bluuebunny/crossref_metadata_2025_split huggingface dataset:
Transcriptional profiling of mycobacterial antigen-induced responses in infants vaccinated with BCG at birth
Authors: Fletcher Helen A , Keyser Alana , Bowmaker Mark , Sayles Peter C , Kaplan Gilla , Hussey Greg , Hill Adrian VS , Hanekom Willem A 
Published: February 2009

Abstract

Background
Novel tuberculosis (TB) vaccines recently tested in humans have been designed to boost immunity induced by the current vaccine, Mycobacterium bovis Bacille Calmette-Guérin (BCG). Because BCG vaccination is used extensively in infants, this population group is likely to be the first in which efficacy trials of new vaccines will be conducted. However, our understanding of the complexity of immunity to BCG in infants is inadequate, making interpretation of vaccine-induced immune responses difficult.

Methods
To better understand BCG-induced immunity, we performed gene expression profiling in five 10-week old infants routinely vaccinated with BCG at birth. RNA was extracted from 12 hour BCG-stimulated or purified protein derivative of tuberculin (PPD)-stimulated PBMC, isolated from neonatal blood collected 10 weeks after vaccination. RNA was hybridised to the Sentrix® HumanRef-8 Expression BeadChip (Illumina) to measure expression of >16,000 genes.

Results
We found that ex vivo stimulation of PBMC with PPD and BCG induced largely similar gene expression profiles, except that BCG induced greater macrophage activation. The peroxisome proliferator-activated receptor (PPAR) signaling pathway, including PPAR-γ, involved in activation of the alternative, anti-inflammatory macrophage response was down-regulated following stimulation with both antigens. In contrast, up-regulation of genes associated with the classic, pro-inflammatory macrophage response was noted. Further analysis revealed a decrease in the expression of cell adhesion molecules (CAMs), including integrin alpha M (ITGAM), which is known to be important for entry of mycobacteria into the macrophage. Interestingly, more leukocyte genes were down-regulated than up-regulated.

Conclusion
Our results suggest that a combination of suppressed and up-regulated genes may be key in determining development of protective immunity to TB induced by vaccination with BCG.
Determination of HER2 phosphorylation at tyrosine 1221/1222 improves prediction of poor survival for breast cancer patients with hormone receptor-positive tumors
Authors: Frogne Thomas , Laenkholm Anne-Vibeke , Lyng Maria B , Henriksen Katrine Lütken , Lykkesfeldt Anne E 
Published: February 2009

Abstract
Introduction
High expression of total HER2 protein confers poor prognosis for breast cancer patients. HER2 is a member of the HER family consisting of four receptors, HER1 to HER4. HER receptor activity is regulated by a variety of mechanisms, and phosphorylation of the C-terminal part of the HER receptors is a marker for active signaling. The importance of phosphorylation and thereby activation of the HER1 to HER4 receptors, however, has not been investigated concomitantly in breast tumors. In the present study we examined the importance of active HER signaling in breast tumor biopsies and paired metastases, by evaluating the expression of phosphorylated HER1, HER2, HER3, Erk, Akt and the total level of HER4 and HER2.

Methods
Immunohistochemical analysis was performed on 268 primary breast tumors and 30 paired metastatic lesions from postmenopausal women with hormone receptor-positive breast tumors, who had received adjuvant tamoxifen therapy. The observed protein expression levels were analyzed for co-expression, for correlation to clinicopathological parameters and for prognostic value in relation to disease-free survival and overall survival. Lastly, the difference between protein levels in primary tumors versus metastasis was evaluated.

Results
In the primary tumors, 8%, 18%, 14% and 15% of cases were scored positive for total HER2, pHER1, pHER2 and pHER3 expression, respectively. HER4 was expressed with strong intensity in 68% and at moderate intensity in 29% of cases. The activated forms of Akt and Erk were quite uniformly expressed in the categories; negative, moderate or strong. In univariate analysis, expression of total HER2, pHER1, pHER2 and pHER3 was significantly associated with poor disease-free survival. Strong HER4 expression was associated with prolonged disease-free as well as with overall survival. Expression of pAkt and pErk was not correlated with survival. In multivariate analysis, pHER2 expression was clearly an independent marker for poor disease-free survival and overall survival when tested against tumor size, tumor grade, nodal status and HER2. Lastly, comparison of HER receptor expression in metastatic versus primary tumors showed a significant increase in expression of pHER1 and pHER3 in the metastases.

Conclusions
In hormone receptor-positive breast cancer, determination of pHER2 yields additional prognostic information about poor prognosis compared with the current clinical standard for measuring HER2.
Prediction of paclitaxel sensitivity by CDK1 and CDK2 activity in human breast cancer cells
Authors: Nakayama Satoshi , Torikoshi Yasuhiro , Takahashi Takeshi , Yoshida Tomokazu , Sudo Tamotsu , Matsushima Tomoko , Kawasaki Yuko , Katayama Aya , Gohda Keigo , Hortobagyi Gabriel N , Noguchi Shinzaburo , Sakai Toshiyuki , Ishihara Hideki , Ueno Naoto T 
Published: February 2009

Abstract
Introduction
Paclitaxel is used widely in the treatment of breast cancer. Not all tumors respond to this drug, however, and the characteristics that distinguish resistant tumors from sensitive tumors are not well defined. Activation of the spindle assembly checkpoint is required for paclitaxel-induced cell death. We hypothesized that cyclin-dependent kinase (CDK) 1 activity and CDK2 activity in cancer cells, which reflect the activation state of the spindle assembly checkpoint and the growth state, respectively, predict sensitivity to paclitaxel.

Methods
Cell viability assays and DNA and chromatin morphology analyses were performed in human breast cancer cell lines to evaluate sensitivity to paclitaxel and the cell cycle response to paclitaxel. We then examined the specific activities of CDK1 and CDK2 in these cell lines and in xenograft models of human breast cancer before and after paclitaxel treatment. Protein expression and kinase activity of CDKs and cyclins were analyzed using a newly developed assay system.

Results
In the cell lines, biological response to paclitaxel in vitro did not accurately predict sensitivity to paclitaxel in vivo. Among the breast cancer xenograft tumors, however, tumors with significantly increased CDK1 specific activity after paclitaxel treatment were sensitive to paclitaxel in vivo, whereas tumors without such an increase were resistant to paclitaxel in vivo. Baseline CDK2 specific activity was higher in tumors that were sensitive to paclitaxel than in tumors that were resistant to paclitaxel.

Conclusions
The change in CDK1 specific activity of xenograft tumors after paclitaxel treatment and the CDK2 specific activity before paclitaxel treatment are both associated with the drug sensitivity in vivo. Analysis of cyclin-dependent kinase activity in the clinical setting could be a powerful approach for predicting paclitaxel sensitivity.
Prediction of extubation outcome: a randomised, controlled trial with automatic tube compensation vs. pressure support ventilation
Authors: Cohen Jonathan , Shapiro Maury , Grozovski Elad , Fox Ben , Lev Shaul , Singer Pierre 
Published: February 2009

Abstract
Introduction
Tolerance of a spontaneous breathing trial is an evidence-based strategy to predict successful weaning from mechanical ventilation. Some patients may not tolerate the trial because of the respiratory load imposed by the endotracheal tube, so varying levels of respiratory support are widely used during the trial. Automatic tube compensation (ATC), specifically developed to overcome the imposed work of breathing because of artificial airways, appears ideally suited for the weaning process. We further evaluated the use of ATC in this setting.

Methods
In a prospective study, patients who had received mechanical ventilation for more than 24 hours and met defined criteria for a weaning trial, underwent a one-hour spontaneous breathing trial with either ATC (n = 87) or pressure support ventilation (PSV; n = 93). Those tolerating the trial were immediately extubated. The primary outcome measure was the ability to maintain spontaneous, unassisted breathing for more than 48 hours after extubation. In addition, we measured the frequency/tidal volume ratio (f/VT) both with (ATC-assisted) and without ATC (unassisted-f/VT) at the start of the breathing trial as a pretrial predictor of extubation outcome.

Results
There were no significant differences in any of the baseline characteristics between the two groups apart from a significantly higher Acute Physiology and Chronic Health Evaluation (APACHE) II score in the ATC group (p = 0.009). In the PSV group, 13 of 93 (14%) patients failed the breathing trial compared with only 6 of 87 (6%) in the ATC group; this observed 8% difference, however, did not reach statistical significance (p = 0.12). The rate of reintubation was not different between the groups (total group = 17.3%; ATC = 18.4% vs. PSV = 12.9%, p = 0.43). The percentage of patients who remained extubated for more than 48 hours was similar in both groups (ATC = 74.7% vs. PSV = 73.1%; p = 0.81). This represented a positive predictive value for PSV of 0.85 and ATC of 0.80 (p = 0.87). Finally, the ATC-assisted f/VT was found to have a significant contribution in predicting successful liberation and extubation compared with the non-significant contribution of the unassisted f/VT (unassisted f/VT, p = 0.19; ATC-assisted f/VT, p = 0.005).

Conclusions
This study confirms the usefulness of ATC during the weaning process, being at least as effective as PSV in predicting successful extubation outcome and significantly improving the predictive value of the f/VT.

Trial registration
Current Controlled Trials ISRCTN16080446
Efficacy of positive end-expiratory pressure titration after the alveolar recruitment manoeuvre in patients with acute respiratory distress syndrome
Authors: Huh Jin Won , Jung Hoon , Choi Hye Sook , Hong Sang-Bum , Lim Chae-Man , Koh Younsuck 
Published: February 2009

Abstract
Introduction
In acute respiratory distress syndrome (ARDS), adequate positive end-expiratory pressure (PEEP) may decrease ventilator-induced lung injury by minimising overinflation and cyclic recruitment-derecruitment of the lung. We evaluated whether setting the PEEP using decremental PEEP titration after an alveolar recruitment manoeuvre (ARM) affects the clinical outcome in patients with ARDS.

Methods
Fifty-seven patients with early ARDS were randomly assigned to a group given decremental PEEP titration following ARM or a table-based PEEP (control) group. PEEP and inspired fraction of oxygen (FiO2) in the control group were set according to the table-based combinations of FiO2 and PEEP of the ARDS network, by which we aimed to achieve a PEEP level compatible with an oxygenation target. In the decremental PEEP titration group, the oxygen saturation and static compliance were monitored as the patients performed the ARM along with the extended sigh method, which is designed to gradually apply and withdraw a high distending pressure over a prolonged period, and the decremental titration of PEEP.

Results
The baseline characteristics did not differ significantly between the control and decremental PEEP titration groups. Initial oxygenation improved more in the decremental PEEP titration group than in the control group. However, dynamic compliance, tidal volume and PEEP were similar in the two groups during the first week. The duration of use of paralysing or sedative agents, mechanical ventilation, stay in the intensive care unit and mortality at 28 days did not differ significantly between the decremental PEEP titration and control groups.

Conclusions
The daily decremental PEEP titration after ARM showed only initial oxygenation improvement compared with the table-based PEEP method. Respiratory mechanics and patient outcomes did not differ between the decremental PEEP titration and control groups.

Trial registration
ClinicalTrials.gov identifier: ISRCTN79027921.
PEMer: a computational framework with simulation-based error models for inferring genomic structural variants from massive paired-end sequencing data
Authors: Korbel Jan O , Abyzov Alexej , Mu Xinmeng Jasmine , Carriero Nicholas , Cayting Philip , Zhang Zhengdong , Snyder Michael , Gerstein Mark B 
Published: February 2009

AbstractPersonal-genomics endeavors, such as the 1000 Genomes project, are generating maps of genomic structural variants by analyzing ends of massively sequenced genome fragments. To process these we developed Paired-End Mapper (PEMer; http://sv.gersteinlab.org/pemer). This comprises an analysis pipeline, compatible with several next-generation sequencing platforms; simulation-based error models, yielding confidence-values for each structural variant; and a back-end database. The simulations demonstrated high structural variant reconstruction efficiency for PEMer's coverage-adjusted multi-cutoff scoring-strategy and showed its relative insensitivity to base-calling errors.
Oxidative modifications of S100 proteins: functional regulation by redox
Authors: Lim Su Yin , Raftery Mark J , Goyette Jesse , Hsu Kenneth , Geczy Carolyn L 
Published: February 2009

Abstract
Alterations in the capability of CF lung macrophage to respond and clear airway pathogens might contribute to the development of lung disease in cystic fibrosis.
Several S100 Ca2+–binding proteins undergo various post–translational modifications that may alter their intracellular and extracellular functions. S100A8 and S100A9, two members of this family, are particularly susceptible to oxidative modification. These proteins, abundantly expressed in neutrophils and activated macrophages, are associated with acute and chronic inflammatory conditions, including microbial infections, cystic fibrosis, rheumatoid arthritis, and atherosclerosis. They have diverse intracellular roles including NADPH oxidase activation and arachidonic acid transport and can be secreted via a Golgi–independent pathway to exert extracellular functions. Many pro–inflammatory functions have been described for S100A8 and S100A9, but they are also implicated in anti–inflammatory roles in wound–healing and protection against excessive oxidative tissue damage, the latter as a result of their exquisite capacity to scavenge oxidants. Similarly, their genes are induced by proinflammatory (LPS and TNF–α) stimuli, but induction is IL–10–dependent, and anti–inflammatory glucocorticoids induce or amplify expression. S100A8 and S100A9 were described recently as damage–associated molecular pattern molecules, which provide a novel, conceptual framework for understanding their functions. However, because of this designation, recent reviews focus solely on their pro–inflammatory functions. Here, we summarize the mounting evidence from functional and gene regulation studies that these proteins may also play protective roles. This review offers an explanation for the disparate, functional roles of S100A8 and S100A9 based on emerging data that post–translational, oxidative modifications may act as a regulatory switch.
Defective IL-10 production in severe phenotypes of Crohn’s disease
Authors: Correa Ismael , Veny Marisol , Esteller Miriam , Piqué Josep M , Yagüe Jordi , Panés Julián , Salas Azucena 
Published: February 2009

AbstractLoss of tolerance toward commensal bacteria has been invoked as a mechanism for Crohn’s disease. IL-10 is a key anti-inflammatory cytokine that plays a role in induction and maintenance of tolerance. The aim of this study is to determine IL-10 production in response to bacterial components in Crohn’s disease patients, who were classified according to their phenotypes as stricturing, penetrating, or inflammatory. Peripheral blood was obtained from Crohn’s disease patients and healthy controls. Cytokine production was measured in whole blood cultures, isolated CD4+ cells, and monocyte-derived dendritic cells (MDDCs). Under unstimulated conditions, IL-10, but not IL-12, was down-regulated significantly in blood cultures of patients with severe phenotypes, compared with inflammatory, nonpenetrating, nonstricturing Crohn’s disease patients. In response to LPS, IL-10 was up-regulated more significantly in patients with no fistulae or fibrosis. Study of IL-10 production by isolated cell subsets showed that DCs, but not CD4+ T cells, from penetrating Crohn’s disease produced significantly less IL-10 in response to LPS. Differences were not associated with the 1082A/G polymorphism in the IL-10 gene promoter. We show a defect in IL-10 production in whole blood cell cultures and MDDCs in patients with severe forms of Crohn’s disease. This defect in IL-10 production by a group of Crohn’s disease patients may represent a mechanism mediating more severe manifestations of the disease. We propose that treatment with IL-10 or IL-10-inducing therapies could be of particular benefit to these group of patients.
Randomized Phase II Trial of Denosumab in Patients With Bone Metastases From Prostate Cancer, Breast Cancer, or Other Neoplasms After Intravenous Bisphosphonates
Authors: Fizazi Karim , Lipton Allan , Mariette Xavier , Body Jean-Jacques , Rahim Yasmin , Gralow Julie R. , Gao Guozhi , Wu Ling , Sohn Winnie , Jun Susie 
Published: February 2009

Purpose Patients with bone metastases and elevated urinary N-telopeptide (uNTx), representing excessive bone resorption, are at increased risk for skeletal-related events (SREs), cancer progression, and death. Osteoclast-mediated bone resorption is regulated by RANKL. We evaluated the effect of denosumab, a fully human monoclonal antibody against RANKL, in patients with bone metastases and elevated uNTx levels despite ongoing intravenous (IV) bisphosphonate (BP) therapy. Patients and Methods Eligible patients had histologically confirmed malignancy, ≥ 1 bone metastases, and uNTx levels higher than 50 nmol/L bone collagen equivalents (BCE)/mM creatinine despite IV BPs. They were stratified by tumor type and screening uNTx levels (50 to 100 or > 100 nmol/L BCE/mM creatinine), and randomly assigned to continue IV BPs every 4 weeks or receive subcutaneous denosumab 180 mg every 4 weeks or every 12 weeks. Results Among 111 patients accrued, the primary end point of uNTx levels lower than 50 nmol/L BCE/mM creatinine (uNTx < 50) at week 13 was achieved by 49 (71%) of 69 patients in the denosumab arms, compared with 10 (29%) of 35 patients in the IV BP arm (P < .001). The proportion of patients with uNTx lower than 50 was maintained at week 25 (64% denosumab arms; 37% IV BP arm; P = .01). The incidence of SREs was six (8%) of 73 and six (17%) of 35 in the denosumab group and IV BP group, respectively. Rates of adverse events were similar between treatment groups. Conclusion Among patients with elevated uNTx despite ongoing IV BP therapy, denosumab normalized uNTx levels more frequently than the continuation of IV BP. Fewer patients receiving denosumab experienced on-study SREs than those receiving IV BPs.
Phase I Trial of AEG35156 Administered as a 7-Day and 3-Day Continuous Intravenous Infusion in Patients With Advanced Refractory Cancer
Authors: Dean Emma , Jodrell Duncan , Connolly Kate , Danson Sarah , Jolivet Jacques , Durkin Jon , Morris Stephen , Jowle Debra , Ward Tim , Cummings Jeff , Dickinson Gemma , Aarons Leon , LaCasse Eric , Robson Lesley , Dive Caroline , Ranson Malcolm 
Published: February 2009

Purpose To establish the maximum-tolerated dose and evaluate tolerability, pharmacokinetics, pharmacodynamic effects, and antitumor activity of AEG35156, a second-generation antisense to X-linked inhibitor of apoptosis (XIAP) protein, in patients with advanced refractory malignant tumors. Patients and Methods This was a first-in-man, open-label, phase I dose-escalation study. AEG35156 was administered by continuous intravenous infusion over 7 days (7DI) or 3 days (3DI) of a 21-day treatment cycle. Dose escalation started at 48 mg/m2/d and continued until consistent dose-limiting toxicity (DLT) was observed. Results Thirty-eight patients were entered in seven cohorts. Grade 3 to 4 adverse events were uncommon and were predominantly abnormal laboratory values: elevated ALT, thrombocytopenia, and lymphopenia. DLTs comprised elevated hepatic enzymes, hypophosphatemia, and thrombocytopenia. The maximum-tolerated doses were defined as 125 mg/m2/d for the 7DI regimen and ≤ 213 mg/m2/d for the 3DI schedule. AEG35156 area under the plasma concentration curve and peak plasma concentration increased proportionally with dose. Suppression of XIAP mRNA levels was maximal at 72 hours (mean suppression, 21%), and this coincided with a dramatic decrease in circulating tumor cells in a patient with non-Hodgkin's lymphoma. Two further patients had unconfirmed partial responses. Circulating biomarkers of cell death and apoptosis altered in association with drug infusion and toxicity. Conclusion In this first-in-man study, AEG35156 was well tolerated, with predictable toxicities, pharmacokinetic properties, and clinical evidence of antitumor activity in patients with refractory lymphoma, melanoma, and breast cancer. Phase I/II trials of AEG35156 chemotherapy combinations are ongoing in patients with pancreatic, breast, non–small-cell lung cancer, acute myeloid leukemia, lymphoma, and solid tumors for which docetaxel is indicated.
Genetic dissection of the mechanisms underlying telomere-associated diseases: impact of the TRF2 telomeric protein on mouse epidermal stem cells
Authors: Stout Gerdine J. , Blasco Maria A. 
Published: February 2009

SUMMARY
TRF2 is a telomere-binding protein involved in the protection of chromosome ends. Interestingly, TRF2 is overexpressed in a number of human cancers. Mice with increased TRF2 expression (K5TRF2 mice) display a severe skin phenotype including an increase in skin cancer and premature skin degeneration, which includes increased skin hyperpigmentation and skin dryness; these pathologies are concomitant with dramatic telomere shortening and increased chromosomal instability. Here, we show that K5TRF2 mice have a severe epidermal stem cell (ESC) dysfunction, which is reversed by abrogation of p53 in the absence of rescue of telomere length. Importantly, p53 deletion also rescues severe skin hyperpigmentation in these mice through regulation of alpha-melanocyte-stimulating hormone (α-MSH). In addition, skin carcinogenesis is accelerated in K5TRF2/p53−/−mice owing to attenuated p21 induction, which enables cell proliferation to resume. Altogether, these results reveal the existence of a DNA damage-dependent checkpoint that acts on ESCs with critically short telomeres and restricts skin proliferation, thereby increasing protection against skin cancer; however, the checkpoint also leads to premature skin aging phenotypes. Finally, the results described here are relevant to our understanding of the pathobiology of those human diseases that are characterized by the presence of critically short telomeres (hereafter referred to as ‘telopathies’), such as dyskeratosis congenita which causes severe skin phenotypes including skin hyperpigmentation and skin cancer.
Synthesis and Photoinduced Cross-linking Reactions of 4,5′,8-Trimethylpsoralen-incorporated Oligodeoxyribonucleotide
Authors: Kobori Akio , Takaya Kazutaka , Higuchi Maiko , Yamayoshi Asako , Murakami Akira 
Published: February 2009

Abstract
Photo-induced cross-linking reaction at a certain position in nucleic acids, occurring in a sequence specific manner, would be the key to inhibitor the growth of carcinoma cells, which has a point mutation in the ras gene. We newly synthesized 4,5′,8-trimethylpsoralen nucleoside and examined its photoinduced cross-linking activities in DNA duplexes after UVA irradiation.