bluuebunny/crossref_metadata_2025 huggingface dataset:
Side-by-side analysis of five clinically tested anti-EpCAM monoclonal antibodies
Authors: Münz Markus , Murr Alexander , Kvesic Majk , Rau Doris , Mangold Susanne , Pflanz Stefan , Lumsden John , Volkland Jörg , Fagerberg Jan , Riethmüller Gert , Rüttinger Dominik , Kufer Peter , Baeuerle Patrick A , Raum Tobias
Published: November 2010

Background

Epithelial cell adhesion molecule (EpCAM) is frequently and highly expressed on human carcinomas. The emerging role of EpCAM as a signalling receptor and activator of the wnt pathway, and its expression on tumor-initiating cells, further add to its attractiveness as target for immunotherapy of cancer. Thus far, five conventional monoclonal IgG antibodies have been tested in cancer patients. These are murine IgG2a edrecolomab and its murine/human chimeric IgG1 antibody version, and humanized, human-engineered and fully human IgG1 antibodies 3622W94, ING-1, and adecatumumab (MT201), respectively. Here we compared all anti-EpCAM antibodies in an attempt to explain differences in clinical activity and safety.

Methods

We recombinantly produced all antibodies but murine edrecolomab and investigated them for binding affinity, EpCAM epitope recognition, ADCC and CDC, and inhibition of breast cancer cell proliferation.

Results

ING-1 and 3622W94 bound to EpCAM with much higher affinity than adecatumumab and edrecolomab. Edrecolomab, ING-1, and 3622W94 all recognized epitopes in the exon 2-encoded N-terminal domain of EpCAM, while adecatumumab recognized a more membrane proximal epitope encoded by exon 5. All antibodies induced lysis of EpCAM-expressing cancer cell lines by both ADCC and CDC with potencies that correlated with their binding affinities. The chimeric version of edrecolomab with a human Fcγ1 domain was much more potent in ADCC than the murine IgG2a version. Only adecatumumab showed a significant inhibition of MCF-7 breast cancer cell proliferation in the absence of complement and immune cells.

Conclusion

A moderate binding affinity and recognition of a distinct domain of EpCAM may best explain why adecatumumab showed a larger therapeutic window in cancer patients than the two high-affinity IgG1 antibodies ING-1 and 3622W94, both of which caused acute pancreatitis.
Increasing CD44+/CD24- tumor stem cells, and upregulation of COX-2 and HDAC6, as major functions of HER2 in breast tumorigenesis
Authors: Wang Kai-Hung , Kao An-Pei , Chang Chia-Cheng , Lee Jau-Nan , Hou Ming-Feng , Long Cheng-Yu , Chen Hung-Sheng , Tsai Eing-Mei
Published: November 2010

Background

Cancer cells are believed to arise primarily from stem cells. CD44+/CD24-have been identified as markers for human breast cancer stem cells. Although, HER2 is a well known breast cancer oncogene, the mechanisms of action of this gene are not completely understood. Previously, we have derived immortal (M13SV1), weakly tumorigenic (M13SV1R2) and highly tumorigenic (M13SV1R2N1) cell lines from a breast epithelial cell type with stem cell phenotypes after successive SV40 large T-antigen transfection, X-ray irradiation and ectopic expression of HER2/C-erbB2/neu. Recently, we found that M13SV1R2 cells became non-tumorigenic after growing in a growth factor/hormone-deprived medium (R2d cells).

Results

In this study, we developed M13SV1R2N1 under the same growth factor/hormone-deprived condition (R2N1d cells). This provides an opportunity to analyze HER2 effect on gene expression associated with tumorigenesis by comparative study of R2d and R2N1d cells with homogeneous genetic background except HER2 expression. The results reveal distinct characters of R2N1d cells that can be ascribed to HER2: 1) development of fast-growing tumors; 2) high frequency of CD44+/CD24-cells (~50% for R2N1d vs. ~10% for R2d); 3) enhanced expression of COX-2, HDAC6 mediated, respectively, by MAPK and PI3K/Akt pathways, and many genes associated with inflammation, metastasis, and angiogenesis. Furthermore, HER2 expression can be down regulated in non-adhering R2N1d cells. These cells showed longer latent period and lower rate of tumor development compared with adhering cells.

Conclusions

HER2 may induce breast cancer by increasing the frequency of tumor stem cells and upregulating the expression of COX-2 and HDAC6 that play pivotal roles in tumor progression.
A strategy of tumor treatment in mice with doxorubicin-cyclophosphamide combination based on dendritic cell activation by human double-stranded DNA preparation
Authors: Alyamkina Ekaterina A , Nikolin Valeriy P , Popova Nelly A , Dolgova Evgenia V , Proskurina Anastasia S , Orishchenko Konstantin E , Efremov Yaroslav R , Chernykh Elena R , Ostanin Alexandr A , Sidorov Sergey V , Ponomarenko Dmitriy M , Zagrebelniy Stanislav N , Bogachev Sergey S , Shurdov Mikhail A
Published: November 2010

Background

Immunization of mice with tumor homogenate after combined treatment with cyclophosphamide (CP) and double-stranded DNA (dsDNA) preparation is effective at inhibition of growth of tumor challenged after the treatment. It was assumed that this inhibition might be due to activation of the antigen-presenting cells. The purpose was to develop improved antitumor strategy using mice. We studied the combined action of cytostatics doxorubicin (Dox) plus CP with subsequent dsDNA preparation on tumor growth.

Methods

Three-month old CBA/Lac mice were used in the experiments. Mice were injected with CP and human dsDNA preparation. The percentage of mature dendritic cells (DCs) was estimated by staining of mononuclear cells isolated from spleen and bone marrow 3, 6, and 9 days later with monoclonal antibodies CD34, CD80, and CD86. In the next set of experiments, mice were given intramuscularly injections of 1-3 × 105tumor cells. Four days later, they were injected intravenously with 6-6.7 mg/kg Dox and intraperitoneally with 100-200 mg/kg CP; 200 mkg human DNA was injected intraperitoneally after CP administration. Differences in tumor size between groups were analyzed for statistical significance by Student's t-test. The MTT-test was done to determine the cytotoxic index of mouse leucocytes from treated groups.

Results

The conducted experiments showed that combined treatment with CP and dsDNA preparation produce an increase in the total amount of mature DCsin vivo. Treatment of tumor bearers with preparation of fragmented dsDNA on the background of pretreatment with Dox plus CP demonstrated a strong suppression of tumor growth in two models. RLS, a weakly immunogenic, resistant to alkalyting cytostatics tumor, grew 3.4-fold slower when compared with the control (p < 0.001). In experiment with Krebs-2 tumor, only 2 of the 10 mice in the Dox+CP+DNA group had a palpable tumor on day 16. The cytotoxic index of leucocytes was 86.5% in the Dox+CP+DNA group, but it was 0% in the Dox+CP group.

Conclusions

Thus, the set of experiments we performed showed that exogenous dsDNA, when administered on the background of pretreatment with Dox plus CP, has an antitumor effect possibly due to DC activation.
Predictors of adherence to antiretroviral therapy among people living with HIV/AIDS in resource-limited setting of southwest ethiopia
Authors: Tiyou Ayele , Belachew Tefera , Alemseged Fisehaye , Biadgilign Sibhatu
Published: November 2010

Background

Good adherence to antiretroviral therapy is necessary to achieve the best virological response, lower the risk that drug resistance will develop, and reduce morbidity and mortality. Little is known about the rate and predictors of adherence in Ethiopia. Therefore this study determines the magnitude and predictors of adherence to antiretroviral therapy among people living with HIV/AIDS in Southwest Ethiopia.

Methods

A cross sectional study was carried out from January 1, 2009 to March 3, 2009 among 319 adult PLWHA (≥ 18 years) attending ART clinic at Jimma university Specialized Hospital (JUSH). Multiple Logistic regression models were constructed with adherence and independent variables to identify the predictors.

Results

About 303(95%) of the study subjects were adherent based on self report of missed doses (dose adherence) in a one-week recall before the actual interview. The rate of self reported adherence in the study based on the combined indicator of the dose, time and food adherence measurement was 72.4%. Patients who got family support were 2 times [2.12(1.25-3.59)] more likely to adhere than those who didn't get family support as an independent predictor of overall adherence (dose, time and food). The reasons given for missing drugs were 9(27.3%) running out of medication/drug, 7(21.2%) being away from home and 7(21.2%) being busy with other things.

Conclusion

The adherence rate found in this study is similar to other resource limited setting and higher than the developed country. This study highlights emphasis should be given for income generating activities and social supports that helps to remember the patients for medication taking and management of opportunistic infections during the course of treatment.
All that glitters is not gold - founder effects complicate associations of flu mutations to disease severity
Authors: Lee Raphael TC , Santos Cecília LS , Maria de Paiva Terezinha , Cui Lin , Sirota Fernanda L , Eisenhaber Frank , Maurer-Stroh Sebastian
Published: November 2010

Background

The recent 2009 (H1N1) influenza A pandemic saw a rapid spread of the virus to essentially all parts of the world. In the course of its evolution, the virus acquired many mutations, some of which have been investigated in the context of increased severity due to high occurrences in fatal cases. For example, statements such as: "42.9% of individuals who died from laboratory-confirmed cases of the pandemic (H1N1) were infected with the hemagglutinin (HA) Q310 H mutant virus." give the impression that HA-Q310 H would be highly dangerous or important, while careful consideration of all available data suggests that this is unlikely to be the case.

Results

We compare the mutations HA-Q310 H, PB2-K340N, HA-D239N and HA-D239G using whole genome phylogenetic trees, structural modeling in their 3 D context and complete epidemiological data from sequences to clinical outcomes. HA-Q310 H and PB2-K340N appear as isolated subtrees in the phylogenetic analysis pointing to founder effects which is consistent with their clustered temporal appearance as well as the lack of an immediate structural basis that could explain a change of phenotypes. Considering the prevailing viral genomic background, shared origin of samples (all from the city of Sao Paulo) and narrow temporal window (all death case samples within 1 month), it becomes clear that HA-Q310 H was actually a generally common mutation in the region at that time which could readily explain its increased occurrence among the few analyzed fatal cases without requiring necessarily an association with severity. In further support of this, we highlight 3 mild cases with the HA-Q310 H mutation.

Conclusions

We argue that claims of severity of any current and future flu mutation need to be critically considered in the light of phylogenetic, structural and detailed epidemiological data to distinguish increased occurrence due to possible founder effects rather than real phenotypic changes.
Effect of smoking status on total energy expenditure
Authors: Bradley David P , Johnson Lindsey A , Zhang Zhumin , Subar Amy F , Troiano Richard P , Schatzkin Arthur , Schoeller Dale A
Published: November 2010

Individuals who smoke generally have a lower body mass index (BMI) than nonsmokers. The relative roles of energy expenditure and energy intake in maintaining the lower BMI, however, remain controversial. We tested the hypothesis that current smokers have higher total energy expenditure than never smokers in 308 adults aged 40-69 years old of which 47 were current smokers. Energy expenditure was measured by doubly labeled water during a two week period in which the subjects lived at home and performed their normal activities. Smoking status was determined by questionnaire. There were no significant differences in mean BMI (mean ± SD) between smokers and never smokers for either males (27.8+5.1 kg/m2 vs. 27.5+4.0 kg/m2) or females (26.5+5.3 kg/m2 vs. 28.1+6.6 kg/m2), although the difference in females was of similar magnitude to previous reports. Similarly, total energy expenditure of male smokers (3069+764 kcal/d) was not significantly different from that of never smokers (2854+468 kcal/d), and that of female smokers (2266+387 kcal/d) was not different from that of never smokers (2330+415 kcal/d). These findings did not change after adjustment for age, fat-free mass and self-reported physical activity. Using doubly labeled water, we found no evidence of increased energy expenditure among smokers, however, it should be noted that BMI differences in this cohort also did not differ by smoking status.
Acupuncture Modulates Temporal Neural Responses in Wide Brain Networks: Evidence from fMRI Study
Authors: Bai Lijun , Tian Jie , Zhong Chongguang , Xue Ting , You Youbo , Liu Zhenyu , Chen Peng , Gong Qiyong , Ai Lin , Qin Wei , Dai Jianping , Liu Yijun
Published: November 2010

Background:

Accumulating neuroimaging studies in humans have shown that acupuncture can modulate a widely distributed brain network, large portions of which are overlapped with the pain-related areas. Recently, a striking feature of acupuncture-induced analgesia is found to be associated with its long-last effect, which has a delayed onset and gradually reaches a peak even after acupuncture needling being terminated. Identifying temporal neural responses in these areas that occur at particular time – both acute and sustained effects during acupuncture processes – may therefore shed lights on how such peripheral inputs are conducted and mediated through the CNS. In the present study, we adopted a non-repeated event-related (NRER) fMRI paradigm and control theory based approach namely change-point analysis in order to capture the detailed temporal profile of neural responses induced by acupuncture.

Results:

Our findings demonstrated that neural activities at the different stages of acupuncture presented distinct temporal patterns, in which consistently positive neural responses were found during the period of acupuncture needling while much more complex and dynamic activities found during a post-acupuncture period. These brain responses had a significant time-dependent effect which showed different onset time and duration of neural activities. The amygdala and perigenual anterior cingulate cortex (pACC), exhibited increased activities during the needling phase while decreased gradually to reach a peak below the baseline. The periaqueductal gray (PAG) and hypothalamus presented saliently intermittent activations across the whole fMRI session. Apart from the time-dependent responses, relatively persistent activities were also identified in the anterior insula and prefrontal cortices. The overall findings indicate that acupuncture may engage differential temporal neural responses as a function of time in a wide range of brain networks.

Conclusions:

Our study has provided evidence supporting a view that acupuncture intervention involves complex modulations of temporal neural response, and its effect can gradually resolve as a function of time. The functional specificity of acupuncture at ST36 may involve multiple levels of differential activities of a wide range of brain networks, which are gradually enhanced even after acupuncture needle being terminated.
Proteomic changes associated with deletion of the Magnaporthe oryzae conidial morphology-regulating gene COM1
Authors: Bhadauria Vijai , Wang Li-Xia , Peng You-Liang
Published: November 2010

Background

The rice blast disease caused by Magnaporthe oryzae is a major constraint on world rice production. The conidia produced by this fungal pathogen are the main source of disease dissemination. The morphology of conidia may be a critical factor in the spore dispersal and virulence of M. oryzae in the field. Deletion of a conidial morphology regulating gene encoding putative transcriptional regulator COM1 in M. oryzae resulted in aberrant conidial shape, reduced conidiation and attenuated virulence.

Results

In this study, a two-dimensional gel electrophoresis/matrix assisted laser desorption ionization- time of flight mass spectrometry (2-DE/MALDI-TOF MS) based proteomics approach was employed to identify the cellular and molecular components regulated by the COM1 protein (COM1p) that might contribute to the aberrant phenotypes in M. oryzae. By comparing the conidial proteomes of COM1 deletion mutant and its isogenic wild-type strain P131, we identified a potpourri of 31 proteins that exhibited statistically significant alterations in their abundance levels. Of these differentially regulated proteins, the abundance levels of nine proteins were elevated and twelve were reduced in the Δcom1 mutant. Three proteins were detected only in the Δcom1 conidial proteome, whereas seven proteins were apparently undetectable. The data obtained in the study suggest that the COM1p plays a key role in transcriptional reprogramming of genes implicated in melanin biosynthesis, carbon and energy metabolism, structural organization of cell, lipid metabolism, amino acid metabolism, etc. Semi-quantitative RT-PCR analysis revealed the down-regulation of genes encoding enzymes involved in melanin biosynthesis in the COM1 mutant.

Conclusions

Our results suggest that the COM1p may regulate the transcription of genes involved in various cellular processes indispensable for conidial development and appressorial penetration. These functions are likely to contribute to the effects of COM1p upon the aberrant phenotypes of M. oryzae.

Reviewers

This article is reviewed by George V. Shpakovski, Karthikeyan Sivaraman (nominated by M. Madan Babu) and Lakshminarayan M. Iyer.
MicroRNA-17-92 significantly enhances radioresistance in human mantle cell lymphoma cells
Authors: Jiang Ping , Rao En Y , Meng Na , Zhao Yong , Wang Jun J
Published: November 2010

The microRNA-17-92 (miRNA-17-92) cluster, at chromosome 13q31-q32, also known as oncomir-1, consists of seven miRNAs that are transcribed as a polycistronic unit. Over-expression of miRNA-17-92 has been observed in lymphomas and other solid tumors. Whether miRNA-17-92 expression affects the response of tumor cells to radiotherapy is not addressed so far. In the present study, we studied the effects of miRNA-17-92 on the radiosensitivity of human mantle cell lymphoma (MCL) cells Z138c. Over-expression of miRNA-17-92 significantly increased survival cell number, cell proliferation and decreased cell death of human MCL cells after different doses of radiation. Immunoblot analysis showed that phosphatase and tension homolog (PTEN) and PHLPP2 was down-modulated and pAkt activity was enhanced in MCL cells after over-expressing miRNA-17-92 after irradiation. These findings are the first direct evidence that over-expression of miRNA-17-92 cluster significantly increases the radioresistance of human MCL cells, which offers a novel target molecule for improving the radiotherapy of MCL in clinic.
Carbonic anhydrase XII expression is associated with histologic grade of cervical cancer and superior radiotherapy outcome
Authors: Yoo Chong Woo , Nam Byung-Ho , Kim Joo-Young , Shin Hye-Jin , Lim Hyunsun , Lee Sun , Lee Su-Kyoung , Lim Myong-Cheol , Song Yong-Jung
Published: November 2010

Background

To investigate whether expression of carbonic anhydrase XII (CA12) is associated with histologic grade of the tumors and radiotherapy outcomes of the patients with invasive cervical cancer.

Methods

CA12 expression was examined by immunohistochemical stains in cervical cancer tissues from 183 radiotherapy patients. Histological grading was classified as well (WD), moderately (MD) or poorly differentiated (PD). Oligonucleotide microarray experiment was performed using seven cervical cancer samples to examine differentially expressed genes between WD and PD cervical cancers. The association between CA12 and histological grade was analyzed by chi-square test. CA12 and histological grades were analyzed individually and as combined CA12 and histologic grade categories for effects on survival outcome.

Results

Immunohistochemical expression of CA12 was highly associated with the histologic grade of cervical cancer. Lack of CA12 expression was associated with PD histology, with an odds ratio of 3.9 (P = 0.01). Microarray analysis showed a fourfold reduction in CA12 gene expression in PD tumors. CA12 expression was marginally associated with superior disease-free survival. Application of the new combined categories resulted in further discrimination of the prognosis of patients with moderate and poorly differentiated tumor grade.

Conclusions

Our study indicates that CA12 may be used as a novel prognostic marker in combination with histologic grade of the tumors.
Phenothiazine-mediated rescue of cognition in tau transgenic mice requires neuroprotection and reduced soluble tau burden
Authors: O'Leary John C , Li Qingyou , Marinec Paul , Blair Laura J , Congdon Erin E , Johnson Amelia G , Jinwal Umesh K , Koren John , Jones Jeffrey R , Kraft Clara , Peters Melinda , Abisambra Jose F , Duff Karen E , Weeber Edwin J , Gestwicki Jason E , Dickey Chad A
Published: November 2010

Background

It has traditionally been thought that the pathological accumulation of tau in Alzheimer's disease and other tauopathies facilitates neurodegeneration, which in turn leads to cognitive impairment. However, recent evidence suggests that tau tangles are not the entity responsible for memory loss, rather it is an intermediate tau species that disrupts neuronal function. Thus, efforts to discover therapeutics for tauopathies emphasize soluble tau reductions as well as neuroprotection.

Results

Here, we found that neuroprotection alone caused by methylene blue (MB), the parent compound of the anti-tau phenothiaziazine drug, Rember™, was insufficient to rescue cognition in a mouse model of the human tauopathy, progressive supranuclear palsy (PSP) and fronto-temporal dementia with parkinsonism linked to chromosome 17 (FTDP17): Only when levels of soluble tau protein were concomitantly reduced by a very high concentration of MB, was cognitive improvement observed. Thus, neurodegeneration can be decoupled from tau accumulation, but phenotypic improvement is only possible when soluble tau levels are also reduced.

Conclusions

Neuroprotection alone is not sufficient to rescue tau-induced memory loss in a transgenic mouse model. Development of neuroprotective agents is an area of intense investigation in the tauopathy drug discovery field. This may ultimately be an unsuccessful approach if soluble toxic tau intermediates are not also reduced. Thus, MB and related compounds, despite their pleiotropic nature, may be the proverbial "magic bullet" because they not only are neuroprotective, but are also able to facilitate soluble tau clearance. Moreover, this shows that neuroprotection is possible without reducing tau levels. This indicates that there is a definitive molecular link between tau and cell death cascades that can be disrupted.
Lobaplatin arrests cell cycle progression in human hepatocellular carcinoma cells
Authors: Wu Qiong , Qin Shu-Kui , Teng Feng-Meng , Chen Chang-Jie , Wang Rui
Published: November 2010

Background

Hepatocellular carcinoma (HCC) still is a big burden for China. In recent years, the third-generation platinum compounds have been proposed as potential active agents for HCC. However, more experimental and clinical data are warranted to support the proposal. In the present study, the effect of lobaplatin was assessed in five HCC cell lines and the underlying molecular mechanisms in terms of cell cycle kinetics were explored.

Methods

Cytotoxicity of lobaplatin to human HCC cell lines was examined using MTT cell proliferation assay. Cell cycle distribution was determined by flow cytometry. Expression of cell cycle-regulated genes was examined at both the mRNA (RT-PCR) and protein (Western blot) levels. The phosphorylation status of cyclin-dependent kinases (CDKs) and retinoblastoma (Rb) protein was also examined using Western blot analysis.

Results

Lobaplatin inhibited proliferation of human HCC cells in a dose-dependent manner. For the most sensitive SMMC-7721 cells, lobaplatin arrested cell cycle progression in G1 and G2/M phases time-dependently which might be associated with the down-regulation of cyclin B, CDK1, CDC25C, phosphorylated CDK1 (pCDK1), pCDK4, Rb, E2F, and pRb, and the up-regulation of p53, p21, and p27.

Conclusion

Cytotoxicity of lobaplatin in human HCC cells might be due to its ability to arrest cell cycle progression which would contribute to the potential use of lobaplatin for the management of HCC.
Campylobacter jejuni induces transcytosis of commensal bacteria across the intestinal epithelium through M-like cells
Authors: Kalischuk Lisa D , Leggett Frances , Inglis G Douglas
Published: November 2010

Background

Recent epidemiological analyses have implicated acute Campylobacter enteritis as a factor that may incite or exacerbate inflammatory bowel disease (IBD) in susceptible individuals. We have demonstrated previously that C. jejuni disrupts the intestinal barrier function by rapidly inducing epithelial translocation of non-invasive commensal bacteria via a transcellular lipid raft-mediated mechanism ('transcytosis'). To further characterize this mechanism, the aim of this current study was to elucidate whether C. jejuni utilizes M cells to facilitate transcytosis of commensal intestinal bacteria.

Results

C. jejuni induced translocation of non-invasive E. coli across confluent Caco-2 epithelial monolayers in the absence of disrupted transepithelial electrical resistance or increased permeability to a 3 kDa dextran probe. C. jejuni-infected monolayers displayed increased numbers of cells expressing the M cell-specific marker, galectin-9, reduced numbers of enterocytes that stained with the absorptive enterocyte marker, Ulex europaeus agglutinin-1, and reduced activities of enzymes typically associated with absorptive enterocytes (namely alkaline phosphatase, lactase, and sucrase). Furthermore, in Campylobacter-infected monolayers, E. coli were observed to be internalized specifically within epithelial cells displaying M-like cell characteristics.

Conclusion

These data indicate that C. jejuni may utilize M cells to promote transcytosis of non-invasive bacteria across the intact intestinal epithelial barrier. This mechanism may contribute to the inflammatory immune responses against commensal intestinal bacteria commonly observed in IBD patients.
The neuronal guidance protein netrin-1 reduces alveolar inflammation in a porcine model of acute lung injury
Authors: Mutz Christian , Mirakaj Valbona , Vagts Dierk A , Westermann Phillipp , Waibler Kristina , König Klemens , Iber Thomas , Nöldge-Schomburg Gabriele , Rosenberger Peter
Published: November 2010

Introduction

Acute lung injury (ALI) is an inflammatory disorder of pulmonary or extrapulmonary origin. We have previously demonstrated that netrin-1 dampens murine ALI, and in an attempt to advance this finding into future clinical practice we evaluated whether netrin-1 would reduce alveolar inflammation during porcine ALI.

Methods

This was a controlled in vivo experimental study in pigs. We induced ALI through lipoploysaccharide (LPS) infusion (50 μg/kg) for 2 hours. Following this, we exposed animals to either vehicle, intravenous netrin-1 (netrin-1 i.v.) or inhaled netrin-1 (netrin-1 inh.). Serum samples and bronchoalveolar lavage (BAL) were obtained to determine levels of tumor necrosis factor-α (TNF-α), interleukin (IL)-1β, interleukin-6 and interleukin-8 at baseline and 6 hours following treatment. Myeloperoxidase activity (MPO) and protein levels were determined in the BAL, and tissue samples were obtained for histological evaluation. Finally, animals were scanned with spiral CT.

Results

Following LPS infusion, animals developed acute pulmonary injury. Serum levels of TNF-α and IL-6 were significantly reduced in the netrin-1 i.v. group. BAL demonstrated significantly reduced cytokine levels 6 hours post-netrin-1 treatment (TNF-α: vehicle 633 ± 172 pg/ml, netrin-1 i.v. 84 ± 5 pg/ml, netrin-1 inh. 168 ± 74 pg/ml; both P < 0.05). MPO activity and protein content were significantly reduced in BAL samples from netrin-1-treated animals. Histological sections confirmed reduced inflammatory changes in the netrin-1-treated animals. Computed tomography corroborated reduced pulmonary damage in both netrin-1-treated groups.

Conclusions

We conclude that treatment with the endogenous anti-inflammatory protein netrin-1 reduces pulmonary inflammation during the initial stages of ALI and should be pursued as a future therapeutic option.
Cost-consequence analysis of remifentanil-based analgo-sedation vs. conventional analgesia and sedation for patients on mechanical ventilation in the Netherlands
Authors: Al Maiwenn J , Hakkaart Leona , Tan SiokSwan , Bakker Jan
Published: November 2010

Introduction

Hospitals are increasingly forced to consider the economics of technology use. We estimated the incremental cost-consequences of remifentanil-based analgo-sedation (RS) vs. conventional analgesia and sedation (CS) in patients requiring mechanical ventilation (MV) in the intensive care unit (ICU), using a modelling approach.

Methods

A Markov model was developed to describe patient flow in the ICU. The hourly probabilities to move from one state to another were derived from UltiSAFE, a Dutch clinical study involving ICU patients with an expected MV-time of two to three days requiring analgesia and sedation. Study medication was either: CS (morphine or fentanyl combined with propofol, midazolam or lorazepam) or: RS (remifentanil, combined with propofol when required). Study drug costs were derived from the trial, whereas all other ICU costs were estimated separately in a Dutch micro-costing study. All costs were measured from the hospital perspective (price level of 2006). Patients were followed in the model for 28 days. We also studied the sub-population where weaning had started within 72 hours.

Results

The average total 28-day costs were €15,626 with RS versus €17,100 with CS, meaning a difference in costs of €1474 (95% CI -2163, 5110). The average length-of-stay (LOS) in the ICU was 7.6 days in the RS group versus 8.5 days in the CS group (difference 1.0, 95% CI -0.7, 2.6), while the average MV time was 5.0 days for RS versus 6.0 days for CS. Similar differences were found in the subgroup analysis.

Conclusions

Compared to CS, RS significantly decreases the overall costs in the ICU.

Trial Registration

Clinicaltrials.gov NCT00158873.
Comorbidity and Mortality Results From a Randomized Prostate Cancer Screening Trial
Authors: Crawford E. David , Grubb Robert , Black Amanda , Andriole Gerald L. , Chen Ming-Hui , Izmirlian Grant , Berg Christine D. , D'Amico Anthony V.
Published: November 2010

Purpose

Estimates of prostate cancer–specific mortality (PCSM) were similar for men randomly assigned to intervention compared with usual care on the Prostate, Lung, Colorectal and Ovarian PC screening study. However, results analyzed by comorbidity strata remain unknown.

Patients and Methods

Between 1993 and 2001, of 76,693 men who were randomly assigned to usual care or intervention at 10 US centers, 73,378 (96%) completed a questionnaire that inquired about comorbidity and prostate-specific antigen (PSA) testing before random assignment. Fine and Gray's multivariable analysis was performed to assess whether the randomized screening arm was associated with the risk of PCSM in men with no or minimal versus at least one significant comorbidity, adjusting for age and prerandomization PSA testing.

Results

After 10 years of follow-up, 9,565 deaths occurred, 164 from PC. A significant decrease in the risk of PCSM (22 v 38 deaths; adjusted hazard ratio [AHR], 0.56; 95% CI, 0.33 to 0.95; P = .03) was observed in men with no or minimal comorbidity randomly assigned to intervention versus usual care, and the additional number needed to treat to prevent one PC death at 10 years was five. Among men with at least one significant comorbidity, those randomly assigned to intervention versus usual care did not have a decreased risk of PCSM (62 v 42 deaths; AHR, 1.43; 95% CI, 0.96 to 2.11; P = .08).

Conclusion

Selective use of PSA screening for men in good health appears to reduce the risk of PCSM with minimal overtreatment.
Strategies for Prolonged Therapy in Patients With Advanced Non–Small-Cell Lung Cancer
Authors: Fidias Panos , Novello Silvia
Published: November 2010

Purpose

A key challenge in the treatment of advanced non–small-cell lung cancer (NSCLC) is improving outcomes for patients who have achieved at least stable disease after standard first-line therapy. Although current guidelines recommend a maximum of six cycles of first-line therapy, even in responding patients, recent trials have shown benefit with maintenance therapy.

Methods

We reviewed the English literature for randomized controlled trials on prolonged therapy for NSCLC conducted between January 1999 and January 2010. The search was supplemented by a review of abstracts presented at the American Society of Clinical Oncology annual meetings (2004 to 2010), the World Lung Cancer Conference (2007 to 2009), and the 2009 Joint European CanCer Organisation-European Society for Medical Oncology conference.

Results

Several alternative strategies for prolongation of chemotherapy have been tested: these can be broadly categorized as continuation (prolongation of the first-line regimen until disease progression, unacceptable toxicity, or administration of a predefined greater number of treatment cycles), switch-maintenance (administration of an active agent immediately after completion of the initial course of chemotherapy), and continuation-maintenance (ongoing administration of a lower intensity version of the first-line chemotherapy regimen). These approaches differ from traditional second line, which is defined as treatment administered after documented clinical progression subsequent to first-line therapy.

Conclusion

There are no data to support continuation chemotherapy in advanced NSCLC. Switch-maintenance trials with erlotinib and pemetrexed have demonstrated an improvement in overall survival. Thus far, continuation-maintenance has shown an improvement in progression-free survival, without an overall survival advantage.
Cooperation of two ADAMTS metalloproteases in closure of the mouse palate identifies a requirement for versican proteolysis in regulating palatal mesenchyme proliferation
Authors: Enomoto Hiroyuki , Nelson Courtney M. , Somerville Robert P. T. , Mielke Katrina , Dixon Laura J. , Powell Kimerly , Apte Suneel S.
Published: November 2010

We have identified a role for two evolutionarily related, secreted metalloproteases of the ADAMTS family, ADAMTS20 and ADAMTS9, in palatogenesis. Adamts20 mutations cause the mouse white-spotting mutant belted (bt), whereas Adamts9 is essential for survival beyond 7.5 days gestation (E7.5). Functional overlap of Adamts9 with Adamts20 was identified using Adamts9+/–;bt/bt mice, which have a fully penetrant cleft palate. Palate closure was delayed, although eventually completed, in both Adamts9+/–;bt/+ and bt/bt mice, demonstrating cooperation of these genes. Adamts20 is expressed in palatal mesenchyme, whereas Adamts9 is expressed exclusively in palate microvascular endothelium. Palatal shelves isolated from Adamts9+/–;bt/bt mice fused in culture, suggesting an intact epithelial TGFβ3 signaling pathway. Cleft palate resulted from a temporally specific delay in palatal shelf elevation and growth towards the midline. Mesenchyme of Adamts9+/–;bt/bt palatal shelves had reduced cell proliferation, a lower cell density and decreased processing of versican (VCAN), an extracellular matrix (ECM) proteoglycan and ADAMTS9/20 substrate, from E13.5 to E14.5. Vcan haploinsufficiency led to greater penetrance of cleft palate in bt mice, with a similar defect in palatal shelf extension as Adamts9+/–;bt/bt mice. Cell density was normal in bt/bt;Vcanhdf/+ mice, consistent with reduced total intact versican in ECM, but impaired proliferation persisted in palate mesenchyme, suggesting that ADAMTS-cleaved versican is required for cell proliferation. These findings support a model in which cooperative versican proteolysis by ADAMTS9 in vascular endothelium and by ADAMTS20 in palate mesenchyme drives palatal shelf sculpting and extension.
Wallerian degeneration of zebrafish trigeminal axons in the skin is required for regeneration and developmental pruning
Authors: Martin Seanna M. , O'Brien Georgeann S. , Portera-Cailliau Carlos , Sagasti Alvaro
Published: November 2010

Fragments of injured axons that detach from their cell body break down by the molecularly regulated process of Wallerian degeneration (WD). Although WD resembles local axon degeneration, a common mechanism for refining neuronal structure, several previously examined instances of developmental pruning were unaffected by WD pathways. We used laser axotomy and time-lapse confocal imaging to characterize and compare peripheral sensory axon WD and developmental pruning in live zebrafish larvae. Detached fragments of single injured axon arbors underwent three stereotyped phases of WD: a lag phase, a fragmentation phase and clearance. The lag phase was developmentally regulated, becoming shorter as embryos aged, while the length of the clearance phase increased with the amount of axon debris. Both cell-specific inhibition of ubiquitylation and overexpression of the Wallerian degeneration slow protein (WldS) lengthened the lag phase dramatically, but neither affected fragmentation. Persistent WldS-expressing axon fragments directly repelled regenerating axon branches of their parent arbor, similar to self-repulsion among sister branches of intact arbors. Expression of WldS also disrupted naturally occurring local axon pruning and axon degeneration in spontaneously dying trigeminal neurons: although pieces of WldS-expressing axons were pruned, and some WldS-expressing cells still died during development, in both cases detached axon fragments failed to degenerate. We propose that spontaneously pruned fragments of peripheral sensory axons must be removed by a WD-like mechanism to permit efficient innervation of the epidermis.
Lemierre's syndrome in pregnancy
Authors: Lucas-Herald Angela , O'Donnell Rachel L , McLaughlin Siobhan , Campbell Alastair J
Published: November 2010

This case report describes the unusual condition of Lemierre's syndrome diagnosed in the first trimester of pregnancy. The diagnosis was made by ultrasound and magnetic resonance imaging. The patient was treated with intravenous antibiotics and was anti-coagulated.
Tuberculous epididymo-orchitis: the role of ultrasound
Authors: Wallage Iraida , Riley Sara J
Published: November 2010

This case began as an investigation using computed tomography of a gluteal tuberculous (TB) abscess. This revealed an incidental testicular lesion that was subsequently evaluated with ultrasound. Ultrasound showed a well-defined testicular lesion, ipsilateral epididymal calcification and a hydrocoele. The presence of tuberculosis at other extrapulmonary sites combined with a positive response of the testicular lesion to anti-TB treatment made it possible to establish a diagnosis of TB epidiymo-orchitis. A reduction in the size of the testicular lesion on ultrasound surveillance enabled conservative management avoiding the need for orchidectomy or biopsy.
Painless ganglion cyst aspiration for patient and clinician
Authors: Clague Gavin , Bradley Mike
Published: November 2010

The management options for ganglion cysts include: observation, aspiration ± injection with steroid and surgical excision. One of the problems encountered during fine needle aspiration is the highly viscous cyst fluid being difficult to withdraw. We propose a modified technique, which improves the ease and speed of achieving complete aspiration of ganglion cysts by using local anaesthetic. Twenty-five patients who were referred from primary care and orthopaedic outpatients were diagnosed with ganglion cysts on ultrasound. The modified aspiration technique involves injecting a small volume of local anaesthetic into the cyst fluid prior to aspiration and was performed on all patients. All cysts were completely drained using this modified technique with no immediate complications and with minimal discomfort to the patient. Our adaptation to the technique of simple aspiration provides a method of achieving complete ganglion resolution with ease and in a time frame appropriate for a standard outpatient appointment. Low immediate complication rates are seen due to the adjunct of ultrasound and the local anaesthetic reduces patient discomfort during the procedure. This method has been particularly effective for large ganglions but can be equally effective for treating smaller lesions.
Ultrasound imaging in the National Health Service Abdominal Aortic Aneurysm Screening Programme
Authors: Earnshaw Jonothan J
Published: November 2010

A screening programme for abdominal aortic aneurysm commenced in England in April 2009. Once rolled out across the country, it is estimated that up to 50% of deaths from ruptured aortic aneurysm will be prevented. Ultrasound imaging of the aorta is the screening test at the core of the programme. Screening will be done by technicians who have had specific training in imaging the aorta. A training programme is being organized that accredits technicians to national standards. There will be a quality assurance programme that will underpin the screening service, analysing both technicians and ultrasound machines. Also, there will be continuing professional development for the technicians to allow them career progression. Finally, the size of the programme will be an incentive for ultrasound machine manufacturers to produce dedicated equipment.
Gibbs fluctuation theory in the context of electrochemical equilibrium noise
Authors: Grafov Boris M.
Published: November 2010

The electrochemical noise verification of the Gibbs fluctuation theory shows that the Gibbs ergodic idea works perfectly with respect to the pair correlations of the electrode charge thermal fluctuations. At the same time, the Gibbs formulae for the triple- and higher-order correlations of the electrode charge thermal fluctuations are outside of the ergodic hypothesis. This failure of the Gibbs ergodic idea suggests that the noise version of the electrochemical charge-transfer theory should be developed. In the context of nano-electrochemistry, the second- and higher-order correlations of the electrochemical noise processes may be considered as the quantities suitable for the nano-electrochemical characterization of both the electrode processes and electrochemical devices.
Fluorescence standards: Classification, terminology, and recommendations on their selection, use, and production (IUPAC Technical Report)
Authors: Resch-Genger Ute , DeRose Paul C.
Published: November 2010

Chromophore-based fluorescence standards for the characterization of photo-luminescence measuring systems and the determination of relevant fluorometric quantities are classified according to their scope and area of application. General and type-specific requirements for suitable standards are derived for each class of standards. Metrological requirements linked to the realization of comparable measurements are addressed and recommendations on selecting, using, and developing fluorescence standards are given.
Remediating Gorilla Girl: Rape Warfare and the Limits of Humanitarian Storytelling
Authors: Whitlock Gillian
Published: October 2010

Dian Fossey and the gorillas remain familiar figures in the global public sphere. But how do their life stories relate to the ongoing presence of mourning and violence in central Africa now? This essay considers feminist engagements with the "distant suffering" of victims of rape warfare at this unique contact zone where species meet.
The Postcolonial Uncanny: The Politics of Dispossession in Amitav Ghosh's The Hungry Tide
Authors: Nayar Pramod K.
Published: October 2010

The essay demonstrates how Amitav Ghosh's novel, The Hungry Tide , uses a spectropoetics, specifically of the uncanny, in order to foreground the condition of dispossession. The essay argues that the uncanny is more than simply a perceptual condition—it is a political context where refugees are made into ghostsin "unhomely" locations by dispossession. The uncanny is engendered through the consistent deployment of visual and sensory ambiguity and doubling, the shifting nature of the land itself, even as mythic and primitive narratives enter into the perceptual frames of the observer. The uncanny open space is the space of the politically dispossessed and one which requires a more intimate knowledge. Finally, the frightening uncanny is rendered safe through the "indigenous canny," of Fokir's ghost, where local knowledge incorporated into the observation and thinking makes the Sundarbans a home.
From Insulin and Insulin-Like Activity to the Insulin Superfamily of Growth-Promoting Peptides: A 20th-Century Odyssey
Authors: Blumenthal Stanley
Published: October 2010

In 1941, Gellhorn reported that administration of human blood to hypophysectomized/adrenodemedullated rats caused a fall in blood sugar. This was among the early demonstrations that human blood possesses glucose-lowering or insulin-like activity (ILA). Gellhorn assumed he had detected only insulin. During the 1960s, however, it became evident that plasma ILA contained at least two components: one, suppressible ILA (SILA), was inactivated by anti-insulin antibody and was therefore considered to be indistinguishable from pancreatic insulin; the other, nonsuppressible ILA (NSILA), was unaffected by anti-insulin antibody. Subsequent work resolved NSILA into insulin-like growth factors I and II (IGF-I and IGF-II), two 7.5 kilodalton peptides with potent mitogenic properties; established their identity with the somatomedins; and investigated both their therapeutic potential and role in the pathogenesis of neoplastic and other human diseases. Insulin and the IGFs exhibit striking homologies in amino acid composition and some degree of overlap in their signaling pathways and actions. Moreover, insulin-like proteins have been identified not only in all vertebrate classes but also in molluscs, insects, and worms. These observations are the basis for the hypothesis that the genes encoding vertebrate insulins and IGFs and invertebrate insulin-like molecules evolved from a common ancestral gene, and for the concept of an insulin superfamily of growth-promoting peptides.
Psychoanalysis and Detective Fiction: a tale of Freud and criminal storytelling
Authors: Yang Amy
Published: October 2010

Much has been written about Freud's influence on popular culture. This article addresses the influence of literature on Freud's psychoanalytical theory, specifically the role that modern detective fiction played in shaping Freudian theory. Edgar Allan Poe gave Freud the literary precedent; Sir Arthur Conan Doyle's creation Sherlock Holmes gave him the analytical model. In turn, the world of crime story-telling embedded Freudian theories in subsequent forms, spinning the tales of crime into a journey into the human mind. As these tales were popularized on the silver screen in the early 20th century, psychoanalytical ideas moved from the lecture halls into the cultural mainstream.