bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phagocytosis of Picornavirus-Infected Cells Induces an RNA-Dependent Antiviral State in Human Dendritic Cells
Authors: Kramer Matthijs , Schulte Barbara M. , Toonen Liza W. J. , Barral Paola M. , Fisher Paul B. , Lanke Kjerstin H. W. , Galama Jochem M. D. , van Kuppeveld Frank J. M. , Adema Gosse J. 
Published: January 2008

ABSTRACT

Dendritic cells (DCs) play a central role in instructing antiviral immune responses. DCs, however, can become targeted by different viruses themselves. We recently demonstrated that human DCs can be productively infected with echoviruses (EVs), but not coxsackie B viruses (CVBs), both of which are RNA viruses belonging to the
Enterovirus
genus of the
Picornaviridae
family. We now show that phagocytosis of CVB-infected, type I interferon-deficient cells induces an antiviral state in human DCs. Uptake of infected cells increased the expression of the cytoplasmic RNA helicases retinoic acid-inducible gene I and melanoma differentiation-associated gene 5 as well as other interferon-stimulated genes and protected DCs against subsequent infection with EV9. These effects depended on recognition of viral RNA and could be mimicked by exposure to the synthetic double-stranded RNA analogue poly(I:C) but not other Toll-like receptor (TLR) ligands. Blocking endosomal acidification abrogated protection, suggesting a role for TLRs in the acquisition of an antiviral state in DCs. In conclusion, recognition of viral RNA rapidly induces an antiviral state in human DCs. This might provide a mechanism by which DCs protect themselves against viruses when attracted to an environment with ongoing infection.
Crystal Structure of Unliganded Influenza B Virus Hemagglutinin
Authors: Wang Qinghua , Cheng Feng , Lu Mingyang , Tian Xia , Ma Jianpeng 
Published: January 2008

ABSTRACT
Here we report the crystal structure of hemagglutinin (HA) from influenza B/Hong Kong/8/73 (B/HK) virus determined to 2.8 Å. At a sequence identity of ∼25% to influenza A virus HAs, B/HK HA shares a similar overall structure and domain organization. More than two dozen amino acid substitutions on influenza B virus HAs have been identified to cause antigenicity alteration in site-specific mutants, monoclonal antibody escape mutants, or field isolates. Mapping these substitutions on the structure of B/HK HA reveals four major epitopes, the 120 loop, the 150 loop, the 160 loop, and the 190 helix, that are located close in space to form a large, continuous antigenic site. Moreover, a systematic comparison of known HA structures across the entire influenza virus family reveals evolutionarily conserved ionizable residues at all regions along the chain and subunit interfaces. These ionizable residues are likely the structural basis for the pH dependence and sensitivity to ionic strength of influenza HA and hemagglutinin-esterase fusion proteins.
Antiviral CD8 T Cells Recognize Borna Disease Virus Antigen Transgenically Expressed in either Neurons or Astrocytes
Authors: Baur Karen , Rauer Mathias , Richter Kirsten , Pagenstecher Axel , Götz Jürgen , Hausmann Jürgen , Staeheli Peter 
Published: January 2008

ABSTRACTBorna disease virus (BDV) can persistently infect the central nervous system (CNS) of mice. The infection remains nonsymptomatic as long as antiviral CD8 T cells do not infiltrate the infected brain. BDV mainly infects neurons which reportedly carry few, if any, major histocompatibility complex class I molecules on the surface. Therefore, it remains unclear whether T cells can recognize replicating virus in these cells or whether cross-presentation of viral antigen by other cell types is important for immune recognition of BDV. To distinguish between these possibilities, we used two lines of transgenic mice that strongly express the N protein of BDV in either neurons (Neuro-N) or astrocytes (Astro-N). Since these animals are tolerant to the neo-self-antigen, we adoptively transferred T cells with specificity for BDV N. In nontransgenic mice persistently infected with BDV, the transferred cells accumulated in the brain parenchyma along with immune cells of host origin and efficiently induced neurological disease. Neurological disease was also observed if antiviral T cells were injected into the brains of Astro-N or Neuro-N but not nontransgenic control mice. Our results demonstrate that CD8 T cells can recognize foreign antigen on neurons and astrocytes even in the absence of infection or inflammation, indicating that these CNS cell types are playing an active role in immune recognition of viruses.
NRF-1genotypes and endurance exercise capacity in young Chinese men
Authors: He Z , Hu Y , Feng L , Li Y , Liu G , Xi Y , Wen L , Lucia A 
Published: January 2008

Background:Nuclear respiratory factor 1 (NRF-1) is a critical component of the energy-sensing mechanism in mammalian cells, and translates physiological signals (particularly those induced by exercise) into increased capacity for mitochondrial biogenesis and oxidative phosphorylation.Objective:To study the possible association between rs2402970, rs6949152 and rs10500120NRF-1genotypes and several phenotypes indicative of maximum (VO2max) and submaximum aerobic capacity (ventilatory threshold (VT) and metabolic cost of submaximum running at 12 km/hour (running economy; RE)) both at baseline and in response to a 18-week endurance training programme in young Chinese men of Han origin (n = 102; 19 (SD 1) years).Results:For rs2402970, a significant genotype effect was seen for VT (p = 0.004) and RE (p = 0.027). For rs6949152, a significant interaction (genotype×training) effect (p = 0.047) was found for VT.Conclusions:There is an association betweenNRF-1genotypes (rs2402970 and rs6949152 polymorphisms) and the baseline and/or training response of human aerobic capacity. More research is needed to corroborate our data in other ethnic groups with lower fitness levels at the pre-training state (particularly Caucasians) and to identify the molecular mechanisms involved in the genotype–phenotype associations we found.
From plasma membrane to cytoskeleton: a novel function for semaphorin 6A
Authors: Prislei Silvia , Mozzetti Simona , Filippetti Flavia , De Donato Marta , Raspaglio Giuseppina , Cicchillitti Lucia , Scambia Giovanni , Ferlini Cristiano 
Published: January 2008

AbstractClass III β-tubulin (TUBB3) overexpression has been reported in ovary, lung, breast, and gastric cancer patients. Currently, no clinical drugs are available for a specific targeting of TUBB3, whereas the investigational drug IDN5390 specifically interacts with TUBB3. To gain insight into the pathways leading to TUBB3 up-regulation, we did a human genome microarray analysis in A2780 cells made resistant to IDN5390 to identify selected pathways specifically disrupted in resistant cells. Using this approach, we discovered that semaphorin 6A (SEMA6A) is down-regulated not only in IDN5390-resistant cells but also in cells made resistant to cisplatin, topotecan, and doxorubicin, whereas no changes were noticed in paclitaxel- and gemcitabine-resistant cells. Acute treatment with IDN5390 was able to down-regulate SEMA6A in cells unselected for drug resistance. TUBB3 expression was assessed in A2780 clones with stable overexpression of SEMA6A and in a panel of clones in which silencing of the protein was obtained. Quantitative PCR was then used to check the modulation of SEMA6A as well as to assess the expression of TUBB3. TUBB3 was increased (median value, 5.4) and reduced (median value, 0.47) in cells with overexpression and silencing of SEMA6A, respectively. Thus, the findings indicate a correlation between the expression of SEMA6A and TUBB3. Then, we found that a form of 83 kDa of SEMA6A is expressed in the cytoskeleton in association with β-actin. These findings suggest for SEMA6A a novel function in the cytoskeleton and a role in modulating tubulin isotype composition and microtubule dynamics. [Mol Cancer Ther 2008;7(1):233–41]
Small interfering RNA-mediated knockdown of PRL phosphatases results in altered Akt phosphorylation and reduced clonogenicity of pancreatic cancer cells
Authors: Stephens Bret , Han Haiyong , Hostetter Galen , Demeure Michael J. , Von Hoff Daniel D. 
Published: January 2008

Abstract
The PRL phosphatases have been implicated in cancer cell growth and metastasis in a variety of tumor types. Using cDNA microarray, we previously identified and reported PRL-1 as being highly up-regulated in pancreatic cancer cell lines. In this study, we sought to further evaluate the expression of all three PRL phosphatases in pancreatic cancer cell lines and extend our findings to in situ analysis of primary pancreatic tumors taken directly from patients. Additionally, we determine if small interfering RNA-mediated knockdown of relevant PRLs confers antitumor effects in pancreatic cancer cells. Using oligonucleotide expression arrays, mRNA levels of PRL-1 and PRL-2 but not PRL-3 were identified as up-regulated in pancreatic cancer cell lines and tumor samples taken directly from patients compared with those of normal pancreas. Focusing on PRL-1 and PRL-2, high levels of both proteins were detected in a subset of pancreatic cancer cell lines and tumor samples using Western blotting and immunohistochemistry, respectively. Small interfering RNA-mediated knockdown of PRL-1 and PRL-2 in combination resulted in a moderate reduction of cellular growth and migration in MIA PaCa-2 and PANC-1 cells. More importantly, knockdown of both PRL-1 and PRL-2 significantly inhibited colony formation of these cells in soft agar as well as serum-induced Akt phosphorylation. These data support the hypothesis that PRL phosphatases regulate key pathways involved in tumorigenesis and metastasis and that knockdown of both PRL-1 and PRL-2 is required to disrupt PRL phosphatase function in pancreatic cancer cells. [Mol Cancer Ther 2008;7(1):202–10]
Association of theCYP1B1*3allele with survival in patients with prostate cancer receiving docetaxel
Authors: Sissung Tristan M. , Danesi Romano , Price Douglas K. , Steinberg Seth M. , de Wit Ronald , Zahid Muhammad , Gaikwad Nilesh , Cavalieri Ercole , Dahut William L. , Sackett Dan L. , Figg William D. , Sparreboom Alex 
Published: January 2008

AbstractUsing a single nucleotide polymorphism association study in 52 men with prostate cancer receiving docetaxel, we found that individuals carrying two copies of the CYP1B1*3 polymorphic variant had a poor prognosis after docetaxel-based therapies compared with individuals carrying at least one copy of the CYP1B1*1 allele (30.6 versus 12.8 months; P = 0.0004). The association between CYP1B1*3 and response to therapy was not observed in similar subjects receiving non-taxane-based therapy (P = 0.18). The systemic clearance of docetaxel was also unrelated to CYP1B1 genotype status (P = 0.39), indicating that the association of CYP1B1*3 with clinical response is not due to docetaxel metabolism. To explain these results, we hypothesized that an indirect gene-drug interaction was interfering with the primary mechanism of action of docetaxel, tubulin polymerization. We therefore conducted tubulin polymerization experiments with taxanes in the presence or absence of certain CYP1B1 estrogen metabolites, which are known to bind to nucleophilic sites in proteins and DNA, that revealed the primary estrogen metabolite of CYP1B1, 4-hydroxyestradiol (4-OHE2), when oxidized to estradiol-3,4-quinone strongly inhibits tubulin polymerization. The 4-OHE2 is also formed more readily by the protein encoded by the CYP1B1*3 allele, validating further our data in patients. Furthermore, estradiol-3,4-quinone reacted in vitro with docetaxel to form the 4-OHE2-docetaxel adduct. This pilot study provides evidence that CYP1B1*3 may be an important marker for estimating docetaxel efficacy in patients with prostate cancer. This link is likely associated with CYP1B1*3 genotype-dependent estrogen metabolism. [Mol Cancer Ther 2008;7(1):19–26]
Early detection of ovarian cancer using group biomarkers
Authors: Tchagang Alain B. , Tewfik Ahmed H. , DeRycke Melissa S. , Skubitz Keith M. , Skubitz Amy P.N. 
Published: January 2008

Abstract
One reason that ovarian cancer is such a deadly disease is because it is not usually diagnosed until it has reached an advanced stage. In this study, we developed a novel algorithm for group biomarkers identification using gene expression data. Group biomarkers consist of coregulated genes across normal and different stage diseased tissues. Unlike prior sets of biomarkers identified by statistical methods, genes in group biomarkers are potentially involved in pathways related to different types of cancer development. They may serve as an alternative to the traditional single biomarkers or combination of biomarkers used for the diagnosis of early-stage and/or recurrent ovarian cancer. We extracted group biomarkers by applying biclustering algorithms that we recently developed on the gene expression data of over 400 normal, cancerous, and diseased tissues. We identified several groups of coregulated genes that encode for secreted proteins and exhibit expression levels in ovarian cancer that are at least 2-fold (in log2 scale) higher than in normal ovary and nonovarian tissues. In particular, three candidate group biomarkers exhibited a conserved biological pattern that may be used for early detection or recurrence of ovarian cancer with specificity greater than 99% and sensitivity equal to 100%. We validated these group biomarkers using publicly available gene expression data sets downloaded from a NIH Web site (http://www.ncbi.nlm.nih.gov/geo). Statistical analysis showed that our methodology identified an optimum combination of genes that have the highest effect on the diagnosis of the disease compared with several computational techniques that we tested. Our study also suggests that single or group biomarkers correlate with the stage of the disease. [Mol Cancer Ther 2008;7(1):27–37]
Increasing uptake of physical activity: a social ecological approach
Authors: Cochrane Thomas , Davey Rachel Caroline 
Published: January 2008

Aims: Increasing population physical activity (PA) is a public health priority. An approach to increasing PA in an urban community, based on the social ecology model, is presented and evaluated. Methods: A quasi-experimental (non-equivalent control group) design was chosen to test whether this approach can increase, significantly, the population proportion that is physically active. Two deprived inner-city electoral ward areas of Sheffield, UK, with similar socio-demographic and health profiles were selected. Implementation was carried out in five phases over 21 months: preparation and piloting, initial survey estimates, community awareness campaign, PA intervention and evaluation. Impact was evaluated by recording uptake and attendance at all sessions, and using a post-intervention postal survey. At follow-up, questionnaires were sent to 2500 randomly selected addresses in both areas, which assessed changes in PA, health and PA participation over the last year. Results: A pilot baseline survey confirmed similar proportions taking some form of PA on most days: intervention 36% (25—47), control 33% (21—45). At follow-up, 38 different activity groups were in place and 1275 individuals had attended at least one activity. Satisfactorily completed responses were received from 1532 (31%), 55% (846) intervention, 45% (686) control. Relative to the control, the intervention sample demonstrated trends towards: being more physically active compared with one year ago, greater readiness to take up PA, better general health and improved health compared with one year ago (p ≤ 0.001). Further, 30.6% (intervention) vs 18.3% (control) reported an increase in PA compared with one year ago, while 13.7% (intervention) vs 24.5% (control) reported no intention to exercise. These differences in proportions translated to an overall effect size estimate of 0.23 for the intervention. Relative to those whose PA had remained the same, intervention area residents were more likely to report being more active (odds ratio (95% confidence interval) = 1.79 (1.38—2.32), p < 60; 0.001). Conclusion: These results suggest that, even within one of the most deprived inner-city areas in the UK, a community-based social ecological approach can positively change PA behaviour and attitudes.
Lessons to be learned — Langerhans' cell histiocytosis
Authors: Dewan Madhu , Al-Ghamdi Abdulmonem Almutawa , Zahrani Mubarak B. 
Published: January 2008

Langerhans' cell histiocytosis (LCH) is a neoplastic disease due to uncontrolled proliferation of Langerhans' cells (LCs); damage to organs involved appears to be due to the various cytokines secreted. The true cause of LCH remains a mystery. LCH can present at any age; there is female predominance and the skin is often the first site to be involved. Scaly papules, vesicles, purpuric nodules, plaques and ulcers are the main diverse presentations typically found on the scalp, flexures (including the perineum), crease below the breast, palms, soles and nails. The patient described here is a 35-year-old Saudi Arabian woman with a vulval ulcer that had been misdiagnosed as an infective lesion 11 months before the correct diagnosis of LCH was made by means of biopsy examination. Diffuse infiltration of LCs with large pale reniform/convoluted nuclei and abundant amphophilic cytoplasm in the company of neutrophils, eosinophils, lymphocytes and plasma cells were observed on light microscopy. Immunohistochemical staining, indicating S100 protein positivity in LCs and the demonstration of Birbeck granules by means of electron microscopy, confirmed the diagnosis. The `skin-only' LCH may later progress to involve other organs; alternatively skin lesions may be part of the multisystem, disseminated disease. There is need for careful follow-up of all LCH patients, as the course of the disease cannot be reliably predicted from either the clinical presentation or histology of the lesion. In many cases the prognosis is good, there being limited involvement that does not progress. Surgery or local steroids might suffice as therapy. However, for severely symptomatic disease, in which there are complications associated with dysfunction (or failure) of vital organs such as the liver, lungs, and central nervous system, the use of a variety of immunosuppressive treatments — and the recently described 2-chloro-2-deoxyadenosine (2CdA) (cladribine) — have been suggested; however, the type and extent of disease that will respond to this therapy has not yet been clarified. Solid laboratory research and rigorous clinical trials are required for more effective and less toxic therapies for patients with progressive LCH.
Attitudes towards health and exercise of overweight women
Authors: Khanam Salma , Costarelli Vassiliki 
Published: January 2008

Aim: To investigate the attitudes and beliefs held by UK Bangladeshi women on health and exercise and explore possible ways of increasing levels of physical activity in this group. Methods: A survey based on an interview-guided questionnaire, with 25 British Bangladeshi females, 30—60 years old, from the Borough of Tower Hamlets, East London, who have been referred to a gym by their general practitioner (GP) in order to improve health. Main reasons for referral were: obesity, metabolic syndrome, risk of type 2 diabetes and high blood pressure. Results: Forty per cent of the subjects were obese (BMI > 30 kg/m2) and the remaining 60% were overweight (BMI 25—30 kg/m2). The great majority of the subjects (96%) reported that they were only willing to take up exercise if they were referred to the gym by their GP as an alternative or additional treatment for their complaints. They would not exercise voluntarily. Even though all women in our sample were either overweight or obese, 16% of the subjects reported that they did not know if they were overweight and 20% thought that they were actually of normal weight. Most women identified swimming as the type of physical activity of preference, if they had to exercise, followed by slow walking, with running being the least enjoyed activity. Conclusion: Bangladeshi women take little regular exercise to improve their health, predominant because of certain cultural beliefs and attitudes. More needs to be done to encourage levels and types of exercise that would be more appropriate for this ethnic group.
Monocyte migration to inflamed skin and lymph nodes is differentially controlled by L-selectin and PSGL-1
Authors: León Beatriz , Ardavín Carlos 
Published: January 2008

AbstractMonocyte recruitment and differentiation into dendritic cells or macrophages play a critical role in defense mechanisms against pathogens and in inflammatory and autoimmune diseases. Important contributions have been made on the molecular events controlling neutrophil and lymphocyte extravasation under steady state or inflammation. However, the molecules involved in monocyte rolling during their migration to antigen capture areas and lymphoid organs during infection remain undefined. Here we have analyzed the homing molecules controlling mouse monocyte rolling in an experimental model of Leishmania major infection. Monocyte migration through inflamed dermal venules was dependent on interactions of PSGL-1 with P- and E-selectins, and of L-selectin with PNAd, whereas migration through lymph node high endothelial venules relied essentially on L-selectin–PNAd interactions. These results might have important implications regarding the induction of immune responses against pathogens and future immunotherapeutic protocols of inflammatory and autoimmune diseases, based on selective inhibition of monocyte migration to specific inflammatory foci.
Potentiation of antileukemic therapies by the dual PI3K/PDK-1 inhibitor, BAG956: effects on BCR-ABL– and mutant FLT3-expressing cells
Authors: Weisberg Ellen , Banerji Lolita , Wright Renee D. , Barrett Rosemary , Ray Arghya , Moreno Daisy , Catley Laurence , Jiang Jingrui , Hall-Meyers Elizabeth , Sauveur-Michel Maira , Stone Richard , Galinsky Ilene , Fox Edward , Kung Andrew L. , Griffin James D. 
Published: January 2008

AbstractMediators of PI3K/AKT signaling have been implicated in chronic myeloid leukemia (CML) and acute myeloid leukemia (AML). Studies have shown that inhibitors of PI3K/AKT signaling, such as wortmannin and LY294002, are able to inhibit CML and AML cell proliferation and synergize with targeted tyrosine kinase inhi-bitors. We investigated the ability of BAG956, a dual PI3K/PDK-1 inhibitor, to be used in combination with inhibitors of BCR-ABL and mutant FLT3, as well as with the mTOR inhibitor, rapamycin, and the rapamycin derivative, RAD001. BAG956 was shown to block AKT phosphorylation induced by BCR-ABL–, and induce apoptosis of BCR-ABL–expressing cell lines and patient bone marrow cells at concentrations that also inhibit PI3K signaling. Enhancement of the inhibitory effects of the tyrosine kinase inhibitors, imatinib and nilotinib, by BAG956 was demonstrated against BCR-ABL expressing cells both in vitro and in vivo. We have also shown that BAG956 is effective against mutant FLT3-expressing cell lines and AML patient bone marrow cells. Enhancement of the inhibitory effects of the tyrosine kinase inhibitor, PKC412, by BAG956 was demonstrated against mutant FLT3-expressing cells. Finally, BAG956 and rapamycin/RAD001 were shown to combine in a nonantagonistic fashion against BCR-ABL– and mutant FLT3-expressing cells both in vitro and in vivo.