bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prediction of HIV-1 virus-host protein interactions using virus and host sequence motifs
Authors: Evans Perry , Dampier William , Ungar Lyle , Tozeren Aydin 
Published: May 2009

Abstract

Background
Host protein-protein interaction networks are altered by invading virus proteins, which create new interactions, and modify or destroy others. The resulting network topology favors excessive amounts of virus production in a stressed host cell network. Short linear peptide motifs common to both virus and host provide the basis for host network modification.

Methods
We focused our host-pathogen study on the binding and competing interactions of HIV-1 and human proteins. We showed that peptide motifs conserved across 70% of HIV-1 subtype B and C samples occurred in similar positions on HIV-1 proteins, and we documented protein domains that interact with these conserved motifs. We predicted which human proteins may be targeted by HIV-1 by taking pairs of human proteins that may interact via a motif conserved in HIV-1 and the corresponding interacting protein domain.

Results
Our predictions were enriched with host proteins known to interact with HIV-1 proteins ENV, NEF, and TAT (p-value < 4.26E-21). Cellular pathways statistically enriched for our predictions include the T cell receptor signaling, natural killer cell mediated cytotoxicity, cell cycle, and apoptosis pathways. Gene Ontology molecular function level 5 categories enriched with both predicted and confirmed HIV-1 targeted proteins included categories associated with phosphorylation events and adenyl ribonucleotide binding.

Conclusion
A list of host proteins highly enriched with those targeted by HIV-1 proteins can be obtained by searching for host protein motifs along virus protein sequences. The resulting set of host proteins predicted to be targeted by virus proteins will become more accurate with better annotations of motifs and domains. Nevertheless, our study validates the role of linear binding motifs shared by virus and host proteins as an important part of the crosstalk between virus and host.
Magnetically retainable microparticles for drug delivery to the joint: efficacy studies in an antigen-induced arthritis model in mice
Authors: Butoescu Nicoleta , Seemayer Christian A , Palmer Gaby , Guerne Pierre-André , Gabay Cem , Doelker Eric , Jordan Olivier 
Published: May 2009

Abstract
Introduction
Conventional corticosteroid suspensions for the intra-articular treatment of arthritis suffer from limitations such as crystal formation or rapid clearance from the joint. The purpose of this study was to investigate an innovative alternative consisting of corticosteroid encapsulation into magnetically retainable microparticles.

Methods
Microparticles (1 or 10 μm) containing both superparamagnetic iron oxide nanoparticles (SPIONs) and dexamethasone 21-acetate (DXM) were prepared. In a preliminary study, we compared the persistence of microparticles of both sizes in the joint. A second study evaluated the influence of a subcutaneously implanted magnet near the knee on the retention of magnetic microparticles in the joint by in vivo imaging. Finally, the efficacy of 10-μm microparticles was investigated using a model of antigen-induced arthritis (AIA) in mice. Phosphate-buffered saline, DXM suspension, SPION suspension, blank microparticles and microparticles containing only SPIONs were used as controls. Arthritis severity was assessed using 99mTc accumulation and histological scoring.

Results
Due to their capacity of encapsulating more corticosteroid and their increased joint retention, the 10-μm microparticles were more suitable vectors than the 1-μm microparticles for corticosteroid delivery to the joint. The presence of a magnet resulted in higher magnetic retention in the joint, as demonstrated by a higher fluorescence signal. The therapeutic efficacy in AIA of 10-μm microparticles containing DXM and SPIONs was similar to that of the DXM suspension, proving that the bioactive agent is released. Moreover, the anti-inflammatory effect of DXM-containing microparticles was more important than that of blank microparticles or microparticles containing only SPIONs. The presence of a magnet did not induce a greater inflammatory reaction.

Conclusions
This study confirms the effectiveness of an innovative approach of using magnetically retainable microparticles as intra-articular drug delivery systems. A major advantage comes from a versatile polymer matrix, which allows the encapsulation of many classes of therapeutic agents (for example, p38 mitogen-activated protein kinase inhibitors), which may reduce systemic side effects.
Model for predicting short-term mortality of severe sepsis
Authors: Adrie Christophe , Francais Adrien , Alvarez-Gonzalez Antonio , Mounier Roman , Azoulay Elie , Zahar Jean-Ralph , Clec'h Christophe , Goldgran-Toledano Dany , Hammer Laure , Descorps-Declere Adrien , Jamali Samir , Timsit Jean-Francois ,   the Outcomerea Study Group
Published: May 2009

Abstract
Introduction
To establish a prognostic model for predicting 14-day mortality in ICU patients with severe sepsis overall and according to place of infection acquisition and to sepsis episode number.

Methods
In this prospective multicentre observational study on a multicentre database (OUTCOMEREA) including data from 12 ICUs, 2268 patients with 2737 episodes of severe sepsis were randomly divided into a training cohort (n = 1458) and a validation cohort (n = 810). Up to four consecutive severe sepsis episodes per patient occurring within the first 28 ICU days were included. We developed a prognostic model for predicting death within 14 days after each episode, based on patient data available at sepsis onset.

Results
Independent predictors of death were logistic organ dysfunction (odds ratio (OR), 1.22 per point, P < 10-4), septic shock (OR, 1.40; P = 0.01), rank of severe sepsis episode (1 reference, 2: OR, 1.26; P = 0.10 ≥ 3: OR, 2.64; P < 10-3), multiple sources of infection (OR; 1.45, P = 0.03), simplified acute physiology score II (OR, 1.02 per point; P < 10-4), McCabe score ([greater than or equal to]2) (OR, 1.96; P < 10-4), and number of chronic co-morbidities (1: OR, 1.75; P < 10-3, ≥ 2: OR, 2.24, P < 10-3). Validity of the model was good in whole cohorts (AUC-ROC, 0.76; 95%CI, 0.74 to 0.79; and HL Chi-square: 15.3 (P = 0.06) for all episodes pooled).

Conclusions
In ICU patients, a prognostic model based on a few easily obtained variables is effective in predicting death within 14 days after the first to fourth episode of severe sepsis complicating community-, hospital-, or ICU-acquired infection.
Intravenous glutamine decreases lung and distal organ injury in an experimental model of abdominal sepsis
Authors: Oliveira Gisele P , Oliveira Mariana BG , Santos Raquel S , Lima Letícia D , Dias Cristina M , AB' Saber Alexandre M , Teodoro Walcy R , Capelozzi Vera L , Gomes Rachel N , Bozza Patricia T , Pelosi Paolo , Rocco Patricia RM 
Published: May 2009

Abstract
Introduction
The protective effect of glutamine, as a pharmacological agent against lung injury, has been reported in experimental sepsis; however, its efficacy at improving oxygenation and lung mechanics, attenuating diaphragm and distal organ injury has to be better elucidated. In the present study, we tested the hypothesis that a single early intravenous dose of glutamine was associated not only with the improvement of lung morpho-function, but also the reduction of the inflammatory process and epithelial cell apoptosis in kidney, liver, and intestine villi.

Methods
Seventy-two Wistar rats were randomly assigned into four groups. Sepsis was induced by cecal ligation and puncture surgery (CLP), while a sham operated group was used as control (C). One hour after surgery, C and CLP groups were further randomized into subgroups receiving intravenous saline (1 ml, SAL) or glutamine (0.75 g/kg, Gln). At 48 hours, animals were anesthetized, and the following parameters were measured: arterial oxygenation, pulmonary mechanics, and diaphragm, lung, kidney, liver, and small intestine villi histology. At 18 and 48 hours, Cytokine-Induced Neutrophil Chemoattractant (CINC)-1, interleukin (IL)-6 and 10 were quantified in bronchoalveolar and peritoneal lavage fluids (BALF and PLF, respectively).

Results
CLP induced: a) deterioration of lung mechanics and gas exchange; b) ultrastructural changes of lung parenchyma and diaphragm; and c) lung and distal organ epithelial cell apoptosis. Glutamine improved survival rate, oxygenation and lung mechanics, minimized pulmonary and diaphragmatic changes, attenuating lung and distal organ epithelial cell apoptosis. Glutamine increased IL-10 in peritoneal lavage fluid at 18 hours and bronchoalveolar lavage fluid at 48 hours, but decreased CINC-1 and IL-6 in BALF and PLF only at 18 hours.

Conclusions
In an experimental model of abdominal sepsis, a single intravenous dose of glutamine administered after sepsis induction may modulate the inflammatory process reducing not only the risk of lung injury, but also distal organ impairment. These results suggest that intravenous glutamine may be a potentially beneficial therapy for abdominal sepsis.
Dexmedetomidine vs. haloperidol in delirious, agitated, intubated patients: a randomised open-label trial
Authors: Reade Michael C , O'Sullivan Kim , Bates Samantha , Goldsmith Donna , Ainslie William RSTJ , Bellomo Rinaldo 
Published: May 2009

Abstract
Introduction
Agitated delirium is common in patients undergoing mechanical ventilation, and is often treated with haloperidol despite concerns about safety and efficacy. Use of conventional sedatives to control agitation can preclude extubation. Dexmedetomidine, a novel sedative and anxiolytic agent, may have particular utility in these patients. We sought to compare the efficacy of haloperidol and dexmedetomidine in facilitating extubation.

Methods
We conducted a randomised, open-label, parallel-groups pilot trial in the medical and surgical intensive care unit of a university hospital. Twenty patients undergoing mechanical ventilation in whom extubation was not possible solely because of agitated delirium were randomised to receive an infusion of either haloperidol 0.5 to 2 mg/hour or dexmedetomidine 0.2 to 0.7 μg/kg/hr, with or without loading doses of 2.5 mg haloperidol or 1 μg/kg dexmedetomidine, according to clinician preference.

Results
Dexmedetomidine significantly shortened median time to extubation from 42.5 (IQR 23.2 to 117.8) to 19.9 (IQR 7.3 to 24) hours (P = 0.016). Dexmedetomidine significantly decreased ICU length of stay, from 6.5 (IQR 4 to 9) to 1.5 (IQR 1 to 3) days (P = 0.004) after study drug commencement. Of patients who required ongoing propofol sedation, the proportion of time propofol was required was halved in those who received dexmedetomidine (79.5% (95% CI 61.8 to 97.2%) vs. 41.2% (95% CI 0 to 88.1%) of the time intubated; P = 0.05). No patients were reintubated; three receiving haloperidol could not be successfully extubated and underwent tracheostomy. One patient prematurely discontinued haloperidol due to QTc interval prolongation.

Conclusions
In this preliminary pilot study, we found dexmedetomidine a promising agent for the treatment of ICU-associated delirious agitation, and we suggest this warrants further testing in a definitive double-blind multi-centre trial.

Trial registration
Clinicaltrials.gov NCT00505804
Conserved features of cohesin binding along fission yeast chromosomes
Authors: Schmidt Christine K , Brookes Neil , Uhlmann Frank 
Published: May 2009

Abstract
Background
Cohesin holds sister chromatids together to enable their accurate segregation in mitosis. How, and where, cohesin binds to chromosomes are still poorly understood, and recent genome-wide surveys have revealed an apparent disparity between its chromosomal association patterns in different organisms.

Results
Here, we present the high-resolution analysis of cohesin localization along fission yeast chromosomes. This reveals that several determinants, thought specific for different organisms, come together to shape the overall distribution. Cohesin is detected at chromosomal loading sites, characterized by the cohesin loader Mis4/Ssl3, in regions of strong transcriptional activity. Cohesin also responds to transcription by downstream translocation and accumulation at convergent transcriptional terminators surrounding the loading sites. As cells enter mitosis, a fraction of cohesin leaves chromosomes in a cleavage-independent reaction, while a substantial pool of cohesin dissociates when it is cleaved at anaphase onset. We furthermore observe that centromeric cohesin spreads out onto chromosome arms during mitosis, dependent on Aurora B kinase activity, emphasizing the plasticity of cohesin behavior.

Conclusions
Our findings suggest that features that were thought to differentiate cohesin between organisms collectively define the overall behavior of fission yeast cohesin. Apparent differences between organisms might reflect an emphasis on different aspects, rather than different principles, of cohesin action.
CC chemokine ligand-2 synergizes with the nonchemokine G protein-coupled receptor ligand fMLP in monocyte chemotaxis, and it cooperates with the TLR ligand LPS via induction of CXCL8
Authors: Gouwy Mieke , Struyf Sofie , Verbeke Hannelien , Put Willy , Proost Paul , Opdenakker Ghislain , Van Damme Jo 
Published: May 2009

Abstract
Novel mechanism of enhancing monocyte chemotaxis during bacterial infections with gram-negative bacteria demonstrates the importance of local contexts in inflammatory and infectious insults.
During inflammatory reactions, endogenously produced cytokines and chemokines act in a network and interact with hormones and neurotransmitters to regulate host immune responses. These signaling circuitries are even more interfaced during infections, when microbial agonists activate TLR, RLR, and NLR receptors. On the basis of the discovery of synergy between chemokines for neutrophil attraction, we extend here this phenomenon between the chemokine MCP-1/CCL2 and the GPCR ligand fMLP or the TLR4 agonist LPS on monocytes. In fact, the bacterial tripeptide fMLP, but not the cytokines IL-1β or IFN-γ, significantly and dose-dependently synergized with CCL2 in monocyte chemotaxis. Furthermore, LPS rapidly induced the expression of IL-8/CXCL8 but not of the CCL2 receptor CCR2 in monocytic cells. In turn, the induced CXCL8 synergized with CCL2 for mononuclear cell chemotaxis, and the chemotactic effect was mediated by CXCR1/CXCR2, because CXCL8 receptor antagonists or antibodies were capable of blocking the synergy, while keeping the responsiveness to CCL2 intact. These data recapitulate in vitro the complexity of innate immune regulation, provide a novel mechanism of enhancing monocyte chemotaxis during bacterial infections with gram-negative bacteria and demonstrate the importance of local contexts in inflammatory and infectious insults.
The endogenous Toll–like receptor 4 agonist S100A8/S100A9 (calprotectin) as innate amplifier of infection, autoimmunity, and cancer
Authors: Ehrchen Jan M , Sunderkötter Cord , Foell Dirk , Vogl Thomas , Roth Johannes 
Published: May 2009

Abstract
S100A8 and S100A9 are novel members of the group of damage–associated molecular pattern molecules (DAMP) which are early amplifiers of innate immune responses to tissue damage or danger signals.
The innate immune system is crucial for initiation and amplification of inflammatory responses. During this process, phagocytes are activated by PAMPs that are recognized by PRRs. Phagocytes are also activated by endogenous danger signals called alarmins or DAMPs via partly specific, partly common PRRs. Two members of the S100 protein family, S100A8 and S100A9, have been identified recently as important endogenous DAMPs. The complex of S100A8 and S100A9 (also called calprotectin) is actively secreted during the stress response of phagocytes. The association of inflammation and S100A8/S100A9 was discovered more than 20 years ago, but only now are the molecular mechanisms involved in danger signaling by extracellular S100A8/S100A9 beginning to emerge. Taking advantage of mice lacking the functional S100A8/S100A9 complex, these molecules have been identified as endogenous activators of TLR4 and have been shown to promote lethal, endotoxin–induced shock. Importantly, S100A8/S100A9 is not only involved in promoting the inflammatory response in infections but was also identified as a potent amplifier of inflammation in autoimmunity as well as in cancer development and tumor spread. This proinflammatory action of S100A8/S100A9 involves autocrine and paracrine mechanisms in phagocytes, endothelium, and other cells. As a net result, extravasation of leukocytes into inflamed tissues and their subsequent activation are increased. Thus, S100A8/S100A9 plays a pivotal role during amplification of inflammation and represents a promising new therapeutic target.
Improved Survival for Stage IV Melanoma From an Unknown Primary Site
Authors: Lee Chris C. , Faries Mark B. , Wanek Leslie A. , Morton Donald L. 
Published: May 2009

Purpose We previously demonstrated a survival advantage for nodal metastasis of melanoma from an unknown primary (MUP) versus melanoma from a known primary (MKP). We hypothesized that this survival benefit would extend to MUP patients with distant (stage IV) metastasis. Patients and Methods We reviewed prospectively acquired data for 2,247 patients diagnosed with American Joint Committee on Cancer stage IV melanoma at our cancer center between 1971 and 2005. Cox regression analysis in a multivariate model identified prognostic factors significant for survival. MUP and MKP patients were then matched by significant covariates. Overall survival (OS) was estimated by Kaplan-Meier method and compared by log-rank analysis. Results There were 1,849 MKP and 398 MUP patients. Multivariate analysis of patients with complete data sets identified known/unknown primary (hazard ratio [HR], 1.141; P = .032) and five other significant covariates: age (HR, 1.148; P = .007), sex (HR, 1.17; P = .001), site of metastasis (HR, 1.336; P < .001), number of different metastatic sites (HR, 1.303; P < .001), and decade of diagnosis (HR, 0.713; P < .001). Prognostic matching yielded 392 MUP-MKP pairs. Median OS and 5-year OS rate were significantly greater (P < .001) for MUP patients than for all matched MKP patients or for MKP patients matched by M1 category (for M1b and M1c) or number of metastatic sites. Conclusion The survival advantage previously reported for patients with stage III MUP also applies to patients with stage IV MUP. The mechanism responsible for this improved survival may provide clues for more effective treatment of stage IV melanoma and therefore warrants further investigation. The improved results for MUP suggest that these patients deserve aggressive therapy.
Blood-Brain Barrier Disruption and Intra-Arterial Methotrexate-Based Therapy for Newly Diagnosed Primary CNS Lymphoma: A Multi-Institutional Experience
Authors: Angelov Lilyana , Doolittle Nancy D. , Kraemer Dale F. , Siegal Tali , Barnett Gene H. , Peereboom David M. , Stevens Glen , McGregor John , Jahnke Kristoph , Lacy Cynthia A. , Hedrick Nancy A. , Shalom Edna , Ference Sandra , Bell Susan , Sorenson Lisa , Tyson Rose Marie , Haluska Marianne , Neuwelt Edward A. 
Published: May 2009

Purpose Primary CNS lymphoma (PCNSL) is confined to the CNS and/or the eyes at presentation and is usually initially treated with intravenous methotrexate-based chemotherapy and whole-brain radiotherapy (WBRT). However, the intact blood-brain barrier (BBB) can limit diffusion of methotrexate into brain and tumor. With BBB disruption (BBBD), enhanced drug delivery to the tumor can be achieved. Patients and Methods This report summarizes the multi-institutional experience of 149 newly diagnosed (with no prior WBRT) patients with PCNSL treated with osmotic BBBD and intra-arterial (IA) methotrexate at four institutions from 1982 to 2005. In this series, 47.6% of patients were age ≥ 60 years, and 42.3% had Karnofsky performance score (KPS) less than 70 at diagnosis. Results The overall response rate was 81.9% (57.8% complete; 24.2% partial). Median overall survival (OS) was 3.1 years (25% estimated survival at 8.5 years). Median progression-free survival (PFS) was 1.8 years, with 5-year PFS of 31% and 7-year PFS of 25%. In low-risk patients (age < 60 years and KPS ≥ 70), median OS was approximately 14 years, with a plateau after approximately 8 years. Procedures were generally well tolerated; focal seizures (9.2%) were the most frequent side effect and lacked long-term sequelae. Conclusion This large series of patients treated over a 23-year period demonstrates that BBBD/IA methotrexate-based chemotherapy results in successful and durable tumor control and outcomes that are comparable or superior to other PCNSL treatment regimens.
Circulating Tumor Cells and [18F]Fluorodeoxyglucose Positron Emission Tomography/Computed Tomography for Outcome Prediction in Metastatic Breast Cancer
Authors: De Giorgi Ugo , Valero Vicente , Rohren Eric , Dawood Shaheenah , Ueno Naoto T. , Miller M. Craig , Doyle Gerald V. , Jackson Summer , Andreopoulou Eleni , Handy Beverly C. , Reuben James M. , Fritsche Herbert A. , Macapinlac Homer A. , Hortobagyi Gabriel N. , Cristofanilli Massimo 
Published: May 2009

Purpose Circulating tumor cells (CTCs) and [18F]fluorodeoxyglucose (FDG) positron emission tomography (PET)/computed tomography (CT) are two new promising tools for therapeutic monitoring. In this study, we compared the prognostic value of CTC and FDG-PET/CT monitoring during systemic therapy for metastatic breast cancer (MBC). Patients and Methods A retrospective analyses of 115 MBC patients who started a new line of therapy and who had CTC counts and FDG-PET/CT scans performed at baseline and at 9 to 12 weeks during therapy (midtherapy) was performed. Patients were categorized according to midtherapy CTC counts as favorable (ie, < five CTCs/7.5 mL blood) or unfavorable (≥ five CTCs/7.5 mL blood) outcomes. CTC counts and FDG-PET/CT response at midtherapy were compared, and univariate and multivariate analyses were performed to identify factors associated with survival. Results In 102 evaluable patients, the median overall survival time was 14 months (range, 1 to > 41 months). Midtherapy CTC levels correlated with FDG-PET/CT response in 68 (67%) of 102 evaluable patients. In univariate analysis, midtherapy CTC counts and FDG-PET/CT response predicted overall survival (P < .001 and P = .001, respectively). FDG-PET/CT predicted overall survival (P = .0086) in 31 (91%) of 34 discordant patients who had fewer than five CTCs at midtherapy. Only midtherapy CTC levels remained significant in a multivariate analysis (P = .004). Conclusion Detection of five or more CTCs during therapeutic monitoring can accurately predict prognosis in MBC beyond metabolic response. FDG-PET/CT deserves a role in patients who have fewer than five CTCs at midtherapy. Prospective trials should evaluate the most sensitive and cost-effective modality for therapeutic monitoring in MBC.