bluuebunny/crossref_metadata_2025_split huggingface dataset:
Expression of Late Cell Cycle Genes and an Increased Proliferative Capacity Characterize Very Early Relapse of Childhood Acute Lymphoblastic Leukemia
Authors: Kirschner-Schwabe Renate , Lottaz Claudio , Tödling Jörn , Rhein Peter , Karawajew Leonid , Eckert Cornelia , von Stackelberg Arend , Ungethüm Ute , Kostka Dennis , Kulozik Andreas E. , Ludwig Wolf-Dieter , Henze Günter , Spang Rainer , Hagemeier Christian , Seeger Karl 
Published: August 2006

AbstractPurpose: In childhood acute lymphoblastic leukemia (ALL), ∼25% of patients suffer from relapse. In recurrent disease, despite intensified therapy, overall cure rates of 40% remain unsatisfactory and survival rates are particularly poor in certain subgroups. The probability of long-term survival after relapse is predicted from well-established prognostic factors (i.e., time and site of relapse, immunophenotype, and minimal residual disease). However, the underlying biological determinants of these prognostic factors remain poorly understood.Experimental Design: Aiming at identifying molecular pathways associated with these clinically well-defined prognostic factors, we did gene expression profiling on 60 prospectively collected samples of first relapse patients enrolled on the relapse trial ALL-REZ BFM 2002 of the Berlin-Frankfurt-Münster study group.Results: We show here that patients with very early relapse of ALL are characterized by a distinctive gene expression pattern. We identified a set of 83 genes differentially expressed in very early relapsed ALL compared with late relapsed disease. The vast majority of genes were up-regulated and many were late cell cycle genes with a function in mitosis. In addition, samples from patients with very early relapse showed a significant increase in the percentage of S and G2-M phase cells and this correlated well with the expression level of cell cycle genes.Conclusions: Very early relapse of ALL is characterized by an increased proliferative capacity of leukemic blasts and up-regulated mitotic genes. The latter suggests that novel drugs, targeting late cell cycle proteins, might be beneficial for these patients that typically face a dismal prognosis.
Predicting Cancer Drug Response by Proteomic Profiling
Authors: Ma Yan , Ding Zhenyu , Qian Yong , Shi Xianglin , Castranova Vince , Harner E. James , Guo Lan 
Published: August 2006

Abstract
Purpose: Accurate prediction of an individual patient's drug response is an important prerequisite of personalized medicine. Recent pharmacogenomics research in chemosensitivity prediction has studied the gene-drug correlation based on transcriptional profiling. However, proteomic profiling will more directly solve the current functional and pharmacologic problems. We sought to determine whether proteomic signatures of untreated cells were sufficient for the prediction of drug response.
Experimental Design: In this study, a machine learning model system was developed to classify cell line chemosensitivity exclusively based on proteomic profiling. Using reverse-phase protein lysate microarrays, protein expression levels were measured by 52 antibodies in a panel of 60 human cancer cell (NCI-60) lines. The model system combined several well-known algorithms, including random forests, Relief, and the nearest neighbor methods, to construct the protein expression–based chemosensitivity classifiers. The classifiers were designed to be independent of the tissue origin of the cells.
Results: A total of 118 classifiers of the complete range of drug responses (sensitive, intermediate, and resistant) were generated for the evaluated anticancer drugs, one for each agent. The accuracy of chemosensitivity prediction of all the evaluated 118 agents was significantly higher (P &lt; 0.02) than that of random prediction. Furthermore, our study found that the proteomic determinants for chemosensitivity of 5-fluorouracil were also potential diagnostic markers of colon cancer.
Conclusions: The results showed that it was feasible to accurately predict chemosensitivity by proteomic approaches. This study provides a basis for the prediction of drug response based on protein markers in the untreated tumors.
A Phase I Study of Intravenous LBH589, a Novel Cinnamic Hydroxamic Acid Analogue Histone Deacetylase Inhibitor, in Patients with Refractory Hematologic Malignancies
Authors: Giles Francis , Fischer Thomas , Cortes Jorge , Garcia-Manero Guillermo , Beck Joachim , Ravandi Farhad , Masson Eric , Rae Patricia , Laird Glen , Sharma Sunil , Kantarjian Hagop , Dugan Margaret , Albitar Maher , Bhalla Kapil 
Published: August 2006

Abstract
Purpose: LBH589 is a novel histone deacetylase inhibitor that inhibits proliferation and induces apoptosis in tumor cell lines. In this phase I study, LBH589 was administered i.v. as a 30-minute infusion on days 1 to 7 of a 21-day cycle.
Experimental Design: Fifteen patients (median age, 63 years; range, 42-87 years) with acute myeloid leukemia (13 patients), acute lymphocytic leukemia (1 patient), or myelodysplastic syndrome (1 patient) were treated with LBH589 at the following dose levels (mg/m2): 4.8 (3 patients), 7.2 (3 patients), 9.0 (1 patient), 11.5 (3 patient), and 14.0 (5 patients). The levels of histone acetylation were measured using quantitative flow cytometry and plasma LBH589 concentrations were assayed.
Results: Four dose-limiting toxicities (grade 3 QTcF prolongation) were observed, four at 14.0 mg/m2 and one at 11.5 mg/m2. QTcF prolongation was asymptomatic and reversed on LBH589 discontinuation. Other potentially LBH589-related toxicities included nausea (40%), diarrhea (33%), vomiting (33%), hypokalemia (27%), loss of appetite (13%), and thrombocytopenia (13%). In 8 of 11 patients with peripheral blasts, transient reductions occurred with a rebound following the 7-day treatment period. H3 acetylation increase was significant in B-cells (CD19+; P = 0.02) and blasts (CD34+; P = 0.04). The increase in H2B acetylation was highest in CD19+ and CD34+ cells [3.8-fold (P = 0.01) and 4.4-fold (P = 0.03), respectively]. The median acetylation of histones H2B and H3 in CD34+ and CD19+ cells significantly increased on therapy as did apoptosis in CD14+ cells. Area under the curve increased proportionally with dose with a terminal half-life of ∼11 hours.
Conclusion: Intravenous administration of LBH589 was well tolerated at doses &lt;11.5 mg/m2 with consistent transient antileukemic and biological effects.
Minicircle-IFNγ Induces Antiproliferative and Antitumoral Effects in Human Nasopharyngeal Carcinoma
Authors: Wu Jiangxue , Xiao Xia , Zhao Peng , Xue Gang , Zhu Yinghui , Zhu Xiaofeng , Zheng Limin , Zeng Yixin , Huang Wenlin 
Published: August 2006

Abstract
Purpose: The aims of this work were to investigate the antitumor effect of IFNγ gene transfer on human nasopharyngeal carcinoma (NPC) and to assess the potential of minicircle vector for antitumor gene therapy.
Experimental Design: We developed a recombinant minicircle vector carrying the human IFNγ gene and evaluated the effects of minicircle-mediated IFNγ gene transfer on NPC cell lines in vitro and on xenografts in vivo.
Results: Relative to p2ΦC31-IFNγ, minicircle-mediated IFNγ gene transfer in vitro resulted in 19- to 102-fold greater IFNγ expression levels in transfected cells (293, NIH 3T3, CNE-1, CNE-2, and C666-1) and inhibited the growth of CNE-1, CNE-2, and C666-1 cells more efficiently, reducing relative growth rates to 7.1 ± 1.6%, 2.7 ± 1.0%, and 6.1 ± 1.6%, respectively. Flow cytometry and caspase-3 activity assays suggested that the antiproliferative effects of IFNγ gene transfer on NPC cell lines could be attributed to G0-G1 arrest and apoptosis. Minicircle-mediated intratumoral IFNγ expression in vivo was 11 to 14 times higher than p2ΦC31-IFNγ in CNE-2- and C666-1-xenografted mice and lasted for 21 days. Compared with p2ΦC31-IFNγ treatment, minicircle-IFNγ treatment significantly increased survival and achieved inhibition rates of 77.5% and 83%, respectively.
Conclusions: Our data indicate that IFNγ gene transfer exerts antiproliferative effects on NPC cells in vitro and leads to a profound antitumor effect in vivo. Minicircle-IFNγ is more efficient than corresponding conventional plasmids due to its capability of mediating long-lasting high levels of IFNγ gene expression. Therefore, minicircle-mediated IFNγ gene transfer is a promising novel approach in the treatment of NPC.
Temozolomide-Mediated Radiation Enhancement in Glioblastoma: A Report on Underlying Mechanisms
Authors: Chakravarti Arnab , Erkkinen Michael G. , Nestler Ulf , Stupp Roger , Mehta Minesh , Aldape Ken , Gilbert Mark R. , Black Peter McL. , Loeffler Jay S. 
Published: August 2006

Abstract
Purpose: In this study, we investigated the mechanisms by which temozolomide enhances radiation response in glioblastoma cells.
Experimental Design: Using a panel of four primary human glioblastoma cell lines with heterogeneous O6-methylguanine-DNA methyltransferase (MGMT) protein expression, normal human astrocytes, and U87 xenografts, we investigated (a) the relationship of MGMT status with efficacy of temozolomide-based chemoradiation using a panel of in vitro and in vivo assays; (b) underlying mechanisms by which temozolomide enhances radiation effect in glioblastoma cells; and (c) strategies to overcome resistance to radiation + temozolomide.
Results: Temozolomide enhances radiation response most effectively in glioblastomas without detectable MGMT expression. On concurrent radiation + temozolomide administration in MGMT-negative glioblastomas, there seems to be decreased double-strand DNA (dsDNA) repair capacity and enhanced dsDNA damage compared either with radiation alone or with sequentially administered temozolomide. Our data suggest that O6-benzylguanine can enhance the antitumor effects of concurrent radiation + temozolomide in MGMT-positive cells by enhancing apoptosis and the degree of dsDNA damage. O6-Benzylguanine was most effective when administered concurrently with radiation + temozolomide and had less of an effect when administered with temozolomide in the absence of radiation or when administered sequentially with radiation. Our in vivo data using U87 xenografts confirmed our in vitro findings.
Conclusions: The present study shows that temozolomide enhances radiation response most effectively in MGMT-negative glioblastomas by increasing the degree of radiation-induced double-strand DNA damage. In MGMT-positive glioblastomas, depletion of MGMT by the addition of O6-benzylguanine significantly enhances the antitumor effect of concurrent radiation + temozolomide. These are among the first data showing mechanisms of synergy between radiation and temozolomide and the effect of MGMT.
Statistical Analysis of DNA Microarray Data in Cancer Research
Authors: Fan Jianqing , Ren Yi 
Published: August 2006

Abstract
Microarray techniques have been widely used to monitor gene expression in many areas of biomedical research. They have been widely used for tumor diagnosis and classification, prediction of prognoses and treatment, and understanding of molecular mechanisms, biochemical pathways, and gene networks. Statistical methods are vital for these scientific endeavors. This article reviews recent developments of statistical methods for analyzing data from microarray experiments. Emphasis has been given to normalization of expression from multiple arrays, selecting significantly differentially expressed genes, tumor classifications, and gene expression pathways and networks.
Developmental kinetics, turnover, and stimulatory capacity of thymic epithelial cells
Authors: Gray Daniel H. D. , Seach Natalie , Ueno Tomoo , Milton Morag K. , Liston Adrian , Lew Andrew M. , Goodnow Christopher C. , Boyd Richard L. 
Published: August 2006

AbstractDespite the importance of thymic stromal cells to T-cell development, relatively little is known about their biology. Here, we use single-cell analysis of stromal cells to analyze extensive changes in the number and composition of thymic stroma throughout life, revealing a surprisingly dynamic population. Phenotypic progression of thymic epithelial subsets was assessed at high resolution in young mice to provide a developmental framework. The cellular and molecular requirements of adult epithelium were studied, using various mutant mice to demonstrate new cross talk checkpoints dependent on RelB in the cortex and CD40 in the medulla. With the use of Ki67 and BrdU labeling, the turnover of thymic epithelium was found to be rapid, but then diminished on thymic involution. The various defects in stromal turnover and composition that accompanied involution were rapidly reversed following sex steroid ablation. Unexpectedly, mature cortical and medullary epithelium showed a potent capacity to stimulate naive T cells, comparable to that of thymic dendritic cells. Overall, these studies show that the thymic stroma is a surprisingly dynamic population and may have a more direct role in negative selection than previously thought.
Receptor-type protein tyrosine phosphatase gamma (PTPγ), a new identifier for myeloid dendritic cells and specialized macrophages
Authors: Lissandrini Daniele , Vermi William , Vezzalini Marzia , Sozzani Silvano , Facchetti Fabio , Bellone Graziella , Mafficini Andrea , Gentili Francesca , Ennas Maria Grazia , Tecchio Cristina , Sorio Claudio 
Published: August 2006

AbstractProtein tyrosine phosphatase (PTPγ) is a receptor-like molecule with a known role in murine hematopoiesis. We analyzed the regulation of PTPγ expression in the human hematopoietic system, where it was detected in human peripheral blood monocytes and dendritic cells (DCs) of myeloid and plasmacytoid phenotypes. Its expression was maintained during in vitro monocyte differentiation to dendritic cells (moDC) and was further increased after maturation with bacterial lipopolysaccharide (LPS), CD40L, and TNFα. But PTPγ was absent when monocytes from the same donor were induced to differentiate in macrophages. B and T lymphocytes did not express PTPγ. Rather, PTPγ mRNA was expressed in primary and secondary lymphoid tissues, and the highest expression was in the spleen. PTPγ was detected by immunohistochemistry in subsets of myeloid-derived DCs and specialized macrophages (tingible bodies, sinus and alveolar macrophages). Classic macrophages in infective or reactive granulomatous reactions did not express PTPγ. Increased PTPγ expression was associated with a decreased ability to induce proliferation and interferon-γ secretion in T cells by moDCs from patients with advanced pancreatic cancer. Taken together, these results indicate that PTPγ is a finely regulated protein in DC and macrophage subsets in vitro and in vivo.
Can volunteer companions prevent falls among inpatients? A feasibility study using a pre-post comparative design
Authors: Giles Lynne C , Bolch Denise , Rouvray Robyn , McErlean Beth , Whitehead Craig H , Phillips Paddy A , Crotty Maria 
Published: August 2006

Abstract

Background
Falls in hospital are frequent and their consequences place an increased burden on health services. We evaluated a falls prevention strategy consisting of the introduction of volunteers to 'sit' with patients identified as being at high risk of falling.

Methods
Two four bed 'safety bays' located on medical wards in two hospitals within southern Adelaide were used. Ward fall rates (expressed as falls per 1000 occupied bed days) were compared in the baseline period (February-May 2002) with the implementation period (February – May 2003) using incident rate ratios and 95% confidence intervals. The number of hours of volunteered time was also collected.

Results
No patient falls occurred on either site when volunteers were present. However, there was no significant impact on overall ward fall rates. In the baseline period, there were 70 falls in 4828 OBDs (14.5 falls per 1000 OBDs). During the implementation period, there were 82 falls in 5300 OBDs (15.5 falls per 1000 OBD). The IRR for falls in the implementation versus baseline period was 1.07 (95%CI 0.77 – 1.49; P = 0.346). Volunteers carried out care activities (e.g. cutting up food), provided company, and on occasions advocated on behalf of the patients. Volunteers donated 2345 hours, at an estimated value to the hospitals of almost $57,000.

Conclusion
Volunteers may play an important and cost-effective role in enhancing health care and can prevent falls in older hospital patients when they are present. Full implementation of this program would require the recruitment of adequate numbers of volunteers willing to sit with all patients considered at risk of falling in hospital. The challenge for future work in this area remains the sustainability of falls prevention strategies.
Down-regulation of c-Myc following MEK/ERK inhibition halts the expression of malignant phenotype in rhabdomyosarcoma and in non muscle-derived human tumors
Authors: Marampon Francesco , Ciccarelli Carmela , Zani Bianca M 
Published: August 2006

Abstract

Background
Expression of c-myc proto-oncogene is inappropriate in a wide range of human tumors, and is a downstream target of Ras/Raf/ERK pathway, which promotes c-Myc stability by enhancing c-Myc expression and activity.
The aim of this study was to investigate whether the oncogenic phenotype in the human muscle-derived Rhabdomyosarcoma (RD) cell line and in non muscle-derived human tumor cell lines (SW403, IGR39 and PC3) can be blocked by disrupting the c-Myc pathway either by means of pharmacological MEK/ERK inhibition or by direct inactivation of the c-Myc protein.

Results
We demonstrate that, in all the tumor cell lines used, the MEK/ERK inhibitor U0126 rapidly induces c-Myc de-phosphorylation, which is followed by a marked reduction in its expression level, by inhibition of proliferation and by reversion of anchorage-independent growth. These data suggest that the targeting of pathways controlling c-Myc expression or stability reverses deregulated growth of different tumor-derived cell lines. Indeed, in RD cells, we found a marked down-regulation of cyclins E2, A and B and CDK2, all of which are known to be targets of c-Myc. Moreover, ectopic MadMyc chimera, a c-Myc function antagonist, causes dramatic growth arrest, CDK and cyclin modulation as well as inhibition of anchorage-independent growth in RD cells, as occurs in U0126-treated cells. In particular, we found that the mere inhibition of c-Myc by MadMyc chimera rescues the myogenic program, MHC expression and the acquisition of the myogenic-like phenotype in RD cells.

Conclusion
Our data provide evidence of the key role played by the MEK/ERK pathway in the growth arrest and transformation phenotype of Rhabdomyosarcoma and of non muscle-derived tumor cell lines. In fact, MEK/ERK inhibitor, U0126, induces growth arrest, anchorage-dependent growth of these cell lines. In addition, the results of this study demonstrate that the direct inactivation of c-Myc by Mad/Myc chimera rescues myogenic program and leads to the reversal of the Rhabdomyosarcoma phenotype. In conclusion these data strongly suggest that the targeting of c-Myc by means of the MEK inhibitor can be tested as a promising strategy in anti-cancer therapy.
Barriers and facilitators to implementing shared decision-making in clinical practice: a systematic review of health professionals' perceptions
Authors: Gravel Karine , Légaré France , Graham Ian D 
Published: August 2006

Abstract

Background
Shared decision-making is advocated because of its potential to improve the quality of the decision-making process for patients and ultimately, patient outcomes. However, current evidence suggests that shared decision-making has not yet been widely adopted by health professionals. Therefore, a systematic review was performed on the barriers and facilitators to implementing shared decision-making in clinical practice as perceived by health professionals.

Methods
Covering the period from 1990 to March 2006, PubMed, Embase, CINHAL, PsycINFO, and Dissertation Abstracts were searched for studies in English or French. The references from included studies also were consulted. Studies were included if they reported on health professionals' perceived barriers and facilitators to implementing shared decision-making in their practices. Shared decision-making was defined as a joint process of decision making between health professionals and patients, or as decision support interventions including decision aids, or as the active participation of patients in decision making. No study design was excluded. Quality of the studies included was assessed independently by two of the authors. Using a pre-established taxonomy of barriers and facilitators to implementing clinical practice guidelines in practice, content analysis was performed.

Results
Thirty-one publications covering 28 unique studies were included. Eleven studies were from the UK, eight from the USA, four from Canada, two from the Netherlands, and one from each of the following countries: France, Mexico, and Australia. Most of the studies used qualitative methods exclusively (18/28). Overall, the vast majority of participants (n = 2784) were physicians (89%). The three most often reported barriers were: time constraints (18/28), lack of applicability due to patient characteristics (12/28), and lack of applicability due to the clinical situation (12/28). The three most often reported facilitators were: provider motivation (15/28), positive impact on the clinical process (11/28), and positive impact on patient outcomes (10/28).

Conclusion
This systematic review reveals that interventions to foster implementation of shared decision-making in clinical practice will need to address a broad range of factors. It also reveals that on this subject there is very little known about any health professionals others than physicians. Future studies about implementation of shared decision-making should target a more diverse group of health professionals.
Effects of 17β-estradiol and flutamide on inflammatory response and distant organ damage following trauma-hemorrhage in metestrus females
Authors: Hildebrand Frank , Hubbard William J , Choudhry Mashkoor A , Thobe Bjoern M , Pape Hans-Christoph , Chaudry Irshad H 
Published: August 2006

Abstract
We hypothesized that administration of androgen receptors antagonist flutamide following trauma-hemorrhage (T-H) in metestrus females will maintain immune function and reduce remote organ damage under those conditions. Female B57BL/J6 mice (metestrus state, 8–12 weeks old) underwent laparotomy and hemorrhagic shock (35.0±5.0 mmHg for 90 min) and then received 17β-estradiol (E2; 50 μg/25 g), flutamide (625 μg/25 g), or E2 + flutamide. Four hours after resuscitation, plasma cytokine and chemokine (TNF-α, IL-6, IL-10, IFN-γ, and MCP-1) concentrations and their release in vitro by hepatic and pulmonary tissue macrophages (MΦ) were determined by flow cytometry. Organ damage was assessed by edema formation (wet-to-dry weight ratio) and neutrophil infiltration [myeloperoxidase (MPO) activity]. Administration of E2, flutamide, or E2 + flutamide following T-H resulted in a significant decrease in systemic TNF-α, IL-6, and MCP-1 concentrations under those conditions. This was accompanied by significantly decreased in vitro TNF-α release by Kupffer cells after administration of E2, flutamide, or E2 + flutamide. The in vitro release of proinflammatory cytokines by alveolar MΦ, however, was reduced significantly only by the addition of E2 or E2 + flutamide but not by the addition of flutamide. A significant decrease in pulmonary and hepatic edema formation as well as neutrophil infiltration in the lung was observed after E2, flutamide and E2 + flutamide administration. In contrast, hepatic neutrophil infiltration was only significantly reduced following E2 and E2 + flutamide administration. Thus, although flutamide does not produce synergistic, salutary effects with E2, its administration in females following T-H also produces salutary effects on the immune and organ function, similar to E2 administration under those conditions.