bluuebunny/crossref_metadata_2025_split huggingface dataset:
Successful Treatment of Castleman's Disease with Interleukin-1 Receptor Antagonist (Anakinra)
Authors: El-Osta Hazem , Janku Filip , Kurzrock Razelle 
Published: May 2010

Abstract
Castleman's disease (CD) is a very rare lymphoproliferative disorder whose underlying pathophysiology is not fully understood and for which no standard treatment exists. Because interleukin-1 (IL-1) might promote the production of interleukin-6 (IL-6), a key pathogenic factor for the disease, we hypothesized that blocking the interleukin-1 receptor would be a useful therapy for CD. We report the case of a 61-year-old woman with CD who had undergone multiple treatments, including cladribine, rituximab, steroids, etanercept, and anti-IL-6 monoclonal antibody, and whose disease was refractory to all of these treatments. She was started on the recombinant IL-1 receptor antagonist, Anakinra, at a subcutaneous dose of 100 mg daily. Within one week, her fatigue and anorexia markedly improved, and her laboratory abnormalities, including anemia, thrombocytosis, leukocytosis, and elevated markers of inflammation, all resolved. Our observation suggests that Anakinra may be an attractive therapeutic approach for refractory multicentric CD. Mol Cancer Ther; 9(6); 1485–8. ©2010 AACR.
The Deubiquitinating Enzyme USP26 Is a Regulator of Androgen Receptor Signaling
Authors: Dirac Annette M.G. , Bernards René 
Published: May 2010

Abstract
The androgen receptor (AR) is a member of the nuclear receptor superfamily and is essential for male sexual development and maturation, as well as prostate cancer development. Regulation of AR signaling activity depends on several posttranslational modifications, one of these being ubiquitination. We screened a short hairpin library targeting members of the deubiquitination enzyme family and identified the X-linked deubiquitination enzyme USP26 as a novel regulator of AR signaling. USP26 is a nuclear protein that binds to AR via three important nuclear receptor interaction motifs, and modulates AR ubiquitination, consequently influencing AR activity and stability. Our data suggest that USP26 assembles with AR and other cofactors in subnuclear foci, and serves to counteract hormone-induced AR ubiquitination, thereby contributing to the regulation of AR transcriptional activity. Mol Cancer Res; 8(6); 844–54. ©2010 AACR.
Identification of Genes Correlated with Early-Stage Bladder Cancer Progression
Authors: Stone Randolph , Sabichi Anita L. , Gill Jennifer , Lee I-ling , Adegboyega Patrick , Dai Michael S. , Loganantharaj Raja , Trutschl Marjan , Cvek Urska , Clifford John L. 
Published: May 2010

Abstract
Transitional cell carcinoma (TCC) of the bladder ranks fourth in incidence of all cancers in the developed world, yet the mechanisms of its origin and progression remain poorly understood. There are also few useful diagnostic or prognostic biomarkers for this disease. We have combined a transgenic mouse model for invasive bladder cancer (UPII-SV40Tag mice) with DNA microarray technology to determine molecular mechanisms involved in early TCC development and to identify new biomarkers for detection, diagnosis, and prognosis of TCC. We have identified genes that are differentially expressed between the bladders of UPII-SV40Tag mice and their age-matched wild-type littermates at 3, 6, 20, and 30 weeks of age. These are ages that correspond to premalignant, carcinoma in situ, and early-stage and later stage invasive TCC, respectively. Our preliminary analysis of the microarray data sets has revealed ∼1,900 unique genes differentially expressed (≥3-fold difference at one or more time points) between wild-type and UPII-SV40Tag urothelium during the time course of tumor development. Among these, there were a high proportion of cell cycle regulatory genes and a proliferation signaling genes that are more strongly expressed in the UPII-SV40Tag bladder urothelium. We show that several of the genes upregulated in UPII-SV40Tag urothelium, including RacGAP1, PCNA, and Hmmr, are expressed at high levels in superficial bladder TCC patient samples. These findings provide insight into the earliest events in the development of bladder TCC as well as identify several promising early-stage biomarkers. Cancer Prev Res; 3(6); 776–86. ©2010 AACR.
‘Oh God, not a Palliative’: out-of-hours general practitioners within the domain of palliative care
Authors: Taubert Mark , Nelson Annmarie 
Published: May 2010

To date, the experiences of out-of-hours general practitioners with regard to palliative care patients and their management are yet to be evaluated, since the new General Medical Services contract came into force. In 2007 the National Institute for Health Research highlighted the need to identify factors that improve and hinder the delivery of optimum palliative out-of-hours care. By interviewing general practitioners who work out-of-hours shifts, this project explored factors influencing confidence in dealing with symptom control and palliative care provision outside regular working hours. Face-to-face semi-structured interviews were conducted with nine out-of-hours general practitioners employed by Serco. Interviews were conducted by a specialist doctor in palliative care who had in the past worked as an out-of-hours general practitioner. Interviews were analysed using Interpretative Phenomenological Analysis. General practitioners expressed concerns relating to constraints within the system provided by the private company-owned out-of-hours provider. Data from interviews was thematically very rich and brought out many different subject areas, some similar to previous interviews, some different. Sub-themes related to the process-driven aspects of working in out-of-hours: • Motivation • Time-pressure constraints and continuity • The out-of-hours doctor within the domain of palliative care • Isolation within system General practitioners stated that their motivation was mainly financial. There was clear concern about the lack of continuity, and inadequacy of notes and follow-up, and there was a demonstrated need for more learning on the topic of palliative care. Pressure from the out-of-hours provider to see more patients was felt to be oppositional with the need to spend adequate time with this vulnerable patient group. General practitioners felt as unwanted strangers who were viewed with suspicion by patients and carers in palliative care situations. It was clear that most of the doctors interviewed felt a strong sense of isolation when working out-of-hours shifts, and some felt less inclined to contact specialist palliative care services.
Angiotensin II upregulates the expression of placental growth factor in human vascular endothelial cells and smooth muscle cells
Authors: Pan Pingxi , Fu Hua , Zhang Lingjun , Huang He , Luo Fengming , Wu Wenchao , Guo Yingqiang , Liu Xiaojing 
Published: May 2010

Abstract

Background
Atherosclerosis is now recognized as a chronic inflammatory disease. Angiotensin II (Ang II) is a critical factor in inflammatory responses, which promotes the pathogenesis of atherosclerosis. Placental growth factor (PlGF) is a member of the vascular endothelial growth factor (VEGF) family cytokines and is associated with inflammatory progress of atherosclerosis. However, the potential link between PlGF and Ang II has not been investigated. In the current study, whether Ang II could regulate PlGF expression, and the effect of PlGF on cell proliferation, was investigated in human vascular endothelial cells (VECs) and smooth muscle cells (VSMCs).

Results
In growth-arrested human VECs and VSMCs, Ang II induced PlGF mRNA expression after 4 hour treatment, and peaked at 24 hours. 10-6 mol/L Ang II increased PlGF protein production after 8 hour treatment, and peaked at 24 hours. Stimulation with Ang II also induced mRNA expression of VEGF receptor-1 and -2(VEGFR-1 and -2) in these cells. The Ang II type I receptor (AT1R) antagonist blocked Ang II-induced PlGF gene expression and protein production. Several intracellular signals elicited by Ang II were involved in PlGF synthesis, including activation of protein kinase C, extracellular signal-regulated kinase 1/2 (ERK1/2) and PI3-kinase. A neutralizing antibody against PlGF partially inhibited the Ang II-induced proliferation of VECs and VSMCs. However, this antibody showed little effect on the basal proliferation in these cells, whereas blocking antibody of VEGF could suppress both basal and Ang II-induced proliferation in VECs and VSMCs.

Conclusion
Our results showed for the first time that Ang II could induce the gene expression and protein production of PlGF in VECs and VSMCs, which might play an important role in the pathogenesis of vascular inflammation and atherosclerosis.
Transcriptome analysis of the mobile genome ICEclc in Pseudomonas knackmussii B13
Authors: Gaillard Muriel , Pradervand Nicolas , Minoia Marco , Sentchilo Vladimir , Johnson David R , van der Meer Jan Roelof 
Published: May 2010

Abstract

Background
Integrative and conjugative elements (ICE) form a diverse group of DNA elements that are integrated in the chromosome of the bacterial host, but can occasionally excise and horizontally transfer to a new host cell. ICE come in different families, typically with a conserved core for functions controlling the element's behavior and a variable region providing auxiliary functions to the host. The ICEclc element of Pseudomonas knackmussii strain B13 is representative for a large family of chromosomal islands detected by genome sequencing approaches. It provides the host with the capacity to degrade chloroaromatics and 2-aminophenol.

Results
Here we study the transcriptional organization of the ICEclc core region. By northern hybridizations, reverse-transcriptase polymerase chain reaction (RT-PCR) and Rapid Amplification of cDNA Ends (5'-RACE) fifteen transcripts were mapped in the core region. The occurrence and location of those transcripts were further confirmed by hybridizing labeled cDNA to a semi-tiling micro-array probing both strands of the ICEclc core region. Dot blot and semi-tiling array hybridizations demonstrated most of the core transcripts to be upregulated during stationary phase on 3-chlorobenzoate, but not on succinate or glucose.

Conclusions
The transcription analysis of the ICEclc core region provides detailed insights in the mode of regulatory organization and will help to further understand the complex mode of behavior of this class of mobile elements. We conclude that ICEclc core transcription is concerted at a global level, more reminiscent of a phage program than of plasmid conjugation.
Histone H4 deacetylation plays a critical role in early gene silencing during neuronal apoptosis
Authors: Pelzel Heather R , Schlamp Cassandra L , Nickells Robert W 
Published: May 2010

Abstract

Background
Silencing of normal gene expression occurs early in the apoptosis of neurons, well before the cell is committed to the death pathway, and has been extensively characterized in injured retinal ganglion cells. The causative mechanism of this widespread change in gene expression is unknown. We investigated whether an epigenetic change in active chromatin, specifically histone H4 deacetylation, was an underlying mechanism of gene silencing in apoptotic retinal ganglion cells (RGCs) following an acute injury to the optic nerve.

Results
Histone deacetylase 3 (HDAC3) translocates to the nuclei of dying cells shortly after lesion of the optic nerve and is associated with an increase in nuclear HDAC activity and widespread histone deacetylation. H4 in promoters of representative genes was rapidly and indiscriminately deacetylated, regardless of the gene examined. As apoptosis progressed, H4 of silenced genes remained deacetylated, while H4 of newly activated genes regained, or even increased, its acetylated state. Inhibition of retinal HDAC activity with trichostatin A (TSA) was able to both preserve the expression of a representative RGC-specific gene and attenuate cell loss in response to optic nerve damage.

Conclusions
These data indicate that histone deacetylation plays a central role in transcriptional dysregulation in dying RGCs. The data also suggests that HDAC3, in particular, may feature heavily in apoptotic gene silencing.
Visual fixation in the vegetative state: an observational case series PET study
Authors: Bruno Marie-Aurélie , Vanhaudenhuyse Audrey , Schnakers Caroline , Boly Mélanie , Gosseries Olivia , Demertzi Athena , Majerus Steve , Moonen Gustave , Hustinx Roland , Laureys Steven 
Published: May 2010

Abstract

Background
Assessment of visual fixation is commonly used in the clinical examination of patients with disorders of consciousness. However, different international guidelines seem to disagree whether fixation is compatible with the diagnosis of the vegetative state (i.e., represents "automatic" subcortical processing) or is a sufficient sign of consciousness and higher order cortical processing.

Methods
We here studied cerebral metabolism in ten patients with chronic post-anoxic encephalopathy and 39 age-matched healthy controls. Five patients were in a vegetative state (without fixation) and five presented visual fixation but otherwise showed all criteria typical of the vegetative state. Patients were matched for age, etiology and time since insult and were followed by repeated Coma Recovery Scale-Revised (CRS-R) assessments for at least 1 year. Sustained visual fixation was considered as present when the eyes refixated a moving target for more than 2 seconds as defined by CRS-R criteria.

Results
Patients without fixation showed metabolic dysfunction in a widespread fronto-parietal cortical network (with only sparing of the brainstem and cerebellum) which was not different from the brain function seen in patients with visual fixation. Cortico-cortical functional connectivity with visual cortex showed no difference between both patient groups. Recovery rates did not differ between patients without or with fixation (none of the patients showed good outcome).

Conclusions
Our findings suggest that sustained visual fixation in (non-traumatic) disorders of consciousness does not necessarily reflect consciousness and higher order cortical brain function.
Expression signatures of TP53 mutations in serous ovarian cancers
Authors: Bernardini Marcus Q , Baba Tsukasa , Lee Paula S , Barnett Jason C , Sfakianos Gregory P , Secord Angeles Alvarez , Murphy Susan K , Iversen Edwin , Marks Jeffrey R , Berchuck Andrew 
Published: May 2010

Abstract

Background
Mutations in the TP53 gene are extremely common and occur very early in the progression of serous ovarian cancers. Gene expression patterns that relate to mutational status may provide insight into the etiology and biology of the disease.

Methods
The TP53 coding region was sequenced in 89 frozen serous ovarian cancers, 40 early stage (I/II) and 49 advanced stage (III/IV). Affymetrix U133A expression data was used to define gene expression patterns by mutation, type of mutation, and cancer stage.

Results
Missense or chain terminating (null) mutations in TP53 were found in 59/89 (66%) ovarian cancers. Early stage cancers had a significantly higher rate of null mutations than late stage disease (38% vs. 8%, p < 0.03). In advanced stage cases, mutations were more prevalent in short term survivors than long term survivors (81% vs. 30%, p = 0.0004). Gene expression patterns had a robust ability to predict TP53 status within training data. By using early versus late stage disease for out of sample predictions, the signature derived from early stage cancers could accurately (86%) predict mutation status of late stage cancers.

Conclusions
This represents the first attempt to define a genomic signature of TP53 mutation in ovarian cancer. Patterns of gene expression characteristic of TP53 mutation could be discerned and included several genes that are known p53 targets or have been described in the context of expression signatures of TP53 mutation in breast cancer.
Assessing agonistic potential of a candidate therapeutic anti-IL21R antibody
Authors: Guo Yongjing , Hill Andrew A , Ramsey Renee C , Immermann Frederick W , Corcoran Christopher , Young Deborah , LaVallie Edward R , Ryan Mark , Bechard Theresa , Pfeifer Richard , Warner Garvin , Bologna Marcia , Bloom Laird , O'Toole Margot 
Published: May 2010

Abstract

Background
Selective neutralization of the IL21/IL21R signaling pathway is a promising approach for the treatment of a variety of autoimmune diseases. Ab-01 is a human neutralizing anti-IL21R antibody. In order to ensure that the activities of Ab-01 are restricted to neutralization even under in vitro cross-linking and in vivo conditions, a comprehensive assessment of agonistic potential of Ab-01 was undertaken.

Methods

In vitro antibody cross-linking and cell culture protocols reported for studies with a human agonistic antibody, TGN1412, were followed for Ab-01. rhIL21, the agonist ligand of the targeted receptor, and cross-linked anti-CD28 were used as positive controls for signal transduction. In vivo agonistic potential of Ab-01 was assessed by measuring expression levels of cytokine storm-associated and IL21 pathway genes in blood of cynomolgus monkeys before and after IV administration of Ab-01.

Results
Using a comprehensive set of assays that detected multiple activation signals in the presence of the positive control agonists, in vitro Ab-01-dependent activation was not detected in either PBMCs or the rhIL21-responsive cell line Daudi. Furthermore, no difference in gene expression levels was detected in blood before and after in vivo Ab-01 dosing of cynomolgus monkeys.

Conclusions
Despite efforts to intentionally force an agonistic signal from Ab-01, none could be detected.
Relationship between Asthma and Rhinitis: Epidemiologic, Pathophysiologic, and Therapeutic Aspects
Authors: Bergeron Celine , Hamid Qutayba 
Published: May 2010

Abstract
Over the last few years, the evidence of links between rhinitis and asthma has been strengthened. This has led to the introduction of the concept of united airway disease. Rhinitis and asthma appear to be interrelated at the epidemiologic level and at the pathophysiologic level. This article reviews current epidemiologic and pathophysiologic evidence of the relationship between rhinitis and asthma and discusses the effect of treatment of one site on the other site.
Spartin activates atrophin-1-interacting protein 4 (AIP4) E3 ubiquitin ligase and promotes ubiquitination of adipophilin on lipid droplets
Authors: Hooper Christopher , Puttamadappa Swamy S , Loring Zak , Shekhtman Alexander , Bakowska Joanna C 
Published: May 2010

Abstract

Background
Spartin protein is involved in degradation of epidermal growth factor receptor and turnover of lipid droplets and a lack of expression of this protein is responsible for hereditary spastic paraplegia type 20 (SPG20). Spartin is a multifunctional protein that associates with many cellular organelles, including lipid droplets. Recent studies showed that spartin interacts with E3 ubiquitin ligases that belong to the neural precursor cell-expressed developmentally downregulated gene (Nedd4) family, including atrophin-1-interacting protein 4 (AIP4/ITCH). However, the biological importance of the spartin-AIP4 interaction remains unknown.

Results
In this study, we show that spartin is not a substrate for AIP4 activity and that spartin's binding to AIP4 significantly increases self-ubiquitination of this E3 ligase, indicating that spartin disrupts the AIP4 autoinhibitory intramolecular interaction. Correspondingly, spartin has a seven times higher binding affinity to the WW region of AIP4 than the binding of the WW region has to the catalytic homologues of the E6-associated protein C-terminus (HECT) domain, as measured by enzyme-linked immunosorbent assay. We also show that spartin recruits AIP4 to lipid droplets and promotes ubiquitination of lipid droplet-associated protein, adipophilin, which regulates turnover of lipid droplets.

Conclusions
Our findings demonstrate that spartin acts as an adaptor protein that activates and recruits AIP4 E3 ubiquitin ligase to lipid droplets and by this means regulates the level of ubiquitination of adipophilin and potentially other lipid-associated proteins. We propose that this is one of the mechanisms by which spartin regulates lipid droplet turnover and might contribute to the pathology of SPG20.
In vivo Patch-Clamp Analysis of Response Properties of Rat Primary Somatosensory Cortical Neurons Responding to Noxious Stimulation of the Facial Skin
Authors: Takeda Mamoru , Takahashi Masayuki , Nasu Masanori , Matsumoto Shigeji 
Published: May 2010

Background: Although it has been widely accepted that the primary somatosensory (SI) cortex plays an important role in pain perception, it still remains unclear how the nociceptive mechanisms of synaptic transmission occur at the single neuron level. The aim of the present study was to examine whether noxious stimulation applied to the orofacial area evokes the synaptic response of SI neurons in urethane-anesthetized rats using an in vivo patch-clamp technique. Results: In vivo whole-cell current-clamp recordings were performed in rat SI neurons (layers III-IV). Twenty-seven out of 63 neurons were identified in the mechanical receptive field of the orofacial area (36 neurons showed no receptive field) and they were classified as non-nociceptive (low-threshold mechanoreceptive; 6/27, 22%) and nociceptive neurons. Nociceptive neurons were further divided into wide-dynamic range neurons (3/27, 11 %) and nociceptive-specific neurons (18/27, 67%). In the majority of these neurons, a proportion of the excitatory postsynaptic potentials (EPSPs) reached the threshold, and then generated random discharges of action potentials. Noxious mechanical stimuli applied to the receptive field elicited a discharge of action potentials on the barrage of EPSPs. In the case of noxious chemical stimulation applied as mustard oil to the orofacial area, the membrane potential shifted depolarization and the rate of spontaneous discharges gradually increased as did the noxious pinch-evoked discharge rates, which were usually associated with potentiated EPSP amplitudes. Conclusions: The present study provides evidence that SI neurons in deep layers III–V respond to the temporal summation of EPSPs due to noxious mechanical and chemical stimulation applied to the orofacial area and that these neurons may contribute to the processing of nociceptive information, including hyperalgesia.