bluuebunny/crossref_metadata_2025 huggingface dataset:
Applying the organizational failure diagnosis model to the study of information systems failure
Authors: Goulielmos Markos
Published: July 2005

Purpose

Proposes to analyze known case studies of information systems failure.

Design/methodology/approach

Uses the organizational failure diagnosis model.

Findings

Finds that there is the need to assess the organization's “health” prior to information systems development and to raise the organization's actual capacity for systems development to the necessary levels for success.

Originality/value

Previous studying of these cases has underplayed the role of technical problems as the surface manifestations of deeper‐rooted organizational pathologies causing the failure. The usefulness of the organizational failure diagnosis model is shown in recognizing these deeper‐rooted issues and a number of suggestions are made for the prevention of failure.
Ground subsidence: a silent disaster in Himalaya
Authors: Rautela Piyoosh
Published: July 2005

Purpose

It is observed that the slow onslaught disasters do not normally catch media attention as these often do not result in human casualties. Inadequate media attention results in insufficient rehabilitation support for the victims. The paper aims at highlighting the problem of ground subsidence in the Himalayan terrain together with the hardships of the victims.

Design/methodology/approach

The paper is based on the detailed field investigations carried out by the author in the remote Himalayan habitations of Garbyang in Dharchula block of Pithoragarh, Talla Dhumar and Umli‐Bhandarigaon in Munsyari block of Pithoragarh and Bagi in Uttarkashi district in the state of Uttaranchal in India. All these habitations are being affected by ground subsidence and the inhabitants of these villages are facing severe resource crisis.

Findings

Garbyang village in Central Himalaya is observed to be situated over the varve deposits laid down in the proglacial lake abutting against Chialekh ridge and is witnessing the problem of ground subsidence resulting in the destruction of the once thriving and prosperous habitation. The studies relate the subsidence at Garbyang with the seismicity in the region as also the subsequent toe erosion and downslope mass movement. The other sites discussed in the paper are witnessing the problem of ground subsidence due to the active toe erosion by rivers and streams.

Research limitations/implications

There exist no records of the exact date of initiation of the ground subsidence in the investigated areas and these are grossly based on the information provided by the village elders.

Originality/value

The article would help in making the disaster managers responsive to the problems the masses are facing due to ground subsidence in this fragile zone and this would result in mustering resources for reducing the hardships of the masses.
Making room for career change
Authors: Hind Patricia
Published: July 2005

Purpose

This paper aims to explore a model, “The Four Roomed Apartment of Change” developed by Swedish psychologist claes Janssen which uses existential psychology to understand and manage the processes of change. The model has been used extensively in organisations as a diagnostic tool to facilitate changes in organisations, which involve some psychological discomfort. This paper specifically examines whether the model is equally useful when applied to the management of personal career change.

Design/methodology/approach

The paper considers the roots of existential psychology and outlines and critically reviews the “Four Roomed Apartment” model. The paper also provides evaluative analysis of the links between existential psychology and career development.

Findings

The paper finds that change may be thought of as a cyclical process involving different frames of mind and different emotions and that understanding those frames of mind is the key to successful, well managed change. The paper concludes that the model offered by the Four Roomed Apartment does provide a useful framework for understanding the emotions and feelings experienced during career change, and offers some guidance as to how to manage the process.

Originality/value

Career success today is measured against a broad raft of criteria, such as fulfilling work, work/life balance, skill utilisation and valued relationships. In order to achieve this success today, individuals must be acutely aware of their experiences and sufficiently reflective to understand their emotional significance. This model offers a helpful framework for that reflection and provides answers to some of the questions that must be answered for successful career management.
Career‐focused employee transfer processes
Authors: Prince J. Bruce
Published: July 2005

Purpose

The employee selection process has generally focused on the near‐term performance potential of internal candidates in filling vacant positions. This research addresses the potential influence of adding a career development emphasis to the employee transfer decision process. In a career‐focused transfer process the applicants' individual career development needs and growth opportunities are a key basis for internal selection decisions.

Design/methodology/approach

Using web‐based survey methodology, a US financial services firm is used to evaluate the relationship between the use of career‐focused employee transfer criteria and key employee attitudes.

Findings

The study finds that the use of career‐focused processes are positively related to employees' developmental opportunity satisfaction and perceived support for career development. Regression analyses finds that these two attitudes mediate the positive relationship between the use of career‐focused transfer criteria and perceived organization support (POS). Other research efforts (e.g. Allen and Shore) have linked POS to a variety of positive outcomes, including lower employee turnover. Past research, however, has not considered how specific human resource practices can be the basis for the development of key attitudes.

Research limitations/implications

This research – while limited due to it cross‐sectional methodology – builds on that stream of research by focuses on the design of the employee transfer process and how it can be a key practice for achieving a developmental focus and associated benefits.

Originality/value

The results suggest that focusing on performance potential of applicants and career‐focused criteria are not necessarily antagonistic but can be used jointly to make internal selection decisions.
The consulting career in transition: from partnership to corporate
Authors: Adams Susan M. , Zanzi Alberto
Published: July 2005

Purpose

The consulting industry is facing an inflection point as it shifts to being more populated by publicly traded entities than by private firms. Associated career patterns are affected in ways that have not yet been explored.

Design/methodology/approach

In this paper we describe the industry shift to public ownership and resulting changes in consulting careers from a psychological contract perspective. We conclude by discussing the impact of emerging career dynamics that could impact the future effectiveness of the consulting industry.

Findings

There are dramatic transitions underway regarding career dynamics of professionals in major consultancies. We foresee a troublesome picture in some respects and a promising outlook in other respects for individuals and their firms in the consulting profession.

Practical implications

Aspiring consultants will find this paper informative as a way to assess fit with career models offered by consulting firms. Firms can use points in the paper to understand their potential shortcomings associated with their current and evolving career models to manage career transitions and negative consequences.

Originality/value

This conceptual paper draws attention to the potentially negative consequences of inappropriate career models for consultancies in general, and with different firm strategies. It is a first look at career changes in consulting due to the drastic shift of the industry to public entities.
VESPUCCI REDISCOVERS AMERICA: THE PICTORIAL RHETORIC OF CANNIBALISM IN EARLY MODERN CULTURE
Authors: Schreffler Michael J.
Published: July 2005

Studies of the representation of cannibalism have noted that the discourse on that practice that emerged in the sixteenth century operated as a differencing mechanism, a counterpoint to ideas about the ideal and individuated Christian subject of early modern Europe. But how were these associations and differences articulated within visual culture? This essay examines Jan Van der Straet's Amerigo Vespucci Rediscovers America and other visual images that present cannibalism as an attribute and/or practice of the inhabitants of the Americas. It identifies the strategies of visual rhetoric through which that association operated in the construction and maintenance of relationships of colonial power and subordination in the early modern Atlantic world.
BODILY AND PICTORIAL SURFACES: SKIN IN FRENCH ART AND MEDICINE, 1790–1860
Authors: Fend Mechthild
Published: July 2005

This essay argues for the shared quality of skin and painting as signifying surfaces. When representing the surface of the body the artist engages with questions about the borders of the body and relations between the interior and the exterior. Portraits by Jacques‐Louis David and Jean‐Auguste‐Dominique Ingres are considered in relation to several discursive fields: medical definitions of skin from the Enlightenment, nineteenth‐century artistic anatomy and art theory. While David's rendering of skin is understood in terms of Xavier Bichat's definition of skin as a ‘limite sensitive’, the hermetically sealed and opaque skin of Ingres's figures negates contemporary notions of skin as a communicative membrane. Scientific knowledge notwithstanding, these very different approaches to the representation of skin may be seen as reflecting upon different ways to produce meaning as well as different conceptions of the body.

Mechthild Fend is a research scholar at the Max Planck Institute for the History of Science in Berlin, where she is working on a project on the history and representation of skin in late eighteenth‐ and nineteenth‐century France. Her recent books deal with the representation of masculinity: Männlichkeit im Blick. Visuelle Inszenierungen in der Kunst seit der Frühen Neuzeit (co‐edited with Marianne Koos, Cologne, 2004), and Grenzen der Männlichkeit. Der Androgyn in der französischen Kunst und Kunsttheorie Zwischen Aufkl.arung und Restauration (Berlin, 2003).
REVIVING THE ROCOCO: ENTERPRISING ITALIAN ARTISTS IN SECOND EMPIRE PARIS
Authors: Igra Caroline
Published: July 2005

Faced with a dearth of artistic opportunity at home and the promise of cultural riches elsewhere, Italian artists flocked to Paris in the mid‐nineteenth century. Seeking assimilation and acceptance, they adapted a fashionable painting style that was not French in origin but Spanish, and primarily based on the work of Mariano Fortuny. This revival of eighteenth‐century rococo genre painting, popular in, and promoted by, the Second Empire, brought these Italian artists financial success and artistic recognition, as individuals and as representatives of a nation. Giovanni Boldini and Giuseppe de Nittis were among the very few Italian artists to enjoy fame and fortune in Paris. Their practice in the French capital demonstrates how artistic choices and careers could be shaped by the demands of the art market and the conditions for success, and the pressures levied by discussions about the significance of national schools of art.
AUTHORSHIP AND IDENTITY IN MAX ERNST'S LOPLOP
Authors: Kavky Samantha
Published: July 2005

From 1928 to 1932 an avian creature named Loplop, Bird Superior, appears regularly in the collages and paintings of the surrealist artist Max Ernst. In this article I suggest that Ernst models Loplop on the father/totem, as defined by Sigmund Freud in his Totem and Taboo of 1913. An exploration of Ernst's interpretation of Freudian theory in creating Loplop illuminates the character's surprising complexity and centrality to Ernst's oeuvre. As a totem, Loplop emerges from a primary oedipal conflict on which Ernst structures his artistic identity and practice. Equating traditional notions of creative authorship with various forms of patriarchal authority, Ernst's constructed totem signifies his personal, aesthetic and political rejection of individual mastery in favour of his fraternal allegiance to the surrealist group and his embrace of surrealist automatist practices.
Hfr‐2, a wheat cytolytic toxin‐like gene, is up‐regulated by virulent Hessian fly larval feeding‡
Authors: PUTHOFF DAVID P. , SARDESAI NAGESH , SUBRAMANYAM SUBHASHREE , NEMACHECK JILL A. , WILLIAMS CHRISTIE E.
Published: July 2005

Both yield and grain‐quality are dramatically decreased when susceptible wheat (Triticum aestivum) plants are infested by Hessian fly (Mayetiola destructor) larvae. Examination of the changes in wheat gene expression during infestation by virulent Hessian fly larvae has identified the up‐regulation of a gene, Hessian fly responsive‐2 (Hfr‐2), which contains regions similar to genes encoding seed‐specific agglutinin proteins from Amaranthus. Hfr‐2, however, did not accumulate in developing seeds, as do other wheat seed storage proteins. Additionally, a separate region of the HFR‐2 predicted amino acid sequence is similar to haemolytic proteins, from both mushroom and bacteria, that are able to form pores in cell membranes of mammalian red blood cells. The involvement of Hfr‐2 in interactions with insects was supported by experiments demonstrating its up‐regulation by both fall armyworm (Spodoptera frugiperda) and bird cherry‐oat aphid (Rhopalosiphum padi) infestations but not by virus infection. Examination of wheat defence response pathways showed Hfr‐2 up‐regulation following methyl jasmonate treatment and only slight up‐regulation in response to salicylic acid, abscisic acid and wounding treatments. Like related proteins, HFR‐2 may normally function in defence against certain insects or pathogens. However, we propose that as virulent Hessian fly larvae manipulate the physiology of the susceptible host, the HFR‐2 protein inserts in plant cell membranes at the feeding sites and by forming pores provides water, ions and other small nutritive molecules to the developing larvae.
Molecular analysis of the interaction between Olea europaea and the biotrophic fungus Spilocaea oleagina
Authors: BENITEZ YOSELIN , BOTELLA MIGUEL A. , TRAPERO ANTONIO , ALSALIMIYA MOHAMMED , CABALLERO JOSE LUIS , DORADO GABRIEL , MUÑOZ‐BLANCO JUAN
Published: July 2005

The mitosporic fungus Spilocaea oleagina is an obligate biotroph of olive (Olea europaea) causing a scab disease associated with leaf fall and substantial losses in production. Using differential display we have identified 162 cDNA fragments corresponding to transcripts that show altered abundance during the defence response of a resistant olive cultivar to S. oleagina. Detailed analyses of 21 selected genes by real‐time quantitative RT‐PCR revealed different kinetics of induction. Genes involved in signalling, transcriptional control, oxidative stress, biotic and abiotic stress, and several genes with unknown function were found to be induced rapidly after infection. In contrast, genes involved in metabolism and cellular maintenance showed delayed induction. The induction of the selected genes in a susceptible cultivar was delayed and/or reduced during the response to S. oleagina. Interestingly, the basal expression of some genes in the uninfected resistant cultivar was higher than in the susceptible one, suggesting a constitutive activation of defence responses. Expression of these genes in response to salicylic acid, methyl jasmonate, a mixture of both, ethephon, hydrogen peroxide, menadione and wounding was also investigated. The results are discussed in relation to the molecular bases and signalling events involved in this biotrophic interaction.
Genotypic and phenotypic diversity in Colletotrichum acutatum, a cosmopolitan pathogen causing anthracnose on a wide range of hosts
Authors: SREENIVASAPRASAD S. , TALHINHAS PEDRO
Published: July 2005

Colletotrichum acutatum causes anthracnose on a wide range of hosts including woody and herbaceous crops, ornamentals, fruits and conifers. Almond, citrus, lupin, olive and strawberry are some of the crops in which C. acutatum diseases are economically important. With the application of molecular markers and diagnostic PCR over the last 10–15 years, C. acutatum was identified as a major pathogen on a number of hosts instead of or along with C. gloeosporioides. C. acutatum displays high levels of genotypic and phenotypic diversity. The global populations of this cosmopolitan pathogen fit into at least eight distinct molecular groups, A1–A8, which show some degree of correlation with the morphological characteristics and varying patterns of host association and geographical distribution. The pathogen has complex epidemiology, exhibiting pathogenic and non‐pathogenic lifestyles on target hosts, non‐target crops and weeds. C. acutatum populations also show pathogenic variability and cross‐infection potential in relation to a number of hosts. Molecular genetic tools are being developed to investigate the pathogenicity mechanisms of this key pathogen. This article mainly focuses on the global population diversity in C. acutatum, pathogen epidemiology and diagnosis, host colonization processes, and the development of tools for the identification and analysis of genes associated with pathogenicity. Background information on the pathogen origin, host range, disease symptoms and disease management strategies is also provided.
Cladosporium fulvum (syn. Passalora fulva), a highly specialized plant pathogen as a model for functional studies on plant pathogenic Mycosphaerellaceae
Authors: THOMMA BART P. H. J. , VAN ESSE H. PETER , CROUS PEDRO W. , DE WIT PIERRE J. G. M.
Published: July 2005

Taxonomy:  Cladosporium fulvum is an asexual fungus for which no sexual stage is currently known. Molecular data, however, support C. fulvum as a member of the Mycosphaerellaceae, clustering with other taxa having Mycosphaerella teleomorphs. C. fulvum has recently been placed in the anamorph genus Passalora as P. fulva. Its taxonomic disposition is supported by its DNA phylogeny, as well as the distinct scars on its conidial hila, which are typical of Passalora, and unlike Cladosporium s.s., which has teleomorphs that reside in Davidiella, and not Mycosphaerella.

Host range and disease symptoms:  The presently known sole host of C. fulvum is tomato (members of the genusLycopersicon). C. fulvum is mainly a foliar pathogen. Disease symptoms are most obvious on the abaxial side of the leaf and include patches of white mould that turn brown upon sporulation. Due to stomatal clogging, curling of leaves and wilting can occur, leading to defoliation.

C. fulvum as a model pathogen:  The interaction between C. fulvum and tomato is governed by a gene‐for‐gene relationship. A total of eight Avr and Ecp genes, and for four of these also the corresponding plant Cf genes, have been cloned. Obtaining conclusive evidence for gene‐for‐gene relationships is complicated by the poor availability of genetic tools for most Mycosphaerellaceae–plant interactions. Newly developed tools, including Agrobacterium‐mediated transformation and RNAi, added to the genome sequence of its host tomato, which will be available within a few years, render C. fulvum attractive as a model species for plant pathogenic Mycosphaerellaceae.

Useful websites:  http://www.sgn.cornell.edu/help/about/index.html; http://cogeme.ex.ac.uk
Odontoglossum ringspot virus host range restriction in Nicotiana sylvestris maps to the replicase gene
Authors: RABINDRAN SHAILAJA , ROBERTSON CECILE , ACHOR DIANN , GERMAN‐RETANA SYLVIE , A. HOLT CURTIS , DAWSON WILLIAM O.
Published: July 2005

The experimental host range of Odontoglossum ringspot virus (ORSV), a member of the tobamoviruses, includes several species of Nicotiana, but not N. sylvestris. However, ORSV was able to replicate in protoplasts from N. sylvestris leaves. By using the green fluorescent protein (GFP) as a marker inserted into ORSV, it was found that a small number of single epidermal cells became infected in mechanically inoculated leaves, but the virus did not move cell to cell. The ORSV movement protein (MP) and coat protein (CP) were examined for their ability to effect movement by substitution into Tobacco mosaic virus (TMV) hybrids. Both proteins and the 3′ non‐translated region (NTR) of ORSV allowed movement of TMV hybrids in N. sylvestris. These results suggested that the inability of ORSV to move in N. sylvestris was due to the replicase gene or the 5′NTR. One possibility was that the replicase gene could indirectly affect movement by failing to produce subgenomic (sg) RNAs for expression of MP or CP, but this appeared not to be the case as ORSV replicated and produced MP and CP sgRNAs, both of which were translated in N. sylvestris protoplasts. Additionally, genomic RNA was encapsidated into virions in N. sylvestris protoplasts. Because the 5′NTR permitted efficient replication and production of replicase proteins, these findings suggest that the replicase of ORSV is responsible for the defect in cell‐to‐cell movement of ORSV in N. sylvestris.
Conifer root and butt rot caused by Heterobasidion annosum (Fr.) Bref. s.l.
Authors: ASIEGBU FRED O. , ADOMAS ALEKSANDRA , STENLID JAN
Published: July 2005

The root and butt rot caused by Heterobasidon annosum is one of the most destructive diseases of conifers in the northern temperate regions of the world, particularly in Europe. Economic losses attributable to Heterobasidion infection in Europe are estimated at 800 million euros annually. The fungus has been classified into three separate European intersterile species P (H. annosum), S (H. parviporum) and F (H. abietinum) based on their main host preferences: pine, spruce and fir, respectively. In North America, two intersterile groups are present, P and S/F, but these have not been given scientific names. The ecology of the disease spread has been intensively studied but the genetics, biochemistry and molecular aspects of pathogen virulence have been relatively little examined. Recent advances in transcript profiling, molecular characterization of pathogenicity factors and establishment of DNA‐transformation systems have paved the way for future advances in our understanding of this pathosystem.

Taxonomy:  Heterobasidion annosum (Fr.) Bref., H. parviporum Niemelä & Korhonen and H. abietinum Niemelä & Korhonen; kingdom Fungi; class Basidiomycotina; order Aphyllophorales; family Bondarzewiaceae; genus Heterobasidion.

Identification:  presence of the fungus fruit bodies, basidiocarps whitish in the margins, upper surface is tan to dark brown, usually irregular shaped, 3.5 (−7) cm thick and up to 40 cm in diameter; pores 5–19, 7–22 and 13–26 mm2 for the P, F and S groups, respectively. Small brownish non‐sporulating postules develop on the outside of infected roots. Asexual spores (conidiospores) are 3.8–6.6 × 2.8–5.0 µm in size. Mating tests are necessary for identification of intersterility groups.

Host range:  The fungus attacks many coniferous tree species. In Europe, particularly trees of the genera Pinus and Juniperus (P), Picea (S), Abies (F) and in North America Pinus (P) and Picea, Tsuga and Abies (S/F). To a lesser extent it causes root rot on some decidous trees (Betula and Quercus).

Disease symptoms:  symptoms (e.g. exhudation of resin, crown deterioration) due to Heterobasidion root rot in living trees are not particularly characteristic and in most cases cannot be distinguished from those caused by other root pathogens. Heterobasidion annosum s.l. is a white rot fungus. Initial growth in wood causes a stain that varies in colour depending on host tree species. Incipient decay is normally pale yellow and it develops into a light brown decay to become a white pocket rot with black flecks in its advanced stage.

Control:  silvicultural methods (e.g. stump removal), chemicals (urea, borates) and biological control agent (Phlebiopsis gigantea, marketed as PG Suspension® in the UK, PG IBL® in Poland and Rotstop® in Fennoscandia) are commonly used approaches for minimizing the disease spread.
Nitrogen‐responsive genes are differentially regulated in planta during Fusarium oxyspsorum f. sp. lycopersici infection
Authors: DIVON HEGE H. , ROTHAN‐DENOYES BEATRICE , DAVYDOV OLGA , DI PIETRO ANTONIO , FLUHR ROBERT
Published: July 2005

Nitrogen is an essential growth component whose availability will limit microbial spread, and as such it serves as a key control point in dictating an organism's adaptation to various environments. Little is known about fungal nutrition in planta. To enhance our understanding of this process we examined the transcriptional adaptation of Fusarium oxysporum f. sp. lycopersici, the causal agent for vascular wilt in tomato, during nutritional stress and plant colonization. Using RT‐PCR and microarray technology we compared fungal gene expression in planta to axenic nitrogen starvation culture. Several expressed sequence tags, representing at least four genes, were identified that are concomitantly induced during nitrogen starvation and in planta growth. Three of these genes show similarity to a general amino acid permease, a peptide transporter and an uricase, all functioning in organic nitrogen acquisition. We further show that these genes represent a distinguishable subset of the nitrogen‐responsive transcripts that respond to amino acids commonly available in the plant. Our results indicate that nitrogen starvation partially mimics in planta growth conditions, and further suggest that minute levels of organic nitrogen sources dictate the final outcome of fungal gene expression in planta. The nature of the identified transcripts suggests modes of nutrient uptake and survival for Fusarium during colonization.
The immune response to fungal infections
Authors: Shoham Shmuel , Levitz Stuart M.
Published: July 2005

During the past two decades, invasive fungal infections have emerged as a major threat to immunocompromised hosts. Patients with neoplastic diseases are at significant risk for such infections as a result of their underlying illness and its therapy. Aspergillus, Candida, Cryptococcus and emerging pathogens, such as the zygomycetes, dark walled fungi, Trichosporon and Fusarium, are largely opportunists, causing infection when host defences are breached. The immune response varies with respect to the fungal species and morphotype encountered. The risk for particular infections differs, depending upon which aspect of immunity is impaired. This article reviews the current understanding of the role and relative importance of innate and adaptive immunity to common and emerging fungal pathogens. An understanding of the host response to these organisms is important in decisions regarding use of currently available antifungal therapies and in the design of new therapeutic modalities.
Molecular mechanisms of fibrinolysis
Authors: Cesarman‐Maus Gabriela , Hajjar Katherine A.
Published: July 2005

The molecular mechanisms that finely co‐ordinate fibrin formation and fibrinolysis are now well defined. The structure and function of all major fibrinolytic proteins, which include serine proteases, their inhibitors, activators and receptors, have been characterized. Measurements of real time, dynamic molecular interactions during fibrinolysis of whole blood clots can now be carried out in vitro. The development of gene‐targeted mice deficient in one or more fibrinolytic protein(s) has demonstrated expected and unexpected roles for these proteins in both intravascular and extravascular settings. In addition, genetic analysis of human deficiency syndromes has revealed specific mutations that result in human disorders that are reflective of either fibrinolytic deficiency or excess. Elucidation of the fine control of fibrinolysis under different physiological and pathological haemostatic states will undoubtedly lead to novel therapeutic interventions. Here, we review the fundamental features of intravascular plasmin generation, and consider the major clinical syndromes resulting from abnormalities in fibrinolysis.
Aberrant somatic hypermutation and expression of activation‐induced cytidine deaminase mRNA in mediastinal large B‐cell lymphoma
Authors: Bödör Csaba , Bognár Ágnes , Reiniger Lilla , Szepesi Ágota , Tóth Erika , Kopper László , Matolcsy András
Published: July 2005

To determine the possible role of aberrant somatic hypermutation (ASHM) and activation‐induced cytidine deaminase (AID) expression in the pathogenesis of mediastinal large B‐cell lymphoma (MBL), the mutational status of genes affected by ASHM, including c‐MYC, PAX‐5 and RhoH, was analysed, and the expression level of AID mRNA in tumour specimens from six patients with MBL was determined. Mutations in one or more genes and high expression of AID mRNA were detected in all the six cases of MBL. These results suggest that ASHM and AID expression may have a role in the pathogenesis of MBL.
Killing of non‐Hodgkin lymphoma cells by autologous CD19 engineered T cells
Authors: Cheadle Eleanor J. , Gilham David E. , Thistlethwaite Fiona C. , Radford John A. , Hawkins Robert E.
Published: July 2005

Adoptive immunotherapy with tumour‐specific T cells is an emerging technology that may be applicable to a broad range of cancers. However, tumours can avoid T cell‐mediated attack through multiple mechanisms including downregulation of major histocompatability complex (MHC). Consequently, engineering T cells to target intact protein antigen directly, thus bypassing the need for MHC presentation, can facilitate T cell targeting of tumour cells. Peripheral blood lymphocytes from nine of nine patients with non‐Hodgkin lymphoma (NHL) were successfully gene‐modified to express a receptor consisting of a CD19 single chain variable fragment (scFv) fused to the T cell CD3ζ signalling molecule. These T cells were functionally active against the CD19+ Raji Burkitt's lymphoma cell line. Importantly, engineered T cells from seven of nine NHL patients efficiently lysed autologous lymph node tumour biopsy cells. There was a clear correlation between levels of CD19 expression on the tumour and effective killing by the engineered T cells. For two patients with a low or absent CD19+ cells within the biopsy, no significant killing was observed. These results demonstrate that patients with CD19+ NHL would be suitable candidates for this form of therapy in the setting of a phase I clinical trial.
Somatic PTPN11 mutations in childhood acute myeloid leukaemia
Authors: Tartaglia Marco , Martinelli Simone , Iavarone Ivano , Cazzaniga Giovanni , Spinelli Monica , Giarin Emanuela , Petrangeli Valentina , Carta Claudio , Masetti Riccardo , Aricò Maurizio , Locatelli Franco , Basso Giuseppe , Sorcini Mariella , Pession Andrea , Biondi Andrea
Published: July 2005

Somatic mutations in PTPN11, the gene encoding the transducer SHP‐2, have emerged as a novel class of lesions that upregulate RAS signalling and contribute to leukaemogenesis. In a recent study of 69 children and adolescents with de novo acute myeloid leukaemia (AML), we documented a non‐random distribution of PTPN11 mutations among French–American–British (FAB) subtypes. Lesions were restricted to FAB‐M5 cases, where they were relatively common (four of 12 cases). Here, we report on the results of a molecular screening performed on 181 additional unselected patients, enrolled in participating institutions of the Associazione Italiana Ematologia Oncologia Pediatrica–AML Study Group, to provide a more accurate picture of the prevalence, spectrum and distribution of PTPN11 mutations in childhood AML and to investigate their clinical relevance. We concluded that PTPN11 defects do not represent a frequent event in this heterogeneous group of malignancies (4·4%), although they recur in a considerable percentage of patients with FAB‐M5 (18%). PTPN11 lesions rarely occur in other subtypes. Within the FAB‐M5 group no clear association of PTPN11 mutations with any clinical variable was evident. Nearly two third of the patients with this subtype were found to harbour an activating mutation in PTPN11, NRAS, KRAS2 or FLT3.
UTY‐specific TCR‐transfer generates potential graft‐versus‐leukaemia effector T cells
Authors: Ivanov Roman , Hol Samantha , Aarts Tineke , Hagenbeek Anton , Slager Elisabeth H. , Ebeling Saskia
Published: July 2005

Immunotherapeutic approaches that target antigens that are differentially recognized on haematopoietic and non‐haematopoietic cells may specifically enhance the graft‐versus‐leukaemia (GVL) effect of donor lymphocyte infusion. In this study, we have characterized a new HLA‐B*5201‐restricted epitope of the UTY gene. Unusually, presentation of this epitope was restricted to lymphoblasts. As a result, a T cell clone specific to this epitope recognized normal and malignant male B and T lymphoblasts, while showing little reactivity towards male HLA‐B*5201+ fibroblasts. Transfer of its T cell receptor (TCR) into donor T cells led to the generation of large numbers of T cells, which acquired the specificity of the original clone, its avidity and the differential pattern of reactivity towards lymphoblasts and fibroblasts. Remarkably, the specific response of TCR‐transferred T cells was significantly higher than that of the original clone. This is the first demonstration of the possibility to preserve the specific pattern of a T cell response to a differentially expressed antigen after TCR‐transfer and to augment the amplitude of this response concomitantly. These results indicate that it may be feasible to enhance the GVL effect of donor lymphocyte infusions in lymphoproliferative malignancies by the transfer of TCRs specific to epitopes that are differentially recognized on lymphoblasts.
Chronic oxidative stress reduces the respiratory burst response of neutrophils from beta‐thalassaemia patients
Authors: Amer Johnny , Fibach Eitan
Published: July 2005

Beta‐thalassaemia patients are susceptible to infections by mechanisms that are not fully understood. Polymorphonuclear neutrophils (PMN) destroy microbes by producing a burst of reactive oxygen species (ROS) (respiratory burst) in response to bacterial components, as well as to phorbol‐myristate‐acetate (PMA). In the present study, we compared ROS generation by normal and β‐thalassaemia PMN and assessed their response to PMA. Blood cells were subjected to gelatin separation, staining with dichlorofluorescin‐diacetate and flow cytometry. At basal level, the fluorescence (mean fluorescence channel) of normal and thalassaemia PMN were 12·7 ± 4·5 and 95·6 ± 19·8 respectively; it changed to 283·4 ± 72·5 and 39·5 ± 14·3, respectively, upon PMA stimulation, indicating that thalassaemia PMN have a higher basal ROS but a reduced response to PMA. When normal PMN were treated with the oxidants hydrogen peroxide and butyl‐hydroxyperoxide, as well as iron and haemin, which are elevated in thalassaemia, their basal ROS increased 5–22‐fold, but the PMA response was abolished. Treating thalassaemic PMN with antioxidants (N‐acetyl‐l‐cysteine or vitamins C and E) reduced their basal ROS but enhanced their PMA response. Our findings indicate that chronically stressed PMN, e.g. in thalassaemia, have reduced capacity to elicit a respiratory burst, which may compromise their antibacterial capacity, and imply prophylactic treatment with antioxidants for recurrent infections.
Haplotypes in the tumour necrosis factor region and myeloma
Authors: Morgan Gareth J. , Adamson Peter J. , Mensah Fiona K. , Spink Charlotte F. , Law Graham R. , Keen Leigh J. , Roman Eve , Davies Faith E. , Rollinson Sara , Child J. A. , Bidwell Jeffrey L.
Published: July 2005

This study described the haplotypic structure across a region of chromosome 6 including the tumour necrosis factor (TNF) gene, and investigated its influence on the aetiology of myeloma. A total of 181 myeloma cases from the Medical Research Council Myeloma VII trial and 233 controls from the Leukaemia Research Fund Case Control Study of Adult Acute Leukaemia were included in the analysis. Genotyping by induced heteroduplex generator analysis was carried out for single nucleotide polymorphisms (SNP) located at positions −1031, −863, −857, −308 and −238 of the 5′ promoter region of TNF‐α gene, and 252 in the LT‐α gene; and five microsatellites, TNFa, b, c, d and e. Haplotypes were inferred statistically using the phase algorithm. A limited diversity of haplotypes was observed, with the majority of variation described by 12 frequent haplotypes. Detailed characterization of the haplotype did not provide greater determination of disease risk beyond that described by the TNF‐α−308 SNP. Some evidence was provided for a decreased risk of myeloma associated with the TNF‐α−308 variant allele A, odds ratio, 0·57; 95% confidence interval, 0·38–0·86. The results of this study did not support our starting hypothesis; that high producer haplotypes at the TNF locus are associated with an increased risk of developing myeloma.
Oneversustwo high‐dose cytarabine‐based consolidation before autologous stem cell transplantation for young acute myeloblastic leukaemia patients in first complete remission
Authors: Jourdan Eric , Rigal‐Huguet Françoise , Marit Gerald , Vey Norbert , Dastugue Nicole , Fegueux Nathalie , Molina Lysiane , Gastaut Jean‐Albert , Legros Laurence , Zerazhi Hacene , Cailleres Sylvie , Bauduer Frédéric , Bordessoule Dominique , Attal Michel , Blaise Didier , Pigneux Arnaud ,   the BGMT Study Group
Published: July 2005

We report on a randomized trial aimed to determine the impact of a second consolidative high‐dose cytarabine‐based chemotherapy (HiDAC) in patients with acute myeloid leukaemia prior to an autologous stem cell transplantation (ASCT). Patients aged 18–60 years, in complete remission (CR) received a first consolidation with daunorubicin and cytarabine at reduced dose. Patients not allocated to allogeneic transplantation received one course of HiDAC and then were randomized to receive an ASCT immediately (HiDAC 1 group) or after one more course of HiDAC (HiDAC 2 group). Out of the 437 initial patients, 351 achieved CR (80%), of those 277 (79%) were eligible for first HiDAC, and 128 (36%) were randomized (HiDAC 1: 65, HiDAC 2: 63). Overall survival, leukaemia‐free survival and cumulative incidence of relapse and non‐relapse deaths were 41% and 53% (P = 0·14), 39% and 48% (P = 0·12), 57% and 47% (P = 0·11), 8% and 8% (P = 0·95) for HiDAC 1 and HiDAC 2 groups, respectively. Further studies are warranted with a larger number of patients to test the place of a second course of HiDAC in this setting.
Efficient identification of T‐cell clones associated with graft‐versus‐host disease in target tissue allows for subsequent detection in peripheral blood
Authors: Beck Rose C. , Wlodarski Marcin , Gondek Lukasz , Theil Karl S. , Tuthill Ralph J. , Sobeck Ronald , Bolwell Brian , Maciejewski Jaroslaw P.
Published: July 2005

Graft‐versus‐host disease (GVHD) causes severe morbidity and mortality in allogeneic haematopoietic stem cell transplantation (HSCT) because of destruction of recipient tissues by donor alloreactive T cells. We hypothesized that GVHD‐specific T‐cell clones are expanded within affected tissue of HSCT patients and can also be detected in blood at the time of active disease. A multiplex polymerase chain reaction (PCR) was used to amplify T‐cell receptor (TCR) variable beta (VB) chain rearrangements in skin biopsies from eight allogeneic HSCT patients. Molecular analysis of the complementarity‐determining region 3 (CDR3) of amplified products defined expanded, potentially disease‐associated ‘clonotypes’ and enabled the design of clonotype‐specific PCR assays. We detected immunodominant clones in seven of eight GVHD‐positive skin biopsies. In serial skin biopsies from the same patient, the identical clone was found in each biopsy. In a patient who underwent two successive HSCTs from different donors, distinct clones were identified for each engraftment. Using clonotypic PCR assays, individual tissue‐derived clones could be identified in peripheral blood samples obtained during active GVHD. We hypothesize that clonotypic sequences derived from target tissue can serve as markers for GVHD and may have utility in diagnosis and monitoring response to therapy, as well as enable future therapies targeted against pathogenic clones.
The International Prognostic Index determines the outcome of patients with nodal mature T‐cell lymphomas
Authors: Sonnen Ruth , Schmidt Wolf‐Peter , Müller‐Hermelink Hans Konrad , Schmitz Norbert
Published: July 2005

The World Health Organization (WHO) lymphoma classification recognises anaplastic large cell lymphoma (ALCL), angioimmunoblastic lymphoma (AIL) and peripheral T‐cell lymphoma, unspecified (PTCU) as nodal mature T‐cell lymphomas. Little is known about long‐term outcome and prognostic factors of these diseases. A retrospective analysis on 125 patients with ALCL, AIL or PTCU was performed to evaluate outcome parameters, taking into account histological subtype and the International Prognostic Index (IPI). Median age was 54 years (range 17–90 years). Complete remission (CR) was achieved in 51% of patients. Five‐year overall survival (OS) was 43%, and 5‐year relapse‐free survival was 69%. Five‐year OS was 61% for ALCL, 45% for PTCU and 28% for AIL. With regard to the IPI, 5‐year OS was 74%, 49%, 21% and 6% for the low, low‐intermediate, high‐intermediate and high risk groups, respectively. In the multivariate analysis, the IPI but not the histological subtype significantly predicted survival. To a large extent, the IPI score explains the differences in survival between histological subtypes of nodal mature T‐cell lymphomas. The IPI may therefore be used for risk stratification in clinical trials to identify patients who would benefit most from new treatment strategies, such as high‐dose chemotherapy followed by stem cell or bone marrow transplantation.
Cytokines and fungal infections
Authors: Antachopoulos Charalampos , Roilides Emmanuel
Published: July 2005

The very poor outcome of invasive fungal infections (IFI) in patients with haematological malignancies or recipients of haematopoietic stem cell transplantation is largely attributed to their compromised host defence mechanisms. The restoration or augmentation of immune responses in these patients is now considered as one of the cornerstones of effective antifungal therapy. Major advances in the field of experimental immunology have provided insight on the important regulatory role of cytokines in both innate and adaptive immunity to fungal pathogens. Preclinical studies have convincingly demonstrated that immunomodulation with cytokines can enhance the antifungal activity of neutrophils and monocytes/macrophages as well as upregulate protective T‐helper type 1 adaptive immune responses. Evidence on the clinical use of cytokines in immunocompromised hosts with IFI is, however, still scant and inconclusive. The present review summarizes experimental and clinical data on the role of cytokines in the immune response to fungal pathogens and on their potential use for prevention or treatment of fungal infections. Implications for future research are also briefly discussed.
Haematopoietic stem cell transplantation in haemophagocytic lymphohistiocytosis
Authors: Horne AnnaCarin , Janka Gritta , Maarten Egeler R. , Gadner Helmut , Imashuku Shinsaku , Ladisch Stephan , Locatelli Franco , Montgomery Scott M. , Webb David , Winiarski Jacek , Filipovich Alexandra H. , Henter Jan‐Inge ,   the Histiocyte Society
Published: July 2005

Haemophagocytic lymphohistiocytosis (HLH) poses major therapeutic challenges, and the primary inherited form, familial haemophagocytic lymphohistiocytosis (FHL), is usually fatal. We evaluated, including Cox regression analysis, survival in 86 children (29 familial) that received HLH‐94‐therapy (etoposide, dexamethasone, ciclosporin) followed by allogeneic stem cell transplantation (SCT) between 1995 and 2000. The overall estimated 3‐year‐survival post‐SCT was 64% [confidence interval (CI) = ±10%] (n = 86); 71 ± 18% in those patients with a matched related donor (MRD, n = 24), 70 ± 16% with a matched unrelated donor (MUD, n = 33), 50 ± 24% with a family haploidentical donor (haploidentical, n = 16), and 54 ± 27% with a mismatched unrelated donor (MMUD, n = 13). After adjustment for potential confounding factors, estimated odds ratios (OR) for mortality were 1·93 (CI =0·61–6·19) for MUD, 3·31 (1·02–10·76) for haploidentical, and 3·01 (0·91–9·97) for MMUD, compared with MRD. In children with active disease after 2‐months of therapy (n = 43) the OR was 2·75 (1·26–5·99), compared with inactive disease (n = 43). In children with active disease at SCT (n = 37), the OR was 1·80 (0·80–4·06) compared with inactive disease (n = 49), after adjustment for disease activity at 2‐months. Mortality was predominantly transplant‐related. Most HLH patients survived SCT using MRD or MUD, and survival with partially mismatched donors was also acceptable. Patients that responded well to initial pretransplant‐induction therapy fared best, but some persisting HLH activity should not automatically preclude performing SCT.
Deguelin, A PI3K/AKT inhibitor, enhances chemosensitivity of leukaemia cells with an active PI3K/AKT pathway
Authors: Bortul Roberta , Tazzari Pier Luigi , Billi Anna Maria , Tabellini Giovanna , Mantovani Irina , Cappellini Alessandra , Grafone Tiziana , Martinelli Giovanni , Conte Roberto , Martelli Alberto M.
Published: July 2005

Activation of the phosphoinositide 3 kinase (PI3K)/Akt signalling pathway has been linked with resistance to chemotherapeutic drugs, and its downregulation, by means of PI3K inhibitors, lowers resistance to various types of therapy in tumour cell lines. Recently, it has been reported that deguelin, a naturally occurring rotenoid, is a powerful inhibitor of PI3K. We investigated whether or not deguelin could enhance the sensitivity to chemotherapeutic drugs of human U937 leukaemia cells and acute myeloid leukaemia (AML) blasts with an activated PI3K/Akt network. Deguelin (10 nmol/l) induced S phase arrest with interference of progression to G2/M, and at 100 nmol/l significantly increased apoptotic cell death of U937. At 10–100 nmol/l concentrations, deguelin downregulated Akt phosphorylation of leukaemia cells and markedly increased sensitivity of U937 cells to etoposide or cytarabine. A 10 nmol/l concentration of deguelin did not negatively affect the survival rate of human cord blood CD34+ cells, whereas it increased sensitivity of AML blasts to cytarabine. Deguelin was less toxic than wortmannin on erythropoietin‐ and stem cell factor‐induced erythropoiesis from CD34+ progenitor cells. Overall, our results indicate that deguelin might be used in the future for increasing sensitivity to therapeutic treatments of leukaemia cells with an active PI3K/Akt signalling network.