bluuebunny/crossref_metadata_2025 huggingface dataset:
Estimation of flows of organic matter and nitrogen components in postruminal digesta and effects of level of dietary intake and physical form of protein supplement on such estimates
Authors: Mcallan A. B. , Smith R. H.
Published: February 2005

1. Steers fitted with simple rumen, abomasal and sometimes duodenal cannulas were given isonitrogenous and isoenergetic diets consisting of pellets containing equal amounts of rolled barley and chopped straw together with tapioca alone (B), or with some tapioca replaced by coarse soya-bean meal (M) or finely ground soya-bean flour (F). Diet B had an estimated rumen degradable nitrogen (RDN): metabolizable energy (ME) value of approximately 0·8 g/MJ. The corresponding value for each of the supplemented diets was 1·3–1·4. Diets were given at two levels of intake designed respectively to provide ME intakes to support weight gains of 0·5 kg/d (L) and 1·0 kg/d (H). Chromic oxide and polyethylene glycol were given as indigestible markers. Values were calculated for flows (g/24 h) at the abomasum of organic matter (OM), non-ammonia-N (NAN) and microbial (bacterial)-N (MN). Estimates of MN were based on RNA and α-ε;-diaminopimelic acid (DAP) measurements. The steers had low rumen protozoal counts throughout the whole experiment with fewer than 8000 ciliate protozoa/ml of rumen fluid.

2. Proportions of OM apparently digested between the mouth and abomasum were significantly lower for H than for L intakes but showed no other significant differences. Mean estimated efficiency of microbial protein synthesis was approximately 17 g N/kg OM apparently digested in the rumen for the LB diet, but was significantly greater at approximately 26 g N/kg OM apparently digested for the HB diet. The protein-supplemented diets gave values of 31–32 which were significantly greater than the value for the LB but not the HB diet.

3. Amounts of feed nitrogenous constituents surviving between the mouth and the abomasum were estimated from NAN minus MN corrected for endogenous N. Values for the proportions of feed N degraded, derived from these estimates, were 0·71, 0·66, 0·72, 0·69, 0·67 and 0·70 for diets LB, HB, LM, HM, LF and HF respectively. There were no significant differences due to level of feeding, supplementary protein or the physical form of that protein.

4. Estimates of MN flows at the abomasum based on RNA determinations in fresh samples did not differ significantly from estimates based on DAP determinations. However, storage of aqueous suspensions of mixed rumen bacteria by deep-freezing or freeze-drying resulted in significant losses of RNA. No such losses were observed for abomasal digesta. This meant that if samples were stored by these means before analysis, the use of RNA as a microbial marker was vitiated.

5. In some experiments digesta samples were taken from the duodenum as well as the abomasum. Estimates of total N flows did not differ significantly between these sites.
Adaptive increase in phytate digestibility by phosphorus-deprived rats and the relationship of intestinal phytase (EC 3.1.3.8) and alkaline phosphatase (EC 3.1.3.1) to phytate utilization
Authors: Moore Robert J. , Veum Trygve L.
Published: February 2005

1. The effects of phosphorus deprivation on phytate digestibility, phosphorus utilization and intestinal phytase (EC3.1.3.8) and alkaline phosphatase (EC3.1.3.1) in rats were investigated.

2. P deprivation was achieved by giving rats a diet containing 3 g P/kg and resulted in hypophosphataemia, hypercalcaemia, hypercalciuria, and lower levels of P absorbed and retained, and calcium retained.

3. Rats adapted to P deprivation by increasing the digestion of total dietary-P and phytate-P.

4. Levels of intestinal alkaline phosphatase and alkaline phytase were not different between the two treatment groups.

5. P deprivation in the rats given the marginal-P diet may be a result of a lower absorption of total dietary-P or increased absorption of inositol phosphates formed during the enzymic hydrolysis of phytate which are not readily utilized by the rat.

6. These results suggest that intestinal phytase and alkaline phosphatase do not play a role in the adaptive increase in phytate digestibility by rats given marginal-P diets. The adaptation may result from enhanced phytase or alkaline phosphatase synthesis by the gastrointestinal microflora stimulated by a lower level of P in the digesta.
Saturation kinetics of magnesium efflux across the rumen wall in heifers
Authors: Martens H.
Published: February 2005

1. Absorption of magnesium from the temporarily-isolated, emptied and washed rumen of four 10–12-month-old heifers was measured at five different Mg concentrations (2·5, 5·0, 7·5, 12·5 and 20 mmol/l).

2. Net absorption of Mg was observed at all concentrations. Saturation occurred at a concentration of 12·5 mmol Mg/l.

3. Using an Eadie–Hofstee plot, the Michaelis–Menten constant (Km; 11·43 mmol/l) and maximal efflux (Vmax; 120·3 μmol/min) were estimated.

4. The phenomenon of saturation supports the assumption that Mg transport across the rumen wall of heifers is an active process.
Pathological pattern formation and cortical propagation of epileptic seizures
Authors: Kramer Mark A , Kirsch Heidi E , Szeri Andrew J
Published: February 2005

The stochastic partial differential equations (SPDEs) stated by Steyn-Ross and co-workers constitute a model of mesoscopic electrical activity of the human cortex. A simplification in which spatial variation and stochastic input are neglected yields ordinary differential equations (ODEs), which are amenable to analysis by techniques of dynamical systems theory. Bifurcation diagrams are developed for the ODEs with increased subcortical excitation, showing that the model predicts oscillatory electrical activity in a large range of parameters. The full SPDEs with increased subcortical excitation produce travelling waves of electrical activity. These model results are compared with electrocortical data recorded at two subdural electrodes from a human subject undergoing a seizure. The model and observational results agree in two important respects during seizure: (i) the average frequency of maximum power, and (ii) the speed of spatial propagation of voltage peaks. This suggests that seizing activity on the human cortex may be understood as an example of pathological pattern formation. Included is a discussion of the applications and limitations of these results.
Pancrustacean phylogeny: hexapods are terrestrial crustaceans and maxillopods are not monophyletic
Authors: Regier Jerome C. , Shultz Jeffrey W. , Kambic Robert E.
Published: February 2005

Recent molecular analyses indicate that crustaceans and hexapods form a clade (Pancrustacea or Tetraconata), but relationships among its constituent lineages, including monophyly of crustaceans, are controversial. Our phylogenetic analysis of three protein–coding nuclear genes from 62 arthropods and lobopods (Onychophora and Tardigrada) demonstrates that Hexapoda is most closely related to the crustaceans Branchiopoda (fairy shrimp, water fleas, etc.) and Cephalocarida + Remipedia, thereby making hexapods terrestrial crustaceans and the traditionally defined Crustacea paraphyletic. Additional findings are that Malacostraca (crabs, isopods, etc.) unites with Cirripedia (barnacles, etc.) and they, in turn, with Copepoda, making the traditional crustacean class Maxillopoda paraphyletic. Ostracoda (seed shrimp)—either all or a subgroup—is associated with Branchiura (fish lice) and likely to be basal to all other pancrustaceans. A Bayesian statistical (non–clock) estimate of divergence times suggests a Precambrian origin for Pancrustacea (600 Myr ago or more), which precedes the first unambiguous arthropod fossils by over 60 Myr.
Playback of colony sound alters the breeding schedule and clutch size in zebra finch (Taeniopygia guttata) colonies
Authors: Waas Joseph R. , Colgan Patrick W. , Boag Peter T.
Published: February 2005

The hypothesis that social stimulation, derived from the presence and activities of conspecifics, can hasten and synchronize breeding in colonies of birds was tested. A modified playback/recorder system was used to continuously exaggerate the amount of colony sound available to zebra finches throughout their courtship period. Males that heard ‘sound supplements’ generated from their own colony sang more than males in control colonies that did not receive playback; males that heard samples from a different colony, sang at an intermediate level. Females that were exposed to the vocalizations of their mate and playback from a colony other than their own, laid eggs earlier and more synchronously than females in control colonies. Females that heard the vocalizations of their mate along with playback samples generated from their own colony, laid eggs more synchronously but not earlier than control females. Both acoustic treatments caused females to lay larger clutches. Social stimulation influences the breeding schedule and clutch size in zebra finch colonies. If there are advantages associated with these effects, social stimulation may contribute to the maintenance of colonial breeding systems.
Unrelated helpers will not fully compensate for costs imposed on breeders when they pay to stay
Authors: Hamilton Ian M. , Taborsky Michael
Published: February 2005

Unrelated subordinates may invest in costly help to avoid being evicted from groups (the ‘pay–to–stay’ hypothesis). However, the effectiveness of eviction to enforce help should depend on its being applied accurately and on the costs it imposes on both dominants and subordinates. The relative cost of being evicted is a function of the population frequency of eviction when population growth is limited by density–dependent factors. We describe a stage–structured pay–to–stay model incorporating density–dependent population growth, costly eviction and occasional errors. Breeders demand some amount of help and evict subordinates that do not provide it. Helpers decide on the amount of help they will provide. The threat of eviction alone is sufficient to enforce helping. However, helping will not be favoured if helpers do not impose costs on breeders. The amount of help provided is less than the cost that subordinates impose upon breeders, when any help is provided. Thus, the net fitness effect of a helper under pay–to–stay alone is negative, even if it is investing in cooperative behaviour. Constraints on dispersal have no effect on the amount of help, although they may influence the tolerance threshold of breeders and group stability, depending on the mechanism of density dependence.
Co–infection ofMycobacterium tuberculosisandMycobacterium lepraein human archaeological samples: a possible explanation for the historical decline of leprosy
Authors: Donoghue Helen D. , Marcsik Antónia , Matheson Carney , Vernon Kim , Nuorala Emilia , Molto Joseph E. , Greenblatt Charles L. , Spigelman Mark
Published: February 2005

Both leprosy and tuberculosis were prevalent in Europe during the first millennium but thereafter leprosy declined. It is not known why this occurred, but one suggestion is that cross–immunity protected tuberculosis patients from leprosy. To investigate any relationship between the two diseases, selected archaeological samples, dating from the Roman period to the thirteenth century, were examined for bothMycobacterium lepraeandMycobacterium tuberculosisDNA, using PCR. The work was carried out and verified in geographically separate and independent laboratories. Several specimens with palaeopathological signs of leprosy were found to contain DNA from both pathogens, indicating that these diseases coexisted in the past. We suggest that the immunological changes found in multi–bacillary leprosy, in association with the socio–economic impact on those suffering from the disease, led to increased mortality from tuberculosis and therefore to the historical decline in leprosy.
Aposematism: what should our starting point be?
Authors: Speed Michael P. , Ruxton Graeme D.
Published: February 2005

The evolution of aposematism is considered to be a major evolutionary problem because if new aposematic forms emerged in defended cryptic populations, they would face the dual problems of rarity and conspicuousness. We argue that this commonly assumed starting point might not have wide validity. We describe a novel evolutionary computer model in which prey evolve secondary defences and become conspicuous by moving widely over a visually heterogeneous habitat. Unless crypsis imposes high opportunity costs (for instance, preventing prey from efficient foraging, thermoregulation and communication), costly secondary defences are not predicted to evolve at all. However, when crypsis imposes opportunity costs, prey evolve secondary defences that facilitate raised behavioural conspicuousness as prey exploit opportunities within their environment. Optimal levels of secondary defence and of behavioural conspicuousness increase with population sizes and the costs imposed by crypsis. When prey are already conspicuous by virtue of their behaviours, the evolution of aposematic appearances (bright coloration, etc.) is much easier to explain because aposematic traits add little further costs of conspicuousness, but can bring large benefits.
Report on the 2nd International Conference on Repository Libraries
Authors: Di Tillio Corrado
Published: February 2005

Purpose

To introduce the papers presented at the 2nd International Conference on Repository Libraries, organised by the Finnish National Repository Library and sponsored by IFLA, with many leading institutions participating in programme planning.

Design/methodology/approach

Provides a brief outline of each paper, discussing the state of health of repository libraries of any kind: national, academic, shared, etc.

Findings

Participating librarians presented a feasible future model, which has been called “URL” (“Universal Repository Library”), which encompassed the following characteristics: digital delivery 24/7 to end‐users; information for free (or support of minimal charges); performance and retention of public agreements; focus on existing strengths with multilingual approaches; virtual union catalogue linking repository catalogues; strong local support of regional repositories; international focal points; and the development of local support to bridge into URL.

Originality/value

The creation of a model of repository libraries for today, the near future and the distant future.
Depositories and repositories: changing models of library storage in the USA
Authors: Payne Lizanne
Published: February 2005

Purpose

To identify the issues faced by shared library storage facilities involving collection ownership, services, and governance.

Design/methodology/approach

Literature‐based review describing the operations of shared library storage facilities in the USA.

Findings

There are 50 or more library storage facilities in the USA (including separate compact shelving buildings or wings), with others in various stages of planning and construction. Most of the existing facilities are operated by individual academic libraries for their own collections, but increasing numbers of shared facilities are being planned and built. As more and more US academic libraries operate or share storage facilities, they face issues involving collection ownership, services, and governance within their own constituencies. These shared facilities can form the infrastructure for the evolving international network of print repositories.

Originality/value

Provides models for operating shared library storage facilities and outlines next steps to develop an international repository network.
From printed world to a digital environment
Authors: Saarti Jarmo
Published: February 2005

Purpose

To determine and define the role of repository libraries in Finland for a medium‐sized university library in the digital environment.

Design/methodology/approach

Literature and strategy‐based conceptual analysis and a case study of the role of different types of scientific library and information service actors in Finland.

Findings

The Finnish University Libraries and Ministry of Education have made strategic solutions in order to ensure an effective national collection policy. Digital materials are acquired mainly via the University Libraries' consortium, FinELib. The older and less used printed materials are collected in the National Repository Library. Modern technologies and logistic solutions are used in ensuring the effective end‐user services. Thus each library can make its own strategic collection policy decisions based on these national services.

Research limitations/implications

Based on conditions in Finland.

Practical implications

Gives an example of a national collection policy and co‐operation.

Originality/value

Provides a model to be tested and developed for collection policy decisions.
Access to print materials – role of print repositories
Authors: Vattulainen Pentti
Published: February 2005

Purpose

To highlight the role of print repositories in accessing print materials.

Design/methodology/approach

Highlights the repository library in the professional literature. Provides an overview of the National Repository Library (NRL) in Finland and the Kuopio conferences. Offers some calculations on the economics of access to print materials, with particular focus on Finland.

Findings

The role of the repository library creates savings in total storage costs on a national level. The NRL is a vital link in the Finland library network and acts as a bright signpost of cooperation on a national level. Libraries continue to function on local level in universities, polytechnics, research institutions and in communities while the NRL creates savings in space costs. By transferring material to the Repository Library libraries can free space for IT‐services, new acquisitions and active collections. As libraries get access to a growing number of de‐duplicated materials each library has a potential to become a zero growth library.

Originality/value

One of the important consequences of the success of the NRL is that the zero growth library has to rely more on resource sharing and must develop its ILL systems for better services for its patrons.
Distributed collections and central repository in France
Authors: Sanz Pascal
Published: February 2005

Purpose

Aims to assess and identify the main trends of shared conservation of library collections in France.

Design/methodology/approach

Presents two co‐existing approaches to the subject: first, an approach based on the principle of distributed conservation, spread around a certain number of establishments; and second, a centralised approach in which a given network of libraries shares pooled conservation. Compares drawbacks and advantages of these two approaches.

Findings

The drawbacks of the “distributed” system are as follows. Sometimes the participating libraries' lack of experience causes problems for the physical transfer of documents from one library to another. There is the risk of the scheme slowing down or stopping altogether. The advantages of this approach are that it can be launched without major initial investment. The “centralised” shared conservation system also has drawbacks. It requires an initial investment in terms of a building, capital equipment and job creation. However, this system has numerous advantages. The CTLes is seen as a real participant in the inter‐library cooperation network.

Originality/value

A new project in France will probably provide an opportunity to combine the two approaches. This is the shared conservation scheme for medical periodicals among university libraries in the Paris region (Ile de France). If it succeeds, the methodology used could be adopted or adapted to other disciplines and other regions.
Newspapers at the National Library of Norway
Authors: Clausen Søren
Published: February 2005

Purpose

Aims to describe the development of the Newspaper Collection at the National Library of Norway.

Design/methodology/approach

Describes the historical and organizational development of the collection, analysis of registration systems and the role of newspapers in historical research.

Findings

Provides possible solutions for organization and cataloguing.

Originality/value

Provides a first description of the use of MAVIS (Merged Audio Visual Information System) as a cataloguing solution for a newspaper collection.
The print block and the digital cylinder
Authors: McCarthy J.P.
Published: February 2005

Purpose

To consider the economic and physical impact of electronic journals on remotely stored print stock.

Design/methodology/approach

A collection of print journals was used as an object for consideration. Physical and heritage aspects of the collection are examined and questions are posed regarding the wisdom of future retention in response to increased demand for electronic alternatives.

Findings

Emerging trends predict a predominance of periodical literature in electronic form. The future of local remote storage for low demand printed journal collections needs to be evaluated in economic as well as cultural terms.

Research limitations/implications

Based on a collection at the Boole Library, University College Cork, Ireland.

Practical implications

Similar consideration should be given to collections in other regional libraries.

Originality/value

Contributes to discussions on the long‐term value of retaining print journal holdings.
From traditional stacks to an automated storage and retrieval system
Authors: Mathisen Kari
Published: February 2005

Purpose

Aims to illustrate how the Repository Library at the National Library in Norway met the need for a considerable increase in capacity with the introduction of an automated store.

Design/methodology/approach

Describes the project planning and the financial survey for the DEPOT II project. Provides details of the automated storage and retrieval system and discusses storage boxes and folders, media, the retrieval centre and orders.

Findings

Cost savings have been considerable. The automated store eases collection development and gives better control with the flow of documents.

Originality/value

The Repository Library has transformed into a mixture of industrial and cultural traditions, helping to improve services to the library community in Norway as well as abroad. The collection development has been optimised and there is better control over document flow. It is now much easier to obtain and to verify the material.
Preserving American Print Resources
Authors: Reilly Bernard F.
Published: February 2005

Purpose

Aims to provide a background to the Center for Research Libraries (CRL)'s Preserving America's Print Resources (PAPR) initiative.

Design/methodology/approach

Describes the CRL conference and planning event, entitled “Preserving America's print resources: toward a national strategic effort”, held in Chicago, July 2003 and highlights some of the programs on which the CRL are working.

Findings

Affirms the CRL's role of “convening” and facilitating strategic action by the major North American research libraries and libraries of last resort to enable the community to move deliberatively and safely away from excessive redundancy in its print holdings. The goal is to enable North American libraries to act in concert, to make the best use of scarce resources, and to provide for scholars of the future the most rich and diverse pool of knowledge possible.

Originality/value

Promoting the worthy goal of enabling North American libraries to act in concert, to make the best use of scarce resources, and to provide for scholars of the future the most rich and diverse pool of knowledge possible is central to the Center's mission. The PAPR conference reaffirmed the importance of this role for the years ahead.
STI571 (Glivec) inhibits the interaction between c‐KIT and heat shock protein 90 of the gastrointestinal stromal tumor cell line, GIST‐T1
Authors: Nakatani Hajime , Kobayashi Michiya , Jin Toufeng , Taguchi Takahiro , Sugimoto Takeki , Nakano Takumi , Hamada Shinichi , Araki Keijiro
Published: February 2005

The gastrointestinal stromal tumor cell line, GIST‐T1, has a heterogenic 57‐base pair deletion in exon 11 of the c‐kit mutation, and the c‐KIT protein in the GIST‐T1 cells constitutively activated. We report that STI571 (Glivec; Novartis, Basel, Switzerland), a specific inhibitor of c‐KIT, inhibits the clustering of c‐KIT at the cell membrane of the GIST‐T1 cells. Furthermore, STI571 prevents the interaction between c‐KIT and the molecular chaperone, heat shock protein 90 (Hsp90). Geldanamycin, an inhibitor of Hsp90, also prevents interaction between c‐KIT and Hsp90, and inhibits tyrosine phosphorylation of c‐KIT. Our results indicate that c‐KIT molecules are assembled on the cell surface of the GIST‐T1 cells, and that the interaction between c‐KIT and Hsp90 plays an important role in c‐KIT activation. (Cancer Sci 2005; 96: 116–119)
β‐Catenin mutations in a mouse model of inflammation‐related colon carcinogenesis induced by 1,2‐dimethylhydrazine and dextran sodium sulfate
Authors: Kohno Hiroyuki , Suzuki Rikako , Sugie Shigeyuki , Tanaka Takuji
Published: February 2005

In a previous study, we developed a novel mouse model for colitis‐related carcinogenesis, utilizing a single dose of azoxymethane (AOM) followed by dextran sodium sulfate (DSS) in drinking water. In the present study, we investigated whether colonic neoplasms can be developed in mice initiated with a single injection of another genotoxic colonic carcinogen 1,2‐dimethylhydrazine (DMH), instead of AOM and followed by exposure of DSS in drinking water. Male crj: CD‐1 (ICR) mice were given a single intraperitoneal administration (10, 20 or 40 mg/kg body weight) of DMH and 1‐week oral exposure (2% in drinking water) of a non‐genotoxic carcinogen, DSS. All animals were killed at week 20, histological alterations and immunohistochemical expression of β‐catenin, cyclooxygenase (COX‐2) and inducible nitric oxide synthase (iNOS) were examined in induced colonic epithelial lesions (colonic dysplasias and neoplasms). Also, the β‐catenin gene mutations in paraffin‐embedded colonic adenocarcinomas were analyzed by the single strand conformation polymorphism method, restriction enzyme fragment length polymorphism and direct sequencing. The incidences of colonic neoplasms with dysplastic lesions developed were 100% with 2.29 ± 0.95 multiplicity, and 100% with 10.38 ± 4.00 multiplicity in mice given DMH at doses of 10 mg/kg or 20 mg/kg and 2%DSS, respectively. Although approximately half of the mice given DMH at a dose of 40 mg/kg bodyweight were dead after 2–3 days after the injection, mice who received DMH 40 mg/kg and 2%DSS had 100% incidence of colonic neoplasms with 9.75 ± 6.29 multiplicity. Immunohistochemical investigation revealed that adnocarcinomas, induced by DMH at all doses and 2%DSS, showed positive reactivities against β‐catenin, COX‐2 and iNOS. In DMH/DSS‐induced adenocarcinomas, 10 of 11 (90.9%) adenocacrcinomas had β‐catenin gene mutations. Half of the mutations were detected at codon 37 or 41, encoding serine and threonine that are direct targets for phosphorylation by glycogen synthase kinase‐3β. The present results suggests that, as in the previously reported model (AOM/DSS) our experimental protocol, DMH initiation followed by DSS, may provide a novel and useful mouse model for investigating inflammation‐related colon carcinogenesis and for identifying xenobiotics with modifying effects. (Cancer Sci 2005; 96: 69–76)
Selective inhibition of cyclooxygenase‐2 inhibits colon cancer cell adhesion to extracellular matrix by decreased expression of β1 integrin
Authors: Yazawa Kentaro , Tsuno Nelson H. , Kitayama Joji , Kawai Kazushige , Okaji Yurai , Asakage Masahiro , Sunami Eiji , Kaisaki Shoichi , Hori Nobukazu , Watanabe Toshiaki , Takahashi Koki , Nagawa Hirokazu
Published: February 2005

High level expression of cyclooxygenase (COX)‐2 is reported in 80–90% of colorectal adenocarcinomas. In the recent years, selective inhibitors of COX‐2 have been developed, and are shown to effectively protect against cancer development and progression. Colon cancer cells, as well as the epithelial cells in general, are dependent on appropriate interactions with the extracellular matrix (ECM) proteins to achieve a number of important functions, such as proliferation, differentiation, invasion and survival. These interactions are mediated via a family of cell‐surface receptors called integrins, which interact with cytoskeletal proteins on the cytoplasmic side of the plasma membrane and thereby provide a link between the ECM and the cytoskeleton. In the present study, a high‐COX‐2 (high level COX‐2 expression) colon cancer cell line, HT‐29, and a low‐COX‐2 (low level COX‐2 expression), DLD‐1, were used to investigate the anticolon cancer effect of the selective COX‐2 inhibitor, JTE‐522. Moreover, to clarify its mechanisms of action, we focused especially on the ability to adhere to and to migrate on ECM. We could clearly demonstrate that, in addition to the decrease of the proliferative activity, JTE‐522 caused a dose‐dependent decrease in both the ability of colon cancer cells to adhere to and to migrate on ECM. These effects were, at least in part, dependent on the down‐regulation of β1‐integrin expression, which was evident in HT‐29, the high‐COX‐2 colon cancer cells, but not the low‐COX‐2, DLD‐1. In addition, prostaglandin E2 almost completely reversed the effect of JTE‐522, strongly suggesting the involvement of a COX‐2‐dependent pathway. In conclusion, for the first time, we could demonstrate the down‐regulation of β1 integrin caused by COX‐2 inhibition, with consequent impairment of the ability of cancer cells to adhere to and to migrate on ECM, which are crucial steps for cancer metastases to develop. (Cancer Sci 2005; 96: 93–99)
Low molecular weight heparin in pregnancy: current issues
Authors: Greer Ian , Hunt Beverley J.
Published: February 2005

Low molecular weight heparin (LMWH) is now the most commonly used anticoagulant for prophylaxis and treatment of venous thromboembolism in pregnancy and the puerperium in the UK. The reliable pharmacokinetics of LMWHs and their long half‐life, resulting in the need for less frequent injections than unfractionated heparin (UFH), makes them attractive for practical use in the 9 months of pregnancy. Widespread use over the last 10 years has shown that LMWHs are safer than UFH in pregnancy. There is, however, poor consensus and wide disparity of views among experts with regard to the appropriate dose for the varying indications, the duration of treatment, and whether and how LMWH should be monitored because of the lack of an evidence base. These areas of uncertainty reflect the fact that clinical practice has grown largely through the publication of small trials, observational studies, personal experience and anecdote. Good clinical trials are urgently required.
Children with myelodysplastic syndrome (MDS) and increasing mixed chimaerism after allogeneic stem cell transplantation have a poor outcome which can be improved by pre‐emptive immunotherapy
Authors: Bader Peter , Niemeyer Charlotte , Willasch Andre , Kreyenberg Hermann , Strahm Brigitte , Kremens Bernhard , Gruhn Bernd , Dilloo Dagmar , Vormoor Josef , Lang Peter , Niethammer Dietrich , Klingebiel Thomas , Beck James F.
Published: February 2005

We recently reported that virtually all children with acute leukaemia and myelodysplastic syndrome (MDS) who develop the phenotype of increasing mixed chimaerism (MC) after allogeneic stem cell transplantation (allo‐SCT) will relapse. We therefore performed a prospective, multi‐centre study focused on children with MDS (n = 65; advanced MDS = 44, refractory cytopenia = 21) after allo‐SCT in order to determine to what extent relapse can be prevented by pre‐emptive immunotherapy on the basis of increasing MC. Analyses of chimaerism in 44 patients with advanced MDS revealed 31 cases with complete chimaerism (CC)/low‐level MC/transient MC, 11 cases with increasing MC and two cases with decreasing MC. The same analyses in 21 MDS patients with refractory cytopenia revealed 17 cases with CC/low‐level MC, one case with increasing MC and three cases with decreasing MC. Pre‐emptive immunotherapy performed on each patient that showed increasing MC improved event‐free survival from 0%, as seen in prior studies, to 50%. We therefore conclude that pre‐emptive immunotherapy is an effective treatment option to prevent impending relapse in children with MDS after allo‐SCT.
Autocrine secretion of osteopontin results in degradation of IκB in Bcr‐Abl‐expressing cells
Authors: Vejda Susanne , Piwocka Katarzyna , McKenna Sharon L. , Cotter Thomas G.
Published: February 2005

Osteopontin has been identified as a marker of metastasis formation and its increased expression has been correlated with the malignancy of cancer. In this study we provide evidence that increased expression of osteopontin may also be associated with progression of Bcr‐Abl‐expressing leukaemia cells. The Bcr‐Abl fusion protein, generated by the Philadelphia translocation, is the hallmark of chronic myeloid leukaemia (CML). CML exhibits clinically distinct phases. Advanced disease shows defective differentiation, bone marrow infiltration and drug resistance. The critical signalling mediating this disease progression is unknown. Increased aggressiveness of the disease has been correlated with elevated amounts of Bcr‐Abl. We generated a 32D cell line model to study the consequences of different expression levels of Bcr‐Abl. Osteopontin was identified by microarray analysis as highly upregulated in cells expressing elevated amounts of Bcr‐Abl. Moreover, in high Bcr‐Abl expressing cells, an additional 50 kDa isoform of osteopontin was detected. It was found that this protein was secreted and that myeloid progenitor cells also expressed appropriate receptors for autocrine activation. We demonstrated that secretion of osteopontin resulted in enhanced degradation of IκB, the inhibitor of NF‐κB. These data indicate a novel consequence of elevated Bcr‐Abl expression, which may contribute to the progression of CML.
Association of NAT and GST polymorphisms with non‐Hodgkin's lymphoma: a population‐based case–control study
Authors: Chiu Brian C.‐H. , Kolar Carol , Gapstur Susan M. , Lawson Terence , Anderson James R. , Weisenburger Dennis D.
Published: February 2005

Several chemicals have been associated with risk of non‐Hodgkin's lymphoma (NHL), many of which are substrates for N‐acetyltransferase (NAT) and glutathione S‐transferase (GST) enzymes. We investigated the association between polymorphisms in genes coding for these enzymes and NHL risk in a population‐based study (389 cases and 535 controls). NAT1 slow genotype was associated with a slightly increased risk in women [odds ratios (OR) = 1·4; 95% confidence interval (CI) = 0·9–2·3], but not in men. NAT2 slow genotype was not associated with risk in either sex. The two slow genotypes of NAT1 and NAT2 combined were associated with a minor increase of risk in women (OR = 1·4; 0·8–2·4). There was no association with the GSTM1 or GSTT1 null genotype in either sex, irrespective of histological subtypes. Individuals with GSTP1 Val homozygotes had non‐significant excessive risk of marginal zone lymphoma (OR = 1·8; 0·6–5·1) and ‘other’ B‐cell NHLs (OR = 1·6; 0·7–3·6), but lower risk of diffuse large B‐cell lymphoma (OR = 0·2; 0·1–0·96). Risk did not elevate with an increasing number of high‐risk GST alleles in either sex. In summary, although NAT1, NAT2, GSTM1, GSTT1, or GSTP1 polymorphisms do not appear to be associated with NHL risk overall, there might be gender‐specific and subtype‐specific associations that require confirmation.
Low‐grade primary central nervous system lymphoma in immunocompetent patients
Authors: Jahnke Kristoph , Thiel Eckhard , Schilling Andreas , Herrlinger Ulrich , Weller Michael , Coupland Sarah E. , Krümpelmann Ulrich , Stein Harald , Korfel Agnieszka
Published: February 2005

Primary central nervous system lymphomas (PCNSL) are usually diffuse large B‐cell non‐Hodgkin's lymphomas (NHL). Here we characterize the clinical presentation, course and outcome of patients with low‐grade PCNSL. Records of 332 patients screened for inclusion in three multicentre prospective trials were reviewed. Ten patients (3%) with a median age of 59 years and a median Karnofsky performance status of 70% were identified. Seven patients had B‐cell and three had T‐cell lymphoma. The median growth fraction was 4%. The radiological morphology was unusual for PCNSL in eight patients. Three patients underwent complete tumour resection, combined with chemotherapy in one patient and with chemotherapy plus local radiotherapy in another. Four patients received chemotherapy and three received chemotherapy plus whole‐brain irradiation, resulting in four complete remissions, two no‐change situations and one progressive disease. Patients had an overall survival (OAS) of 2–58+ months with a 2‐year OAS of 67%. Low‐grade PCNSL may differ from classical high‐grade PCNSL in its clinical features and radiological morphology. The clinical course may be variable and frequently more indolent than in classical PCNSL.
Targeting malignant B‐cell lymphoma with a humanized anti‐CD22 scFv‐angiogenin immunoenzyme‡
Authors: Krauss Jürgen , Arndt Michaela A.E. , Vu Bang K. , Newton Dianne L. , Rybak Susanna M.
Published: February 2005

We report on the generation and functional characterization of a humanized immunoenzyme comprising a stable humanized single chain Fv (scFv) with grafted specificity of the anti‐CD22 murine monoclonal antibody RFB4 and the human ribonuclease angiogenin (ANG). The fusion protein produced from transiently transfected mammalian Chinese hamster ovary cells could easily be purified to homogeneity, retained full ribonucleolytic activity, and efficiently killed CD22+ tumour cells with an IC50 of 56 nmol/l. In contrast, incubation of tumour cells with either ANG or scFv alone did not result in any cytotoxicity. Potent receptor‐mediated killing of target cells, expected lack of extracellular toxicity, predictable low immunogenic potential, and ease of production, suggest that this novel immunoenzyme has potential for the immunotherapy of CD22+ malignancies.
Activity of sirolimus in patients with myelodysplastic syndrome – results of a pilot study
Authors: Platzbecker U. , Haase M. , Herbst R. , Hänel A. , Voigtmann K. , Thiede C. H. , Mohr B. , Schleyer E. , Leopold T. , Orth M. , Hänel M. , Ehninger G. , Bornhäuser M.
Published: February 2005

The pathophysiology of the myelodysplastic syndromes (MDS) involves disturbed regulation of angiogenesis, apoptosis, proliferation and differentiation as well as immune surveillance. Increasing data suggest that sirolimus might affect these pathways positively, thus being of possible therapeutic benefit in patients with this disease. Nineteen patients (n = 19) with a median age of 72 years (range 54–80 years) diagnosed with MDS received sirolimus orally with a target blood concentration of 3–12 ng/ml. Sirolimus was administered for a median of 3·7 months (range 0·3–11 months). Three patients [1 × refractory anaemia with excess blasts (RAEB)‐2, 1 × RAEB‐1, 1 × refractory cytopenia with multilineage dysplasia] showed either a major (1 × platelet, 1 × neutrophil) or a minor (1 × erythroid, 2 × platelet) haematological response according to International Working Group criteria. Major side‐effects were hyperlipidaemia (n = 4), stomatitis (n = 3), thrombocytopenia (n = 2) and urinary tract infection (n = 1). These data suggest that sirolimus has activity in a subset of patients with more advanced MDS.
Allogeneic peripheral blood stem cell graft composition affects early T‐cell chimaerism and later clinical outcomes after non‐myeloablative conditioning
Authors: Panse J. P. , Heimfeld S. , Guthrie K. A. , Maris M. B. , Maloney D. G. , Baril B. B. , Little M.‐T. , Chauncey T. R. , Storer B. E. , Storb R. , Sandmaier B. M.
Published: February 2005

We have studied the influence of cell subsets [CD34, CD3, CD4, CD8, CD14, CD20, natural killer (NK; CD3−/CD56+), NKT (CD3+/CD56+), DC1, and DC2 cells] of granulocyte colony‐stimulating factor mobilized peripheral blood stem cells (PBSC) on early T‐cell chimaerism and later clinical outcomes in 125 patients with haematological malignancies who received human leucocyte antigen (HLA)‐matched related grafts after non‐myeloablative conditioning. Conditioning consisted of 2 Gy total body irradiation (TBI) alone (n = 28), or 2 Gy TBI preceded by either 90 mg/m2fludarabine (n = 62) or planned autologous haematopoietic cell transplantation (HCT) (n = 35). Post‐transplant immunosuppression included mycophenolate mofetil and ciclosporin. Multivariate analysis showed that higher numbers of grafted NK cells predicted higher early T‐cell chimaerism (P = 0·03), while higher numbers of B cells were associated with better clinical outcomes and a higher risk for chronic graft‐versus‐host disease (P = 0·05). Higher numbers of CD14+cells were associated with worse overall survival (P = 0·03), while higher numbers of CD34+cells showed better survival (P = 0·03). The addition of fludarabine or autologous HCT predicted higher early T‐cell chimaerism (P = 0·001), while advanced donor age predicted lower chimaerism (P ≤ 0·02). Patients with aggressive diseases were at higher risk for relapse/disease progression, and shorter progression‐free and overall survival (P < 0·01). These results suggest that the dosing of certain cellular subsets of PBSC products can influence important outcomes post‐HCT after non‐myeloablative conditioning.
Persistence of recipient plasma cells and anti‐donor isohaemagglutinins in patients with delayed donor erythropoiesis after major ABO incompatible non‐myeloablative haematopoietic cell transplantation
Authors: Griffith L. M. , McCoy J. P. , Bolan C. D. , Stroncek D. F. , Pickett A. C. , Linton G. F. , Lundqvist A. , Srinivasan R. , Leitman S. F. , Childs R. W.
Published: February 2005

Delayed donor erythropoiesis and pure red‐cell aplasia (PRCA) complicate major‐ABO mismatched non‐myeloablative allogeneic stem‐cell transplantation. To characterize these events, we analysed red‐cell serology and chimaerism in lymphohaematopoietic lineages, including plasma cells and B cells, in 12 consecutive major‐ABO incompatible transplants following cyclophosphamide/fludarabine‐based conditioning. Donor erythropoiesis was delayed to more than 100 days in nine (75%) patients including six (50%) who developed PRCA. During PRCA, all patients had persistent anti‐donor isohaemagglutinins and recipient plasma cells (5–42%), while myeloid and T cells were completely donor in origin. In contrast, B‐cell chimaerism was frequently full‐donor when significant anti‐donor isohaemagglutinins persisted. Four patients with early mixed haematopoietic chimaerism and the prolonged presence of anti‐donor isohaemagglutinins and recipient plasma cells developed delayed‐onset (>100 days post‐transplant) red cell transfusion dependence and PRCA after myeloid chimaerism converted from mixed to full donor. These findings confirm that donor‐erythropoiesis is impacted by temporal disparities in donor immune‐mediated eradication of recipient lymphohaematopoietic cells during major‐ABO incompatibility and suggest that plasma cells are relatively resistant to graft‐versus‐host haematopoietic effects.
Heterogeneity of the ɛγδβ‐thalassaemias: characterization of three novel English deletions
Authors: Rooks Helen , Bergounioux Jean , Game Laurence , Close James Paul , Osborne Cameron , Best Steve , Senior Tania , Height Susan , Thompson Richard , Hadzic Nedim , Fraser Peter , Bolton‐Maggs Paula , Thein Swee Lay
Published: February 2005

We have characterized three novel ɛγδβ‐thalassaemia deletions in three English families. Two of the deletions, 114 and 439 kb, removed the entire β‐globin gene complex, including a variable number of flanking olfactory receptor (HOR) genes. The 98‐kb deletion extended 90‐kb upstream of the ɛ gene to 8 kb upstream of the Gγ‐gene, leaving the γ,δ and β‐genes intact. The 439 kb deletion is the largest deletion reported so far to cause ɛγδβ‐thalassaemia; heterozygotes for this deletion were variably affected by neonatal haemolytic anaemia. Two of the deletions were de novo. Breakpoints of all three deletions occurred within regions of L1 or Alu repeats and contained short regions of direct homology between the flanking sequences, a feature that is likely to have contributed to the illegitimate recombinations.
Difference in absolute risk of venous and arterial thrombosis between familial protein S deficiency type I and type III. Results from a family cohort study to assess the clinical impact of a laboratory test‐based classification
Authors: Brouwer Jan‐Leendert P. , Veeger Nic J. G. M. , Schaaf Wim van der , Kluin‐Nelemans Hanneke C. , Meer Jan van der
Published: February 2005

Hereditary protein S (PS) deficiency type I is an established risk factor for venous thromboembolism. Contradictionary data on type III deficiency suggests a difference in risk between both types. We studied 156 first degree relatives (90% of eligible relatives) from type I deficient probands (cohort 1) and 268 (88%) from type III deficient probands (cohort 2) to determine the absolute risk of venous and arterial thromboembolism. Annual incidences of venous thromboembolism were 1·47 and 0·17 per 100 person‐years in deficient and non‐deficient relatives in cohort 1 [relative risk (RR) 8·9; 95% confidence interval (CI) 2·6–30·0], and 0·27 vs. 0·24 in cohort 2 (RR 0·9; 95% CI 0·4–2·2). Type III deficiency was demonstrated in 20% of non‐deficient relatives in cohort 1 and the annual incidence in this subgroup was 0·70 (RR 4·3;0·95–19·0). The cut‐off level of free PS to identify subjects at risk was 30%, the lower limit of its normal range (65%). PS deficiency was not a risk factor for arterial thromboembolism. In conclusion, type I deficiency was found to be a strong risk factor for venous thromboembolism, in contrast with type III deficiency. This was because of lower free PS levels in type I deficient subjects and a free PS cut‐off level far below the lower limit of its normal range.
Impact of chimaerism analysis and kinetics on allogeneic haematopoietic stem cell transplantation outcome after conventional and reduced‐intensity conditioning regimens
Authors: Michallet Anne‐Sophie , Fürst Sabine , Le Quoc Hung , Dubois Valérie , Praire Aline , Nicolini Franck , Thomas Xavier , Rafii Hanadi , Gebuhrer Lucette , Michallet Mauricette
Published: February 2005

This retrospective study aimed to analyse the impact on overall survival (OS) and event‐free survival (EFS) of chimaerism status and kinetics following allogeneic conventional and reduced‐intensity conditioning haematopoietic stem cell transplantation, and to compare this with the impact of other well‐known factors. We investigated the chimaerism status of 187 patients [84 females, 103 males; median age 39·5 years (range, 17–62 years)]. After transplantation, 121 patients (65%) presented full donor chimaerism (FDC) and 63 (34%) mixed chimaerism (MC). For MC, we divided the population into patients who presented regressive mixed chimaerism (RMC) (21 patients: 11%), stable mixed chimaerism (SMC) (20 patients: 11%) and progressive mixed chimaerism (PMC) (22 patients: 12%). At last follow‐up, 71 patients were alive and 116 had died (48% from disease progression and 52% from transplant‐related causes). With a mean follow‐up of 39·4 and 34·8 months, the 5‐year probabilities of OS and EFS for the total group were, respectively, 55% and 43%: 69·5% and 61% for FDC, 35·4% and 25% for RMC, 42·6% and 28·6% for SMC, and 21% and 10·4% for PMC (P < 0·0001 and P < 0·0001). Multivariate analysis only showed a significant impact of chimaerism status on OS, as well as acute and chronic graft‐versus‐host disease on EFS, with a trend for conditioning regimen.