bluuebunny/crossref_metadata_2025_split huggingface dataset:
Alterations of T cell activation signalling and cytokine production by postmenopausal estrogen levels
Authors: Ku Lowell T , Gercel-Taylor Cicek , Nakajima Steven T , Taylor Douglas D 
Published: March 2009

Abstract

Background
Immunosenescence is an age-associated disorder occurring primarily in T cell compartments, including altered subset composition, functions, and activation. In women, evidence implicates diminished estrogen in the postmenopausal period as a contributing factor to diminished T cell responsiveness. Since hypoestrogenism is present in postmenopausal women, our objective focused on whether T cell activation, defined as signalling molecule expressions and activation, and function, identified as IL-2 production, were affected by low estrogen.

Methods
Using Jurkat 6.1 T cells, consequences of 4 pg/ml (corresponding to postmenopausal levels) or 40 pg/ml (premenopausal levels) of estradiol (E2) were analyzed on signalling proteins, CD3-zeta, JAK2, and JAK3, determined by Western immunoblotting. These consequences were correlated with corresponding gene expressions, quantified by real time-polymerase chain reaction. Tyrosine phosphorylation of CD3-zeta was defined by immunoprecipitation and western immunoblotting following activation by T cell receptor (TcR) cross-linking. CD3-zeta expression and modulation was also confirmed in T cells from pre- and postmenopausal women. To assess functional consequences, IL-2 production, induced by PMA and ionomycin, was determined using enzyme-linked immunosorbent spot assay (ELISpot).

Results
At 40 pg/ml E2, the level of signalling protein CD3-zeta was elevated 1.57-fold, compared with cells exposed to 4 pg/ml E2. The CD3-zeta proteins also exhibited altered levels of activation-induced phosphorylation in the presence of 40 pg/ml E2 versus 4 pg/ml: 23 kD phosphorylated form increased 2.64-fold and the 21 kD form was elevated 2.95-fold. Examination of kinases associated with activation signalling also demonstrated that, in the presence of 40 pg/ml E2, JAK2 protein expression was increased 1.64-fold (p < 0.001) and JAK3 enhanced 1.79-fold (p < 0.001) compared to 4 pg/ml. mRNA levels for CD3-zeta, JAK2, and JAK3 were significantly increased following exposure to 40 pg/ml E2 (2.39, 2.01, and 2.21 fold, respectively) versus 4 pg/ml. These findings were confirmed in vivo, since T cells from postmenopausal women exhibited 7.2-fold diminished CD3-zeta expression, compared to pre-menopausal controls and this expression was elevated 3.8-fold by addition of 40 pg/ml E2. Functionally, Jurkat cells exposed to 40 pg/ml E2 and activated exhibited significantly elevated numbers of IL-2 producing colonies compared to 4 pg/ml (75.3 ± 2.2 versus 55.7 ± 2.1 colonies, p < 0.0001).

Conclusion
Jurkat T cells exposed to 4 pg/ml E2 expressed significantly diminished activation signalling proteins, correlating with reduced IL-2 production. Lower signalling protein levels appear to result from decreased CD3-zeta, JAK2, and JAK3 gene expressions. These findings may provide a molecular basis for immunosenescence associated with the postmenopausal state.
Using non-invasive brain stimulation to augment motor training-induced plasticity
Authors: Bolognini Nadia , Pascual-Leone Alvaro , Fregni Felipe 
Published: March 2009

AbstractTherapies for motor recovery after stroke or traumatic brain injury are still not satisfactory. To date the best approach seems to be the intensive physical therapy. However the results are limited and functional gains are often minimal. The goal of motor training is to minimize functional disability and optimize functional motor recovery. This is thought to be achieved by modulation of plastic changes in the brain. Therefore, adjunct interventions that can augment the response of the motor system to the behavioural training might be useful to enhance the therapy-induced recovery in neurological populations. In this context, noninvasive brain stimulation appears to be an interesting option as an add-on intervention to standard physical therapies. Two non-invasive methods of inducing electrical currents into the brain have proved to be promising for inducing long-lasting plastic changes in motor systems: transcranial magnetic stimulation (TMS) and transcranial direct current stimulation (tDCS). These techniques represent powerful methods for priming cortical excitability for a subsequent motor task, demand, or stimulation. Thus, their mutual use can optimize the plastic changes induced by motor practice, leading to more remarkable and outlasting clinical gains in rehabilitation. In this review we discuss how these techniques can enhance the effects of a behavioural intervention and the clinical evidence to date.
MUTYH Gln324His gene polymorphism and genetic susceptibility for lung cancer in a Japanese population
Authors: Miyaishi Aiko , Osawa Kayo , Osawa Yasunori , Inoue Natsuko , Yoshida Kana , Kasahara Mayumi , Tsutou Akimitsu , Tabuchi Yoshiki , Sakamoto Kazuo , Tsubota Noriaki , Takahashi Juro 
Published: March 2009

Abstract

Background
Genetic polymorphisms of DNA repair enzymes in the base excision repair (BER) pathway, may lead to genetic instability and lung cancer carcinogenesis. We investigated the interactions among the gene polymorphisms in DNA repair genes and lung cancer.

Methods
We analyzed associations among OGG1 Ser326Cys and MUTYH Gln324His gene polymorphisms in relation to lung cancer risk using PCR-RFLP. The study involved 108 lung cancer patients and 121 non-cancer controls divided into non-smokers, smokers according to pack-years smoked in Japanese.

Results
The results showed that the MUTYH His/His genotype compared with Gln/Gln genotype showed an increased risk for lung cancer (adjusted odds ratio [OR] 3.03, confidence interval [95%CI], 1.31–7.00, p = 0.010), whereas there was no significant increase for the Gln/His genotype (adjusted OR 1.35, 95%CI 0.70–2.61, p = 0.376). The MUTYH His/His genotype was at a borderline increased risk for both adenocarcinoma and squamous cell carcinoma (adjusted OR 2.50, 95%CI 0.95–6.62, p = 0.065 for adenocarcinoma; adjusted OR 3.20, 95%CI 0.89–11.49, p = 0.075 for squamous cell carcinoma, respectively). However, the OGG1 Ser/Cys or Cys/Cys genotypes compared with the Ser/Ser genotype did not have significantly increased risk for lung cancer, containing either adenocarcinoma or squamous cell carcinoma. The joint effect of tobacco exposure and the MUTYH His/His genotype compared with the Gln/Gln genotype showed a significant association with lung cancer risk in smokers, and there was not significantly increased in non-smokers (adjusted OR 3.82, 95%CI 1.22–12.00, p = 0.022 for smokers; adjusted OR 2.60, 95%CI 0.60–11.25, p = 0.200 for non-smokers, respectively). The effect of tobacco exposure and the OGG1 Ser326Cys showed also no significant risk for lung cancer.

Conclusion
Our findings suggest that the MUTYH Gln324His polymorphism appear to play an important role in modifying the risk for lung cancer in the Japanese population.
Procalcitonin kinetics within the first days of sepsis: relationship with the appropriateness of antibiotic therapy and the outcome
Authors: Charles Pierre Emmanuel , Tinel Claire , Barbar Saber , Aho Serge , Prin Sébastien , Doise Jean Marc , Olsson Nils Olivier , Blettery Bernard , Quenot Jean Pierre 
Published: March 2009

Abstract
Introduction
Management of the early stage of sepsis is a critical issue. As part of it, infection control including appropriate antibiotic therapy administration should be prompt. However, microbiological findings, if any, are generally obtained late during the course of the disease. The potential interest of procalcitonin (PCT) as a way to assess the clinical efficacy of the empirical antibiotic therapy was addressed in the present study.

Methods
An observational cohort study including 180 patients with documented sepsis was conducted in our 15-bed medical intensive care unit (ICU). Procalcitonin measurement was obtained daily over a 4-day period following the onset of sepsis (day 1 (D1) to D4). The PCT time course was analyzed according to the appropriateness of the first-line empirical antibiotic therapy as well as according to the patient outcome.

Results
Appropriate first-line empirical antibiotic therapy (n = 135) was associated with a significantly greater decrease in PCT between D2 and D3 (ΔPCT D2–D3) (-3.9 (35.9) vs. +5.0 (29.7), respectively; P < 0.01). In addition, ΔPCT D2–D3 was found to be an independent predictor of first-line empirical antibiotic therapy appropriateness. In addition, a trend toward a greater rise in PCT between D1 and D2 was observed in patients with inappropriate antibiotics as compared with those with appropriate therapy (+5.2 (47.4) and +1.7 (35.0), respectively; P = 0.20). The D1 PCT level failed to predict outcome, but higher levels were measured in the nonsurvivors (n = 51) when compared with the survivors (n = 121) as early as D3 (40.8 (85.7) and 21.3 (41.0), respectively; P = 0.04). Moreover, PCT kinetics between D2 and D3 were also found to be significantly different, since a decrease ≥ 30% was expected in the survivors (log-rank test, P = 0.04), and was found to be an independent predictor of survival (odds ratio = 2.94; 95% confidence interval 1.22 to 7.09; P = 0.02).

Conclusions
In our study in an ICU, appropriateness of the empirical antibiotic therapy and the overall survival were associated with a greater decline in PCT between D2 and D3. Further studies are needed to assess the utility of the daily monitoring of PCT in addition to clinical evaluation during the early management of sepsis.
Candidate Genes on Chromosome 9q33-34 Involved in the Progression of Childhood Ependymomas
Authors: Puget Stéphanie , Grill Jacques , Valent Alexander , Bieche Ivan , Dantas-Barbosa Carmela , Kauffmann Audrey , Dessen Philippe , Lacroix Ludovic , Geoerger Birgit , Job Bastien , Dirven Clemens , Varlet Pascale , Peyre Mathieu , Dirks Peter B. , Sainte-Rose Christian , Vassal Gilles 
Published: March 2009

Purpose The molecular pathogenesis of pediatric ependymoma remains unclear. Our study was designed to identify genetic changes implicated in ependymoma progression. Patients and Methods We characterized 59 ependymoma samples (33 at diagnosis and 26 at relapse) using array-comparative genomic hybridization (aCGH). Specific chromosomal imbalances were confirmed by fluorescent in situ hybridization, and candidate genes were assessed by real-time quantitative polymerase chain reaction (qPCR), immunohistochemistry, sequencing, and in vitro functional studies. Results aCGH analysis revealed a significant increase in genomic imbalances on relapse compared with diagnosis, such as gain of 9qter and 1q (54% v 21% and 12% v 0%, respectively) and loss of 6q (27% v 6%). Supervised tumor classification showed that gain of 9qter was associated with tumor recurrence, age older than 3 years, and posterior fossa location. Using a candidate-gene strategy, we found an overexpression of two potential oncogenes at the locus 9qter: Tenascin-C and Notch1. Moreover, Notch pathway analysis (qPCR) revealed overexpression of Notch ligands, receptors, and target genes (Hes-1, Hey2, and c-Myc), and downregulation of Notch repressor Fbxw7. We confirmed by immunohistochemistry the overexpression of Tenascin-C and Hes-1. We detected Notch1 missense mutations in 8.3% of the tumors (only in the posterior fossa location and in case of 9q33-34 gain). Furthermore, inhibition of Notch pathway with a γ-secretase inhibitor impaired the growth of ependymoma stem cell cultures. Conclusion The activation of the Notch pathway and Tenascin-C seem to be important events in ependymoma progression and may represent future targets for therapy. We report, to our knowledge for the first time, recurrent oncogenic mutations in pediatric posterior fossa ependymomas.
Genomic Strategy for Targeting Therapy in Castration-Resistant Prostate Cancer
Authors: Mendiratta Prateek , Mostaghel Elahe , Guinney Justin , Tewari Alok K. , Porrello Alessandro , Barry William T. , Nelson Peter S. , Febbo Phillip G. 
Published: March 2009

Purpose Despite treatments which lower circulating androgens, advanced prostate cancers often maintain androgen receptor (AR) signaling. The variable response to secondary hormonal manipulations in men with castrate-resistant prostate cancer (CRPC) creates a compelling need for strategies to individualize therapy based on the molecular features of each patient's tumor. Methods A transcription-based AR activity signature was developed from an androgen-sensitive prostate cancer cell (LNCaP) and tested on independent data sets of prostate cancer cell lines and human tumors to assess its precision and accuracy in detecting AR activity. The AR signature was applied to multiple sets of prostate specimens to determine how AR activity changes with hormone therapy and progression and oncogenic pathway analysis was used to identify biologic pathways correlating with AR activity. Results A robust AR signature accurately predicts AR activity in multiple prostate cancer cell lines, has minimal variation between replicate samples, and accurately reflects an individual's hormone status and intraprostatic dihydrotestosterone levels. The AR signature finds AR activity to be high in local, untreated prostate tumors and decreased in prostate tissue after neoadjuvant hormone therapy and in CRPC. Heterogeneity of AR activity exists along the spectrum of prostate cancer progression and decreasing predicted AR activity correlates with increasing predicted Src activity and sensitivity to dasatinib (Src-targeting kinase inhibitor). Conclusion A transcription-based AR signature can detect AR activity within individual prostate cancer specimens and has the potential to help individualize and improve care for patients with CRPC.
Systematic Review and Meta-Analysis of Randomized and Nonrandomized Trials on Safety and Efficacy of Video-Assisted Thoracic Surgery Lobectomy for Early-Stage Non–Small-Cell Lung Cancer
Authors: Yan Tristan D. , Black Deborah , Bannon Paul G. , McCaughan Brian C. 
Published: March 2009

Purpose The current randomized trials comparing video-assisted thoracic surgery (VATS) lobectomy with open lobectomy for patients with early-stage non–small-cell lung cancer (NSCLC) have been of small size. We performed the present meta-analysis of the randomized and nonrandomized comparative studies in an attempt to assess the safety and efficacy of VATS lobectomy. Methods Electronic searches identified 21 eligible comparative studies (two randomized and 19 nonrandomized) for inclusion. Two reviewers independently appraised each study. Meta-analysis was performed by combining the results of reported incidence of morbidity and mortality, recurrence, and 5-year mortality rates. The relative risk (RR) was used as a summary statistic. Results There were no significant statistical differences between VATS and open lobectomy in terms of postoperative prolonged air leak (P = .71), arrhythmia (P = .86), pneumonia (P = .09), and mortality (P = .49). VATS did not demonstrate any significant difference in locoregional recurrence (P = .24), as compared with the open lobectomy arm, but the data suggested a reduced systemic recurrence rate (P = .03) and an improved 5-year mortality rate of VATS (P = .04). There was no evidence to suggest heterogeneity of trial results. Fourteen studies reported VATS to open lobectomy conversion rate ranging from 0% to 15.7% (median = 8.1%). Conclusion Both randomized and nonrandomized trials suggest that VATS lobectomy is an appropriate procedure for selected patients with early-stage NSCLC when compared with open surgery.
Phase II Study of Picoplatin As Second-Line Therapy for Patients With Small-Cell Lung Cancer
Authors: Eckardt John R. , Bentsion Dimitri L. , Lipatov Oleg N. , Polyakov Igor S. , MacKintosh Frederick R. , Karlin David A. , Baker Gizelle S. , Breitz Hazel B. 
Published: March 2009

Purpose This study was designed to confirm the efficacy and safety of picoplatin, a cisplatin analog designed to overcome platinum resistance, in patients with small-cell lung cancer (SCLC) with platinum-refractory/-resistant disease. Patients and Methods All patients received intravenous picoplatin 150 mg/m2 every 3 weeks. Tumor response, progression-free survival, and overall survival were evaluated. Adverse events were assessed for frequency, severity, and relationship to treatment. Quality of life was assessed with the Lung Cancer Symptom Scale instrument. Results Seventy-seven patients were treated with picoplatin (median number of cycles, two; range one to 10). Three patients (4%) had a partial response, 33 (43%) had stable disease (four of these were unconfirmed partial responses), 36 (47%) had progressive disease, and five were not assessable for response. Median progression-free survival was 9.1 weeks (95% CI, 7.0 to 12.1 weeks). Median overall survival was 26.9 weeks (95% CI, 21.1 to 33.4). The most common grade 3 and 4 toxicities were thrombocytopenia (48%), neutropenia (25%), and anemia (20%). The most commonly reported adverse events of any severity included thrombocytopenia (64%), anemia (49%), neutropenia (39%), nausea (27%), fatigue (16%), and dyspnea (16%). No severe neurotoxicity or nephrotoxicity were observed. There were no treatment-related deaths. Conclusion Picoplatin demonstrated clinical efficacy in platinum-refractory SCLC. The major toxicity was hematologic. These results warrant further evaluation in this patient population.
Trastuzumab Beyond Progression in Human Epidermal Growth Factor Receptor 2–Positive Advanced Breast Cancer: A German Breast Group 26/Breast International Group 03-05 Study
Authors: von Minckwitz Gunter , du Bois Andreas , Schmidt Marcus , Maass Nicolai , Cufer Tanja , de Jongh Felix E. , Maartense Eduard , Zielinski Christoph , Kaufmann Manfred , Bauer Wolfgang , Baumann Klaus H. , Clemens Michael R. , Duerr Ralph , Uleer Christoph , Andersson Michael , Stein Robert C. , Nekljudova Valentina , Loibl Sibylle 
Published: March 2009

Purpose Trastuzumab shows clinical activity in human epidermal growth factor receptor 2 (HER-2)–positive early and advanced breast cancer. In the German Breast Group 26/Breast International Group 03-05 trial, we investigated if trastuzumab treatment should be continued beyond progression. Methods Patients with HER-2–positive breast cancer that progresses during treatment with trastuzumab were randomly assigned to receive capecitabine (2,500 mg/m2 body-surface area on days 1 through 14 [1,250 mg/m2 semi-daily]) alone or with continuation of trastuzumab (6 mg/kg body weight) in 3-week cycles. The primary end point was time to progression. Results We randomly assigned 78 patients to capecitabine and 78 patients to capecitabine plus trastuzumab. Sixty-five events and 38 deaths in the capecitabine group and 62 events and 33 deaths in the capecitabine-plus-trastuzumab group occurred during 15.6 months of follow-up. Median times to progression were 5.6 months in the capecitabine group and 8.2 months in the capecitabine-plus-trastuzumab group with an unadjusted hazard ratio of 0.69 (95% CI, 0.48 to 0.97; two-sided log-rank P = .0338). Overall survival rates were 20.4 months (95% CI, 17.8 to 24.7) in the capecitabine group and 25.5 months (95% CI, 19.0 to 30.7) in the capecitabine-plus-trastuzumab group (P = .257). Overall response rates were 27.0% with capecitabine and 48.1% with capecitabine plus trastuzumab (odds ratio, 2.50; P = .0115). Continuation of trastuzumab beyond progression was not associated with increased toxicity. Conclusion Continuation of trastuzumab plus capecitabine showed a significant improvement in overall response and time to progression compared with capecitabine alone in women with HER-2–positive breast cancer who experienced progression during trastuzumab treatment.
Baseline C-Reactive Protein Is Associated With Incident Cancer and Survival in Patients With Cancer
Authors: Allin Kristine H. , Bojesen Stig E. , Nordestgaard Børge G. 
Published: March 2009

Purpose We tested the hypothesis that baseline plasma levels of C-reactive protein (CRP) are associated with risk of incident cancer in the general population and early death in patients with cancer. Patients and Methods A total of 10,408 individuals from the Danish general population who had CRP measured at baseline were observed for up to 16 years; 1,624 developed cancer, and of these, 998 patients died during follow-up. Follow-up was 100% complete. We excluded individuals with a cancer diagnosis at baseline. Results Baseline CRP levels more than 3 versus less than 1 mg/L were associated with multifactorially adjusted hazard ratios of 1.3 (95% CI, 1.0 to 1.6) for cancer of any type, 2.2 (95% CI, 1.0 to 4.6) for lung cancer, 1.9 (95% CI, 0.8 to 4.6) for colorectal cancer, and 0.7 (95% CI, 0.4 to 1.4) for breast cancer. Corresponding hazard ratios for the highest versus the lowest quintile of baseline CRP levels were 1.3 (95% CI, 1.0 to 1.6), 2.1 (95% CI, 1.2 to 3.8), 1.7 (95% CI, 0.8 to 3.2), and 0.9 (95% CI, 0.5 to 1.7), respectively. Multifactorially adjusted hazard ratios for early death in patients with cancer were 1.8 (95% CI, 1.2 to 2.7) for CRP more than 3 versus less than 1 mg/L and 1.4 (95% CI, 1.1 to 1.7) for the highest versus the lowest quintile. Elevated CRP levels were associated with early death in patients with cancer having localized disease, but not in those with metastases (interaction; P = .03). Conclusion Elevated levels of CRP in cancer-free individuals are associated with increased risk of cancer of any type, of lung cancer, and possibly of colorectal cancer. Moreover, elevated levels of baseline CRP associate with early death after a diagnosis of any cancer, particularly in patients without metastases.
Predictors of Postoperative Quality of Life After Esophagectomy for Cancer
Authors: Djärv Therese , Blazeby Jane M. , Lagergren Pernilla 
Published: March 2009

Purpose To identify factors predictive of health-related quality of life (HRQL) 6 months after surgery for esophageal cancer. Patients and Methods A Swedish nationwide population-based study of patients undergoing esophagectomy for cancer was undertaken between 2001 and 2005. Clinical details (sex, age, body mass index [BMI], comorbidity) and tumor details (histology, stage, and location) were prospectively recorded and validated. HRQL questionnaires (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaires C30 and OES18) were used to assess HRQL 6 months postoperatively. HRQL outcome was categorized as good or poor by collapsing the four response categories. Logistic regression models adjusting for potential confounding factors were used to assess the association between preoperative patient and tumor characteristics and HRQL outcome 6 months after surgery. Results A total of 355 patients (77% of eligible) responded to the HRQL questionnaires. Age, sex, and BMI showed no associations with HRQL 6 months after surgery, but patients with comorbidity, a more advanced tumor stage (III to IV), or a tumor located in the middle or upper esophagus had an increased risk of poor HRQL. Patients with adenocarcinoma had a lower risk of poor HRQL than patients with squamous cell carcinoma. Conclusion Knowledge of risk factors for poor postoperative HRQL may be relevant for clinical decision making. More research to see whether these factors are further predictive of poor HRQL in long-term survivors is needed.