therapy. In assessing the role of MES cells in relapse development, TRAIL was identified to specifically induce apoptosis in MES cells and to suppress MES tumor growth. Addition of TRAIL to ALKi treatment of neuroblastoma xenografts delayed relapses in a subset of the animals, suggesting a role for MES cells in relapse formation. While ADRN cells resembled normal embryonal neuroblasts, MES cells resembled immature precursor cells, which also lacked ALK expression. Resistance to targeted drugs can therefore be an intrinsic property of immature cancer cells based on their resemblance to developmental precursors. Significance: In neuroblastoma, mesenchymal tumor cells lack expression of the tumor-driving ALK oncogene and are resistant to ALKi, but dual treatment with ALKi and mesenchymal cell–targeting TRAIL delays tumor relapse.

Elizabeth Crosby (1888-1983) is a beloved and well-respected titan of neuroanatomy. Her contributions to our understanding of neuroanatomy are rooted in her seminal text, The Comparative Anatomy of the Nervous System of Vertebrates, Including Man, published in 1936, which is a masterful and comprehensive account of comparative neuroanatomy. Her later texts, Correlative Neurosurgery and Correlative Anatomy of the Nervous System, are standard reference texts to this day. Her mentorship of graduate students, close work with the University of Michigan neurosurgery department, and the quality of her research and scientific publications were recognized with many awards, culminating in the National Medal of Science presented by President Carter in 1980.

To address the paucity of research investigating the implementation of multi-domain dementia prevention interventions, we implemented and evaluated a 24-week, bi-weekly multi-domain program for older adults at risk of cognitive impairment at neighborhood senior centres (SCs). It comprised dual-task exercises, cognitive training, and mobile application-based nutritional guidance. An RCT design informed by the Reach, Effectiveness, Adoption, Implementation, Maintenance framework was adopted. Outcome measures include cognition, quality of life, blood parameters, and physical performance. Implementation was evaluated through questionnaires administered to participants, implementers, SC managers, attendance lists, and observations. The program reached almost 50% of eligible participants, had an attrition rate of 22%, and was adopted by 8.7% of the SCs approached. It was implemented as intended; only the nutritional component was re-designed due to participants’ unfamiliarity with the mobile application. While there were no between-group differences in cognition, quality of life, and blood parameters, quality of life reduced in the control group and physical function improved in the intervention group after 24 weeks. The program was well-received by participants and SCs. Our findings show that a multi-domain program for at-risk older adults has benefits and can be implemented through neighborhood SCs. Areas of improvement are discussed.Trial registration: ClinicalTrials.gov NCT04440969 retrospectively registered on 22 June 2020.

Background: Posterior fossa tumors (PFTs) are a morbid group of central nervous system tumors that most often present in childhood. While early diagnosis is critical to drive appropriate treatment, definitive diagnosis is currently only achievable through invasive tissue collection and histopathological analyses. Machine learning has been investigated as an alternative means of diagnosis. In this systematic review and meta-analysis, we evaluated the primary literature to identify all machine learning algorithms developed to classify and diagnose pediatric PFTs using imaging or molecular data. Methods: Of the 433 primary papers identified in PubMed, EMBASE, and Web of Science, 25 ultimately met the inclusion criteria. The included papers were extracted for algorithm architecture, study parameters, performance, strengths, and limitations. Results: The algorithms exhibited variable performance based on sample size, classifier(s) used, and individual tumor types being investigated. Ependymoma, medulloblastoma, and pilocytic astrocytoma were the most studied tumors with algorithm accuracies ranging from 37.5% to 94.5%. A minority of studies compared the developed algorithm to a trained neuroradiologist, with three imaging-based algorithms yielding superior performance. Common algorithm and study limitations included small sample sizes, uneven representation of individual tumor types, inconsistent performance reporting, and a lack of application in the clinical environment. Conclusions: Artificial intelligence has the potential to improve the speed and accuracy of diagnosis in this field if the right algorithm is applied to the right scenario. Work is needed to standardize outcome reporting and facilitate additional trials to allow for clinical uptake.

Neuroblastoma is a pediatric tumor of the adrenergic sympathetic lineage. Most high risk neuroblastoma go in complete clinical remission by chemotherapy, which is subsequently complemented by retinoic acid (RA) maintenance therapy. However, by unresolved mechanisms most tumors ultimately relapse as therapy-resistant disease. Neuroblastoma cell lines were recently found to include, besides lineage committed adrenergic (ADRN) tumor cells, also immature mesenchymal (MES) tumor cells. Here, we report that MES-type cells synthesize RA and require this metabolite for proliferation and motility. MES cells are even resistant to RA in vitro. MES cells appear to resemble Schwann Cell Precursors (SCP), which are motile precursors of the adrenergic lineage. MES and SCP cells express shared RA-synthesis and RA-target genes. Endogenous RA synthesis and RA resistance thus stem from normal programs of lineage precursors that are maintained in an immature tumor cell fraction. These cells are fully malignant in orthotopic patient-derived xenograft models and may mediate development of drug-resistant relapses.

We present a deep recurrent convolutional neural network (CNN) approach to solve the problem of hockey player identification in NHL broadcast videos. Player identification is a difficult computer vision problem mainly because of the players’ similar appearance, occlusion, and blurry facial and physical features. However, we can observe players’ jersey numbers over time by processing variable length image sequences of players (aka ‘tracklets’). We propose an end-to-end trainable ResNet+LSTM network, with a residual network (ResNet) base and a long short-term memory (LSTM) layer, to discover spatio-temporal features of jersey numbers over time and learn long-term dependencies. Additionally, we employ a secondary 1-dimensional convolutional neural network classifier as a late score-level fusion method to classify the output of the ResNet+LSTM network. For this work, we created a new hockey player tracklet dataset that contains sequences of hockey player bounding boxes. This achieves an overall player identification accuracy score over 87% on the test split of our new dataset.

Background The efficacy of multi-domain interventions for dementia prevention has been investigated in a few large randomized controlled trials (RCT). To link research to community action, we evaluated the implementation and effectiveness of a community-based multi-domain program for older adults at risk of cognitive impairment. Methods Three enterprises implemented a 24-week, bi-weekly, multi-domain program for older adults at risk of cognitive impairment through neighborhood senior centres (SCs). The program comprised a combination of dual-task group physical exercise, pen-and-paper cognitive games, computerised cognitive training, and mobile application-based personalized nutritional guidance. An effectiveness-implementation hybrid design using a RCT design and informed by the RE-AIM (Reach, Effectiveness, Adoption, Implementation, Maintenance) framework was adopted to evaluate the program. Cognition and quality of life were assessed using the Repeatable Battery for the Assessment of Neuropsychological Status (RBANS), and EuroQol EQ-5D-5L (EQ-5D) respectively, at baseline and 24-weeks. Blood lipid panel and physical assessments were also conducted. Questionnaires on implementation outcomes were administered at the participants-, provider- and community-levels to participants, implementers, and SC managers. Program schedules and attendance were obtained from implementers and the research team conducted unannounced, random and non-intrusive observations of the program. Results The intervention program reached almost 50% of eligible participants, had an attrition rate of 22%, and was adopted by 8.7% of the SCs approached. The intervention was implemented as intended, except the nutritional component that was re-designed due to participants’ unfamiliarity with the application. There were no between-group differences in cognition, quality of life, and blood lipid panel, though there was a reduction in quality of life in the control group and improved physical function in the intervention group at 24-weeks. Intervention group participants reported improvement in their physical and cognitive functions. The program was well-received by participants and centre managers, who wanted the intervention to continue post-study. Conclusions A six-month multi-domain program for older adults at risk of cognitive impairment can be implemented through neighborhood SCs and elicit improvement in physical but not cognitive performance. Implementation evaluation highlight areas to improve on the uptake of such community-based interventions. Trial registration Trial registration: ClinicalTrials.gov NCT04440969. Registered 22 June 2020 - Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT04440969

Over one billion people lack access to electricity and many of them in rural areas far from existing infrastructure. Off-grid systems can provide an alternative to extending the grid network and using renewable energy, for example solar photovoltaics (PV) and battery storage, can mitigate greenhouse gas emissions from electricity that would otherwise come from fossil fuel sources. This paper presents a model capable of comparing several mature and emerging PV technologies for rural electrification with diesel generation and grid extension for locations in India in terms of both the levelised cost and lifecycle emissions intensity of electricity. The levelised cost of used electricity, ranging from $0.46–1.20/kWh, and greenhouse gas emissions are highly dependent on the PV technology chosen, with battery storage contributing significantly to both metrics. The conditions under which PV and storage becomes more favourable than grid extension are calculated and hybrid systems of PV, storage and diesel generation are evaluated. Analysis of expected price evolutions suggest that the most cost-effective hybrid systems will be dominated by PV generation around 2018.

The performance of concentrator photovoltaic systems can be characterised by the power output under reference conditions and the output energy yield under realistic solar illumination. For a range of locations, the frequency distribution of individual atmospheric parameters and their quantitative impact on power output of a concentrator photovoltaic system have been evaluated, with aerosols shown to have a substantial impact on performance at many sites. Limited knowledge of atmospheric parameters results in a difference of up to 75% in simulated energy yield over an annual period and up to 75% deviation in the expected levelised cost of energy. Copyright © 2013 John Wiley & Sons, Ltd.

The band gap of the quantum well (QW) solar cell can be adapted to the incident spectral conditions by tailoring the QW depth. The single-junction strain-balanced quantum well solar cell (SB-QWSC) has achieved an efficiency of 28.3%. The dominant loss mechanism at the high concentrator cell operating bias is due to radiative recombination, so a major route to further efficiency improvement requires a restriction of the optical losses. It has been found that (100) biaxial compressive strain suppresses a mode of radiative recombination in the plane of the QWs. As biaxial strain can only be engineered into a solar cell on the nanoscale, SB-QWSCs are seen to have a fundamental efficiency advantage over equivalent bulk cells. Strain-balanced quantum wells in multi-junction solar cells can current match the sub-cells without the introduction of dislocations. Calculations are shown which predict efficiency limits as a function of QW absorption and band gap for such cells. A dual-junction InGaP/GaAs solar cell with QWs in the bottom sub-cell has been grown and characterized. Laboratory and calculated efficiencies relative to control cells are presented for the reported cell and a modeled device, respectively. Copyright © 2011 John Wiley & Sons, Ltd.

While there is an increasing number of companies realizing the potential that the diverse ethnic markets in Australia possess, majority still do not see the potential. When compared to the United States, ethnic marketing in Australia is still in a developmental stage. For many marketers, the problem is in knowing where to start. Looking from the practitioner’s perspective, this paper demonstrates how to apply readily available secondary data in identifying the potential of the ethnic markets in Australia for selected goods and services. By showing where and how to start, we hope that more marketers in Australia will see the potential of ethnic marketing and in the long run ethnic marketing will be an integral part of any marketing campaign run by a company. Marketers should reassess the usefulness and importance of secondary data in facilitating their formulation of strategic marketing decisions in different marketing mix areas.

Neuroblastomas are embryonal tumours of the sympathoadrenal lineage with a clinical course ranging from spontaneous regression to fatal progression. The Phox2B homeobox transcription factor functions in the differentiation of the sympatho-adrenal lineage. Targets of Phox2B are, for example, genes of the ( nor) adrenalin synthesis route, like Dopamine Beta Hydroxylase (DBH). Congenital Central Hypoventilation Syndrome was recently found to result from Phox2B mutations and two such patients in addition developed neuroblastoma. A germline mutation in Phox2B was identified in a family with hereditary neuroblastoma. Here, we report the first analysis of Phox2B in a series of 237 sporadic neuroblastomas and 22 cell lines. Six frameshift mutations were found in exons 2 and 3; including one in cell line SK-N-SH. Two patients showed de novo constitutional mutations. One of them was diagnosed with Haddad syndrome. All analysed cases expressed the mutated and wild-type Phox2B alleles. Ectopic expression of TrkA, the Nerve Growth Factor receptor, strongly downregulated Phox2B and DBH expression in cell line SH-SY5Y. However, TrkA and Phox2B showed a positive correlation in a panel of 66 neuroblastoma tumours. Although Phox2B mutations are infrequent ( 2.3%), they implicate a role for the Phox2B pathway in oncogenesis

The childhood tumour neuroblastoma originates from neural crest-derived progenitors of the sympathetic nervous system. By Serial Analysis of Gene Expression (SAGE), we previously identified the Drosophila Delta homologue Dlk1 as one of the genes most highly expressed in the neuroblastoma cell line SK-N-F1. The Delta-Notch pathway controls many differentiation steps in Drosophila and man. We analysed expression of 21 genes of this pathway in 21 neuroblastoma cell lines. Dlk1 expression was very high in 5 cell lines, while another subset expressed Notch3. The imprinting of Dlk1 was faithfully preserved in neuroblastomas. The single paternal allele can therefore produce over 0.5% of all cellular mRNAs. Dlk1 maps to 14q32, a region that exhibited LOH in 31/170 (18%) tumours. The random parental origin of the deleted alleles excluded Dlk1 as target of the LOH. In addition, Dlk1 was not amplified, rearranged or mutated in neuroblastoma cell lines and tumours. We therefore analysed whether high Dlk1 expression marks a specific differentiation stage of the sympatho-adrenal lineage. Many neuroblastomas arise in the adrenal medulla, which predominantly consists of chromaffin cells. Normal adrenal medulla exhibited equally high Dlk1 levels as the SK-N-F1 cell line. Chromaffin cells in young children are marked by noradrenalin production, which is mediated by dopamine-beta-hydroxylase (DBH). DBH expression in the neuroblastoma cell lines almost perfectly corresponded to Dlk1 expression. Neuroblastoma cell lines with high Dlk1 expression are therefore arrested in a relatively late stage of chromaffin lineage differentiation, while Notch3 expression might correspond to earlier precursor stages or to an alternative developmental fate. (C) 2003 Wiley-Liss, Inc

Purpose: Neuroblastoma is a childhood tumor of the peripheral sympathetic nervous system with an often lethal outcome due to metastatic disease. Migration and epithelial–mesenchymal transitions have been implicated in metastasis but they are hardly investigated in neuroblastoma. Experimental Design: Cell migration of 16 neuroblastoma cell lines was quantified in Transwell migration assays. Gene expression profiling was used to derive a migration signature, which was applied to classify samples in a neuroblastoma tumor series. Differential expression of transcription factors was analyzed in the subsets. NOTCH3 was prioritized, and inducible transgene expression studies in cell lines were used to establish whether it functions as a master switch for motility. Results: We identified a 36-gene expression signature that predicts cell migration. This signature was used to analyse expression profiles of 88 neuroblastoma tumors and identified a group with distant metastases and a poor prognosis. This group also expressed a known mesenchymal gene signature established in glioblastoma. Neuroblastomas recognized by the motility and mesenchymal signatures strongly expressed genes of the NOTCH pathway. Inducible expression of a NOTCH intracellular (NOTCH3-IC) transgene conferred a highly motile phenotype to neuroblastoma cells. NOTCH3-IC strongly induced expression of motility- and mesenchymal marker genes. Many of these genes were significantly coexpressed with NOTCH3 in neuroblastoma, as well as colon, kidney, ovary, and breast tumor series. Conclusion: The NOTCH3 transcription factor is a master regulator of motility in neuroblastoma. A subset of neuroblastoma with high expression of NOTCH3 and its downstream-regulated genes has mesenchymal characteristics, increased incidence of metastases, and a poor prognosis. Clin Cancer Res; 19(13); 3485–94. ©2013 AACR.

Chromosomal region 1p36.2 harbors an intriguing gene cluster of about 1 Mb. In addition to normal high-copy-number repeats, this cluster consists entirely of locally repeated sequences among which there are tRNA and small nuclear RNA (snRNA) genes. In 23 PACs and YACs from the 1p36.2 cluster, we identified eight different copies of a sequence with about 97% homology to the macrophage stimulating protein (MSP) gene located on chromosomal band 3p21. These MSP-like (MSPL) sequences on 1p36.2 are scattered over the repeat region. Nucleotide substitutions and single nucleotide deletions in exons of all identified MSPL genes on 1p36.2 mark them as pseudogenes. We constructed a phylogenetic tree of these sequences with their most likely order of origin in evolution. MSP from 3p21 could be identified as the ancestral sequence, a copy of which was captured into the cluster of tRNA and snRNA genes on 1p36.2 about 6 million years (MY) ago. MSP subsequently coamplified with the other sequences in the cluster. Analysis of the DNA of 18 individuals shows that the MSPL copy number is polymorphic, with a range of four to seven or more copies per haploid genome. Analysis of corresponding clusters in macaque chromosomes indicated an age for the tRNA/snRNA cluster of at least 30 MY. The MSPL sequence thus functions as a probe for the more recent primate evolution of this cluster and suggests a continuation of its unusual activity over the last 6 MY.

Adult-type hematopoietic stem cells (HSCs) emerge in the aorta-gonad-mesonephros (AGM) region in the mid-gestation mouse embryo. Thereafter, HSCs migrate to the fetal liver (FL) and at birth, colonize the adult bone marrow. The molecular signaling cascades controlling HSCs in the AGM region is not yet known. Exogenous Hedgehog (Hh) added to AGM explants prior to HSC generation induces AGM HSCs and BMP pathway inhibition abolishes AGM HSC activity. In the FL, the BMP signaling pathway is not required for hematopoiesis. A role for the MAPK signaling pathway has been demonstrated in the adult hematopoiesis, but whether this pathway also controls AGM HSCs is not known. We hypothesize that Hh and BMP control the induction/expansion of AGM HSCs and cooperate with the MAPK pathway to control their maintenance and differentiation. To test whether HSCs are directly activated by BMP, we used transgenic BMP-response element (BRE)-gfp mice, in which GFP expression is an indicator of BMP pathway activation. When BRE-gfp E11 AGM cells were sorted for GFP expression and injected into adult irradiated mice, all long term repopulating HSCs were found in the BMP activated (GFP+) fraction. We next asked whether HSCs in the FL are activated by BMP. Surprisingly, we found high level, multilineage, self-renewing HSCs in both GFP+ and GFPfractions. This suggests that subsets of HSCs shift from an exclusively BMP-activated state, to a state of non-activation. This shift may be involved in the expansion of HSCs in the FL. Since HSCs expand in explant cultures of E11 AGMs, we examined whether after explant, AGM HSCs remain BMP-activated. Interestingly, after explant, both GFP+ and GFPfractions contained multilineage, self-renewing HSCs. In such explants when Hh or MAPK pathways are inhibited, only the non-BMP-activated HSC activity is abolished. The Hh inhibition effect on AGM HSCs could be rescued by exogeneous VEGF addition, but VEGF could not rescue the HSC defects caused by MAPK inhibition. These results suggest that VEGF acts downstream of Hh and further activates the MAPK pathway to control AGM HSCs. In conclusion, our data provide clear evidence of an interactive molecular cascade involving the BMP, Hh and MAPK signaling pathways in the control of AGM HSC development. P1087 TWO ADULT-TYPE HSC SUBSETS COEXISTENT IN MOUSE Mihaela Crisan, Chris Vink, Tomoko Yamada-Inagawa, Alex Neagu, Caterina Purini, Sofia Karkanpouna, Reinir van der Linden, and Elaine Dzierzak Cell Biology, Erasmus MC Stem Cell Institute, Rotterdam, Netherlands; Dept. of Molecular and Cell Biology, Centre of Biomedical Genetics, Leiden, Netherlands