bluuebunny/crossref_metadata_2025 huggingface dataset:
The Use of Transdermal Fentanyl in Cancer Pain—A Compliance Study of Outpatients in Taiwan
Authors: Chiou Tzeon-Jye , Liu Chun-Yu , Tzeng Woan-Fang , Su Yu-Chieh , Weng Yih-Chyang , Hung Chih-Jen , Tang Yeh , Chen Yu-Jen ,   Taiwan Cancer Pain Study Group
Published: October 2009

The aim of this study is to investigate cancer patients’ response and side effects associated with transdermal therapeutic fentanyl (TTS-F), whose pain was hardly controlled by nonweak/weak opioids in Taiwan. From 2005 to 2006, 822 outpatients received TTS-F to collect pain assessment forms and diaries for 4 weeks. Most (78.7%) patients were initially prescribed 25 μg/h TTS-F. Doses were adjusted weekly at clinicians’ discretion, according to pain assessment and side effects. Patients receiving 50 μg/h, 75 μg/h, and > 75 μg/h TTS-F had increased from 17.5% to 32.1%, 1.8% to 3.4%, and 1.9% to 2.2%, respectively, by week 2; further small increases were found in weeks 3 and 4. Pain palliation improved from 60.6% during week 1 to 78.6% at week 4. The common adverse effects were nausea/vomiting. Patient’s compliance was >90%. This study found that the TTS-F is effective and well tolerated.
The Divide Between Diversity Training and Diversity Education: Integrating Best Practices
Authors: King Eden B. , Gulick Lisa M. V. , Avery Derek R.
Published: October 2009

The fields of diversity training and diversity education have developed in a disconnected manner. This divide ensures that each field advances slowly and with narrow focus. The authors argue here that the divide should be bridged with attention to the best practices that diversity training and diversity education offer. By integrating the best that each perspective has to offer as outlined here, both fields of inquiry and practice may be enhanced.
Pink or Blue ... Black and Blue? Examining Pregnancy as a Predictor of Intimate Partner Violence and Femicide
Authors: Taylor Rae , Nabors Erin L.
Published: October 2009

This study explores the effect of pregnancy on women’s risk of IPV victimization. Previous studies have produced conflicting findings and have been limited by comparing only two categories of IPV. The current study included analyses of the effect of pregnancy on three statuses of IPV: no abuse, nonlethal abuse, and lethal abuse. The data used for this project are taken from the first phase of the Chicago Women’s Health Risk Study (CWHRS). Findings suggest that both nonlethal and lethal abuse statuses differ significantly from no abuse in that women’s risk of IPV victimization may decrease during pregnancy.
Spiritual Abuse: An Additional Dimension of Abuse Experienced by Abused Haredi (Ultraorthodox) Jewish Wives
Authors: Dehan Nicole , Levi Zipi
Published: October 2009

This article aims to conceptualize spiritual abuse as an additional dimension to physical, psychological, sexual, and economic abuse. Growing out of an interpretivist participatory action research study in a therapeutic Haredi (Jewish ultraorthodox) group of eight abused women, spiritual abuse has been defined as any attempt to impair the woman’s spiritual life, spiritual self, or spiritual well-being, with three levels of intensity: (a) belittling her spiritual worth, beliefs, or deeds; (b) preventing her from performing spiritual acts; and (c) causing her to transgress spiritual obligations or prohibitions. The concept and its typology are illustrated by means of examples from the women’s abusive experiences and may be of theoretical and therapeutic worldwide relevance.
Parsimonious Model for Predicting Mean Cabinet Duration On the Basis of Electoral System
Authors: Taagepera Rein , Sikk Allan
Published: October 2009

This study joins two existing logical models and tests the resulting predictions of mean cabinet duration (C). One of these models predicts C based on effective number of parties (N): C = k/N2, where k is found to be around 42 years. The other predicts N on the basis of number of seats in the assembly (S) and district magnitude (M). The new combined model leads to a prediction for the mean cabinet duration in terms of these two institutional factors: C = 42 years/(MS)1/3. Three-quarters of the actual mean durations agree with the prediction within a factor of 2. For the purposes of institutional engineering, the model predicts that doubling the district magnitude would reduce the mean cabinet duration by 21 percent ceteris paribus.
Sirolimus-eluting stent placement for refractory renal artery in-stent restenosis: sustained patency and clinical benefit at 24 months
Authors: Lookstein Robert A , Talenfeld Adam D , Raju Roman , Vorchheimer David A , Olin Jeffrey W , Marin Michael L
Published: October 2009

Abstract

Renal artery stenosis may cause or exacerbate hypertension and renal failure. Percutaneous transluminal renal artery stent placement, increasingly the first-line therapy for ostial atherosclerotic renal artery stenosis, can be complicated by in-stent restenosis weeks to months after the procedure. There is currently no consensus for the treatment of in-stent restenosis. Sirolimus-eluting stents have been shown to be effective to treat in-stent restenosis in the coronary circulation. We report a case of sustained 24-month patency after repair of recurrent renal artery in-stent restenosis with use of a sirolimus-eluting stent.
High-resolution 3D contrast-enhanced MRA with parallel imaging techniques before endovascular interventional treatment of arterial stenosis
Authors: Lin Jiang , Li Dan , Yan Fuhua
Published: October 2009

Abstract

This study aimed to evaluate the efficacy of high-resolution 3D contrast-enhanced magnetic resonance angiography (3D CE MRA) with parallel imaging techniques for the diagnosis of various arterial stenoses and its value for planning endovascular interventional treatment. Thirty-five patients underwent 3D CE MRA before endovascular interventional treatment. Numbers of patients were as follows: clinically documented renal artery stenosis ( n = 10), renal transplant artery stenosis ( n = 1), carotid artery stenosis ( n = 12), iliac artery stenosis ( n = 11) and femoro-popliteal artery stenosis ( n = 1). A total of 39 arterial segments were treated. The depiction of various arterial stenoses was evaluated. The degree and length of the stenoses were compared and analyzed between 3D CE MRA and digital subtraction angiography (DSA). The accuracy of MRA in depicting lesion characteristics (ulceration, eccentricity, post-stenotic dilatation) was reviewed. The overall value of 3D CE MRA in planning interventional treatment was determined. The quality of 3D CE MRA in the demonstration of various arterial stenoses was judged excellent or good. A strong correlation was noted between 3D CE MRA and DSA regarding severity and length of stenosis. The accuracy of 3D CE MRA in depicting lesion characteristics was good. 3D CE MRA overestimated three severe iliac artery stenoses. Except in these three segments, the value of 3D CE MRA analysis was judged high. 3D CE MRA was found to be better than DSA in revealing the distal reconstitution and occluded segment in cases of iliac artery stenosis. 3D CE MRA is accurate in demonstrating the relevant anatomy necessary to plan endovascular interventional treatment for patients with arterial stenosis.
Novel markers of peripheral arterial disease
Authors: Khawaja Farhan J , Kullo Iftikhar J
Published: October 2009

Abstract

Peripheral arterial disease (PAD), a relatively common manifestation of atherosclerotic vascular disease, is associated with significant morbidity and mortality. Although conventional risk factors contribute to the onset and progression of PAD, the role of ‘novel’ biomarkers in pathways of inflammation, thrombosis, lipoprotein metabolism, and oxidative stress in determining susceptibility to PAD is being increasingly recognized. Validation of novel risk factors for PAD may allow earlier detection, an improved understanding of disease etiology and progression, and the development of new therapies. In this review, we discuss available evidence for associations between novel circulating markers and several aspects of PAD including disease susceptibility, progression, functional limitation, and adverse outcomes.
Advocacy Evaluation: What It Is and Where to Find Out More About It
Authors: Fagen Michael C. , Reed Ehren , Kaye Jackie Williams , Jack Leonard
Published: October 2009

Advocacy and policy change have become increasingly important strategies in health promotion efforts. As a result, advocacy evaluation is emerging as a necessary competency for health promotion practitioners. This article introduces the growing field of advocacy evaluation by describing its typical features, which include using prospective evaluation designs, emphasizing real-time data collection and use, monitoring and responding to changing environmental conditions, and assessing both individual and organizational capacity building. A number of freely available resources for learning more about advocacy evaluation’s key concepts and methods are highlighted.
Settings for Health Promotion: An Analytic Framework to Guide Intervention Design and Implementation
Authors: Poland Blake , Krupa Gene , McCall Douglas
Published: October 2009

Taking a settings approach to health promotion means addressing the contexts within which people live, work, and play and making these the object of inquiry and intervention as well as the needs and capacities of people to be found in different settings. This approach can increase the likelihood of success because it offers opportunities to situate practice in its context. Members of the setting can optimize interventions for specific contextual contingencies, target crucial factors in the organizational context influencing behavior, and render settings themselves more health promoting. A number of attempts have been made to systematize evidence regarding the effectiveness of interventions in different types of settings (e.g., school-based health promotion, community development). Few, if any, attempts have been made to systematically develop a template or framework for analyzing those features of settings that should influence intervention design and delivery. This article lays out the core elements of such a framework in the form of a nested series of questions to guide analysis. Furthermore, it offers advice on additional considerations that should be taken into account when operationalizing a settings approach in the field.
Integrating Cell Phones and Mobile Technologies Into Public Health Practice: A Social Marketing Perspective
Authors: Lefebvre Craig
Published: October 2009

Mobile communications are being used for many purposes, from instant messaging (IM), mobile or microblogging (Twitter), social networking sites (Facebook, MySpace), e-mail to basic voicemail. A brief background on cell phone and mobile technology use in public health is reviewed. The focus of the article is framing the use of mobile technologies in public health from a social marketer’s perspective—using the 4 P s marketing mix as a guide.
Review: Hepatocellular carcinoma: review of current treatment with a focus on targeted molecular therapies
Authors: Olsen Sonja K. , Brown Robert S. , Siegel Abby B.
Published: October 2009

The treatment of hepatocellular carcinoma (HCC) remains a challenge, with 1- and 3-year survival rates of 20% and 5%, respectively, and a median survival of 8 months. However, a better understanding of the pathogenesis of HCC, and advances in targeted molecular therapies provide physicians treating this disease with new hope. The treatment of HCC is multidisciplinary, requiring surgeons, hepatologists, interventional radiologists and oncologists. Thus, there is enormous potential to combine various treatment modalities to improve survival for patients. This review will describe what is currently known about the molecular pathogenesis of HCC, explore current and future treatments based on these pathways, and describe how these new therapies fit into existing approaches to HCC treatment.
The microtubule modulator RanBP10 plays a critical role in regulation of platelet discoid shape and degranulation
Authors: Kunert Stefan , Meyer Imke , Fleischhauer Silke , Wannack Martin , Fiedler Janine , Shivdasani Ramesh A. , Schulze Harald
Published: October 2009

Terminally mature megakaryocytes undergo dramatic cellular reorganization to produce hundreds of virtually identical platelets. A hallmark feature of this process is the generation of an elaborate system of branched protrusions called proplatelets. We recently identified RanBP10 as a tubulin-binding protein that is concentrated along polymerized microtubules in mature megakaryocytes. RanBP10 depletion in vitro caused the disturbance of polymerized filaments. Here we study the function of RanBP10 in vivo by generating deficient mice using a gene-trap approach. Mutant mice show normal platelet counts, and fetal liver-derived megakaryocytes reveal only slightly reduced proplatelet formation. However, ultrastructural analysis unveiled a significantly increased geometric axis ratio for resting platelets, and many platelets exhibited disorders in microtubule filament numbers and localization. Mutant mice showed a markedly prolonged bleeding time. Granule release, a process that depends on internal contraction of the microtubule marginal coil, also was reduced. Flow cytometry analysis revealed reduced expression of CD62P and CD63 after PAR4-peptide stimulation. These data suggest that RanBP10 plays an essential role in hemostasis and in maintaining microtubule dynamics with respect to both platelet shape and function.
Relationship of differential gene expression profiles in CD34+ myelodysplastic syndrome marrow cells to disease subtype and progression
Authors: Sridhar Kunju , Ross Douglas T. , Tibshirani Robert , Butte Atul J. , Greenberg Peter L.
Published: October 2009

Microarray analysis with 40 000 cDNA gene chip arrays determined differential gene expression profiles (GEPs) in CD34+ marrow cells from myelodysplastic syndrome (MDS) patients compared with healthy persons. Using focused bioinformatics analyses, we found 1175 genes significantly differentially expressed by MDS versus normal, requiring a minimum of 39 genes to separately classify these patients. Major GEP differences were demonstrated between healthy and MDS patients and between several MDS subgroups: (1) those whose disease remained stable and those who subsequently transformed (tMDS) to acute myeloid leukemia; (2) between del(5q) and other MDS patients. A 6-gene “poor risk” signature was defined, which was associated with acute myeloid leukemia transformation and provided additive prognostic information for International Prognostic Scoring System Intermediate-1 patients. Overexpression of genes generating ribosomal proteins and for other signaling pathways was demonstrated in the tMDS patients. Comparison of del(5q) with the remaining MDS patients showed 1924 differentially expressed genes, with underexpression of 1014 genes, 11 of which were within the 5q31-32 commonly deleted region. These data demonstrated (1) GEPs distinguishing MDS patients from healthy and between those with differing clinical outcomes (tMDS vs those whose disease remained stable) and cytogenetics [eg, del(5q)]; and (2) molecular criteria refining prognostic categorization and associated biologic processes in MDS.
Enhancing navigation in biomedical databases by community voting and database-driven text classification
Authors: Duchrow Timo , Shtatland Timur , Guettler Daniel , Pivovarov Misha , Kramer Stefan , Weissleder Ralph
Published: October 2009

Background

The breadth of biological databases and their information content continues to increase exponentially. Unfortunately, our ability to query such sources is still often suboptimal. Here, we introduce and apply community voting, database-driven text classification, and visual aids as a means to incorporate distributed expert knowledge, to automatically classify database entries and to efficiently retrieve them.

Results

Using a previously developed peptide database as an example, we compared several machine learning algorithms in their ability to classify abstracts of published literature results into categories relevant to peptide research, such as related or not related to cancer, angiogenesis, molecular imaging, etc. Ensembles of bagged decision trees met the requirements of our application best. No other algorithm consistently performed better in comparative testing. Moreover, we show that the algorithm produces meaningful class probability estimates, which can be used to visualize the confidence of automatic classification during the retrieval process. To allow viewing long lists of search results enriched by automatic classifications, we added a dynamic heat map to the web interface. We take advantage of community knowledge by enabling users to cast votes in Web 2.0 style in order to correct automated classification errors, which triggers reclassification of all entries. We used a novel framework in which the database "drives" the entire vote aggregation and reclassification process to increase speed while conserving computational resources and keeping the method scalable. In our experiments, we simulate community voting by adding various levels of noise to nearly perfectly labelled instances, and show that, under such conditions, classification can be improved significantly.

Conclusion

Using PepBank as a model database, we show how to build a classification-aided retrieval system that gathers training data from the community, is completely controlled by the database, scales well with concurrent change events, and can be adapted to add text classification capability to other biomedical databases.

The system can be accessed at http://pepbank.mgh.harvard.edu.
Identification of SH3 domain interaction partners of human FasL (CD178) by phage display screening
Authors: Voss Matthias , Lettau Marcus , Janssen Ottmar
Published: October 2009

Background -

Fas ligand is a cytotoxic effector molecule of T and NK cells which is characterized by an intracellular N-terminal polyproline region that serves as a docking site for SH3 and WW domain proteins. Several previously described Fas ligand-interacting SH3 domain proteins turned out to be crucial for the regulation of storage, expression and function of the death factor. Recent observations, however, indicate that Fas ligand is also subject to posttranslational modifications including shedding and intramembrane proteolysis. This results in the generation of short intracellular fragments that might either be degraded or translocate to the nucleus to influence transcription. So far, protein-protein interactions that specifically regulate the fate of the intracellular fragments have not been identified.

Results -

In order to further define the SH3 domain interactome of the intracellular region of Fas ligand, we now screened a human SH3 domain phage display library. In addition to known SH3 domains mediating binding to the Fas ligand proline-rich domain, we were able to identify a number of additional SH3 domains that might also associate with FasL. Potential functional implications of the new binding proteins for the death factor's biology are discussed. For Tec kinases and sorting nexins, the observed interactions were verified in cellular systems by pulldown experiments.

Conclusion -

We provide an extended list of putative Fas ligand interaction partners, confirming previously identified interactions, but also introducing several novel SH3 domain proteins that might be important regulators of Fas ligand function.
Role of key-regulator genes in melanoma susceptibility and pathogenesis among patients from South Italy
Authors: Casula Milena , Muggiano Antonio , Cossu Antonio , Budroni Mario , Caracò Corrado , Ascierto Paolo A , Pagani Elena , Stanganelli Ignazio , Canzanella Sergio , Sini MariaCristina , Palomba Grazia ,   The Italian Melanoma Intergroup (IMI), Palmieri Giuseppe
Published: October 2009

Background

Several genetic alterations have been demonstrated to contribute to the development and progression of melanoma. In this study, we further investigated the impact of key-regulator genes in susceptibility and pathogenesis of such a disease.

Methods

A large series (N = 846) of sporadic and familial cases originating from South Italy was screened for germline mutations in p16

CDKN2A
, BRCA2, and MC1R genes by DHPLC analysis and automated DNA sequencing. Paired primary melanomas and lymph node metastases from same patients (N = 35) as well as melanoma cell lines (N = 18) were analyzed for somatic mutations in NRAS, BRAF, and p16

CDKN2A
genes.

Results

For melanoma susceptibility, investigations at germline level indicated that p16

CDKN2A
was exclusively mutated in 16/545 (2.9%) non-Sardinian patients, whereas BRCA2 germline mutations were observed in 4/91 (4.4%) patients from North Sardinia only. Two MC1R germline variants, Arg151Cys and Asp294His, were significantly associated with melanoma in Sardinia. Regarding genetic events involved in melanoma pathogenesis at somatic level, mutually-exclusive mutations of NRAS and BRAF genes were observed at quite same rate (about two thirds) in cultured and in vivo melanomas (either primary or metastatic lesions). Conversely, p16

CDKN2A
gene alterations were observed at increased rates moving from primary to metastatic melanomas and melanoma cell lines. Activation of the ERK gene product was demonstrated to be consistently induced by a combination of molecular alterations (NRAS/BRAF mutations and p16

CDKN2A
silencing).

Conclusion

Our findings further clarified that: a) mutation prevalence in melanoma susceptibility genes may vary within each specific geographical area; b) multiple molecular events are accumulating during melanomagenesis.
Recurrence in oral and pharyngeal cancer is associated with quantitative MGMT promoter methylation
Authors: Taioli Emanuela , Ragin Camille , Wang Xiao-hong , Chen Jiangying , Langevin Scott M , Brown Ashley R , Gollin Susanne M , Garte Seymour , Sobol Robert W
Published: October 2009

Background

Biomarkers that predict clinical response, tumor recurrence or patient survival are severely lacking for most cancers, particularly for oral and pharyngeal cancer. This study examines whether gene-promoter methylation of tumor DNA correlates with survival and recurrence rates in a population of patients with oral or pharyngeal cancer.

Methods

The promoter methylation status of the DNA repair geneMGMTand the tumor suppressor genesCDKN2A and RASSF1were evaluated by methylation-specific PCR in 88 primary oral and pharyngeal tumors and correlated with survival and tumor recurrence. QuantitativeMGMTmethylation was also assessed.

Results

29.6% of the tumors presented withMGMTmethylation, 11.5% withCDKN2Amethylation and 12.1% withRASSF1methylation.MGMTpromoter methylation was significantly associated with poorer overall and disease-free survival. No differences in methylation status ofMGMTandRASSF1with HPV infection, smoking or drinking habits were observed. A significant inverse trend with the amount ofMGMTmethylation and overall and disease-free survival was observed (ptrend= 0.002 and 0.001 respectively).

Conclusion

These results implicateMGMTpromoter methylation as a possible biomarker for oral and pharyngeal cancer prognosis. The critical role of MGMT in DNA repair suggests that defective DNA repair may be correlative in the observed association betweenMGMTpromoter methylation and tumor recurrence. Follow-up studies should include further quantitative MSP-PCR measurement, global methylation profiling and detailed analysis of downstream DNA repair genes regulated by promoter methylation.
A theoretical framework to describe communication processes during medical disability assessment interviews
Authors: van Rijssen H Jolanda , Schellart Antonius JM , Anema Johannes R , van der Beek Allard J
Published: October 2009

Background

Research in different fields of medicine suggests that communication is important in physician-patient encounters and influences satisfaction with these encounters. It is argued that this also applies to the non-curative tasks that physicians perform, such as sickness certification and medical disability assessments. However, there is no conceptualised theoretical framework that can be used to describe intentions with regard to communication behaviour, communication behaviour itself, and satisfaction with communication behaviour in a medical disability assessment context.

Objective

The objective of this paper is to describe the conceptualisation of a model for the communication behaviour of physicians performing medical disability assessments in a social insurance context and of their claimants, in face-to-face encounters during medical disability assessment interviews and the preparation thereof.

Conceptualisation

The behavioural model, based on the Theory of Planned Behaviour (TPB), is conceptualised for the communication behaviour of social insurance physicians and claimants separately, but also combined during the assessment interview. Other important concepts in the model are the evaluation of communication behaviour (satisfaction), intentions, attitudes, skills, and barriers for communication.

Conclusion

The conceptualisation of the TPB-based behavioural model will help to provide insight into the communication behaviour of social insurance physicians and claimants during disability assessment interviews. After empirical testing of the relationships in the model, it can be used in other studies to obtain more insight into communication behaviour in non-curative medicine, and it could help social insurance physicians to adapt their communication behaviour to their task when performing disability assessments.
Replication of an empirical approach to delineate the heterogeneity of chronic unexplained fatigue
Authors: Aslakson Eric , Vollmer-Conna Uté , Reeves William C , White Peter D
Published: October 2009

Background

Chronic fatigue syndrome (CFS) is defined by self-reported symptoms. There are no diagnostic signs or laboratory markers, and the pathophysiology remains inchoate. In part, difficulties identifying and replicating biomarkers and elucidating the pathophysiology reflect the heterogeneous nature of the syndromic illness CFS. We conducted this analysis of people from defined metropolitan, urban, and rural populations to replicate our earlier empirical delineation of medically unexplained chronic fatigue and CFS into discrete endophenotypes. Both the earlier and current analyses utilized quantitative measures of functional impairment and symptoms as well as laboratory data. This study and the earlier one enrolled participants from defined populations and measured the internal milieu, which differentiates them from studies of clinic referrals that examine only clinical phenotypes.

Methods

This analysis evaluated 386 women identified in a population-based survey of chronic fatigue and unwellness in metropolitan, urban, and rural populations of the state of Georgia, USA. We used variables previously demonstrated to effectively delineate endophenotypes in an attempt to replicate identification of these endophenotypes. Latent class analyses were used to derive the classes, and these were compared and contrasted to those described in the previous study based in Wichita, Kansas.

Results

We identified five classes in the best fit analysis. Participants in Class 1 (25%) were polysymptomatic, with sleep problems and depressed mood. Class 2 (24%) was also polysymptomatic, with insomnia and depression, but participants were also obese with associated metabolic strain. Class 3 (20%) had more selective symptoms but was equally obese with metabolic strain. Class 4 (20%) and Class 5 (11%) consisted of nonfatigued, less symptomatic individuals, Class 4 being older and Class 5 younger. The classes were generally validated by independent variables. People with CFS fell equally into Classes 1 and 2. Similarities to the Wichita findings included the same four main defining variables of obesity, sleep problems, depression, and the multiplicity of symptoms. Four out of five classes were similar across both studies.

Conclusion

These data support the hypothesis that chronic medically unexplained fatigue is heterogeneous and can be delineated into discrete endophenotypes that can be replicated. The data do not support the current perception that CFS represents a unique homogeneous disease and suggests broader criteria may be more explanatory. This replication suggests that delineation of endophenotypes of CFS and associated ill health may be necessary in order to better understand etiology and provide more patient-focused treatments.
Chemokine receptor expression and functional effects of chemokines on B cells: implication in the pathogenesis of rheumatoid arthritis
Authors: Nanki Toshihiro , Takada Kazuki , Komano Yukiko , Morio Tomohiro , Kanegane Hirokazu , Nakajima Atsuo , Lipsky Peter E , Miyasaka Nobuyuki
Published: October 2009

Introduction

Accumulation of B cells in the rheumatoid arthritis (RA) synovium has been reported, and it has been thought that these cells might contribute to the pathogenesis of RA by antigen presentation, autoantibody production, and/or inflammatory cytokine production. Chemokines could enhance the accumulation of B cells in the synovium. The aims of this study were to determine chemokine receptor expression by B cells both in the peripheral blood of normal donors and subjects with RA, and at the inflammatory site in RA, and the effects of chemokines on B cell activation.

Methods

Cell surface molecule expression was analyzed by flow cytometry. Cellular migration was assessed using chemotaxis chambers. Cellular proliferation was examined by 3H-thymidine incorporation. Tumor necrosis factor (TNF) production was assayed by enzyme-linked immunosorbent assay.

Results

Significant numbers of peripheral blood B cells of healthy donors and subjects with RA expressed CC chemokine receptor (CCR)5 and CXCR3, and most B cells expressed CCR6, CCR7, CXCR4 and CXCR5. CCR5 expression was more frequent on CD27+ than CD27- peripheral blood B cells of healthy donors and RA. Synovial B cells more frequently expressed CCR5, but less often expressed CCR6, CCR7 and CXCR5 compared to peripheral blood in RA. Further functional analyses were performed on peripheral blood B cells from healthy donors. Migration of peripheral blood B cells, especially CD27+ B cells, was enhanced by CC chemokine ligand (CCL)20, CCL19, CCL21 and CXCL12. All four chemokines alone induced B cell proliferation; with CCL21 being the most effective. CCL21 also enhanced the proliferation of anti-immunoglobulin (Ig)M-stimulated B cells and blockade of CCR7 inhibited this effect. CCL20, CCL21 and CXCL12 enhanced TNF production by anti-IgM mAb-stimulated B cells. Finally, stimulation with CXCL12, but not CCL20, CCL19 and CCL21, enhanced inducible costimulator-ligand (ICOSL) expression by peripheral blood B cells of healthy donors and RA, but did not increase B cell-activating factor receptor or transmembrane activator and CAML-interactor.

Conclusions

The data suggest that CCR5, CCR6, CCR7, CXCR3, CXCR4 and CXCR5 may be important for the B cell migration into the synovium of RA patients, and also their local proliferation, cytokine production and ICOSL expression in the synovium.
MethMarker: user-friendly design and optimization of gene-specific DNA methylation assays
Authors: Schüffler Peter , Mikeska Thomas , Waha Andreas , Lengauer Thomas , Bock Christoph
Published: October 2009

DNA methylation is a key mechanism of epigenetic regulation that is frequently altered in diseases such as cancer. To confirm the biological or clinical relevance of such changes, gene-specific DNA methylation changes need to be validated in multiple samples. We have developed the MethMarker http://methmarker.mpi-inf.mpg.de/ software to help design robust and cost-efficient DNA methylation assays for six widely used methods. Furthermore, MethMarker implements a bioinformatic workflow for transforming disease-specific differentially methylated genomic regions into robust clinical biomarkers.
Draft genome sequence of the Daphnia pathogen Octosporea bayeri: insights into the gene content of a large microsporidian genome and a model for host-parasite interactions
Authors: Corradi Nicolas , Haag Karen L , Pombert Jean-François , Ebert Dieter , Keeling Patrick J
Published: October 2009

Background

The highly compacted 2.9-Mb genome of Encephalitozoon cuniculi placed the microsporidia in the spotlight, encoding a mere 2,000 proteins and a highly reduced suite of biochemical pathways. This extreme level of reduction is not universal across the microsporidia, with genomes known to vary up to sixfold in size, suggesting that some genomes may harbor a gene content that is not as reduced as that of Enc. cuniculi. In this study, we present an in-depth survey of the large genome of Octosporea bayeri, a pathogen of Daphnia magna, with an estimated genome size of 24 Mb, in order to shed light on the organization and content of a large microsporidian genome.

Results

Using Illumina sequencing, 898 Mb of O. bayeri genome sequence was generated, resulting in 13.3 Mb of unique sequence. We annotated a total of 2,174 genes, of which 893 encodes proteins with assigned function. The gene density of the O. bayeri genome is very low on average, but also highly uneven, so gene-dense regions also occur. The data presented here suggest that the O. bayeri proteome is well represented in this analysis and is more complex that that of Enc. cuniculi. Functional annotation of O. bayeri proteins suggests that this species might be less biochemically dependent on its host for its metabolism than its more reduced relatives.

Conclusions

The combination of the data presented here, together with the imminent annotated genome of Daphnia magna, will provide a wealth of genetic and genomic tools to study host-parasite interactions in an interesting model for pathogenesis.
Regulation of TNF-induced oxygen radical production in human neutrophils: role of δ-PKC
Authors: Kilpatrick Laurie E , Sun Shuang , Li Haiying , Vary Thomas C , Korchak Helen M
Published: October 2009

δ-PKC is a key regulator of early events in the assembly and activation of the NADPH oxidase elicited by TNF in adherent neutrophils.

In human neutrophils, TNF-elicited O2− production requires adherence and integrin activation. How this cooperative signaling between TNFRs and integrins regulates O2− generation has yet to be fully elucidated. Previously, we identified δ-PKC as a critical early regulator of TNF signaling in adherent neutrophils. In this study, we demonstrate that inhibition of δ-PKC with a dominant-negative δ-PKC TAT peptide resulted in a significant delay in the onset time of TNF-elicited O2− generation but had no effect on Vmax, indicating an involvement of δ-PKC in the initiation of O2− production. In contrast, fMLP-elicited O2− production in adherent and nonadherent neutrophils was δ-PKC-independent, suggesting differential regulation of O2− production. An important step in activation of the NADPH oxidase is phosphorylation of the cytosolic p47phox component. In adherent neutrophils, TNF triggered a time-dependent association of δ-PKC with p47phox, which was associated with p47phox phosphorylation, indicating a role for δ-PKC in regulating O2− production at the level of p47phox. Activation of ERK and p38 MAPK is also required for TNF-elicited O2− generation. TNF-mediated ERK but not p38 MAPK recruitment to p47phox was δ-PKC-dependent. δ-PKC activity is controlled through serine/threonine phosphorylation, and phosphorylation of δ-PKC (Ser643) and δ-PKC (Thr505) was increased significantly by TNF in adherent cells via a PI3K-dependent process. Thus, signaling for TNF-elicited O2− generation is regulated by δ-PKC. Adherence-dependent cooperative signaling activates PI3K signaling, δ-PKC phosphorylation, and δ-PKC recruitment to p47phox. δ-PKC activates p47phox by serine phosphorylation or indirectly through control of ERK recruitment to p47phox.
HIV-1 regulation of latency in the monocyte-macrophage lineage and in CD4+ T lymphocytes
Authors: Redel Laetitia , Le Douce Valentin , Cherrier Thomas , Marban Céline , Janossy Andrea , Aunis Dominique , Van Lint Carine , Rohr Olivier , Schwartz Christian
Published: October 2009

Review of molecular mechanisms of latency used by HIV-1 to establish viral reservoirs within CD4 T cells and/or macrophages.

The introduction in 1996 of the HAART raised hopes for the eradication of HIV-1. Unfortunately, the discovery of latent HIV-1 reservoirs in CD4+ T cells and in the monocyte-macrophage lineage proved the optimism to be premature. The long-lived HIV-1 reservoirs constitute a major obstacle to the eradication of HIV-1. In this review, we focus on the establishment and maintenance of HIV-1 latency in the two major targets for HIV-1: the CD4+ T cells and the monocyte-macrophage lineage. Understanding the cell-type molecular mechanisms of establishment, maintenance, and reactivation of HIV-1 latency in these reservoirs is crucial for efficient therapeutic intervention. A complete viral eradication, the holy graal for clinicians, might be achieved by strategic interventions targeting latently and productively infected cells. We suggest that new approaches, such as the combination of different kinds of proviral activators, may help to reduce dramatically the size of latent HIV-1 reservoirs in patients on HAART.
Interleukin 27: a double-edged sword for offense and defense
Authors: Yoshida Hiroki , Nakaya Mako , Miyazaki Yoshiyuki
Published: October 2009

Interleukin 27 has pro- and anti-inflammatory features and is a potent target for therapy of various immune diseases.

Cytokine-mediated immunity plays a crucial role in the pathogenesis of various diseases including infection and autoimmune diseases. IL-27, along with IL-12, −23, and −35, belongs to the IL-12 cytokine family. These family members play roles in regulation of Th cell differentiation. IL-27 is unique in that although it induces Th1 differentiation, the same cytokine suppresses immune responses. In the absence of IL-27-mediated immunosuppression, hyperproduction of various proinflammatory cytokines concomitant with severe inflammation is observed. The immunosuppressive effects of IL-27 depend on IL-2 suppression, inhibition of Th17 development, and induction of IL-10 production. Administration of IL-27 suppresses some diseases of autoimmune or allergic origin, demonstrating its potential in therapy of diseases mediated by inflammatory cytokines. In this review, we discuss recent studies about the role of IL-27 in immune regulation in view of its pro- and anti-inflammatory properties and possible therapeutic application.
Risk of Relapse of Childhood Acute Lymphoblastic Leukemia Is Predicted By Flow Cytometric Measurement of Residual Disease on Day 15 Bone Marrow
Authors: Basso Giuseppe , Veltroni Marinella , Valsecchi Maria Grazia , Dworzak Michael N. , Ratei Richard , Silvestri Daniela , Benetello Alessandra , Buldini Barbara , Maglia Oscar , Masera Giuseppe , Conter Valentino , Arico Maurizio , Biondi Andrea , Gaipa Giuseppe
Published: October 2009

Purpose

Speed of blast clearance is an indicator of outcome in childhood acute lymphoblastic leukemia (ALL). Availability of measurement of minimal residual disease (MRD) at an early time point with a reduced-cost method is of clinical relevance. In the AIEOP-BFM-ALL (Associazione Italiana Ematologia Oncologia Pediatrica and Berlin-Frankfurt-Münster Study Group) 2000 trial, patients were stratified by levels of polymerase chain reaction (PCR) MRD at day +33 and +78. AIEOP studied the prognostic impact of MRD measured by flow cytometry (FCM) at day 15 of induction therapy.

Patients and Methods

Bone marrow samples from 830 Italian patients were collected on day 15, after 14 days of steroids, and one dose of intrathecal methotrexate, vincristine, daunorubicine, and asparaginase. Cells were analyzed by four-color FCM for detection of leukemia-associated immunophenotypes.

Results

Three patient risk groups were identified by FCM: standard (< 0.1% blast cells; 42% of the total), intermediate (0.1 to < 10%; 47%), and high (≥ 10%; 11%). Their 5-year cumulative incidences of relapse were 7.5% (SE, 1.5), 17.5% (SE, 2.1), and 47.2% (SE, 5.9), respectively. In multivariate analysis, FCM was the most important prognostic factor among those available by day 15, with two-fold and five-fold increase in the risk of relapse compared with patients with less than 0.1%. PCR MRD, when added to the model, had significant prognostic impact; yet high levels of FCM MRD retained an independent ability to detect a significantly higher risk of relapse.

Conclusion

Measurement of FCM MRD in day 15 bone marrow was the most powerful early predictor of relapse, applicable to virtually all patients; it may complement PCR MRD–based stratification including later time points, thus allowing additional treatment tailoring.
Novel Breast Tissue Feature Strongly Associated With Risk of Breast Cancer
Authors: McKian Kevin P. , Reynolds Carol A. , Visscher Daniel W. , Nassar Aziza , Radisky Derek C. , Vierkant Robert A. , Degnim Amy C. , Boughey Judy C. , Ghosh Karthik , Anderson Stephanie S. , Minot Douglas , Caudill Jill L. , Vachon Celine M. , Frost Marlene H. , Pankratz V. Shane , Hartmann Lynn C.
Published: October 2009

Purpose

Accurate, individualized risk prediction for breast cancer is lacking. Tissue-based features may help to stratify women into different risk levels. Breast lobules are the anatomic sites of origin of breast cancer. As women age, these lobular structures should regress, which results in reduced breast cancer risk. However, this does not occur in all women.

Methods

We have quantified the extent of lobule regression on a benign breast biopsy in 85 patients who developed breast cancer and 142 age-matched controls from the Mayo Benign Breast Disease Cohort, by determining number of acini per lobule and lobular area. We also calculated Gail model 5-year predicted risks for these women.

Results

There is a step-wise increase in breast cancer risk with increasing numbers of acini per lobule (P = .0004). Adjusting for Gail model score, parity, histology, and family history did not attenuate this association. Lobular area was similarly associated with risk. The Gail model estimates were associated with risk of breast cancer (P = .03). We examined the individual accuracy of these measures using the concordance (c) statistic. The Gail model c statistic was 0.60 (95% CI, 0.50 to 0.70); the acinar count c statistic was 0.65 (95% CI, 0.54 to 0.75). Combining acinar count and lobular area, the c statistic was 0.68 (95% CI, 0.58 to 0.78). Adding the Gail model to these measures did not improve the c statistic.

Conclusion

Novel, tissue-based features that reflect the status of a woman's normal breast lobules are associated with breast cancer risk. These features may offer a novel strategy for risk prediction.
Phase III Trial of Casopitant, a Novel Neurokinin-1 Receptor Antagonist, for the Prevention of Nausea and Vomiting in Patients Receiving Moderately Emetogenic Chemotherapy
Authors: Herrstedt Jørn , Apornwirat Wichit , Shaharyar Ahmed , Aziz Zeba , Roila Fausto , Van Belle Simon , Russo Mark W. , Levin Jeremey , Ranganathan Salabha , Guckert Mary , Grunberg Steven M.
Published: October 2009

Purpose

The purpose of this phase III trial was to evaluate the efficacy and safety of regimens containing casopitant, a novel neurokinin-1 receptor antagonist, for the prevention of chemotherapy-induced nausea and vomiting during the first cycle in patients receiving moderately emetogenic chemotherapy (MEC).

Patients and Methods

Predominantly female patients (98%) diagnosed with breast cancer (96%) who were chemotherapy-naïve and scheduled to receive an anthracycline and cyclophosphamide (AC) –based regimen were enrolled onto this multinational, randomized, double-blind, parallel-group, placebo-controlled clinical trial. All patients received dexamethasone 8 mg intravenously (IV) on day 1 and oral ondansetron 8 mg twice daily on days 1 to 3. Patients were randomly assigned to a control arm (placebo), a single oral dose casopitant arm (150 mg orally [PO] on day 1), a 3-day oral casopitant arm (150 mg PO on day 1 plus 50 mg PO on days 2 to 3), or a 3-day IV/oral casopitant arm (90 mg IV on day 1 plus 50 mg PO on days 2 to 3). The primary end point was the proportion of patients achieving complete response (no vomiting/retching or rescue medications) in the first 120 hours after the initiation of MEC.

Results

A significantly greater proportion of patients in the single-dose oral casopitant arm, 3-day oral casopitant arm, and 3-day IV/oral casopitant arm achieved complete response (73%, 73%, and 74%, respectively) versus control (59%; P < .0001). The study did not demonstrate a reduced proportion of patients with nausea or significant nausea in those receiving casopitant. Adverse events were balanced among study arms.

Conclusion

All casopitant regimens studied were more effective than the control regimen. Casopitant was generally well tolerated.
Alpha-Fetoprotein Response After Locoregional Therapy for Hepatocellular Carcinoma: Oncologic Marker of Radiologic Response, Progression, and Survival
Authors: Riaz Ahsun , Ryu Robert K. , Kulik Laura M. , Mulcahy Mary F. , Lewandowski Robert J. , Minocha Jeet , Ibrahim Saad M. , Sato Kent T. , Baker Talia , Miller Frank H. , Newman Steven , Omary Reed , Abecassis Michael , Benson Al B. , Salem Riad
Published: October 2009

Purpose

Alpha-fetoprotein (AFP) is considered to be an indicator of tumor activity in hepatocellular carcinoma (HCC). We present a novel correlation of AFP response to radiologic response, time-to-progression (TTP), progression-free survival (PFS), and overall survival (OS) in patients treated with locoregional therapies.

Patients and Methods

Four hundred sixty-three patients with HCC were treated with chemoembolization or radioembolization at our institution. One hundred twenty-five patients with baseline AFP higher than 200 ng/mL were studied for this analysis. AFP response was defined as more than 50% decrease from baseline. One hundred nineteen patients with follow-up imaging were studied for the AFP imaging correlation analysis. AFP response was correlated to radiologic response, TTP, PFS, and OS. Multivariate analyses were performed.

Results

Eighty-one patients (65%) showed AFP response. AFP response was seen in 26 (55%) of 47 and 55 (70%) of 78 of patients treated with chemoembolization and radioembolization, respectively (P = .12). WHO response was seen in 41 (53%) of 77 and 10 (24%) of 42 of AFP responders and nonresponders, respectively (P = .002). The hazard ratio (HR) for TTP in AFP nonresponders compared with responders was 2.8 (95% CI, 1.5 to 5.1). The HR for PFS was 4.2 (95% CI, 2.4 to 7.2) in AFP nonresponders compared with responders. The HR for OS in AFP nonresponders compared with responders was 5.5 (95% CI, 3.1 to 9.9) and 2.7 (95% CI, 1.6 to 4.6) on univariate and multivariate analyses, respectively.

Conclusion

The data presented support the use of AFP response seen after locoregional therapy as an ancillary method of assessing tumor response and survival, as well as an early objective screening tool for progression by imaging.