bluuebunny/crossref_metadata_2025_split huggingface dataset:
RelB-Dependent Differential Radiosensitization Effect of STI571 on Prostate Cancer Cells
Authors: Xu Yong , Fang Fang , Sun Yulan , St. Clair Daret K. , St. Clair William H. 
Published: April 2010

AbstractRadiation therapy is an effective treatment for localized prostate cancer. However, when high-risk factors are present, such as increased prostate-specific antigen, elevated Gleason scores and advanced T stage, undetected spreading of the cancer, and development of radiation-resistant cancer cells are concerns. Thus, additional therapeutic agents that can selectively sensitize advanced prostate cancer to radiation therapy are needed. Imatinib mesylate (Gleevec, STI571), a tyrosine kinase inhibitor, was evaluated for its potential to enhance the efficacy of ionizing radiation (IR) against aggressive prostate cancer cells. STI571 significantly enhances the IR-induced cytotoxicity of androgen-independent prostate cancer cells but not of androgen-responsive prostate cancer cells. The differential cytotoxic effects due to STI571 are associated with the nuclear level of RelB in prostate cancer cells. STI571 inhibits IR-induced RelB nuclear translocation, leading to increased radiosensitivity in aggressive androgen-independent PC-3 and DU-145 cells. In contrast, STI571 enhances RelB nuclear translocation in androgen-responsive LNCaP cells. The different effects of STI571 on RelB nuclear translocation are consistent with RelB DNA binding activity and related target gene expression. STI571 inhibits the phosphoinositide 3-kinase-AKT-IκB kinase-α pathway in PC-3 cells by decreasing the phosphorylation levels of phosphoinositide 3-kinase (Tyr458) and AKT (Ser473), whereas STI571 increases NF-κB inducible kinase (Thr559) phosphorylation, leading to activation of IκB kinase-α in LNCaP cells. These results reveal that STI571 exhibits differential effects on the upstream kinases leading to different downstream effects on the NF-κB alternative pathway in prostate cancer cells and suggest that STI571 is effective for the treatment of androgen-independent prostate cancer in the context of high constitutive levels of RelB. Mol Cancer Ther; 9(4); 803–12. ©2010 AACR.
Vinblastine Induces Acute, Cell Cycle Phase–Independent Apoptosis in Some Leukemias and Lymphomas and Can Induce Acute Apoptosis in Others when Mcl-1 Is Suppressed
Authors: Salerni Bethany L. , Bates Darcy J. , Albershardt Tina C. , Lowrey Christopher H. , Eastman Alan 
Published: April 2010

Abstract
Chemotherapeutic agents modify intracellular signaling that culminates in the inhibition of Bcl-2 family members and initiates apoptosis. Inhibition of the extracellular signal-regulated kinase by PD98059 dramatically accelerates vinblastine-mediated apoptosis in ML-1 leukemia with cells dying in 4 hours from all phases of the cell cycle. Inhibition of protein synthesis by cycloheximide also markedly accelerated vinblastine-induced apoptosis, showing that the proteins required for this acute apoptosis are constitutively expressed. Vinblastine induced the rapid induction of Mcl-1 that was inhibited by PD98059 and cycloheximide. No change in Bcl-2 or Bcl-X was observed. We hypothesize that ML-1 cells use Mcl-1 for protection from the rapid vinblastine-induced apoptosis. This was confirmed by targeting Mcl-1 with short hairpin RNA. We also investigated the response of 13 other leukemia and lymphoma cell lines and cells from seven chronic lymphocytic leukemia patients. Four cell lines and all chronic lymphocytic leukemia cells were killed in 6 hours by vinblastine alone. Two additional cell lines were sensitized to vinblastine by PD98059, which suppressed Mcl-1. This acute apoptosis either alone or in combination with PD98059 required vinblastine-mediated activation of c-Jun-NH2-terminal kinase. PD98059 did not suppress Mcl-1 in other cell lines whereas sorafenib did, but this did not sensitize the cells to vinblastine, suggesting that the acute apoptosis varies depending on which Bcl-2 protein mediates protection. Most of the cell lines were sensitized to vinblastine by cycloheximide, suggesting that inhibition of a short-lived protein in addition to Mcl-1 can acutely sensitize cells. These results suggest several clinical strategies that might provide an effective therapy for selected patients. Mol Cancer Ther; 9(4); 791–802. ©2010 AACR.
Love in a Confucian Climate: The Perils of Intimacy in Eighteenth-Century China
Authors: Theiss Janet 
Published: April 2010

AbstractThis article explores what an eighteenth-century case of adultery in an elite family tells us about the status of Confucian marriage and challenges to it in the mid-Qing. The case illustrates the problematic nature of conjugal love in this period, which puts emotions in conflict with ritual propriety, the marital relationship in conflict with the interests of the patriline, and subjective desires in conflict with social duties. The case also offers insights into the emotional world of the period, providing intimate details of the emotional texture of three interwoven marital or quasi-marital relationships. Each represents a deviation from the ideal of Confucian marriage and presents a different configuration of self, sentiment and ritual propriety. Together they offer a rich picture of the intimate realm of family life and the forces that worked to destabilize it.
Age-related molecular genetic changes of murine bone marrow mesenchymal stem cells
Authors: Wilson Amber , Shehadeh Lina A , Yu Hong , Webster Keith A 
Published: April 2010

Abstract

Background
Mesenchymal stem cells (MSC) are pluripotent cells, present in the bone marrow and other tissues that can differentiate into cells of all germ layers and may be involved in tissue maintenance and repair in adult organisms. Because of their plasticity and accessibility these cells are also prime candidates for regenerative medicine. The contribution of stem cell aging to organismal aging is under debate and one theory is that reparative processes deteriorate as a consequence of stem cell aging and/or decrease in number. Age has been linked with changes in osteogenic and adipogenic potential of MSCs.

Results
Here we report on changes in global gene expression of cultured MSCs isolated from the bone marrow of mice at ages 2, 8, and 26-months. Microarray analyses revealed significant changes in the expression of more than 8000 genes with stage-specific changes of multiple differentiation, cell cycle and growth factor genes. Key markers of adipogenesis including lipoprotein lipase, FABP4, and Itm2a displayed age-dependent declines. Expression of the master cell cycle regulators p53 and p21 and growth factors HGF and VEGF also declined significantly at 26 months. These changes were evident despite multiple cell divisions in vitro after bone marrow isolation.

Conclusions
The results suggest that MSCs are subject to molecular genetic changes during aging that are conserved during passage in culture. These changes may affect the physiological functions and the potential of autologous MSCs for stem cell therapy.
Evaluation design of a systematic, selective, internet-based, Chlamydiascreening implementation in the Netherlands, 2008-2010: implications of first results for the analysis
Authors: van den Broek Ingrid VF , Hoebe Christian JPA , van Bergen Jan EAM , Brouwers Elfi EHG , de Feijter Eva M , Fennema Johannes SA , Götz Hannelore M , Koekenbier Rik H , van Ravesteijn Sander M , Op de Coul Eline LM 
Published: April 2010

Abstract

Background
A selective, systematic, Internet-based, Chlamydia Screening Implementation for 16 to 29-year-old residents started in three regions in the Netherlands in April 2008: in the cities of Amsterdam and Rotterdam and a more rural region, South Limburg. This paper describes the evaluation design and discusses the implications of the findings from the first screening round for the analysis. The evaluation aims to determine the effects of screening on the population prevalence of Chlamydia trachomatis after multiple screening rounds.

Methods
A phased implementation or 'stepped wedge design' was applied by grouping neighbourhoods (hereafter: clusters) into three random, risk-stratified blocks (A, B and C) to allow for impact analyses over time and comparison of prevalences before and after one or two screening rounds. Repeated simulation of pre- and postscreening Chlamydia prevalences was used to predict the minimum detectable decline in prevalence. Real participation and positivity rates per region, block, and risk stratum (high, medium, and low community risk) from the 1st year of screening were used to substantiate predictions.

Results
The results of the 1st year show an overall participation rate of 16% of 261,025 invitees and a positivity rate of 4.2%, with significant differences between regions and blocks. Prediction by simulation methods adjusted with the first-round results indicate that the effect of screening (minimal detectable difference in prevalence) may reach significance levels only if at least a 15% decrease in the Chlamydia positivity rate in the cities and a 25% decrease in the rural region after screening can be reached, and pre- and postscreening differences between blocks need to be larger.

Conclusions
With the current participation rates, the minimal detectable decline of Chlamydia prevalence may reach our defined significance levels at the regional level after the second screening round, but will probably not be significant between blocks of the stepped wedge design. Evaluation will also include other aspects and prediction models to obtain rational advice about future Chlamydia screening in the Netherlands.
STAMP alters the growth of transformed and ovarian cancer cells
Authors: He Yuanzheng , Blackford John A , Kohn Elise C , Simons S Stoney 
Published: April 2010

Abstract

Background
Steroid receptors play major roles in the development, differentiation, and homeostasis of normal and malignant tissue. STAMP is a novel coregulator that not only enhances the ability of p160 coactivator family members TIF2 and SRC-1 to increase gene induction by many of the classical steroid receptors but also modulates the potency (or EC50) of agonists and the partial agonist activity of antisteroids. These modulatory activities of STAMP are not limited to gene induction but are also observed for receptor-mediated gene repression. However, a physiological role for STAMP remains unclear.

Methods
The growth rate of HEK293 cells stably transfected with STAMP plasmid and overexpressing STAMP protein is found to be decreased. We therefore asked whether different STAMP levels might also contribute to the abnormal growth rates of cancer cells. Panels of different stage human cancers were screened for altered levels of STAMP mRNA. Those cancers with the greatest apparent changes in STAMP mRNA were pursued in cultured cancer cell lines.

Results
Higher levels of STAMP are shown to have the physiologically relevant function of reducing the growth of HEK293 cells but, unexpectedly, in a steroid-independent manner. STAMP expression was examined in eight human cancer panels. More extensive studies of ovarian cancers suggested the presence of higher levels of STAMP mRNA. Lowering STAMP mRNA levels with siRNAs alters the proliferation of several ovarian cancer tissue culture lines in a cell line-specific manner. This cell line-specific effect of STAMP is not unique and is also seen for the conventional effects of STAMP on glucocorticoid receptor-regulated gene transactivation.

Conclusions
This study indicates that a physiological function of STAMP in several settings is to modify cell growth rates in a manner that can be independent of steroid hormones. Studies with eleven tissue culture cell lines of ovarian cancer revealed a cell line-dependent effect of reduced STAMP mRNA on cell growth rates. This cell-line dependency is also seen for STAMP effects on glucocorticoid receptor-mediated transactivation. These preliminary findings suggest that further studies of STAMP in ovarian cancer may yield insight into ovarian cancer proliferation and may be useful in the development of biomarker panels.
Growth delay of human bladder cancer cells by Prostate Stem Cell Antigen downregulation is associated with activation of immune signaling pathways
Authors: Marra Emanuele , Uva Paolo , Viti Valentina , Simonelli Valeria , Dogliotti Eugenia , De Rinaldis Emanuele , Lahm Armin , La Monica Nicola , Nicosia Alfredo , Ciliberto Gennaro , Palombo Fabio 
Published: April 2010

Abstract

Background
Prostate stem cell antigen (PSCA) is a glycosylphosphatidylinositol (GPI) anchored protein expressed not only in prostate but also in pancreas and bladder cancer as shown by immunohistochemistry and mRNA analysis. It has been targeted by monoclonal antibodies in preclinical animal models and more recently in a clinical trial in prostate cancer patients. The biological role played in tumor growth is presently unknown. In this report we have characterized the contribution of PSCA expression to tumor growth.

Methods
A bladder cell line was engineered to express a doxycycline (dox) regulated shRNA against PSCA. To shed light on the PSCA biological role in tumor growth, microarray analysis was carried out as a function of PSCA expression. Expression of gene set of interest was further analyzed by qPCR

Results
Down regulation of the PSCA expression was associated with reduced cell proliferation in vitro and in vivo. Mice bearing subcutaneous tumors showed a reduced tumor growth upon treatment with dox, which effectively induced shRNA against PSCA as revealed by GFP expression. Pathway analysis of deregulated genes suggests a statistical significant association between PSCA downregulation and activation of genes downstream of the IFNα/β receptor.

Conclusions
These experiments established for the first time a correlation between the level of PSCA expression and tumor growth and suggest a role of PSCA in counteracting the natural immune response.
The lethal giant larvaetumour suppressor mutation requires dMyc oncoprotein to promote clonal malignancy
Authors: Froldi Francesca , Ziosi Marcello , Garoia Flavio , Pession Andrea , Grzeschik Nicola A , Bellosta Paola , Strand Dennis , Richardson Helena E , Pession Annalisa , Grifoni Daniela 
Published: April 2010

Abstract

Background
Neoplastic overgrowth depends on the cooperation of several mutations ultimately leading to major rearrangements in cellular behaviour. Precancerous cells are often removed by cell death from normal tissues in the early steps of the tumourigenic process, but the molecules responsible for such a fundamental safeguard process remain in part elusive. With the aim to investigate the molecular crosstalk occurring between precancerous and normal cells in vivo, we took advantage of the clonal analysis methods that are available in Drosophila for studying the phenotypes due to lethal giant larvae (lgl) neoplastic mutation induced in different backgrounds and tissues.

Results
We observed that lgl mutant cells growing in wild-type imaginal wing discs show poor viability and are eliminated by Jun N-terminal Kinase (JNK)-dependent cell death. Furthermore, they express very low levels of dMyc oncoprotein compared with those found in the surrounding normal tissue. Evidence that this is a cause of lgl mutant cells elimination was obtained by increasing dMyc levels in lgl mutant clones: their overgrowth potential was indeed re-established, with mutant cells overwhelming the neighbouring tissue and forming tumourous masses displaying several cancer hallmarks. Moreover, when lgl mutant clones were induced in backgrounds of slow-dividing cells, they upregulated dMyc, lost apical-basal cell polarity and were able to overgrow. Those phenotypes were abolished by reducing dMyc levels in the mutant clones, thereby confirming its key role in lgl-induced tumourigenesis. Furthermore, we show that the eiger-dependent Intrinsic Tumour Suppressor pathway plays only a minor role in eliminating lgl mutant cells in the wing pouch; lgl
-/- clonal death in this region is instead driven mainly by dMyc-induced Cell Competition.

Conclusions
Our results provide the first evidence that dMyc oncoprotein is required in lgl tumour suppressor mutant tissue to promote invasive overgrowth in larval and adult epithelial tissues. Moreover, we show that dMyc abundance inside versus outside the mutant clones plays a key role in driving neoplastic overgrowth.
Gait changes precede overt arthritis and strongly correlate with symptoms and histopathological events in pristane-induced arthritis
Authors: Hoffmann Markus H , Hopf Rudolf , Niederreiter Birgit , Redl Heinz , Smolen Josef S , Steiner Günter 
Published: April 2010

Abstract
Introduction
Pristane-induced arthritis (PIA) in the rat has been described as an animal model of inflammatory arthritis which exhibits features similar to rheumatoid arthritis in humans, such as a chronic, destructive, and symmetrical involvement of peripheral joints. However, so far little is known about the earliest inflammatory events and their influence on locomotor behaviour during the course of PIA. To investigate this issue a detailed analysis of the pathologic changes occurring during the prodromal and early stages of PIA was performed.

Methods
Arthritis was induced in DA.rats by injection of 150 μl 2,6,10,4-tetramethyl-pentadecane (pristane) at the base of the tail and changes in locomotor behaviour of the affected paws were monitored using the CatWalk quantitative gait analysis system. The pathologic events occurring in the joints of pristane-injected animals were studied before onset, at onset, and during acute phase of arthritis by histological methods.

Results
Gait analysis revealed that changes in locomotion such as reduced paw print areas and stance phase time are already apparent before the onset of clinically discernible arthritis symptoms (erythema, paw swelling) and correlate with PIA scores. In agreement with these findings, inflammatory tenosynovitis could be observed by histology already before the onset of erythema and swelling of the respective paws. In the most heavily affected rats also irregularities in step sequence patterns occurred A kinetic analysis of clinical and histological findings demonstrated that gait changes precede the pathological changes occurring during the acute phase of pristane-induced arthritis.

Conclusions
Gait analysis allows for pinpointing the initial inflammatory changes in experimental arthritis models such as pristane-induced arthritis. Analysis of early clinically relevant symptoms in arthritis models may facilitate the search for novel therapeutics to interfere with pain, inflammation and joint destruction in patients suffering from inflammatory arthritis.
The urate-lowering efficacy and safety of febuxostat in the treatment of the hyperuricemia of gout: the CONFIRMS trial
Authors: Becker Michael A , Schumacher H Ralph , Espinoza Luis R , Wells Alvin F , MacDonald Patricia , Lloyd Eric , Lademacher Christopher 
Published: April 2010

Abstract
Introduction
The purpose of this study was to compare urate-lowering (UL) efficacy and safety of daily febuxostat and allopurinol in subjects with gout and serum urate (sUA) ≥ 8.0 mg/dL in a six-month trial.

Methods
Subjects (n = 2,269) were randomized to febuxostat 40 mg or 80 mg, or allopurinol 300 mg (200 mg in moderate renal impairment). Endpoints included the proportion of all subjects with sUA <6.0 mg/dL and the proportion of subjects with mild/moderate renal impairment and sUA <6.0 mg/dL. Safety assessments included blinded adjudication of each cardiovascular (CV) adverse event (AE) and death.

Results
Comorbidities included: renal impairment (65%); obesity (64%); hyperlipidemia (42%); and hypertension (53%). In febuxostat 40 mg, febuxostat 80 mg, and allopurinol groups, primary endpoint was achieved in 45%, 67%, and 42%, respectively. Febuxostat 40 mg UL was statistically non-inferior to allopurinol, but febuxostat 80 mg was superior to both (P < 0.001). Achievement of target sUA in subjects with renal impairment was also superior with febuxostat 80 mg (72%; P < 0.001) compared with febuxostat 40 mg (50%) or allopurinol (42%), but febuxostat 40 mg showed greater efficacy than allopurinol (P = 0.021). Rates of AEs did not differ across treatment groups. Adjudicated (APTC) CV event rates were 0.0% for febuxostat 40 mg and 0.4% for both febuxostat 80 mg and allopurinol. One death occurred in each febuxostat group and three in the allopurinol group.

Conclusions
Urate-lowering efficacy of febuxostat 80 mg exceeded that of febuxostat 40 mg and allopurinol (300/200 mg), which were comparable. In subjects with mild/moderate renal impairment, both febuxostat doses were more efficacious than allopurinol and equally safe. At the doses tested, safety of febuxostat and allopurinol was comparable.

Clinical Trial Registration
NCT00430248
Drotrecogin alfa (activated) may attenuate severe sepsis-associated encephalopathy in clinical septic shock
Authors: Spapen Herbert , Nguyen Duc Nam , Troubleyn Joris , Huyghens Luc , Schiettecatte Johan 
Published: April 2010

Abstract
Introduction
Sepsis-associated encephalopathy (SAE) is a diffuse cerebral dysfunction induced by the immuno-inflammatory response to infection. Elevated levels of the brain-specific S100B protein are present in many septic patients and reflect the severity of SAE. Adjunctive treatment with drotrecogin alfa (activated) (DrotAA), the human recombinant form of activated protein C, has been shown to improve mortality in patients with severe sepsis-induced organ failure. We studied the effect of DrotAA on S100B levels in patients with acute septic shock who presented with increased baseline values of this biomarker.

Methods
All patients received standard goal-directed resuscitation treatment. Patients with pre-existing or acute neurological disorders were excluded. Based on the Glasgow coma scale (GCS), patients were classified into two groups: GCS ≥ 13 and GCS <13. DrotAA was given as a continuous infusion of 24 μg/kg/h for 96 h. S100B was measured before sedation and the start of DrotAA (0 h) and at 32 h, 64 h and 96 h and at corresponding time points in patients not treated with DrotAA. The lower limit of normal was < 0.5 μg/L.

Results
Fifty-four patients completed the study. S100B was increased in 29 (54%) patients. Twenty-four patients (9 with GCS ≥ 13 and 15 with GCS <13) received DrotAA. S100B levels in DrotAA-treated patients with a GCS <13, though higher at baseline than in untreated subjects (1.21 ± 0.22 μg/L vs. 0.95 ± 0.12 μg/L; P = 0.07), progressively and significantly decreased during infusion (0.96 ± 0.22 μg/L at 32 h, P = 0.3; 0.73 ± 0.12 μg/L at 64 h, P < 0.05; and 0.70 ± 0.13 μg/L at 96 h, P < 0.05 vs. baseline). This patient group had also significantly lower S100B values at 64 h and at 96 h than their untreated counterparts. In the patients with a GCS ≥ 13, S100B levels were not influenced by DrotAA treatment.

Conclusions
S100B-positivity is present in more than half of the patients with septic shock. When increased S100B levels are used as a surrogate for SAE, adjunctive DrotAA treatment seems to beneficially affect the evolution of severe SAE as discriminated by an admission GCS <13.