bluuebunny/crossref_metadata_2025 huggingface dataset:
Identifying sub-optimal responses to ivermectin in the treatment of River Blindness
Authors: Churcher Thomas S. , Pion Sébastien D. S. , Osei-Atweneboana Mike Y. , Prichard Roger K. , Awadzi Kwablah , Boussinesq Michel , Collins Richard C. , Whitworth James A. , Basáñez María-Gloria
Published: September 2009

Identification of drug resistance before it becomes a public health concern requires a clear distinction between what constitutes a normal and a suboptimal treatment response. A novel method of analyzing drug efficacy studies in human helminthiases is proposed and used to investigate recent claims of atypical responses to ivermectin in the treatment of River Blindness. The variability in the rate at which
Onchocerca volvulus
microfilariae repopulate host's skin following ivermectin treatment is quantified using an individual-based onchocerciasis mathematical model. The model estimates a single skin repopulation rate for every host sampled, allowing reports of suboptimal responses to be statistically compared with responses from populations with no prior exposure to ivermectin. Statistically faster rates of skin repopulation were observed in 3 Ghanaian villages (treated 12–17 times), despite the wide variability in repopulation rates observed in ivermectin-naïve populations. Another village previously thought to have high rates of skin repopulation was shown to be indistinguishable from the normal treatment response. The model is used to generate testable hypotheses to identify whether atypical rates of skin repopulation by microfilariae could result from low treatment coverage alone or provide evidence of decreased ivermectin efficacy. Further work linking phenotypic poor responses to treatment with parasite molecular genetics markers will be required to confirm drug resistance. Limitations of the skin-snipping method for estimating parasite load indicates that changes in the distribution of microfilarial repopulation rates, rather than their absolute values, maybe a more sensitive indicator of emerging ivermectin resistance.
Central role of TRAF-interacting protein in a new model of brain sexual differentiation
Authors: Krishnan Sudha , Intlekofer Karlie A. , Aggison Leah K. , Petersen Sandra L.
Published: September 2009

Sexually dimorphic brain nuclei underlie gender-specific neural functions and susceptibility to disease, but the developmental basis of dimorphisms is poorly understood. In these studies, we focused on the anteroventral periventricular nucleus (AVPV), a nucleus that is larger in females and critical for the female-typical cyclic surge pattern of luteinizing hormone (LH) release. Sex differences in the size and function of the AVPV result from apoptosis that occurs preferentially in the developing male. To identify upstream pathways responsible for sexual differentiation of the AVPV, we used targeted apoptosis microarrays and in vivo and in vitro follow-up studies. We found that the tumor necrosis factor α (TNFα)-TNF receptor 2 (TNFR2)−NFκB cell survival pathway is active in postnatal day 2 (PND2) female AVPV and repressed in male counterparts. Genes encoding key members of this pathway were expressed exclusively in GABAergic neurons. One gene in particular,
TNF receptor-associated factor 2
(
TRAF2
)
-inhibiting protein
(
trip
), was higher in males and it inhibited both TNFα-dependent NFκB activation and
bcl-2
gene expression. The male AVPV also had higher levels of
bax
and
bad
mRNA, but neither of these genes was regulated by either TNFα or TRIP. Finally, the
trip
gene was not expressed in the sexually dimorphic nucleus of the preoptic area (SDN-POA), a nucleus in which apoptosis is higher in females than males. These findings form the basis of a new model of sexual differentiation of the AVPV that may also apply to the development of other sexually dimorphic nuclei.
Triplet repeat length bias and variation in the human transcriptome
Authors: Molla Michael , Delcher Arthur , Sunyaev Shamil , Cantor Charles , Kasif Simon
Published: September 2009

Length variation in short tandem repeats (STRs) is an important family of DNA polymorphisms with numerous applications in genetics, medicine, forensics, and evolutionary analysis. Several major diseases have been associated with length variation of trinucleotide (triplet) repeats including Huntington's disease, hereditary ataxias and spinobulbar muscular atrophy. Using the reference human genome, we have catalogued all triplet repeats in genic regions. This data revealed a bias in noncoding DNA repeat lengths. It also enabled a survey of repeat-length polymorphisms (RLPs) in human genomes and a comparison of the rate of polymorphism in humans versus divergence from chimpanzee. For short repeats, this analysis of three human genomes reveals a relatively low RLP rate in exons and, somewhat surprisingly, in introns. All short RLPs observed in multiple genomes are biallelic (at least in this small sample). In contrast, long repeats are highly polymorphic and some long RLPs are multiallelic. For long repeats, the chimpanzee sequence frequently differs from all observed human alleles. This suggests a high expansion/contraction rate in all long repeats. Expansions and contractions are not, however, affected by natural selection discernable from our comparison of human-chimpanzee divergence with human RLPs. Our catalog of human triplet repeats and their surrounding flanking regions can be used to produce a cost-effective whole-genome assay to test individuals. This repeat assay could someday complement SNP arrays for producing tests that assess the risk of an individual to develop a disease, or become part of personalized genomic strategy that provides therapeutic guidance with respect to drug response.
Physiological function and transplantation of scaffold-free and vascularized human cardiac muscle tissue
Authors: Stevens K. R. , Kreutziger K. L. , Dupras S. K. , Korte F. S. , Regnier M. , Muskheli V. , Nourse M. B. , Bendixen K. , Reinecke H. , Murry C. E.
Published: September 2009

Success of human myocardial tissue engineering for cardiac repair has been limited by adverse effects of scaffold materials, necrosis at the tissue core, and poor survival after transplantation due to ischemic injury. Here, we report the development of scaffold-free prevascularized human heart tissue that survives in vivo transplantation and integrates with the host coronary circulation. Human embryonic stem cells (hESCs) were differentiated to cardiomyocytes by using activin A and BMP-4 and then placed into suspension on a rotating orbital shaker to create human cardiac tissue patches. Optimization of patch culture medium significantly increased cardiomyocyte viability in patch centers. These patches, composed only of enriched cardiomyocytes, did not survive to form significant grafts after implantation in vivo. To test the hypothesis that ischemic injury after transplantation would be attenuated by accelerated angiogenesis, we created “second-generation,” prevascularized, and entirely human patches from cardiomyocytes, endothelial cells (both human umbilical vein and hESC-derived endothelial cells), and fibroblasts. Functionally, vascularized patches actively contracted, could be electrically paced, and exhibited passive mechanics more similar to myocardium than patches comprising only cardiomyocytes. Implantation of these patches resulted in 10-fold larger cell grafts compared with patches composed only of cardiomyocytes. Moreover, the preformed human microvessels anastomosed with the rat host coronary circulation and delivered blood to the grafts. Thus, inclusion of vascular and stromal elements enhanced the in vitro performance of engineered human myocardium and markedly improved viability after transplantation. These studies demonstrate the importance of including vascular and stromal elements when designing human tissues for regenerative therapies.
Teaching Europeans how to be Europeans
Authors: Hellström Anders
Published: September 2009

In this article, the author explores how the question of Europe has been established on the domestic scene. The article focuses on referenda on EU-related issues held in three EU member states, ranging from Ireland in 2001, to Sweden in 2003, and finally France in 2005. In all three cases, the national populations voted against the will of a majority of their representatives, and chose not to follow the defined EU agenda towards greater integration. The study includes analyses of the national news reporting in the three cases as well as responses from Brussels. The author infers that the three No-votes, in the perspective of the political elites, were interpreted as incentives to further the integration process, spelling out a message of that Europeans want Europe, even if some people (i.e. the No-voting majorities) were consideredyetto learn what it means to be, act and think as Europeans in Europe.
London's Tourism: Is a Purely Economic Approach Appropriate?
Authors: Tyler Duncan
Published: September 2009

This article considers the role of tourism in the modern city, the historic growth of London as a tourist destination, the legacy of problems this has bequeathed the city and some recommendations on how these issues may be addressed.
Effect of Plasma Gas Flow Direction on Hydrophilicity of Polymer by Small Zone Cold Plasma Treatment and Hydrophobic Plasma Treatment
Authors: Hsu Sheng-Hsiang , Chen Ko-Shao , Lin Hong-Ru , Chang Shu-Ju , Tang Tzu-Piao
Published: September 2009

Plasma treatment is the most popular surface modification process of polymers. A small cold plasma zone treatment is an important modification technique in modern industry. In this study, the effect of gas flow direction on plasma treatment was investigated. In order to decrease the plasma zone area, we added a separate cylinder to surround the upper electrode. The separate cylinder is effective in limiting the plasma discharge area, and we could find a light and dark area in the vacuum chamber. After O2 plasma treatment, the result shows that only PP nonwoven in the discharge area became hydrophilic, but the other position away from the plasma zone was not affected. The water adsorption of PP nonwoven increased from 34.8% to 537.4%. When the sample is further from the plasma zone, near the up stream of gas flow, the surface property is less hydrophilic. The water contact angle analysis of PS and glass shows the same results as those of PP nonwoven. But PET in plasma zone or dark zone (plasma zone: 75° to 31°, dark zone: 75° to 52°) both show hydrophilic property. The wettability effect in the dark zone may be due to the UV-light irradiation in the process of plasma excitation.
Seeing the Global Forest for the Trees: How US Federalism can Coexist with Global Governance of Forests
Authors: Hudson Blake , Weinthal Erika
Published: September 2009

Both international forest and climate negotiations have failed to produce a legally binding treaty that addresses forest management activities—either comprehensively or more narrowly through carbon capture- due, in part, to lack of US leadership. Though US cooperation is crucial for facilitating both forest and climate negotiations, the role of federalism in constraining these trends has been given scant attention. We argue that, as embodied in the US Constitution, federalism complicates the US's role in creating any legally binding treaty that directly regulates land uses (e.g. forest management). Because federalism reserves primary land use regulatory authority for state governments, voluntary, market-based mechanisms, like REDD and forest certification, should be included within any binding treaty aimed at forest management, in order to facilitate US participation.
Role of the Private Sector in Managing the Asian Environment: A Review
Authors: Gunatilake H. , Gopalakrishnan C. , de Guzman F. D.
Published: September 2009

This paper identifies inadequate effort to use market-based and private sector-led approaches, among others, as a main reason for limited progress in arresting continuing environmental degradation in the Asia and Pacific region. Citing examples, the paper shows that markets can be created for ecosystem protection and provision of ecosystem services under innovative regulatory mechanisms and that the use of market-based approaches can reduce the dependence on unsustainable financing for environmental management. The paper also briefly discusses the role of governments, other stakeholders, and development assistance in creating the policy and institutional framework conducive for introducing private sector-led approaches to environmental management.
Implementing Integrated Land Management in Western Canada: Policy Reform and the Resilience of Clientelism
Authors: Rayner Jeremy , Howlett Michael
Published: September 2009

Much attention in recent years has been focused on the idea of replacing patchworks of public policies in specific issue areas with more coordinated or ‘integrated’ policy strategies (IS). Empirical work on such strategies, however, shows the remarkable resilience of pre-existing policy elements, often leading to policy failures and other sub-optimal outcomes in policy reform efforts. Case studies of Integrated Land Management (ILM) reform efforts in Western Canada reveal the continuing problems pre-existing clientelistic political arrangements cause for governments attempting to replace sector-specific plans with more integrated frameworks.
Interaction between Poly(ADP-ribose) and NuMA Contributes to Mitotic Spindle Pole Assembly
Authors: Chang Paul , Coughlin Margaret , Mitchison Timothy J.
Published: September 2009

Poly(ADP-ribose) (pADPr), made by PARP-5a/tankyrase-1, localizes to the poles of mitotic spindles and is required for bipolar spindle assembly, but its molecular function in the spindle is poorly understood. To investigate this, we localized pADPr at spindle poles by immuno-EM. We then developed a concentrated mitotic lysate system from HeLa cells to probe spindle pole assembly in vitro. Microtubule asters assembled in response to centrosomes and Ran-GTP in this system. Magnetic beads coated with pADPr, extended from PARP-5a, also triggered aster assembly, suggesting a functional role of the pADPr in spindle pole assembly. We found that PARP-5a is much more active in mitosis than interphase. We used mitotic PARP-5a, self-modified with pADPr chains, to capture mitosis-specific pADPr-binding proteins. Candidate binding proteins included the spindle pole protein NuMA previously shown to bind to PARP-5a directly. The rod domain of NuMA, expressed in bacteria, bound directly to pADPr. We propose that pADPr provides a dynamic cross-linking function at spindle poles by extending from covalent modification sites on PARP-5a and NuMA and binding noncovalently to NuMA and that this function helps promote assembly of exactly two poles.
COMPASS: a program for generating serial samples under an infinite sites model
Authors: Jakobsson Mattias
Published: September 2009

Summary: The program COMPASS can generate samples that have been collected at various points in time from a population that is evolving according to a Wright–Fisher model. The samples are generated using coalescence simulations permitting various demographic scenarios and the program uses an infinite sites model to generate polymorphism data for the samples. By generating serially sampled population-genetic data, COMPASS allows investigating properties of polymorphism data that has been collected at different time points, and aid in making inference from ancient polymorphism data.

Availability: The program and the manual are available at: http://www.egs.uu.se/evbiol/Research/JakobssonLab/compass.html

Contact:  mattias.jakobsson@ebc.uu.se
Identifiability of isoform deconvolution from junction arrays and RNA-Seq
Authors: Hiller David , Jiang Hui , Xu Weihong , Wong Wing Hung
Published: September 2009

Motivation: Splice junction microarrays and RNA-seq are two popular ways of quantifying splice variants within a cell. Unfortunately, isoform expressions cannot always be determined from the expressions of individual exons and splice junctions. While this issue has been noted before, the extent of the problem on various platforms has not yet been explored, nor have potential remedies been presented.

Results: We propose criteria that will guarantee identifiability of an isoform deconvolution model on exon and splice junction arrays and in RNA-Seq. We show that up to 97% of 2256 alternatively spliced human genes selected from the RefSeq database lead to identifiable gene models in RNA-seq, with similar results in mouse. However, in the Human Exon array only 26% of these genes lead to identifiable models, and even in the most comprehensive splice junction array only 69% lead to identifiable models.

Contact:  whwong@stanford.edu

Supplementary information:  Supplementary data are available at Bioinformatics online.
Analytical reference points for age-structured models: application to data-poor fisheries
Authors: Brooks Elizabeth N. , Powers Joseph E. , Cortés Enric
Published: September 2009

Brooks, E. N., Powers, J. E., and Cortés, E. 2010. Analytical reference points for age-structured models: application to data-poor fisheries. – ICES Journal of Marine Science, 67: 165–175. Analytical solutions for biological reference points are derived in terms of maximum lifetime reproductive rate. This rate can be calculated directly from biological parameters of maturity, fecundity, and natural mortality or a distribution for this rate can be derived from appropriate metadata. Minimal data needs and assumptions for determining stock status are discussed. The derivations lead to a re-parameterization of the common stock–recruit relationships, Beverton–Holt and Ricker, in terms of spawning potential ratio. Often, parameters in stock–recruit relationships are restricted by tight prior distributions or are fixed based on a hypothesized level of stock resilience. Fixing those parameters is equivalent to specifying the biological reference points. An ability to directly calculate reference points from biological data, or a meta-analysis, without need of a full assessment model or fisheries data, makes the method an attractive option for data-poor fisheries. The derivations reveal an explicit link between the biological characteristics of a species and appropriate management. Predicted stock status for a suite of shark species was compared with recent stock assessment results, and the method successfully identified whether each stock was overfished.
Basal Forebrain Histaminergic Transmission Modulates Electroencephalographic Activity and Emergence from Isoflurane Anesthesia
Authors: Luo Tao , Leung L Stan
Published: September 2009

Background

The tuberomammillary histaminergic neurons are involved in the sedative component of anesthetic action. The nucleus basalis magnocellularis (NBM) in the basal forebrain receives dense excitatory innervation from the tuberomammillary nucleus and is recognized as an important site of sleep-wake regulation. This study investigated whether NBM administration of histaminergic drugs may modulate arousal/emergence from isoflurane anesthesia.

Methods

Microinjections of histaminergic agonists and antagonists were made into the NBM of rats anesthetized with isoflurane. The changes in electroencephalographic activity, including electroencephalographic burst suppression ratio and power spectra, as well as respiratory rate, were recorded under basal conditions and after NBM injection. Time to resumption of righting reflex was recorded as a measure of emergence from anesthesia.

Results

The rats displayed a burst suppression electroencephalographic pattern at inhaled isoflurane concentrations of 1.4-2.1%. Application of histamine (1 microg/0.5 microl) to the NBM reversed the electroencephalographic depressant effect of isoflurane; i.e., electroencephalographic activity shifted from the burst suppression pattern toward delta activity at 1.4% isoflurane, and the burst suppression ratio decreased at 2.1% isoflurane. Histamine-evoked activation of electroencephalography was blocked by NBM pretreatment with a H1 receptor antagonist, triprolidine (5 microg/1 microl), but not by a H2 receptor antagonist, cimetidine (25 microg/1 microl). The respiratory rate was significantly increased after histamine injection. NBM application of histamine facilitated, while triprolidine delayed, emergence from isoflurane anesthesia.

Conclusions

Histamine activation of H1 receptors in the NBM induces electroencephalographic arousal and facilitates emergence from isoflurane anesthesia. The basal forebrain histaminergic pathway appears to play a role in modulating arousal/emergence from anesthesia.
Response of Serum Proteome in Patients Undergoing Infrarenal Aortic Aneurysm Repair
Authors: Modesti Pietro Amedeo , Gamberi Tania , Bazzini Cristina , Borro Marina , Romano Salvatore Mario , Cambi Giulia Elisa , Corvi Andrea , Dorigo Walter , Paparella Laura , Pratesi Carlo , Carini Marco , Gensini GianFranco , Modesti Alessandra
Published: September 2009

Background

Postoperative organ dysfunction in conventional surgery for abdominal aortic aneurysm (AAA) is associated with a complex inflammatory reaction, with activation of coagulation and fibrinolysis. A prospective,observational study was performed to define the complex plasma proteomic changes after AAA repair and to identify factor(s) that may affect myocardial function in uncomplicated procedures.

Methods

Ten patients undergoing infrarenal AAA repair were investigated. Eight subjects subjected to major abdominal surgery served as controls. Hemodynamic changes were continuously monitored by using the pressure recording analytical method technique. The time course of plasma proteins was investigated after induction of anesthesia and at different times after surgery (6 h, 12 h, 24 h, 36 h) by using two-dimensional difference gel electrophoresis, matrix-assisted laser desorption/ionization-time of flight mass spectrometry, and Western blot. The effects of plasma on the functional properties of isolated rat ventricular myocytes were also investigated.

Results

In AAA patients alone, 18 spots were found to change more than two-fold in expression level, spot identification revealing an increased thrombin generation 6 h after surgery. At the same time cardiac cycle efficiency significantly reduced versus baseline (-0.5 +/- 0.9 vs. 0.18 +/- 0.3 in AAA patients, P < 0.01; 0.4 +/- 0.1 vs. 0.2 +/- 0.3 in control surgery, not significant; P < 0.01 group x time interaction at ANOVA). Plasma obtained 6 h after AAA surgery dose-dependently inhibited contractile function of control rat myocytes (percent shortening fell by 51% with 10% of AAA plasma and was abolished with 20% of AAA plasma, P < 0.001 for both). The inhibitory response was abolished by thrombin antagonism.

Conclusions

These findings show for the first time the possible role of thrombin generation within the complex activation of inflammatory response in causing hemodynamic instability in the early postoperative period after AAA surgery.
Adaptive Support Ventilation
Authors: Sulemanji Demet , Marchese Andrew , Garbarini Paul , Wysocki Marc , Kacmarek Robert M.
Published: September 2009

Background

Adaptive support ventilation (ASV) allows the clinician to set a maximum plateau pressure (PP) and automatically adjusts tidal volume to keep PP below the set maximum.

Methods

ASV was compared to a fixed tidal volume of 6 ml/kg. ASV determined the respiratory rate and tidal volume based on its algorithms. Maximum airway pressure limit was 28 cm H2O in ASV. Six sets of lung mechanics were simulated for two ideal body weights: 60 kg, Group I; 80 kg, Group II. Positive end expiratory pressure was 8, 12, and 16 cm H2O, and target minute volume 120%, 150%, and 200% of predicted minute volume.

Results

ASV "sacrificed" tidal volume and minute ventilation to maintain PP in 9 (17%) of 54 scenarios in Group I and 20 (37%) of 54 scenarios in Group II. In Group I, the number of scenarios with PP of 28 cm H2O or more was 14 for ASV (26%) and 19 for 6 ml/kg (35%). In these scenarios, mean PP were ASV 28.8 +/- 0.86 cm H2O (min 28, max 30.3) and 6 ml/kg 33.01 +/- 3.48 cm H2O (min 28, max 37.8) (P = 0.000). In group II, the number of scenarios PP of 28 cm H2O or more was 10 for ASV (19%) and 21 for 6 ml/kg (39%). In these cases, mean PP values were ASV 28.78 +/- 0.54 cm H2O (min 28, max 29.6) and 6 ml/kg 32.66 +/- 3.37 cm H2O (min 28.2, max 38.2) (P = 0.000).

Conclusion

In a lung model with varying mechanics, ASV is better able to prevent the potential damaging effects of excessive PP (greater than 28 cm H2O) than a fixed tidal volume of 6 ml/kg by automatically adjusting airway pressure, resulting in a decreased tidal volume.
An inducible change in Fox-1/A2BP1 splicing modulates the alternative splicing of downstream neuronal target exons
Authors: Lee Ji-Ann , Tang Zhen-Zhi , Black Douglas L.
Published: September 2009

Neuronal depolarization and CaM kinase IV signaling alter the splicing of multiple exons in transcripts for ion channels, neurotransmitter receptors, and other synaptic proteins. These splicing changes are mediated in part by special CaM kinase-responsive RNA elements, within or adjacent to exons that are repressed in the initial phase of chronic depolarization. The splicing of many neuronal transcripts is also regulated by members of the Fox (Feminizing gene on X) protein family, and these Fox targets are also often proteins affecting synaptic activity. We show that Fox-1/Ataxin 2-Binding Protein 1 (A2BP1), a protein implicated in a variety of neurological diseases, can counteract the effects of chronic depolarization on splicing. We find that exon 19 of Fox-1 is itself repressed by depolarization. Fox-1 transcripts missing exon 19 encode a nuclear isoform of Fox-1 that progressively replaces the cytoplasmic Fox-1 isoform as cells are maintained depolarizing media. The resulting increase in nuclear Fox-1 leads to the reactivation of many Fox-1 target exons, including exon 5 of the NMDA receptor 1, that were initially repressed by the high-KCl medium. These results reveal a novel mechanism for the slow modulation of splicing as cells adapt to chronic stimuli: The subcellular localization of a splicing regulator is controlled through its own alternative splicing.
Characteristics of stork feces‐derived H5N1 viruses that are preferentially transmitted to primary human airway epithelial cells
Authors: Suksatu Ampa , Sangsawad Wichayapong , Thitithanyanont Arunee , Smittipat Nat , Fukuda Mark M. , Ubol Sukathida
Published: September 2009

Avian influenza viruses are a possible threat to human health as they may cause an influenza pandemic. Asian open‐bill storks are migratory birds that brought H5N1 viruses into Thailand during the 2004–2005 epidemic. However, to date, there are no reports of direct transmission of stork‐derived H5N1 viruses to Thais. Therefore, we questioned whether or not H5N1 viruses secreted in the feces of infected storks could directly infect cells derived from the human respiratory tract. To answer this question, we used primary NHBE cells as a model. We found that H5N1 viruses from two of the three cloacal swabs rapidly replicated and caused severe structural damage to the infected NHBE cells within the early phase of infection. Viruses from the remaining swab replicated poorly and caused no damage to the infected cells. The rapid‐replicating viruses were able to replicate efficiently even in the presence of a high level of type I IFN production and stimulated a high level of IL‐6 production but not the immunosuppressive cytokine, IL‐10. The genotypic study revealed that the major genotypes of the two rapid‐replicating viruses present in stork feces were the best‐fit genotypes for replication in the primary NHBE cells. In contrast, the major NA‐based genotype found in the cloacal swab containing slow‐replicating viruses could not survive in the primary NHBE cells. Altogether, the data suggested that those stork‐derived H5N1 viruses that preferentially replicated in human airway epithelial cells may exist in nature, and may not require additional mutations in order to defeat the species barrier.
It takes two to tango: Combinations of conventional cytotoxics with compounds targeting the vascular endothelial growth factor–vascular endothelial growth factor receptor pathway in patients with solid malignancies
Authors: Boere Ingrid A. , Hamberg Paul , Sleijfer Stefan
Published: September 2009

Through advances in molecular biology, insight into the mechanisms driving malignancies has improved immensely and as a result, various factors playing an essential role in the biology of numerous tumor types have been revealed. By using compounds that specifically block the function of a single factor being crucial for tumor pathogenesis, it was hoped to exert antitumor activity while avoiding toxicities characteristic for conventional chemotherapy. One of the processes of crucial importance in the development of cancer, and consequently an attractive target, is angiogenesis. In recent years, several key factors for angiogenesis have been identified, including ligands, receptors, and transduction signaling factors. Of these, the vascular endothelial growth factor (VEGF) pathway has been found to be activated in numerous tumor types and considered one of the main drivers of angiogenesis. Roughly, VEGF‐mediated angiogenesis can be inhibited by two approaches: either by monoclonal antibodies directed towards VEGF or its corresponding receptors, or by kinase inhibitors targeting the signal transduction of the VEGF receptors. As monotherapy, several kinase inhibitors exert antitumor activity in tumor types such as renal cell carcinoma. However, in most tumor types, the antitumor activity of compounds targeting the VEGF pathway is limited. In recent years, evidence is mounting that the paradigm of one single factor that drives malignant behavior applies rarely and is an oversimplification for most tumors in which there are multiple driving pathways. Consequently, multitargeting rather than single‐targeting approaches are required. One of the means is by combining targeted agents with conventional cytotoxics. As the VEGF pathway also affects the sensitivity of tumor cells to chemotherapeutics, combinations of compounds targeting this pathway and conventional cytotoxics have been explored. This review addresses such combinations. (Cancer Sci 2009; 00: 000–000)
CD24‐dependent MAPK pathway activation is required for colorectal cancer cell proliferation
Authors: Wang Weifei , Wang Xinying , Peng Liang , Deng Qiliang , Liang Yan , Qing Haitao , Jiang Bo
Published: September 2009

CD24 is a glycosylphosphatidylinositol‐anchored membrane protein reported to be overexpressed in human tumorigenesis and progression. Our purpose was to determine the role of CD24 in the proliferation of colorectal cancer cells and the potential mechanisms in this process. Our data showed that CD24 promoted cell growth and induced activation of extracellular signal‐regulated kinases, Raf‐1, and p38 mitogen‐activated protein kinase. Furthermore, suppression of extracellular signal‐regulated kinases and p38 mitogen‐activated protein kinase activity by their specific inhibitors, U0126 and SB203580, abrogated CD24‐induced proliferation in vitro. By tumorigenicity assay in female BALB/c nude mice, we further demonstrated that CD24 promoted tumor growth in vivo. Immunohistochemical analysis revealed that CD24 expression occurred in 92.5% of human colorectal cancer tissue, and increased with tumor progression. More importantly, the stainings of phospho‐extracellular signal‐regulated kinases and phospho‐p38 mitogen‐activated protein kinase were strongly correlated with CD24 expression. Taken together, our data suggest that CD24‐dependent extracellular signal‐regulated kinases and p38 mitogen‐activated protein kinase activations are required for colorectal cancer cell proliferation in vitro and in vivo. The linkage of CD24 and the mitogen‐activated protein kinase pathway may unravel a novel mechanism in the regulation of colorectal cancer proliferation. (Cancer Sci 2009; 00: 000–000)
The activating splice mutation in intron 3 of the thrombopoietin gene is not found in patients with non‐familial essential thrombocythaemia
Authors: Harrison Claire N. , Gale Rosemary E. , Wiestner Adrian C. , Skoda Radek C. , Linch David C.
Published: September 2009

Essential thrombocythaemia (ET) is a condition of unknown aetiology characterized by sustained thrombocytosis in the absence of a detectable systemic cause. Although usually considered a clonal disease affecting myeloid cells, recent data indicate that a significant proportion of patients have polyclonal haemopoiesis. In some patients the thrombopoietin (TPO) levels are normal or raised. Recently a mutation has been described in the TPO gene in familial thrombocythaemia that results in elevated TPO levels. We have therefore screened 51 patients diagnosed with non‐familial ET for the presence of this mutation, but it was not detected in any patient. The constitutional presence of this mutation is therefore unlikely to contribute to the pathogenesis of ET.
The influence of HLA‐matched sibling donor availability on treatment outcome for patients with AML: an analysis of the AML 8A study of the EORTC Leukaemia Cooperative Group and GIMEMA
Authors: KEATING SUSAN , DE WITTE THEO , SUCIU STEFAN , WILLEMZE ROEL , HAYAT MARCEL , LABAR BORIS , RESEGOTTI LUIGI , FERRINI PIERLUIGI ROSSI , CARONIA FRANCESCO , DARDENNE MURIELLE , SOLBU GABRIEL , PETTI MARIA CONCETTA , VEGNA MARIA LUCE , MANDELLI FRANCO , ZITTOUN ROBERT A. ,   for the European Organization for Research and Treatment of Cancer (EORTC) Leukaemia Cooperative Group and the Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto (GIMEMA)
Published: September 2009

To determine whether patients with a HLA‐identical sibling donor have a better outcome than patients without a donor, an analysis on the basis of intention‐to‐treat principles was performed within the framework of the EORTC‐GIMEMA randomized phase III AML 8A trial. Patients in complete remission (CR) received one intensive consolidation course. Patients with a histocompatible sibling donor were then allocated allogeneic bone marrow transplantation (alloBMT), the patients without a donor were randomized between autologous BMT (ABMT) and a second intensive consolidation (IC2). 831 patients <46 years old and alive >8 weeks from diagnosis were included. HLA typing was performed in 672 patients. AlloBMT was performed during CR1 in 180 (61%) out of 295 patients with a donor. Another 38 patients were allografted: five in resistant disease, 14 during relapse and 19 in CR2. ABMT was performed in 130 (34%) out of 377 patients without a donor in CR1, in six (2%) patients during relapse and in 38 (10%) patients during CR2. The disease‐free survival (DFS) from CR for patients with a donor was significantly longer than for patients without a donor (46% v 33% at 6 years; P = 0.01, RR 0.78, 95% confidence interval 0.63–0.96). The overall survival from diagnosis for patients with a donor was longer, but not statistically significant, than for patients without a donor (48% v 40% at 6 years; logrank P = 0.24). When patients were stratified according to prognostic risk groups, the same trend in favour of patients with a donor was seen for survival duration and the DFS remained significantly longer for this group of patients.
Impaired pneumococcal immunity in children after treatment for acute lymphoblastic leukaemia
Authors: Lehrnbecher Thomas , Schubert Ralf , Behl Michael , Koenig Melanie , Rose Markus A. , Koehl Ulrike , Meisel Roland , Laws Hans‐Jürgen
Published: September 2009

Although the substantial risk for invasive pneumococcal disease is well recognized in children after allogeneic stem cell transplantation, little is known about the specific immunity against pneumococci in children after cytotoxic therapy for acute lymphoblastic leukaemia (ALL). We therefore assessed the spontaneous reconstitution of humoral immunity against pneumococcal antigens, of total IgG and the IgG2 subclass, and of lymphocyte subsets in a total of 53 children treated for ALL. None of the patients had received pneumococcal vaccination prior to or after therapy for ALL. At 3 and 9 months after completion of chemotherapy, most patients had levels of specific antibodies to pneumococcal antigens below the presumed threshold of protection and significantly lower than those of age‐matched unvaccinated healthy controls. In contrast, at 9 months after completion of therapy, only a minority of patients had immunoglobulin concentrations or lymphocyte subset counts below the age‐matched reference value. Our data indicate that patients with ALL who are unvaccinated against pneumococci have a selective immunodeficiency with an impaired antibody protection against pneumococci for up to 9 months after completion of therapy. Therefore, effective prevention, including chemoprophylaxis and active immunization, has to be considered in this patient population.
Daily labile plasma iron as an indicator of chelator activity in Thalassaemia major patients
Authors: Zanninelli Giuliana , Breuer William , Cabantchik Zvi I.
Published: September 2009

Labile plasma iron (LPI), a non‐transferrin‐bound component of plasma iron detected in iron overload disorders is a potential source of cellular iron accumulation and ensuing oxidative damage. Periodic monitoring of LPI over a 24 h time‐span was used to compare the ability of chelation to control daily LPI levels in 40 Thalassaemia major patients (9–11/group) who had been receiving one of three different chelation protocols for more than a year: Group I. deferrioxamine overnight, Group II. deferiprone daily, Group III. deferrioxamine and deferiprone sequentially. An additional group (Group IV) was treated with desferasirox for up to 6 months. The patterns of daily LPI recrudescence showed significant individual variations, especially in patients treated with deferrioxamine or deferiprone, although these patterns were maintained over 6–9 months of treatment in all groups. Group data analysis showed that the proportion of patients whose daily LPI were maintained within the normal range (<0·45 μmol/l) varied with treatment: 6/10 with deferrioxamine, 5/11 with deferiprone, 9/10 with deferrioxamine + deferiprone and 8/10 at the onset and 10/10 after 6 months treatment with deferasirox. Although the clinical significance and therapeutic value of LPI remain to be established, monitoring of daily LPI level may provide an analytical basis for assessing chelation efficacy in preventing daily LPI recrudescence.
Three clonal types of urothelium with different capacities for replication
Authors: Thangappan R. , Kurzrock E. A.
Published: September 2009

Objectives:  Similar to other epithelia, urothelium in vivo has a hierarchal organization of cells each with specific gradients of differentiation. While distinct cell types have been described as important in bladder cancer in vitro, clonal and proliferative capacities of normal urothelial cells have not been characterized.

Materials and methods:  Three cell types and colony types were identified from primary porcine urothelial culture. Proliferative activity, patterns of apoptosis and differentiation, colony forming efficiency and ability to change phenotype with passage were determined and compared.

Results:  Small, T‐I colonies with large flattened (type‐1) cells had low levels of proliferation and high levels of apoptosis. Large T‐III colonies had a central area of small (type‐3) cells surrounded by type‐1 and type‐2 cells. Proliferation and apoptosis were asymmetrically distributed in the periphery of T‐II and T‐III colonies. T‐III colonies proved to be significantly more clonogenic and proliferative. With appropriate induction, type‐1 cells were able to proliferate upon passage and form type‐3 cells, yet long‐term culture demonstrated that progeny of type‐1 cells appeared to have inherited a clonogenic handicap.

Conclusions:  Type‐3 cells in the centre of T‐III colonies appear to harbour stem‐like qualities with a relatively low proliferative and apoptotic index at homeostasis and the ability to become highly proliferative upon passage. This study demonstrates that distinct urothelial cell types with differing clonal capacities can be isolated from the bladder and these cells may have implications for tissue engineering and carcinogenesis.
Gestational age and occurrence of atopy at age 31—a prospective birth cohort study in Finland
Authors: Pekkanen J. , Xu B. , Järvelin M.‐R.
Published: September 2009

It has been suggested that main risk factors for development of allergic diseases operate already during pregnancy and in early childhood.

To study the association between gestational age, birth weight, parity and parental farming with the risk of atopy and asthma in young adults.

In a prospective birth cohort study, 5192 subjects born in Northern Finland in 1966 were followed up at the age of 31. Skin prick tests were done to three of the most common allergens in Finland and to house dust mite. Data on doctor‐diagnosed asthma was obtained from questionnaires. Perinatal data had already been collected during pregnancy.

The risk of atopy increased linearly with increasing length of pregnancy among babies born in the 35th weak of gestation or later. Gestational age equal to, or over 40 weeks compared with less than 36 weeks was associated with an increased risk of atopy (multivariate odds ratio 1.65, 95% CI 1.16, 2.34). The association was stronger among farmers' children (P for interaction 0.01). High parity and being a farmer's child (multivariate odds ratio 0.50, 95% CI 0.42–0.60) was associated with decreased risk of atopy. In contrast, no associations were observed for doctor‐diagnosed asthma.

The results underline the importance of pregnancy and very early childhood in the development of atopy, and suggest that timing of the environmental exposure is of importance for the immune system. No association was observed for asthma, which may be due to the multifactorial origins of asthma.
HLA‐DRB1*07 may have a susceptibility and DRB1*04 a protective effect upon the development of a sensitization to house dust mite Dermatophagoides pteronyssinus
Authors: Kim Y.‐K. , Oh H.‐B. , Oh S.‐Y. , Cho S.‐H. , Kim Y.‐Y. , Min K.‐U.
Published: September 2009

IgE responses to house dust mite‐derived allergens seem to be the most important in the development of atopic asthma and rhinitis, but it has been difficult to demonstrate genetic control of the IgE response to the allergens.

This study was undertaken to investigate the association between sensitization to house dust mite, D. pteronyssinus (DP), and genotypes of HLA‐DRB1 alleles.

DNAs were extracted from two groups of unrelated Koreans: (1) 178 with sensitization to DP; and (2) 99 age‐matched non‐atopic controls. Genotypes of the HLA‐DRB1 alleles were determined using polymerase chain reaction (PCR)‐based methods.

The frequency of HLA‐DRB1*07 was significantly increased in the DP‐sensitive subjects compared with the controls (15.7% vs 4.0%, P = 0.009). Conversely, the frequencies of HLA‐DRB1*04 and *14 were decreased in the DP‐sensitive subjects compared with the controls (27.5% vs 45.5%, P = 0.002; 13.5% vs 24.2%, P = 0.02). Of the DRB1*04 alleles, DRB1*0403 was significantly decreased in the DP‐sensitive subjects compared with the controls (3.9% vs 13.1%, P = 0.005). No significant differences were found in the distributions of the other HLA‐DRB1 alleles between the two groups.

HLA‐DRB1*07 may have a susceptibility, and DRB1*04 and DRB1*14 may have a protective effect, upon the development of a sensitization to DP.
Do combined elimination diet and prolonged breastfeeding of an atopic infant jeopardise maternal bone health?
Authors: Holmberg‐Marttila D. , Sievänen H. , Sarkkinen E. , Erkkilä A. , Salminen S. , Isolauri E.
Published: September 2009

Prolonged breastfeeding, and intervention in the maternal diet during breastfeeding, have been suggested as a means to treat atopic symptoms of infants. The impact of these actions on the mother's skeletal health has remained unclear.

The purpose of this study was to determine factors that are associated with bone mineral density (BMD) and serum lipid fatty acid profile in mothers of atopic infants.

BMD at the lumbar spine, right femoral neck and dominant distal radius of 24 mothers of atopic infants (study group) and 25 mothers of healthy infants (control group) were measured with dual energy X‐ray absorptiometry postpartum after the resumption of menses. In addition, the fatty acid profile of their serum cholesteryl esters was determined.

A systematic trend for 4–6% lower BMD was observed in the study group, but this difference was mainly attributable to a difference in body weight between the groups. In addition, the omega (ω)‐3 fatty acid metabolite EPA showed a positive association with femoral neck BMD. Mothers of atopic infants had a significantly lower proportion of ω‐6 fatty acid parent LA and a higher proportion of ω‐6 fatty acid metabolite GLA than the control mothers. These differences were associated not only with dietary factors but also with the duration of postpartum amenorrhea and total lactation.

Neither the breastfeeding nor the mother's short‐term elimination diet per se seemed to be associated with low BMD in the mothers of atopic infants. Thus, if an elimination diet benefits the infant, it can be recommended for a limited period. However, it may be advisable to give special dietary counselling, especially to low body weight mothers, in order to ensure adequate nutrient intake and to minimize the possible risk of potential bone loss.
Histopathology of the airway epithelium in an experimental dual‐phase model of bronchial asthma
Authors: Tohda Y. , Kubo H. , Ito M. , Fukuoka M. , Nakajima S.
Published: September 2009

Lesions of trachea cuticles are a pathological histological characteristic of bronchial asthma. Furthermore, collected tracheal cuticles desquamated from the respiratory tract are found in patients’ sputum when asthma attacks occur or after the induction of allergen inhalation. From these facts, it is assumed that desquamation of trachea cuticle cells is a pathological symptom of bronchial asthma. However, there has not been any chronological report of desquamation of trachea cuticles through the process of bronchial asthma attacks.

For this report, we made an experimental bronchial asthma model using guinea pigs, and conducted chronological examinations of trachea cuticle lesions related to pathological symptoms of bronchial asthma using a transmission electron microscope and a scanning electron microscope.

The experimental asthma models were made by injection of ovalbumin into the abdominal cavity of guinea pigs. Then the airway responses to inhaled aerosolized ovalbumin were induced. The trachea were enucleated and examined under an optical microscope, a transmission electron microscope (hereafter abbreviated as TEM), and a scanning electron microscope (hereafter abbreviated as SEM) after 1, 2, 4, 8, 12, 24 h and 7 days after the immediate airway responses.

Intercellular oedema of ciliated epithelium was observed in the sensitization groups immediately after the immediate airway response. SEM observation revealed increased mucus secretion and shortening of cilium. A slight case of desquamation or deciduation of ciliated epithelium was also beginning to appear. TEM observation revealed a dilation of ciliated epithelium intervals. Infiltration of eosinophilic leucocytes was already detectable beneath the ciliated epithelium. The degree of ciliated epithelium desquamation and infiltration of eosinophilic leucocytes progressed with time. When the late airway response occurred 4 hours later, eosinophilic leucocytes had increased drastically, and ciliate epithelium had desquamated to the extent that basal cells were exposed. Seven days after the immediate airway response, epithelium intercellular oedema had improved, and cilium had been reproduced.

These results suggest that desquamation of epithelium caused by trachea cuticle lesions appears at an early stage of an asthma attack, owing to the contraction of the trachea, and that the damage is intensified by the infiltration of eosinophilic leucocytes.