bluuebunny/crossref_metadata_2025 huggingface dataset:
Compositional variation of the tennantite–tetrahedrite solid-solution series in the Schwarzwald ore district (SW Germany): The role of mineralization processes and fluid source
Authors: Staude S. , Mordhorst T. , Neumann R. , Prebeck W. , Markl G.
Published: June 2010

The study presents analysis from members of the tennantite–tetrahedrite solid-solution series (‘fahlore’) from 78 locations in the Schwarzwald ore district of SW Germany. Electron microprobe analysis is used to correlate the compositional variations of the fahlores with mineral association, host rock, tectonic history and precipitation mechanisms. Results indicate that most fahlores from gneiss-hosted veins do not have distinctive geochemical characteristics and range from tetrahedrite to tennantite end-member composition with variable trace-element content. However, diagenetically formed fahlore has a near-end-member tennantite composition with very small trace-element content. Red-bed-hosted fahlore formed by fluid mixing is tennantite enriched in Hg that probably has its source in the red-bed sediments. Fahlore formed from granite-related late-magmatic fluids, or from mixing of fluids of which one has equilibrated with granitic basement rocks, is typically As- and Bi-rich (up to 22.2 wt.% Bi). Gneiss-hosted fahlore formed by fluid cooling is Ag-rich near-end-member tetrahedrite. Some fahlores reflect their paragenetic association, e.g. a large Ag content in association with Ag-bearing minerals or a large Co and Ni in association with Co- and Ni-arsenides.

Although they have similar compositions, gneiss-hosted fahlores show systematic variations in Ag contents and Fe/Zn ratios between the Central and the Southern Schwarzwald with Fe-rich fahlore in higher stratigraphic levels (North) and Zn- and Ag-rich fahlore in lower stratigraphic levels (South). We show that fahlore composition varies with precipitation mechanism (cooling vs. mixing vs. diagenesis), depth of formation, paragenetic association and host rock. Comparison with fahlores from other European occurrences indicates that these conclusions are consistent with fahlore systematics found elsewhere, and could be used to infer details of ore-forming processes.
HS1 has a central role in the trafficking and homing of leukemic B cells
Authors: Scielzo Cristina , Bertilaccio Maria T. S. , Simonetti Giorgia , Dagklis Antonis , ten Hacken Elisa , Fazi Claudia , Muzio Marta , Caiolfa Valeria , Kitamura Daisuke , Restuccia Umberto , Bachi Angela , Rocchi Martina , Ponzoni Maurilio , Ghia Paolo , Caligaris-Cappio Federico
Published: June 2010

The function of the intracellular protein hematopoietic cell–specific Lyn substrate-1 (HS1) in B lymphocytes is poorly defined. To investigate its role in migration, trafficking, and homing of leukemic B lymphocytes we have used B cells from HS1−/− mice, the HS1-silenced human chronic lymphocytic leukemia (CLL) MEC1 cell line and primary leukemic B cells from patients with CLL. We have used both in vitro and in vivo models and found that the lack of expression of HS1 causes several important functional effects. In vitro, we observed an impaired cytoskeletal remodeling that resulted in diminished cell migration, abnormal cell adhesion, and increased homotypic aggregation. In vivo, immunodeficient Rag2−/−γc−/− mice injected with HS1-silenced CLL B cells showed a decreased organ infiltration with the notable exception of the bone marrow (BM). The leukemic-prone Eμ-TCL1 transgenic mice crossed with HS1-deficient mice were compared with Eμ-TCL1 mice and showed an earlier disease onset and a reduced survival. These findings show that HS1 is a central regulator of cytoskeleton remodeling that controls lymphocyte trafficking and homing and significantly influences the tissue invasion and infiltration in CLL.
Platelet senescence is regulated by an internal timer, not damage inflicted by hits
Authors: Dowling Mark R. , Josefsson Emma C. , Henley Katya J. , Hodgkin Philip D. , Kile Benjamin T.
Published: June 2010

The mechanisms responsible for the brief life span of blood platelets have been a subject of speculation since the 1950s. The most popular hypothesis to date has been the “multiple-hit” model, whereby damage inflicted by external “hits” triggers recognition and clearance by the reticuloendothelial system. Recently, it was demonstrated that platelets contain an apoptotic pathway that mediates their survival in vivo. Using a novel labeling technique to measure population and cohort survival in mice carrying mutations in this pathway, combined with mathematical modeling, we have studied the internal and external control of platelet fate. Our results cast doubt on the veracity of the multiple-hit model. An alternative model, under which platelets are born with an internal “timer,” provides a more parsimonious interpretation of the data. Thus, at steady state, platelet senescence is probably the product of internal processes rather than external hits.
ADF/n-cofilin–dependent actin turnover determines platelet formation and sizing
Authors: Bender Markus , Eckly Anita , Hartwig John H. , Elvers Margitta , Pleines Irina , Gupta Shuchi , Krohne Georg , Jeanclos Elisabeth , Gohla Antje , Gurniak Christine , Gachet Christian , Witke Walter , Nieswandt Bernhard
Published: June 2010

The cellular and molecular mechanisms orchestrating the complex process by which bone marrow megakaryocytes form and release platelets remain poorly understood. Mature megakaryocytes generate long cytoplasmic extensions, proplatelets, which have the capacity to generate platelets. Although microtubules are the main structural component of proplatelets and microtubule sliding is known to drive proplatelet elongation, the role of actin dynamics in the process of platelet formation has remained elusive. Here, we tailored a mouse model lacking all ADF/n-cofilin–mediated actin dynamics in megakaryocytes to specifically elucidate the role of actin filament turnover in platelet formation. We demonstrate, for the first time, that in vivo actin filament turnover plays a critical role in the late stages of platelet formation from megakaryocytes and the proper sizing of platelets in the periphery. Our results provide the genetic proof that platelet production from megakaryocytes strictly requires dynamic changes in the actin cytoskeleton.
Health-related quality of life and functional status in end-stage COPD: a longitudinal study
Authors: Habraken J.M. , van der Wal W.M. , ter Riet G. , Weersink E.J.M. , Toben F. , Bindels P.J.E.
Published: June 2010

Since there is still a dearth of information about the end stage of chronic obstructive pulmonary disease (COPD), the main aim of this study was to examine the development of health-related quality of life (HRQoL) and functional status over time in COPD patients in Global Initiative for Chronic Obstructive Lung Disease (GOLD) stage IV.

82 Dutch COPD patients completed the St George’s Respiratory Questionnaire (SGRQ) for HRQoL and the Groningen Activities for Daily Living Restriction Scale (GARS) for functional status every 3 months during the year following enrolment. Survival was followed up to 5 yrs after enrolment. Data were analysed by stratifying the study population into severity subgroups according to the lowest, intermediate and highest tertile of SGRQ and GARS at baseline. Outcome measures were change in SGRQ and GARS scores over time and survival time.

In the majority of patients, scores on the SGRQ and GARS declined gradually over time. In the subgroup of 32 patients that died within 2 yrs of enrolment, these scores also declined gradually, without steep deteriorations.

In patients with end-stage COPD, HRQoL and functional status deteriorated gradually over time, indicating that clinicians did not gain much additional support for differentiating the end stage of COPD by considering HRQoL and functional status using the SGRQ and GARS.
Combined exposure to dog and indoor pollution: incident asthma in a high-risk birth cohort
Authors: Carlsten C. , Brauer M. , Dimich-Ward H. , Dybuncio A. , Becker A.B. , Chan-Yeung M.
Published: June 2010

The impact of single exposures on asthma development is better understood than the effect of multiple exposures. The objective of the present study was to evaluate the effect of combined early exposure to dog allergen (Can-f1) plus indoor nitrogen dioxide (NO2) or environmental tobacco smoke (ETS) on asthma and bronchial hyperreactivity (BHR) in a high-risk birth cohort. We also aimed to assess atopy's impact on the effects of these exposures.

Peri-birth ETS exposure was measured using cord blood cotinine (CCot). During year 1, atopy, NO2, Can-f1, and urinary cotinine (UCot) were measured. At 7 yrs of age, 380 children were assessed for asthma and BHR. Exposure effects were determined using stepwise multiple linear regression.

Co-exposure to elevated Can-f1 and NO2, or Can-f1 and ETS (CCot), increased risk for asthma, relative to having neither such exposure (OR 4.8 (95% CI 1.1–21.5) and 2.7 (1.1–7.1), respectively); similar risks resulted when substituting dog ownership for allergen. Atopy increased asthma and BHR risk associated with several exposures; notably, atopy with elevated UCot, relative to atopy without such exposure, increased risk of BHR (OR 3.1 (95% CI 1.1–8.6)).

In a high-risk birth cohort, early co-exposure to Can-f1 and NO2or ETS increased the risk of incident asthma. Atopy increased the risk of asthma and BHR associated with ETS.
Regulation of genes affecting body size and innate immunity by the DBL-1/BMP-like pathway in Caenorhabditis elegans
Authors: Roberts Andrew F , Gumienny Tina L , Gleason Ryan J , Wang Huang , Padgett Richard W
Published: June 2010

Background

Bone morphogenetic proteins (BMPs) are members of the conserved transforming growth factor β (TGFβ superfamily, and play many developmental and homeostatic roles. In C. elegans, a BMP-like pathway, the DBL-1 pathway, controls body size and is involved in innate immunity. How these functions are carried out, though, and what most of the downstream targets of this pathway are, remain unknown.

Results

We performed a microarray analysis and compared expression profiles of animals lacking the SMA-6 DBL-1 receptor, which decreases pathway signaling, with animals that overexpress DBL-1 ligand, which increases pathway signaling. Consistent with a role for DBL-1 in control of body size, we find positive regulation by DBL-1 of genes involved in physical structure, protein synthesis and degradation, and metabolism. However, cell cycle genes were mostly absent from our results. We also identified genes in a hedgehog-related pathway, which may comprise a secondary signaling pathway downstream of DBL-1 that controls body size. In addition, DBL-1 signaling up-regulates pro-innate immunity genes. We identified a reporter for DBL-1 signaling, which is normally repressed but is up-regulated when DBL-1 signaling is reduced.

Conclusions

Our results indicate that body size in C. elegans is controlled in part by regulation of metabolic processes as well as protein synthesis and degradation. This supports the growing body of evidence that suggests cell size is linked to metabolism. Furthermore, this study discovered a possible role for hedgehog-related pathways in transmitting the BMP-like signal from the hypodermis, where the core DBL-1 pathway components are required, to other tissues in the animal. We also identified the up-regulation of genes involved in innate immunity, clarifying the role of DBL-1 in innate immunity. One of the highly regulated genes is expressed at very low levels in wild-type animals, but is strongly up-regulated in Sma/Mab mutants, making it a useful reporter for DBL-1/BMP-like signaling in C. elegans.
The homolog of Ciboulot in the termite (Hodotermopsis sjostedti): a multimeric β-thymosin involved in soldier-specific morphogenesis
Authors: Koshikawa Shigeyuki , Cornette Richard , Matsumoto Tadao , Miura Toru
Published: June 2010

Background

Caste differentiation in social insects is a type of polyphenism that enables division of labor among members of a colony. This elaborate social integration has attracted broad interest, although little is known about its regulatory mechanisms, especially in Isoptera (termites). In this study, we analyzed soldier differentiation in the damp-wood termite Hodotermopsis sjostedti, focusing on a possible effector gene for caste development. The gene for an actin-binding protein, HsjCib, which shows a high level of expression in developing mandibles during soldier differentiation, is characterized in detail.

Results

To examine the HsjCib gene, full-length cDNAs were obtained by rapid amplification of cDNA ends-polymerase chain reaction (RACE-PCR) and sequencing. Multiple isoforms were identified, and on the basis of the results of northern and Southern hybridization analyses, these isoforms were considered to be transcriptional variants from a single gene. On the basis of their sequence similarity to homologous genes of other organisms, functions in actin assembly were assumed to be different among isoforms. Expression analysis revealed high expression in the head during soldier differentiation, which was consistent with their allometric growth. Although isoform expression was observed in various tissues, different expression levels were observed among tissues, suggesting the possibility of tissue-specific morphogenetic regulation by HsjCib isoforms.

Conclusion

This study revealed the characteristics and dynamics of the HsjCib gene during soldier differentiation as a potential representative of downstream effector genes in caste-specific morphogenesis. From the expression patterns observed, this gene is considered to be involved in cephalic morphogenesis and neural reorganization, resulting in the establishment of caste-specific morphology and behavior.
The expression of genes coding for distinct types of glycine-rich proteins varies according to the biology of three metastriate ticks, Rhipicephalus (Boophilus) microplus, Rhipicephalus sanguineus and Amblyomma cajennense
Authors: Maruyama Sandra R , Anatriello Elen , Anderson Jennifer M , Ribeiro José M , Brandão Lucinda G , Valenzuela Jesus G , Ferreira Beatriz R , Garcia Gustavo R , Szabó Matias PJ , Patel Sonal , Bishop Richard , de Miranda-Santos Isabel KF
Published: June 2010

Background

Ticks secrete a cement cone composed of many salivary proteins, some of which are rich in the amino acid glycine in order to attach to their hosts' skin. Glycine-rich proteins (GRPs) are a large family of heterogeneous proteins that have different functions and features; noteworthy are their adhesive and tensile characteristics. These properties may be essential for successful attachment of the metastriate ticks to the host and the prolonged feeding necessary for engorgement. In this work, we analyzed Expressed Sequence Tags (ESTs) similar to GRPs from cDNA libraries constructed from salivary glands of adult female ticks representing three hard, metastriate species in order to verify if their expression correlated with biological differences such as the numbers of hosts ticks feed on during their parasitic life cycle, whether one (monoxenous parasite) or two or more (heteroxenous parasite), and the anatomy of their mouthparts, whether short (Brevirostrata) or long (Longirostrata). These ticks were the monoxenous Brevirostrata tick, Rhipicephalus (Boophilus) microplus, a heteroxenous Brevirostrata tick, Rhipicephalus sanguineus, and a heteroxenous Longirostrata tick, Amblyomma cajennense. To further investigate this relationship, we conducted phylogenetic analyses using sequences of GRPs from these ticks as well as from other species of Brevirostrata and Longirostrata ticks.

Results

cDNA libraries from salivary glands of the monoxenous tick, R. microplus, contained more contigs of glycine-rich proteins than the two representatives of heteroxenous ticks, R. sanguineus and A. cajennense (33 versus, respectively, 16 and 11). Transcripts of ESTs encoding GRPs were significantly more numerous in the salivary glands of the two Brevirostrata species when compared to the number of transcripts in the Longirostrata tick. The salivary gland libraries from Brevirostrata ticks contained numerous contigs significantly similar to silks of true spiders (17 and 8 in, respectively, R. microplus and R. sanguineus), whereas the Longirostrata tick contained only 4 contigs. The phylogenetic analyses of GRPs from various species of ticks showed that distinct clades encoding proteins with different biochemical properties are represented among species according to their biology.

Conclusions

We found that different species of ticks rely on different types and amounts of GRPs in order to attach and feed on their hosts. Metastriate ticks with short mouthparts express more transcripts of GRPs than a tick with long mouthparts and the tick that feeds on a single host during its life cycle contain a greater variety of these proteins than ticks that feed on several hosts.
Newly generated cells are increased in hippocampus of adult mice lacking a serine protease inhibitor
Authors: Lino Maddalena M , Vaillant Catherine , Orolicki Slobodanka , Sticker Melanie , Kvajo Mirna , Monard Denis
Published: June 2010

Background

Neurogenesis in the hippocampal dentate gyrus and the subventricular zone occurs throughout the life of mammals and newly generated neurons can integrate functionally into established neuronal circuits. Neurogenesis levels in the dentate gyrus are modulated by changes in the environment (enrichment, exercise), hippocampal-dependent tasks, NMDA receptor (NMDAR) activity, sonic hedgehog (SHH) and/or other factors.

Results

previously, we showed that Protease Nexin-1 (PN-1), a potent serine protease inhibitor, regulates the NMDAR availability and activity as well as SHH signaling. Compared with wild-type (WT), we detected a significant increase in BrdU-labeled cells in the dentate gyrus of mice lacking PN-1 (PN-1 -/-) both in controls and after running exercise. Patched homologue 1 (Ptc1) and Gli1 mRNA levels were higher and Gli3 down-regulated in mutant mice under standard conditions and to a lesser extent after running exercise. However, the number of surviving BrdU-positive cells did not differ between WT and PN-1 -/- animals. NMDAR availability was altered in the hippocampus of mutant animals after exercise.

Conclusion

All together our results indicate that PN-1 controls progenitors proliferation through an effect on the SHH pathway and suggest an influence of the serpin on the survival of newly generated neurons through modulation of NMDAR availability.
Effects of mannoprotein E1 in liquid diet on inflammatory response and TLR5 expression in the gut of rats infected by Salmonella typhimurium
Authors: Posadas Sinforiano J , Caz Victor , Caballero Isabel , Cendejas Emilio , Quilez Immaculada , Largo Carlota , Elvira Marcos , De Miguel Enrique
Published: June 2010

Background

Mannoproteins are yeast cell wall componend, and rich in mannose. The use of foods rich in mannose as carbohydrate, could have a bioprotective effect against entrobacteria intestinal infection. Nothing is known about mannoproteins' activity in inflammatory bowel processes induced by entrobacteria.

This study investigates the effects of mannoprotein administration via a liquid diet on inflammatory response and TLR5 expression during intestinal tissue injury in a rat model of infection withSalmonella typhimurium.

Methods

Adult Wistar male rats were divided into three groups: control, and mannoprotein E1at 10 or 15%. Animals were fed with a liquid diet supplemented or not with mannoprotein E1. Groups were infected by intragastrical administration ofS. typhimurium. 24 h post-inoculation samples of spleen, ileum and liver were collected for microbiological studies. Gut samples were processed to determine levels of proinflammatory cytokines (mRNA) and TLR5 (mRNA and protein) by quantitative PCR and Western-blot, and the number of proliferative and apoptotic cells determined by immunohistochemistry.

Results

Ininfected levels of proinflammatory cytokines and TLR5 were higher in untreated controls than in the animals receiving mannoprotein. Proliferation was similar in both groups, whereas apoptosis was higher in controls. Curiosly, the mannoprotein effect was dose dependent.

Conclusions

Mannoprotein administration in a liquid diet seems to protect intestinal tissue againstS. typhimuriuminfection. This protection seems to expressed as a lower pro-inflammatory response and TLR5 downregulation in gut epithelium, as well as by an inhibition of apoptosis. Nevertheless, the molecular mechanism by which mannoprotein is able to regulate these responses remain unclear. These results could open up new avenues in the use of mannoproteins as prebiotics in the therapeutic strategy for treatment of inflammatory gut processes induced by microbia.
The microenvironment determines the breast cancer cells' phenotype: organization of MCF7 cells in 3D cultures
Authors: Krause Silva , Maffini Maricel V , Soto Ana M , Sonnenschein Carlos
Published: June 2010

Background

Stromal-epithelial interactions mediate breast development, and the initiation and progression of breast cancer. In the present study, we developed 3-dimensional (3D) in vitro models to study breast cancer tissue organization and the role of the microenvironment in phenotypic determination.

Methods

The human breast cancer MCF7 cells were grown alone or co-cultured with primary human breast fibroblasts. Cells were embedded in matrices containing either type I collagen or a combination of reconstituted basement membrane proteins and type I collagen. The cultures were carried out for up to 6 weeks. For every time point (1-6 weeks), the gels were fixed and processed for histology, and whole-mounted for confocal microscopy evaluation. The epithelial structures were characterized utilizing immunohistochemical techniques; their area and proliferation index were measured using computerized morphometric analysis. Statistical differences between groups were analyzed by ANOVA, Dunnett's T3 post-hoc test and chi-square.

Results

Most of the MCF7 cells grown alone within a collagen matrix died during the first two weeks; those that survived organized into large, round and solid clusters. The presence of fibroblasts in collagen gels reduced MCF7 cell death, induced cell polarity, and the formation of round and elongated epithelial structures containing a lumen. The addition of reconstituted basement membrane to collagen gels by itself had also survival and organizational effects on the MCF7 cells. Regardless of the presence of fibroblasts, the MCF7 cells both polarized and formed a lumen. The addition of fibroblasts to the gel containing reconstituted basement membrane and collagen induced the formation of elongated structures.

Conclusions

Our results indicate that a matrix containing both type I collagen and reconstituted basement membrane, and the presence of normal breast fibroblasts constitute the minimal permissive microenvironment to induce near-complete tumor phenotype reversion. These human breast 3D tissue morphogenesis models promise to become reliable tools for studying tissue interactions, therapeutic screening and drug target validation.
A systematic review of personality disorder, race and ethnicity: prevalence, aetiology and treatment
Authors: McGilloway Angela , Hall Ruth E , Lee Tennyson , Bhui Kamaldeep S
Published: June 2010

Background

Although psychoses and ethnicity are well researched, the importance of culture, race and ethnicity has been overlooked in Personality Disorders (PD) research. This study aimed to review the published literature on ethnic variations of prevalence, aetiology and treatment of PD.

Method

A systematic review of studies of PD and race, culture and ethnicity including a narrative synthesis of observational data and meta-analyses of prevalence data with tests for heterogeneity.

Results

There were few studies with original data on personality disorder and ethnicity. Studies varied in their classification of ethnic group, and few studies defined a specific type of personality disorder. Overall, meta-analyses revealed significant differences in prevalence between black and white groups (OR 0.476, CIs 0.248 - 0.915, p = 0.026) but no differences between Asian or Hispanic groups compared with white groups. Meta-regression analyses found that heterogeneity was explained by some study characteristics: a lower prevalence of PD was reported among black compared with white patients in UK studies, studies using case-note diagnoses rather than structured diagnostic interviews, studies of borderline PD compared with the other PD, studies in secure and inpatient compared with community settings, and among subjects with co-morbid disorders compared to the rest. The evidence base on aetiology and treatment was small.

Conclusion

There is some evidence of ethnic variations in prevalence of personality disorder but methodological characteristics are likely to account for some of the variation. The findings may indicate neglect of PD diagnosis among ethnic groups, or a true lower prevalence amongst black patients. Further studies are required using more precise cultural and ethnic groups.
Response to symptoms of stroke in the UK: a systematic review
Authors: Lecouturier Jan , Murtagh Madeleine J , Thomson Richard G , Ford Gary A , White Martin , Eccles Martin , Rodgers Helen
Published: June 2010

Background

The English National Stroke Strategy suggests that there is a need to improve the response of patients and witnesses to the symptoms of acute stroke to increase rapid access to specialist care. We wished to review the evidence base regarding the knowledge, attitudes and behaviours of stroke patients, witnesses and the public to the symptoms of stroke and the need for an urgent response at the onset of symptoms.

Methods

We conducted a systematic review of UK articles reporting empirical research on a) awareness of and response to the symptoms of acute stroke or TIA, and b) beliefs and attitudes about diagnosis, early treatment and consequences of acute stroke or TIA. Nine electronic databases were searched using a robust search strategy. Citations and abstracts were screened independently by two reviewers. Data were extracted by two researchers independently using agreed criteria.

Results

11 studies out of 7144 citations met the inclusion criteria. Methods of data collection included: postal survey (n = 2); interview survey (n = 6); review of hospital documentation (n = 2) and qualitative interviews (n = 1). Limited data reveal a good level of knowledge of the two commonest stroke symptoms (unilateral weakness and speech disturbance), and of the need for an emergency response among the general public and at risk patients. Despite this, less than half of patients recognised they had suffered a stroke. Symptom recognition did not reduce time to presentation. For the majority, the first point of contact for medical assistance was a general practitioner.

Conclusions

There is an assumption that, in the UK, public knowledge of the symptoms of stroke and of the need for an emergency response is lacking, but there is little published research to support this. Public awareness raising campaigns to improve response to the symptoms of stroke therefore may not produce an increase in desired behaviours. Further research is needed to understand why people who experience or witness stroke symptoms frequently do not call emergency services.
Limited variation in vaccine candidate Plasmodium falciparum Merozoite Surface Protein-6 over multiple transmission seasons
Authors: Neal Aaron T , Jordan Stephen J , Oliveira Ana L , Hernandez Jean N , Branch OraLee H , Rayner Julian C
Published: June 2010

Background

Plasmodium falciparum Merozoite Surface Protein-6 (PfMSP6) is a component of the complex proteinacious coat that surrounds P. falciparum merozoites. This location, and the presence of anti-PfMSP6 antibodies in P. falciparum-exposed individuals, makes PfMSP6 a potential blood stage vaccine target. However, genetic diversity has proven to be a major hurdle for vaccines targeting other blood stage P. falciparum antigens, and few endemic field studies assessing PfMSP6 gene diversity have been conducted. This study follows PfMSP6 diversity in the Peruvian Amazon from 2003 to 2006 and is the first longitudinal assessment of PfMSP6 sequence dynamics.

Methods

Parasite DNA was extracted from 506 distinct P. falciparum infections spanning the transmission seasons from 2003 to 2006 as part of the Malaria Immunology and Genetics in the Amazon (MIGIA) cohort study near Iquitos, Peru. PfMSP6 was amplified from each sample using a nested PCR protocol, genotyped for allele class by agarose gel electrophoresis, and sequenced to detect diversity. Allele frequencies were analysed using JMP v.8.0.1.0 and correlated with clinical and epidemiological data collected as part of the MIGIA project.

Results

Both PfMSP6 allele classes, K1-like and 3D7-like, were detected at the study site, confirming that both are globally distributed. Allele frequencies varied significantly between transmission seasons, with 3D7-class alleles dominating and K1-class alleles nearly disappearing in 2005 and 2006. There was a significant association between allele class and village location (p-value = 0.0008), but no statistically significant association between allele class and age, sex, or symptom status. No intra-allele class sequence diversity was detected.

Conclusions

Both PfMSP6 allele classes are globally distributed, and this study shows that allele frequencies can fluctuate significantly between communities separated by only a few kilometres, and over time in the same community. By contrast, PfMSP6 was highly stable at the sequence level, with no SNPs detected in the 506 samples analysed. This limited diversity supports further investigation of PfMSP6 as a blood stage vaccine candidate, with the clear caveat that any such vaccine must either contain both alleles or generate cross-protective responses that react against both allele classes. Detailed immunoepidemiology studies are needed to establish the viability of these approaches before PfMSP6 advances further down the vaccine development pipeline.
Field evaluation of a rapid diagnostic test (Parascreen™) for malaria diagnosis in the Peruvian Amazon
Authors: Bendezu Jorge , Rosas Angel , Grande Tanilu , Rodriguez Hugo , Llanos-Cuentas Alejandro , Escobedo Jorge , Gamboa Dionicia
Published: June 2010

Background

The rapid diagnostic tests for malaria (RDT) constitute a fast and opportune alternative for non-complicated malaria diagnosis in areas where microscopy is not available. The objective of this study was to validate a RDT named Parascreen™ under field conditions in Iquitos, department of Loreto, Peru. Parascreen™ is a RDT that detects the histidine-rich protein 2 (HRP2) antigen fromPlasmodium falciparumand lactate deshydrogenase from allPlasmodiumspecies.

Methods

Parascreen™ was compared with microscopy performed by experts (EM) and polymerase chain reaction (PCR) using the following indicators: sensitivity (Se), specificity (Sp), positive (PV+) and negative predictive values (PV-), positive (LR+) and negative likehood ratio (LR-).

Results

332 patients with suspected non-complicated malaria who attended to the MOH health centres were enrolled between October and December 2006. ForP. falciparummalaria, Parascreen™ in comparison with EM, had Se: 53.5%, Sp: 98.7%, PV+: 66.7%, PV-: 97.8%, LR+: 42.27 and LR-: 0.47; and for non-P. falciparummalaria, Se: 77.1%, Sp: 97.6%, PV+: 91.4%, PV-: 92.7%, LR+: 32.0 and LR-: 0.22. The comparison of Parascreen™ with PCR showed, forP. falciparummalaria, Se: 81.8%, Sp: 99.1%, PV+: 75%, PV-: 99.4, LR+: 87.27 and LR-: 0.18; and for non-P. falciparummalaria Se: 76.1%, Sp: 99.2%, PV+: 97.1%, PV-: 92.0%, LR+: 92.51 and LR-: 0.24.

Conclusions

The study results indicate that Parascreen™ is not a valid and acceptable test for malaria diagnosis under the field conditions found in the Peruvian Amazon. The relative proportion ofPlasmodiumspecies, in addition to the genetic characteristics of the parasites in the area, must be considered before applying any RDT, especially after the finding ofP. falciparummalaria parasites lackingpfhrp2gene in this region.
Complement activation mediates cetuximab inhibition of non-small cell lung cancer tumor growth in vivo
Authors: Hsu Yi-Fan , Ajona Daniel , Corrales Leticia , Lopez-Picazo Jose M , Gurpide Alfonso , Montuenga Luis M , Pio Ruben
Published: June 2010

Background

Cetuximab, an antibody targeting the epidermal growth factor receptor (EGFR), increases survival in patients with advanced EGFR-positive non-small cell lung cancer when administrated in combination with chemotherapy. In this study, we investigated the role of complement activation in the antitumor mechanism of this therapeutic drug.

Results

EGFR-expressing lung cancer cell lines were able to bind cetuximab and initiate complement activation by the classical pathway, irrespective of the mutational status of EGFR. This activation led to deposition of complement components and increase in complement-mediated cell death. The influence of complement activation on the activity of cetuximab in vivo was evaluated in xenografts of A549 lung cancer cells on nude mice. A549 cells express wild-type EGFR and have a KRAS mutation. Cetuximab activity against A549 xenografts was highly dependent on complement activation, since complement depletion completely abrogated the antitumor efficacy of cetuximab. Moreover, cetuximab activity was significantly higher on A549 cells in which a complement inhibitor, factor H, was genetically downregulated.

Conclusions

We demonstrate for the first time that the in vivo antitumor activity of cetuximab can be associated with a complement-mediated immune response. These results may have important implications for the development of new cetuximab-based therapeutic strategies and for the identification of markers that predict clinical response.
Proteomic analysis of primary duck hepatocytes infected with duck hepatitis B virus
Authors: Zhao Yanfeng , Ben Haijing , Qu Su , Zhou Xinwen , Yan Liang , Xu Bin , Zhou Shuangcheng , Lou Qiang , Ye Rong , Zhou Tianlun , Yang Pengyuan , Qu Di
Published: June 2010

Background

Hepatitis B virus (HBV) is a major cause of liver infection in human. Because of the lack of an appropriate cell culture system for supporting HBV infection efficiently, the cellular and molecular mechanisms of hepadnavirus infection remain incompletely understood. Duck heptatitis B virus (DHBV) can naturally infect primary duck hepatocytes (PDHs) that provide valuable model systems for studying hepadnavirus infection in vitro. In this report, we explored global changes in cellular protein expression in DHBV infected PDHs by two-dimension gel electrophoresis (2-DE) combined with MALDI-TOF/TOF tandem mass spectrometry (MS/MS).

Results

The effects of hepadnavirus infection on hepatocytes were investigated in DHBV infected PDHs by the 2-DE analysis. Proteomic profile of PDHs infected with DHBV were analyzed at 24, 72 and 120 h post-infection by comparing with uninfected PDHs, and 75 differentially expressed protein spots were revealed by 2-DE analysis. Among the selected protein spots, 51 spots were identified corresponding to 42 proteins by MS/MS analysis; most of them were matched to orthologous proteins of Gallus gallus, Anas platyrhynchos or other avian species, including alpha-enolase, lamin A, aconitase 2, cofilin-2 and annexin A2, etc. The down-regulated expression of beta-actin and annexin A2 was confirmed by Western blot analysis, and potential roles of some differentially expressed proteins in the virus-infected cells have been discussed.

Conclusions

Differentially expressed proteins of DHBV infected PDHs revealed by 2-DE, are involved in carbohydrate metabolism, amino acid metabolism, stress responses and cytoskeleton processes etc, providing the insight to understanding of interactions between hepadnavirus and hepatocytes and molecular mechanisms of hepadnavirus pathogenesis.
HIV-1 Vpu and HIV-2 Env counteract BST-2/tetherin by sequestration in a perinuclear compartment
Authors: Hauser Heiko , Lopez Lisa A , Yang Su Jung , Oldenburg Jill E , Exline Colin M , Guatelli John C , Cannon Paula M
Published: June 2010

Background

In the absence of the Vpu protein, newly formed HIV-1 particles can remain attached to the surface of human cells due to the action of an interferon-inducible cellular restriction factor, BST-2/tetherin. Tetherin also restricts the release of other enveloped viral particles and is counteracted by a several viral anti-tetherin factors including the HIV-2 Env, SIV Nef and KSHV K5 proteins.

Results

We observed that a fraction of tetherin is located at the surface of restricting cells, and that co-expression of both HIV-1 Vpu and HIV-2 Env reduced this population. In addition, Vpu, but not the HIV-2 Env, reduced total cellular levels of tetherin. An additional effect observed for both Vpu and the HIV-2 Env was to redirect tetherin to an intracellular perinuclear compartment that overlapped with markers for the TGN (trans-Golgi network). Sequestration of tetherin in this compartment was independent of tetherin's normal endocytosis trafficking pathway.

Conclusions

Both HIV-1 Vpu and HIV-2 Env redirect tetherin away from the cell surface and sequester the protein in a perinuclear compartment, which likely blocks the action of this cellular restriction factor. Vpu also promotes the degradation of tetherin, suggesting that it uses more than one mechanism to counteract tetherin restriction.
Randomized Phase III Trial of Ixabepilone Plus Capecitabine Versus Capecitabine in Patients With Metastatic Breast Cancer Previously Treated With an Anthracycline and a Taxane
Authors: Sparano Joseph A. , Vrdoljak Eduard , Rixe Oliver , Xu Binghe , Manikhas Alexey , Medina Carlos , Ventilari Da Costa Susanne Crocamo , Ro Jungsil , Rubio Gonzalo , Rondinon Monica , Perez Manga Gumersindo , Peck Ronald , Poulart Valerie , Conte Pierfranco
Published: June 2010

Purpose

We sought to determine whether the combination of ixabepilone plus capecitabine improved overall survival (OS) compared with capecitabine alone in patients with metastatic breast cancer (MBC) previously treated with anthracyclines and taxanes.

Patients and Methods

A total of 1,221 patients with MBC previously treated with anthracycline and taxanes were randomly assigned to ixabepilone (40 mg/m2 intravenously on day 1) plus capecitabine (2,000 mg/m2 orally on days 1 through 14) or capecitabine alone (2,500 mg/m2 on the same schedule) given every 21 days. The trial was powered to detect a 20% reduction in the hazard ratio (HR) for death.

Results

There was no significant difference in OS between the combination and capecitabine monotherapy arm, the primary end point (median, 16.4 v 15.6 months; HR = 0.9; 95% CI, 078 to 1.03; P = .1162). The arms were well balanced with the exception of a higher prevalence of impaired performance status (Karnofsky performance status 70% to 80%) in the combination arm (32% v 25%). In a secondary Cox regression analysis adjusted for performance status and other prognostic factors, OS was improved for the combination (HR = 0.85; 95% CI, 0.75 to 0.98; P = .0231). In 79% of patients with measurable disease, the combination significantly improved progression-free survival (PFS; median, 6.2 v 4.2 months; HR = 0.79; P = .0005) and response rate (43% v 29%; P < .0001). Grade 3 to 4 neuropathy occurred in 24% treated with the combination, but was reversible.

Conclusion

This study confirmed a previous trial demonstrating improved PFS and response for the ixabepilone-capecitabine combination compared with capecitabine alone, although this did not result in improved survival.
Emerging Targeted Therapies for Breast Cancer
Authors: Alvarez Ricardo H. , Valero Vicente , Hortobagyi Gabriel N.
Published: June 2010

Increased understanding of the molecular events involved in cancer development has led to the identification of a large number of novel targets and, in parallel, to the development of multiple approaches to anticancer therapy. Targeted therapy focuses on specific molecules in the malignant cell signal transduction machinery, including crucial molecules involved in cell invasion, metastasis, apoptosis, cell-cycle control, and tumor-related angiogenesis. In breast cancer, two new targeted agents have recently been approved: lapatinib, directed against the human epidermal growth factor receptor 2 (HER2); and bevacizumab, directed against vascular endothelial growth factor (VEGF). Multiple other targeted agents are under evaluation in clinical trials, including inhibitors of the epidermal growth factor receptor (EGFR), dual EGFR and HER2 inhibitors, other VEGF or VEGF-receptor inhibitors, and agents that alter crucial signaling pathways, such as RAS/MEK/ERK; phosphatidylinositol-3-kinase/Akt/ mammalian target of rapamycin; insulin-like growth factor/insulin-like growth factor receptor; poly (ADP-ribose) polymerase 1; and others. In this review, we present the most promising studies of these new targeted therapies and novel combinations of targeted therapies with traditional cytotoxic agents.
Characteristics and Predictors of Missed Opportunities in Lung Cancer Diagnosis: An Electronic Health Record–Based Study
Authors: Singh Hardeep , Hirani Kamal , Kadiyala Himabindu , Rudomiotov Olga , Davis Traber , Khan Myrna M. , Wahls Terry L.
Published: June 2010

Purpose

Understanding delays in cancer diagnosis requires detailed information about timely recognition and follow-up of signs and symptoms. This information has been difficult to ascertain from paper-based records. We used an integrated electronic health record (EHR) to identify characteristics and predictors of missed opportunities for earlier diagnosis of lung cancer.

Methods

Using a retrospective cohort design, we evaluated 587 patients of primary lung cancer at two tertiary care facilities. Two physicians independently reviewed each case, and disagreements were resolved by consensus. Type I missed opportunities were defined as failure to recognize predefined clinical clues (ie, no documented follow-up) within 7 days. Type II missed opportunities were defined as failure to complete a requested follow-up action within 30 days.

Results

Reviewers identified missed opportunities in 222 (37.8%) of 587 patients. Median time to diagnosis in cases with and without missed opportunities was 132 days and 19 days, respectively (P < .001). Abnormal chest x-ray was the clue most frequently associated with type I missed opportunities (62%). Follow-up on abnormal chest x-ray (odds ratio [OR], 2.07; 95% CI, 1.04 to 4.13) and completion of first needle biopsy (OR, 3.02; 95% CI, 1.76 to 5.18) were associated with type II missed opportunities. Patient adherence contributed to 44% of patients with missed opportunities.

Conclusion

Preventable delays in lung cancer diagnosis arose mostly from failure to recognize documented abnormal imaging results and failure to complete key diagnostic procedures in a timely manner. Potential solutions include EHR-based strategies to improve recognition of abnormal imaging and track patients with suspected cancers.
Longer-Term Assessment of Trastuzumab-Related Cardiac Adverse Events in the Herceptin Adjuvant (HERA) Trial
Authors: Procter Marion , Suter Thomas M. , de Azambuja Evandro , Dafni Urania , van Dooren Veerle , Muehlbauer Susanne , Climent Miguel Angel , Rechberger Ernst , Liu Walter Tsang-Wu , Toi Mazakasu , Coombes R. Charles , Dodwell David , Pagani Olivia , Madrid Jorge , Hall Marcia , Chen Shin-Cheh , Focan Christian , Muschol Michael , van Veldhuisen Dirk J. , Piccart-Gebhart Martine J.
Published: June 2010

Purpose

We investigated the incidence of cardiac adverse events in patients with early breast cancer in the Herceptin Adjuvant (HERA) trial who were treated with 1 year of trastuzumab after completion of (neo)adjuvant chemotherapy.

Patients and Methods

The HERA trial is a three-group, randomized trial that compared 1 year or 2 years of trastuzumab with observation in women with human epidermal growth factor receptor-2 (HER2) –positive early breast cancer. Eligible patients had normal left ventricular ejection fraction (LVEF; ≥ 55%) after completion of (neo)adjuvant chemotherapy with or without radiotherapy. Cardiac function was monitored throughout the trial. This analysis considers patients randomly assigned to 1 year of trastuzumab treatment or observation.

Results

There were 1,698 patients randomly assigned to observation and 1,703 randomly assigned to 1 year of trastuzumab treatment; 94.1% of patients had been treated with anthracyclines. The incidence of discontinuation of trastuzumab because of cardiac disorders was low (5.1%). At a median follow-up of 3.6 years, the incidence of cardiac end points remained low, though it was higher in the trastuzumab group than in the observation group (severe CHF, 0.8% v 0.0%; confirmed significant LVEF decreases, 3.6% v 0.6%) In the trastuzumab group, 59 of 73 patients with a cardiac end point reached acute recovery; of these 59 patients, 52 were considered by the cardiac advisory board (CAB) to have a favorable outcome from the cardiac end point.

Conclusion

The incidence of cardiac end points remains low even after longer-term follow-up. The cumulative incidence of any type of cardiac end point increases during the scheduled treatment period of 1 year, but it remains relatively constant thereafter.
Report of a Multicenter Phase II Trial Testing a Combination of Biweekly Bevacizumab and Daily Erlotinib in Patients With Unresectable Biliary Cancer: A Phase II Consortium Study
Authors: Lubner Sam J. , Mahoney Michelle R. , Kolesar Jill L. , LoConte Noelle K. , Kim George P. , Pitot Henry C. , Philip Philip A. , Picus Joel , Yong Wei-Peng , Horvath Lisa , Van Hazel Guy , Erlichman Charles E. , Holen Kyle D.
Published: June 2010

Purpose

Biliary cancers overexpress epidermal growth factor receptor (EGFR), and angiogenesis has been correlated with poor outcome. Erlotinib, an EGFR tyrosine kinase inhibitor, and bevacizumab, a vascular endothelial growth factor (VEGF) inhibitor have each been shown to have activity in biliary cancer. The primary objective of this study was to evaluate the response rate by Response Evaluation Criteria in Solid Tumors (RECIST). Secondary end points included overall survival (OS), time to progression (TTP), VEGF levels, and molecular studies of EGFR and k-ras.

Patients and Methods

Eligible patients had advanced cholangiocarcinoma or gallbladder cancer. Patients were treated with bevacizumab 5 mg/kg intravenously on days 1 and 15 and erlotinib 150 mg by mouth daily on days 1 through 28. Responses were evaluated by RECIST. VEGF levels were collected, and samples were analyzed for EGFR mutation by polymerase chain reaction.

Results

Fifty-three eligible patients were enrolled at eight sites. Of 49 evaluable patients, six (12%; 95% CI, 6% to 27%) had a confirmed partial response. Stable disease was documented in another 25 patients (51%). Rash was the most common grade 3 toxicity. Four patients had grade 4 toxicities. Median OS was 9.9 months, and TTP was 4.4 months. Low repeats (< 16) in EGFR intron 1 polymorphism and G>G k-ras Q38 genotype (wild type) were associated with improved outcomes.

Conclusion

Combination chemotherapy with bevacizumab and erlotinib showed clinical activity with infrequent grade 3 and 4 adverse effects in patients with advanced biliary cancers. On the basis of preliminary molecular analysis, presence of a k-ras mutation may alter erlotinib efficacy. The combination of bevacizumab and erlotinib may be a therapeutic alternative in patients with advanced biliary cancer.