bluuebunny/crossref_metadata_2025 huggingface dataset:
Characterization and quantification of clonal heterogeneity among hematopoietic stem cells: a model-based approach
Authors: Roeder Ingo , Horn Katrin , Sieburg Hans-Bernd , Cho Rebecca , Muller-Sieburg Christa , Loeffler Markus
Published: September 2008

Hematopoietic stem cells (HSCs) show pronounced heterogeneity in self-renewal and differentiation behavior, which is reflected in their repopulation kinetics. Here, a single-cell–based mathematical model of HSC organization is used to examine the basis of HSC heterogeneity. Our modeling results, which are based on the analysis of limiting dilution competitive repopulation experiments in mice, demonstrate that small quantitative but clonally fixed differences of cellular properties are necessary and sufficient to account for the observed functional heterogeneity. The model predicts, and experimental data validate, that competitive pressures will amplify small clonal differences into large changes in the number of differentiated progeny. We further predict that the repertoire of HSC clones will evolve over time. Last, our results suggest that larger differences in cellular properties have to be assumed to account for genetically determined differences in HSC behavior as observed in different inbred mice strains. The model provides comprehensive systemic and quantitative insights into the clonal heterogeneity among HSCs with potential applications in predicting the behavior of malignant and/or genetically modified cells.
Vaccination with autologous tumor-loaded dendritic cells induces clinical and immunologic responses in indolent B-cell lymphoma patients with relapsed and measurable disease: a pilot study
Authors: Di Nicola Massimo , Zappasodi Roberta , Carlo-Stella Carmelo , Mortarini Roberta , Pupa Serenella M. , Magni Michele , Devizzi Liliana , Matteucci Paola , Baldassari Paola , Ravagnani Fernando , Cabras Antonello , Anichini Andrea , Gianni Alessandro M.
Published: September 2008

Eighteen relapsed patients with measurable indolent non-Hodgkin lymphoma (NHL) were vaccinated with dendritic cells (DCs) loaded with killed autologous tumor cells. Six patients had objective clinical responses including 3 continuous complete responses (CRs) and 3 partial responses (PRs), with a median follow up of 50.5 months. Eight patients had stable disease, whereas 4 had progressive disease. Clinical responses were significantly associated with a reduction in CD4+CD25+FOXP3+ regulatory T cells, an increase in CD3−CD56dimCD16+ natural killer (NK) cells, and maturation of lymphocytes to the effector memory stage in either postvaccination peripheral blood or tumor specimen samples. In partial responding patients, vaccination significantly boosted the IFN-γ–producing T-cell response to autologous tumor challenge. In one HLA-A*0201+ patient who achieved CR, IL-4 release by circulating T cells in response to tumor-specific IgH-encoded peptides was also documented. Immunohistochemical analysis of tumor biopsies using biotin-conjugated autologous serum samples revealed a tumor-restricted humoral response only in the postvaccination serum from responding patients. Collectively these results demonstrate that vaccination with tumor-loaded DCs may induce both T- and B-cell responses and produces clinical benefits in indolent NHL patients with measurable disease. This study is registered with the Istituto Superiore di Sanità: http://www.iss.it with protocol number 7578-PRE 21-801.
Localization of the Carnation Italian ringspot virus replication protein p36 to the mitochondrial outer membrane is mediated by an internal targeting signal and the TOM complex
Authors: Hwang Yeen Ting , McCartney Andrew W , Gidda Satinder K , Mullen Robert T
Published: September 2008

Background

Carnation Italian ringspot virus (CIRV) is a positive-strand RNA virus that causes massive structural alterations of mitochondria in infected host cells, the most conspicuous being the formation of numerous internal vesicles/spherules that are derived from the mitochondrial outer membrane and serve as the sites for viral RNA replication. While the membrane-bound components of the CIRV replication complex, including a 36-kD RNA-binding protein (p36), are known to be essential for these changes in mitochondrial morphology and are relatively well characterized in terms of their roles in nascent viral RNA synthesis, how these proteins are specifically targeted and inserted into mitochondria is poorly defined.

Results

Here we report on the molecular signal responsible for sorting p36 to the mitochondrial outer membrane. Using a combination of gain-of-function assays with portions of p36 fused to reporter proteins and domain-swapping assays with p36 and another closely-related viral RNA-binding protein, p33, that sorts specifically to the peroxisomal boundary membrane, we show that the mitochondrial targeting information in p36 resides within its two transmembrane domains (TMDs) and intervening hydrophilic loop sequence. Comprehensive mutational analysis of these regions in p36 revealed that the primary targeting determinants are the moderate hydrophobicity of both TMDs and the positively-charged face of an amphipathic helix within the intervening loop sequence. We show also using bimolecular fluorescence complementation (BiFC) that p36 interacts with certain components of the translocase complex in the mitochondrial outer membrane (TOM), but not with the sorting and assembly machinery (SAM).

Conclusion

Our results provide insight to how viruses, such as CIRV, exploit specific host-cell protein sorting pathways to facilitate their replication. The characterization of the targeting and insertion of p36 into the mitochondrial outer membrane also sheds light on the mechanisms involved in sorting of host-cell membrane proteins to mitochondria, a process that has been largely unexplored in plants.
The rules of gene expression in plants: Organ identity and gene body methylation are key factors for regulation of gene expression in Arabidopsis thaliana
Authors: Aceituno Felipe F , Moseyko Nick , Rhee Seung Y , Gutiérrez Rodrigo A
Published: September 2008

Background

Microarray technology is a widely used approach for monitoring genome-wide gene expression. For Arabidopsis, there are over 1,800 microarray hybridizations representing many different experimental conditions on Affymetrix™ ATH1 gene chips alone. This huge amount of data offers a unique opportunity to infer the principles that govern the regulation of gene expression in plants.

Results

We used bioinformatics methods to analyze publicly available data obtained using the ATH1 chip from Affymetrix. A total of 1887 ATH1 hybridizations were normalized and filtered to eliminate low-quality hybridizations. We classified and compared control and treatment hybridizations and determined differential gene expression. The largest differences in gene expression were observed when comparing samples obtained from different organs. On average, ten-fold more genes were differentially expressed between organs as compared to any other experimental variable. We defined "gene responsiveness" as the number of comparisons in which a gene changed its expression significantly. We defined genes with the highest and lowest responsiveness levels as hypervariable and housekeeping genes, respectively. Remarkably, housekeeping genes were best distinguished from hypervariable genes by differences in methylation status in their transcribed regions. Moreover, methylation in the transcribed region was inversely correlated (R2= 0.8) with gene responsiveness on a genome-wide scale. We provide an example of this negative relationship using genes encoding TCA cycle enzymes, by contrasting their regulatory responsiveness to nitrate and methylation status in their transcribed regions.

Conclusion

Our results indicate that the Arabidopsis transcriptome is largely established during development and is comparatively stable when faced with external perturbations. We suggest a novel functional role for DNA methylation in the transcribed region as a key determinant capable of restraining the capacity of a gene to respond to internal/external cues. Our findings suggest a prominent role for epigenetic mechanisms in the regulation of gene expression in plants.
Passive administration of monoclonal antibodies to Anthrolysin O prolong survival in mice lethally infected with Bacillus anthracis
Authors: Nakouzi Antonio , Rivera Johanna , Rest Richard F , Casadevall Arturo
Published: September 2008

Background

Bacillus anthracishas two major virulence factors: a tripartite toxin that produces lethal and edema toxins and a polyglutamic acid capsule. A recent report suggested that a toxin belonging to the cholesterol dependant cytolysin (CDC) family, anthrolysin O (ALO) was a new virulence factor forB. anthracisbut subsequent studies have questioned its relevance in pathogenesis. In this study, we examined the immunogenicity of recombinant anthrolysin O (rALO) in mice.

Results

BALB/c mice immunized with rALO and boosted after two weeks, produce sera with strong Ab responses with a predominance of IgG1 and IgG2a. Five hybridomas to rALO were recovered representing the IgM, IgG1, and IgG2b isotypes. Passive administration of 3 of the five monoclonal antibodies (mAbs) to rALO prior to infection with lethal intravenous (i.v.)B. anthracisSterne strain infection in mice was associated with enhanced average survival and a greater likelihood of surviving infection. A combination of two mAbs to ALO was more effective than either mAb separately. One mAb (64F8) slowed the toxicity of rALO for J774.16 macrophage-like cells.

Conclusion

Our results suggest that ALO contributes to the virulence ofB. anthracisSterne strain in this infection model and that Ab response to ALO may contribute to protection in certain circumstances.
MalVac: Database of malarial vaccine candidates
Authors: Chaudhuri Rupanjali , Ahmed Shakil , Ansari Faraz Alam , Singh Harinder Vir , Ramachandran Srinivasan
Published: September 2008

Background

The sequencing of genomes of the Plasmodium species causing malaria, offers immense opportunities to aid in the development of new therapeutics and vaccine candidates through Bioinformatics tools and resources.

Methods

The starting point of MalVac database is the collection of known vaccine candidates and a set of predicted vaccine candidates identified from the whole proteome sequences of Plasmodium species provided by PlasmoDb 5.4 release (31st October 2007). These predicted vaccine candidates are the adhesins and adhesin-like proteins from Plasmodium species,Plasmodium falciparum,Plasmodium vivaxandPlasmodium yoelii. Subsequently, these protein sequences were analysed through 20 publicly available algorithms to obtain Orthologs, Paralogs, BetaWraps, TargetP, TMHMM, SignalP, CDDSearch, BLAST with Human Ref. Proteins, T-cell epitopes, B-cell epitopes, Discotopes, and allergen predictions. All of this information was collected and organized with the ORFids of the protein sequences as primary keys. This information is relevant from the view point of Reverse Vaccinology in facilitating decision making on the most probable choice for vaccine strategy.

Results

Detailed information on the patterning of the epitopes and other motifs of importance from the viewpoint of reverse vaccinology has been obtained on the most probable protein candidates for vaccine investigation from three major malarial species. Analysis data are available on 161 adhesin proteins fromP. falciparum, 137 adhesin proteins fromP. vivaxand 34 adhesin proteins fromP. yoelii. The results are displayed in convenient tabular format and a facility to export the entire data has been provided. The MalVac database is a "community resource". Users are encouraged to export data and further contribute by value addition. Value added data may be sent back to the community either through MalVac or PlasmoDB.

Conclusion

A web server MalVac for facilitation of the identification of probable vaccine candidates has been developed and can be freely accessed.
Distinction of Plasmodium falciparum recrudescence and re-infection by MSP2 genotyping: A caution about unstandardized classification criteria
Authors: Rouse Petrica , Mkulama Mtawa AP , Thuma Philip E , Mharakurwa Sungano
Published: September 2008

Background

Plasmodium falciparum genotyping with molecular polymorphic markers is widely employed to distinguish recrudescence from re-infection in antimalarial drug efficacy monitoring programmes. However, limitations occur on agarose gel DNA measurements used to resolve the polymorphisms. Without empirical data, the current distinction of pre- and post-treatment bands, as persistent or new infection, is subjective and often varying by author. This study measures empirical tolerance limits for classifying different-sized bands as same or different alleles during MSP2 genotyping.

Methods

P. falciparum field samples from 161 volunteers were genotyped by nested PCR using polymorphic MSP2 family-specific primers. Data were analysed to determine variability of band size measurements between identical MSP2 alleles randomized into different agarose lanes.

Results

The mean (95% CI) paired difference in band size between identical alleles was 9.8 bp (1.48 – 18.16 bp, p = 0.022) for 3D7/IC and 2.54 (-3.04 – 8.05 bp, p = 0.362) for FC27. Based on these findings, pre- and post-treatment samples with 3D7/IC alleles showing less than 18 bp difference corresponded to recrudescence, with 95% confidence, while greater difference indicated new infection. FC27 allele differences were much narrower. For both 3D7/IC and FC27 amplicon, allele detection sensitivity was significantly higher with 13 μl compared to 20 μl or 30 μl lane loading volumes.

Conclusion

During MSP genotyping, it is useful to standardize classifications against measurement of background variability on identical alleles, in order to obtain reliable findings. It is critical to use a fixed optimal lane loading volume for constant allele patency, to avoid the disappearance or false appearance of new infection.
Tissue specific promoters improve specificity of AAV9 mediated transgene expression following intra-vascular gene delivery in neonatal mice
Authors: Pacak Christina A , Sakai Yoshihisa , Thattaliyath Bijoy D , Mah Cathryn S , Byrne Barry J
Published: September 2008

The AAV9 capsid displays a high natural affinity for the heart following a single intravenous (IV) administration in both newborn and adult mice. It also results in substantial albeit relatively lower expression levels in many other tissues. To increase the overall safety of this gene delivery method we sought to identify which one of a group of promoters is able to confer the highest level of cardiac specific expression and concurrently, which is able to provide a broad biodistribution of expression across both cardiac and skeletal muscle. The in vivo behavior of five different promoters was compared: CMV, desmin (Des), alpha-myosin heavy chain (α-MHC), myosin light chain 2 (MLC-2) and cardiac troponin C (cTnC). Following IV administration to newborn mice, LacZ expression was measured by enzyme activity assays. Results showed that rAAV2/9-mediated gene delivery using the α-MHC promoter is effective for focal transgene expression in the heart and the Des promoter is highly suitable for achieving gene expression in cardiac and skeletal muscle following systemic vector administration. Importantly, these promoters provide an added layer of control over transgene activity following systemic gene delivery.
Microbial Diagnostic Array Workstation (MDAW): a web server for diagnostic array data storage, sharing and analysis
Authors: Scaria Joy , Sreedharan Aswathy , Chang Yung-Fu
Published: September 2008

Background

Microarrays are becoming a very popular tool for microbial detection and diagnostics. Although these diagnostic arrays are much simpler when compared to the traditional transcriptome arrays, due to the high throughput nature of the arrays, the data analysis requirements still form a bottle neck for the widespread use of these diagnostic arrays. Hence we developed a new online data sharing and analysis environment customised for diagnostic arrays.

Methods

Microbial Diagnostic Array Workstation (MDAW) is a database driven application designed in MS Access and front end designed in ASP.NET.

Conclusion

MDAW is a new resource that is customised for the data analysis requirements for microbial diagnostic arrays.
Double primary bronchogenic carcinoma of the lung and papillary thyroid carcinoma: a case report
Authors: Cheng Jen-Hsun , Huang Ying-Chieh , Kuo Chih , Lai Yih-Shyong , Wu Tzu-Ching , Tsao Thomas Chang-Yao , Luh Shi-Ping , Tsai Chong-Bin
Published: September 2008

Introduction

Double primary bronchogenic carcinoma and papillary carcinoma of the thyroid are extremely rare. We describe the case of a patient who underwent surgical resection for these two cancers.

Case presentation

A 56-year-old man presented to our hospital complaining of a cough with blood-tinged sputum. A slowly growing mass in the left lobe of the lung had been noted for about 1 year. He underwent video-assisted thoracic surgery of the left lower lobe and mediastinal lymph node dissection through an 8 cm utility incision. Pathology revealed a well-differentiated adenocarcinoma and the dissected lymph nodes were negative for malignancy. He also complained of a mass in his neck, which had grown slowly for over 5 years. A computed tomography scan of the neck revealed a left thyroid mass compressing the trachea towards the right side. There was no cervical lymphadenopathy. A left thyroid lobectomy was performed and pathology revealed a papillary carcinoma. Thus, he underwent a second operation to remove the right lobe of the thyroid. He underwent subsequent adjuvant chemotherapy.

Conclusion

In a review of the literature, it appears that there has only been one previously reported case of these two cancers, which was in Japan. The relationship between these two cancers is still unclear, and more case reports are required to determine this relationship.
HSV-tk/GCV gene therapy mediated by EBV-LMP1 for EBV-associated cancer
Authors: Lifang Yang , Min Tang , Midan Ai , Ya Cao
Published: September 2008

Background

To investigate the feasibility of gene therapy in treating Epstein-Barr virus (EBV)-associated cancer by employing the suicide gene, herpes simplex virus thymidine kinase/ganciclovir (HSV-tk/GCV), which uses the signaling pathway through the HIV-long terminal repeat (LTR) gene which is expressed from a nuclear factor-κB (NF-κB)-binding motif-containing promoter that is regulated by EBV-latent membrane protein 1 (LMP1) via NF-κB.

Methods

First, we constructed the plasmid pVLTR-tk, which was regulated by EBV-LMP1 via NF-κB, and then investigated the cytotoxic effect of the pVLTR-tk/GCV on cancer cells, using MTT assays, clonogenic assays, flow cytometry, and animal experiments.

Results

The activation of TK was increased after transfection of the pVLTR-tk into the EBV-LMP1 positive cells. After GCV treatment, the clonogenicity and survival of the cells substantially declined, and a bystander effect was also observed. The LMP1 positive cells exhibited remarkable apoptosis following pVLTR-tk/GCV treatment, and the pVLTR-tk/GCV restrained tumor growth in vivo for EBV-LMP1 positive cancers.

Conclusion

The pVLTR-tk/GCV suicide gene system may be used as a new gene targeting strategy for EBV-associated cancer.
Evolutionary rate and gene expression across different brain regions
Authors: Tuller Tamir , Kupiec Martin , Ruppin Eytan
Published: September 2008

Background

The evolutionary rate of a protein is a basic measure of evolution at the molecular level. Previous studies have shown that genes expressed in the brain have significantly lower evolutionary rates than those expressed in somatic tissues.

Results

We study the evolutionary rates of genes expressed in 21 different human brain regions. We find that genes highly expressed in the more recent cortical regions of the brain have lower evolutionary rates than genes highly expressed in subcortical regions. This may partially result from the observation that genes that are highly expressed in cortical regions tend to be highly expressed in subcortical regions, and thus their evolution faces a richer set of functional constraints. The frequency of mammal-specific and primate-specific genes is higher in the highly expressed gene sets of subcortical brain regions than in those of cortical brain regions. The basic inverse correlation between evolutionary rate and gene expression is significantly stronger in brain versus nonbrain tissues, and in cortical versus subcortical regions. Extending upon this cortical/subcortical trend, this inverse correlation is generally more marked for tissues that are located higher along the cranial vertical axis during development, giving rise to the possibility that these tissues are also more evolutionarily recent.

Conclusions

We find that cortically expressed genes are more conserved than subcortical ones, and that gene expression levels exert stronger constraints on sequence evolution in cortical versus subcortical regions. Taken together, these findings suggest that cortically expressed genes are under stronger selective pressure than subcortically expressed genes.
Regulation of MHC II and CD1 antigen presentation: from ubiquity to security
Authors: Gelin Catherine , Sloma Ivan , Charron Dominique , Mooney Nuala
Published: September 2008

MHC class II and CD1-mediated antigen presentation on various APCs [B cells, monocytes, and dendritic cells (DC)] are subject to at least three distinct levels of regulation. The first one concerns the expression and structure of the antigen-presenting molecules; the second is based on the extracellular environment and signals of danger detected. However, a third level of regulation, which has been largely overlooked, is determined by lateral associations between antigen-presenting molecules and other proteins, their localization in specialized microdomains within the plasma membrane, and their trafficking pathways. This review focuses on features common to MHC II and CD1 molecules in their ability to activate specific T lymphocytes with the objective of addressing one basic question: What are the mechanisms regulating antigen presentation by MHC II and CD1 molecules within the same cell? Recent studies in immature DC, where MHC II and CD1 are coexpressed, suggest that the invariant chain (Ii) regulates antigen presentation by either protein. Ii could therefore favor MHC II or CD1 antigen presentation and thereby discriminate between antigens.
Osteosarcoma in Patients Older Than 65 Years
Authors: Longhi Alessandra , Errani Costantino , Gonzales-Arabio Daniel , Ferrari Cristina , Mercuri Mario
Published: September 2008

Purpose

We reviewed the outcome of osteosarcoma patients older than 65 years, an age group usually excluded from protocols, to determine the different clinical features and prognostic factors in this age group compared with younger patients.

Patients and Methods

Patients treated at our institute who had high-grade osteosarcoma and were older than 65 years were observed.

Results

Forty-three patients were eligible to be enrolled onto this study; of these, 22 were male and 21 were female. The median age of this group was 69 years (range, 65 to 80 years). Of the 43 patients, 29 patients had localized disease, and 14 patients had metastatic disease. Localizations were appendicular in 33 patients, and axial in 10 patients. Twenty-nine patients had a primary osteosarcoma, 13 patients (30%) had a sarcoma in Paget's disease, and one patient had postradiotherapy (RT) osteosarcoma. The median interval from onset of symptoms to diagnosis was 4 months (range, 0 to 73 months).Thirty-two of 43 patients received surgery for a primary tumor. Of these, 18 patients had limb salvage, 13 patients had an amputation, and one patient had palliative surgery; the remaining 11 patients received palliative RT. Fourteen patients received chemotherapy; two deaths related to chemotherapy were observed. Median overall survival (OS) for all 43 patients was 19 months (range, 3 to 229 months); 5-year OS was 22% (SE = 3%) for the whole group, and 45% OS for those patients with localized primary osteosarcoma. Multivariate analysis demonstrated that stage, volume, and surgery were significant prognostic factors. Insignificant prognostic factors were sex, type of surgery, chemotherapy, and Paget's disease.

Conclusion

Patients older than 65 years with osteosarcoma have a worse prognosis compared with younger patients. This older age group is characterized by a longer time lapse from the onset of symptoms to diagnosis, more metastatic cases at diagnosis, less use of limb salvage, fewer patients receiving chemotherapy, and more patients excluded from clinical trials than a younger age group.
Long-Term Effects of High-Dose Chemotherapy and Radiation for Relapsed and Refractory Hodgkin's Lymphoma
Authors: Goodman Karyn A. , Riedel Elyn , Serrano Victoria , Gulati Subhash , Moskowitz Craig H. , Yahalom Joachim
Published: September 2008

Purpose

To evaluate the risk of late morbidity and mortality, and to assess long-term health-related quality of life (QOL) among patients with relapsed/refractory Hodgkin's lymphoma (HL) after high-dose chemoradiotherapy (HDT) and autologous stem-cell rescue (ASCR).

Patients and Methods

From 1985 to 1998, 218 patients with HL were treated on HDT with ASCR salvage protocols. Of these 218, 153 (70%) who survived ≥ 2 years after ASCR were evaluated for late morbidity and mortality from causes other than HL. QOL information was obtained through self-administered questionnaires. Risk ratios (RR) were calculated to compare observed second malignancy (SM) rates in this cohort with expected SM rates from the Surveillance Epidemiology and End Results (SEER) registry.

Results

Median follow-up after ASCR was 11.5 years. Among 153 patients, there were 53 deaths; 33 from HL and 20 from other causes. Thirteen deaths were caused by SM, with median time from ASCR to SM diagnosis of 9 years (range, 3 to 18 years). The RR of SM was 6.5 (95% CI, 3.6 to 10.7) when compared with the general population, but 2.4 (95% CI, 1.4 to 4.05) when compared with patients with HL. Global QOL of ASCR survivors was comparable with the general population, but for specific domains, respondents’ scores indicated reduced functioning and worse symptoms.

Conclusion

HL accounts for most deaths among patients surviving HDT and ASCR. Survivors of ASCR had an elevated risk of SM compared with the cancer risk in the general population, but when compared with patients with HL in SEER, the risk was less pronounced.
Novel Method for Benchmarking Recruitment of African American Cancer Patients to Clinical Therapeutic Trials
Authors: Morgenlander Keith H. , Winters Sharon B. , Lin Chyongchiou J. , Robertson Linda B. , Heron Dwight E. , Herberman Ronald B.
Published: September 2008

Purpose

The National Cancer Institute (NCI) has historically evaluated the participation of underserved minorities within University of Pittsburgh Cancer Institute (UPCI) clinical trials in relation to the proportion of African Americans in the general population of the UPCI primary service area of Allegheny County (12%). This standard seemed to be unrealistically high as a result of a younger age distribution of African Americans within the county.

Methods

The proportions of African Americans within the following four separate county populations were compared using data from 2000 to 2004: general population; invasive cancer patients; invasive cancer patients diagnosed or treated at UPCI-affiliated facilities; and patients enrolled onto UPCI's clinical therapeutic trials.

Results

Although the proportion of African Americans within the general population was approximately 13%, only 9.8% of patients diagnosed with invasive cancers were African American. Approximately 9.5% of all cancer patients diagnosed or treated at UPCI facilities were African American, which is comparable to the county-wide percentage of African American cancer patients. Recruitment rate of African Americans to oncology clinical trials from within the UPCI patient population was 7.6%. The NCI benchmark did not reflect the actual invasive cancer incidence rate in African American patients. By comparing the percentage of African Americans contributing to cancer incidence with the percentage of African American cancer patients treated at research-affiliated institutions, a more appropriate benchmark was derived.

Conclusion

The method developed by UPCI is recommended as a useful mechanism for benchmarking recruitment of African American cancer patients to clinical therapeutic trials at other cancer centers.
Phase II Trial of Weekly Paclitaxel for Unresectable Angiosarcoma: The ANGIOTAX Study
Authors: Penel Nicolas , Bui Binh Nguyen , Bay Jacques-Olivier , Cupissol Didier , Ray-Coquard Isabelle , Piperno-Neumann Sophie , Kerbrat Pierre , Fournier Charles , Taieb Sophie , Jimenez Marta , Isambert Nicolas , Peyrade Frédéric , Chevreau Christine , Bompas Emmanuelle , Brain Etienne G.C. , Blay Jean-Yves
Published: September 2008

Purpose

The objective of this phase II trial was to assess the efficacy and toxicity of weekly paclitaxel for patients with metastatic or unresectable angiosarcoma.

Patients and Methods

Thirty patients were entered onto the study from April 2005 through October 2006. Paclitaxel was administered intravenously as a 60-minute infusion at a dose of 80 mg/m2 on days 1, 8, and 15 of a 4-week cycle. The primary end point was the nonprogression rate after two cycles.

Results

The progression-free survival rates after 2 and 4 months were 74% and 45%, respectively. With a median follow-up of 8 months, the median time to progression was 4 months and the median overall survival was 8 months. The progression-free survival rate was similar in patients pretreated with chemotherapy and in chemotherapy-naïve patients (77% v 71%). Three patients with locally advanced breast angiosarcoma presented partial response, which enabled a secondary curative-intent surgery with complete histologic response in two cases. One toxic death occurred as a result of a thrombocytopenia episode. Six patients presented with grade 3 toxicities and one patient presented with a grade 4 toxicity. Anemia and fatigue were the most frequently reported toxicities.

Conclusion

Weekly paclitaxel at the dose schedule used in the current study was well tolerated and demonstrated clinical benefit.
Feasibility of Screening for Lynch Syndrome Among Patients With Colorectal Cancer
Authors: Hampel Heather , Frankel Wendy L. , Martin Edward , Arnold Mark , Khanduja Karamjit , Kuebler Philip , Clendenning Mark , Sotamaa Kaisa , Prior Thomas , Westman Judith A. , Panescu Jenny , Fix Dan , Lockman Janet , LaJeunesse Jennifer , Comeras Ilene , de la Chapelle Albert
Published: September 2008

Purpose

Identifying individuals with Lynch syndrome (LS) is highly beneficial. However, it is unclear whether microsatellite instability (MSI) or immunohistochemistry (IHC) should be used as the screening test and whether screening should target all patients with colorectal cancer (CRC) or those in high-risk subgroups.

Patients and Methods

MSI testing and IHC for the four mismatch repair proteins was performed on 500 tumors from unselected patients with CRC. If either MSI or IHC was abnormal, complete mutation analysis for the mismatch repair genes was performed.

Results

Among the 500 patients, 18 patients (3.6%) had LS. All 18 patients detected with LS (100%) had MSI-high tumors; 17 (94%) of 18 patients with LS were correctly predicted by IHC. Of the 18 probands, only eight patients (44%) were diagnosed at age younger than 50 years, and only 13 patients (72%) met the revised Bethesda guidelines. When these results were added to data on 1,066 previously studied patients, the entire study cohort (N = 1,566) showed an overall prevalence of 44 of 1,566 patients (2.8%; 95% CI, 2.1% to 3.8%) for LS. For each proband, on average, three additional family members carried MMR mutations.

Conclusion

One of every 35 patients with CRC has LS, and each has at least three relatives with LS; all of whom can benefit from increased cancer surveillance. For screening, IHC is almost equally sensitive as MSI, but IHC is more readily available and helps to direct gene testing. Limiting tumor analysis to patients who fulfill Bethesda criteria would fail to identify 28% (or one in four) cases of LS.
‘They're more like ordinary stroppy British women’: Attitudes and expectations of maternity care professionals to UK-born ethnic minority women
Authors: Puthussery Shuby , Twamley Katherine , Harding Seeromanie , Mirsky Judith , Baron Maurina , Macfarlane Alison
Published: September 2008

Objective:

To explore the attitudes and expectations of maternity care professionals to UK-born ethnic minority mothers.

Methods:

Qualitative in-depth interviews with 30 professionals from eight NHS maternity units in England that provide services for large proportions of women of black Caribbean, black African, Indian, Pakistani and Irish descent.

Results:

All the professionals reported providing care to both UK-born and migrant mothers from ethnic minorities. Most of them felt that they could differentiate between UK-born and migrant mothers based mainly on language fluency and accent. ‘Westernized dress’ and ‘freedom’ were also cited as indicators. Overall, professionals found it easier to provide services to UK-born mothers and felt that their needs were more like those of white English mothers than those of migrant mothers. UK-born mothers were generally thought to be assertive and expressive, and in control of care-related decision-making whereas some South Asian Muslim women were thought to be constrained by family influences. Preconceived ideas about ethnic minority mothers’ tolerance of pain in labour, use of pharmacological pain relief measures and mode of delivery were recurring themes. Women's education and social class were felt to be major influences on the uptake of maternity care, regardless of ethnicity.

Conclusions:

Professionals appeared to equate the needs of UK-born ethnic minority women with those of white English women. Overall, this has positive implications for care provision. Despite this, specific behavioural expectations and unconscious stereotypical views were evident and have the potential to affect clinical practice.
Factors contributing to nursing leadership: A systematic review
Authors: Cummings Greta , Lee How , Macgregor Tara , Davey Mandy , Wong Carol , Paul Linda , Stafford Erin
Published: September 2008

Objectives:

Leadership practices of health care managers can positively or negatively influence outcomes for organizations, providers and, ultimately, patients. Understanding the factors that contribute to nursing leadership is fundamental to ensuring a future supply of nursing leaders who can positively influence outcomes for health care providers and patients. The purpose of this study was to systematically review the multidisciplinary literature to examine the factors that contribute to nursing leadership and the effectiveness of educational interventions in developing leadership behaviours among nurses.

Methods:

The search strategy began with 10 electronic databases (e.g. CINAHL, Medline). Published quantitative studies were included that examined the factors that contribute to leadership or the development of leadership behaviours in nurse leaders. Quality assessments, data extraction and analysis were completed on all included studies.

Results:

A total of 27,717 titles/abstracts were screened resulting in 26 included manuscripts reporting on 24 studies. Twenty leadership factors were examined and categorized into four groups - behaviours and practices of individual leaders, traits and characteristics of individual leaders, influences of context and practice settings, and leader participation in educational activities. Specific behaviours and practices of individual leaders, such as taking on or practising leadership styles, skills and roles, were reported as significantly influencing leadership in eight studies. Traits and characteristics of individual leaders were examined in six studies with previous leadership experience (three studies) and education levels (two of three studies) having positive effects on observed leadership. Context and practice settings had a moderate influence on leadership effectiveness (three of five studies). Nine studies that examined participation in leadership development programs all reported significant positive influences on observed leadership.

Conclusion:

These findings suggest that leadership can be developed through specific educational activities, and by modelling and practising leadership competencies. However, the relatively weak study designs provide limited evidence for specific factors that could increase the effectiveness of current nursing leadership or guide the identification of future nurse leaders. Robust theory and research on interventions to develop and promote viable nursing leadership for the future are needed to achieve the goal of developing healthy work environments for health care providers and optimizing care for patients.
Consumer involvement in setting the health services research agenda: Persistent questions of value
Authors: Entwistle Vikki , Calnan Michael , Dieppe Paul
Published: September 2008

Interest in consumer involvement in health services research started to gain momentum at around the same time that the MRC Health Services Research Collaboration (HSRC) was established. Consumer involvement was not the focus of a formal research programme within the HSRC, but HSRC members took opportunities to conduct three projects relating to consumer involvement in research agenda-setting activities. These were: (1) a comparison of the focus of published research relating to the management of osteoarthritis of the knee with clinicians’ and patients’ ideas about research priorities; (2) a survey that examined the consumer involvement policies of public- and voluntary-sector organizations that fund health services research in the UK; and (3) a citizens’ jury that was convened to develop priorities for research relating to primary health and social care in the Bristol area. This paper reviews the findings of these projects and highlights the continued need for attention to underlying values in the development and evaluation of future efforts to involve consumers in research agenda setting.
Stakeholders’ views of UK nurse and pharmacist supplementary prescribing
Authors: Cooper Richard , Anderson Claire , Avery Tony , Bissell Paul , Guillaume Louise , Hutchinson Allen , Lymn Joanne , Murphy Elizabeth , Ratcliffe Julie , Ward Paul
Published: September 2008

Objectives:

Supplementary prescribing (SP) by pharmacists and nurses in the UK represents a unique approach to improving patients’ access to medicines and better utilizing health care professionals’ skills. Study aims were to explore the views of stakeholders involved in SP policy, training and practice, focusing upon issues such as SP benefits, facilitators, challenges, safety and costs, thereby informing future practice and policy.

Method:

Qualitative, semi-structured interviews were conducted with 43 purposively sampled UK stakeholders, including pharmacist and nurse supplementary prescribers, doctors, patient groups representatives, academics and policy developers. Analysis of transcribed interviews was undertaken using a process of constant comparison and framework analysis, with coding of emergent themes.

Results:

Stakeholders generally viewed SP positively and perceived benefits in terms of improved access to medicines and fewer delays, along with a range of facilitators and barriers to the implementation of this form of non-medical prescribing. Stakeholders’ views on the economic impact of SP varied, but safety concerns were not considered significant. Future challenges and implications for policy included SP being potentially superseded by independent nurse and pharmacist prescribing, and the need to improve awareness of SP. Several potential tensions emerged including nurses’ versus pharmacists’ existing skills and training needs, supplementary versus independent prescribing, SP theory versus practice and prescribers versus non-prescribing peers.

Conclusion:

SP appeared to be broadly welcomed by stakeholders and was perceived to offer patient benefits. Several years after its introduction in the UK, stakeholders still perceived several implementation barriers and challenges and these, together with various tensions identified, might affect the success of supplementary and other forms of non-medical prescribing.
Research capacity development and training
Authors: Ramkalawan Tina , Dieppe Paul
Published: September 2008

The HSRC was awarded a large core grant specifically for research capacity development and training, with the aim of facilitating future high quality HSR in the UK. This was used to pursue three main areas of activity. First, the provision of small grants to facilitate the development of new work, help create new, multidisciplinary groupings and support junior researchers. Of the various schemes discussed, the research initiation grants (max £6000) and workshop awards (max £3000) appear to have been particularly valuable. Second, appoint cohorts of PhD students to pursue four-year training programmes (rather than the traditional three years), during which they received individualized research training and development opportunities with an emphasis on both multidisciplinary HSR training and generic skills training, as well as pursuing their own research projects. Third, improving research training opportunities by developing networks for research staff at various stages in their careers and organizing workshops and courses in specialist HSR subjects, and for generic skills training. The premature closure of the HSRC prevented us from fully evaluating these initiatives and, arguably, their real value will not be apparent for some years. However, we believe that the programme was successful and that it went some way to helping us break out from the traditional, entrenched approaches to research training, and to helping us think of research capacity development as being as important as doing the research itself. But much more remains to be done.
Trust relations in a changing health service
Authors: Calnan Michael , Rowe Rosemary
Published: September 2008

Objective:

Trust in health care is an important policy area although research has tended to focus on interpersonal trust between patient and practitioner and has neglected trust relations at the organizational and institutional levels. Each of these levels of trust may have been influenced by recent policy and organizational changes in the NHS as well as wider cultural changes. Our aim was to explore the relationship between patients, practitioners and managers to identify if there was any evidence of changes in trust relations.

Method:

A comparative case study design in two different clinical and organizational settings.

Results:

Trust is still important for effective therapeutic and working relationships but the nature of that trust and how it is lost and won appears to be affected by the organizational context in which health services are delivered. The increasing partnership between patients and clinicians in managing health problems and the greater interdependence of clinicians and managers in providing multidisciplinary shared care have changed how patients, clinicians and managers trust each other. For many informants trust can no longer be assumed, it is conditional and has to be earned. However, the sources of trust are the quality of the patient- clinician interaction, the competence and empathy that is displayed rather than informed trust based on abstract disembodied data. Likewise in inter-practitioner relationships and clinician-manager relations trust no longer appears to be primarily based on professional status and seniority, instead it appears to be conditional and may be earned through a variety of strategies that demonstrate honesty, reliability, competence, accessibility and an indication that colleagues share similar values and have a common agenda.

Conclusion:

Trust is still important for effective therapeutic and working relationships.
Reducing the burden of chronic wounds: Prevention and management of the diabetic foot in the context of clinical guidelines
Authors: Searle Aidan , Gale Lone , Campbell Rona , Wetherell Mark , Dawe Karen , Drake Nikki , Dayan Colin , Tarlton John , Miles Jeremy , Vedhara Kavita
Published: September 2008

Objectives:

Chronic wounds such as diabetic foot and venous leg ulcers are a major burden for health services. Our programme was developed to explore the psychological and behavioural factors that may influence both the incidence of chronic wounds and their progression. The present article focuses on two particular aspects of the programme: patient knowledge of diabetic foot ulceration and factors influencing foot-related behaviour in patients with and without foot ulcers; and patient and podiatrist perspectives of consultations for diabetic foot ulcers.

Methods:

Two independent qualitative studies were undertaken: one with diabetic patients without a history of ulceration; and the other with diabetic patients with active ulceration and podiatrists treating these patients.

Results:

We found that patients may find it difficult understanding the rationale underlying prevention and treatment of foot ulcers; ulcerated patients may find it difficult to engage in the management of their foot ulcer outside consultations; and some podiatrists feel frustrated and unsupported in their attempts at empowering and building partnerships with patients.

Conclusion:

Patient and practitioner factors may contribute to the effective implementation of clinical guidelines regarding education, partnership building and shared decision-making. These findings are discussed in relation to patient education, partnership building and shared decision-making as recommended in NICE guidelines.
Patient preferences for treatment for angina: An overview of findings from three studies
Authors: Bowling Ann , Reeves Barnaby , Rowe Gene
Published: September 2008

Background:

Access to cardiac treatments has been documented to vary with patients’ age. It is unknown whether these variations reflect patients’ treatment preferences. We aimed to investigate patients’ preferences for cardiology treatments and develop a Patients’ Preferences Questionnaire.

Methods:

Semi-structured interviews with primary care patients with diagnosed angina with postal follow-up. The resulting Patients’ Preferences Questionnaire was tested with newly admitted inpatients with acute coronary syndrome and with patients in primary care.

Results:

The Patients’ Preferences Questionnaire was psychometrically sound. Analyses of preference subscale scores showed that the most positive preference scores were for medication. Angioplasty scored highest at the negative end of the scale. Detailed analyses showed that older people and women were less likely to prefer coronary artery bypass surgery (CABG), reflecting its greater level of invasiveness. Older people (aged over 75 years, compared to people aged under 75 years), but not women, were also more cautious in their strength of preference for angioplasty. More positive attitudes towards CABG surgery, and more negative attitudes towards medication, were associated with greater impact of the condition on life.

Conclusions:

The research resulted in a psychometrically sound Patients’ Preferences Questionnaire. There was some evidence to support the view that older people's weaker preferences for CABG may contribute slightly to variations in the provision of re-vascularization. There was also variation in preferences within age groups, cautioning against the assumption that all or most older people are more reluctant than younger people to undergo invasive procedures.