bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sphingosine-1-Phosphate Regulates Glioblastoma Cell Invasiveness through the Urokinase Plasminogen Activator System and CCN1/Cyr61
Authors: Young Nicholas , Pearl Dennis K. , Van Brocklyn James R. 
Published: January 2009

AbstractGlioblastoma multiforme (GBM) is an aggressively invasive brain neoplasm with poor patient prognosis. We have previously shown that the bioactive lipid sphingosine-1-phosphate (S1P) stimulates in vitro invasiveness of GBM cells and that high expression levels of the enzyme that forms S1P, sphingosine kinase-1 (SphK1), correlate with shorter survival time of GBM patients. We also recently showed that S1P induces expression of CCN1 (also known as Cyr61), a matricellular protein known to correlate with poor patient prognosis, in GBM cells. In this study, we further explored the role of CCN1 as well as the urokinase plasminogen activator (uPA), a protein known to stimulate GBM cell invasiveness, in S1P-induced invasion using a spheroid invasion assay. We also investigated the roles of various S1P receptors in stimulating invasiveness through these pathways. S1P induced expression of uPA and its receptor, uPAR, in GBM cells. Whereas S1P1, S1P2, and S1P3 receptors all contribute, at least partially, S1P1 overexpression led to the most dramatic induction of the uPA system and of spheroid invasion, even in the absence of added S1P. Furthermore, neutralizing antibodies directed against uPA or CCN1 significantly decreased both basal and S1P-stimulated GBM cell invasiveness. Inhibition of SphK blocked basal expression of uPA and uPAR, as well as glioma cell invasion; however, overexpression of SphK did not augment S1P receptor–mediated enhancement of uPA activity or invasion. Thus, SphK is necessary for basal activity of the uPA system and glioma cell invasion, whereas S1P receptor signaling enhances invasion, partially through uPA and CCN1. (Mol Cancer Res 2009;7(1):23–32)
The Fer Tyrosine Kinase Cooperates with Interleukin-6 to Activate Signal Transducer and Activator of Transcription 3 and Promote Human Prostate Cancer Cell Growth
Authors: Zoubeidi Amina , Rocha Joice , Zouanat Fatima Z. , Hamel Lucie , Scarlata Eleonora , Aprikian Armen G. , Chevalier Simone 
Published: January 2009

AbstractAndrogen withdrawal is the most effective form of systemic therapy for men with advanced prostate cancer. Unfortunately, androgen-independent progression is inevitable, and the development of hormone-refractory disease and death occurs within 2 to 3 years in most men. The understanding of molecular mechanisms promoting the growth of androgen-independent prostate cancer cells is essential for the rational design of agents to treat advanced disease. We previously reported that Fer tyrosine kinase level correlates with the development of prostate cancer and aggressiveness of prostate cancer cell lines. Moreover, knocking down Fer expression interferes with prostate cancer cell growth in vitro. However, the mechanism by which Fer mediates prostate cancer progression remains elusive. We present here that Fer and phospho-Y705 signal transducer and activator of transcription 3 (STAT3) are barely detectable in human benign prostate tissues but constitutively expressed in the cytoplasm and nucleus of the same subsets of tumor cells in human prostate cancer. The interaction between STAT3 and Fer was observed in all prostate cancer cell lines tested, and this interaction is mediated via the Fer Src homology 2 domain and modulated by interleukin-6 (IL-6). Moreover, IL-6 triggered a rapid formation of Fer/gp130 and Fer/STAT3 complexes in a time-dependent manner and consistent with changes in Fer and STAT3 phosphorylation and cytoplasmic/nuclear distribution. The modulation of Fer expression/activation resulted in inhibitory or stimulatory effects on STAT3 phosphorylation, nuclear translocation, and transcriptional activation. These effects translated in IL-6–mediated PC-3 cell growth. Taken together, these results support an important function of Fer in prostate cancer. (Mol Cancer Res 2009;7(1):142–55)
Direct Progesterone Receptor and Indirect Androgen Receptor Interactions with the Kallikrein-Related Peptidase 4 Gene Promoter in Breast and Prostate Cancer
Authors: Lai John , Myers Stephen A. , Lawrence Mitchell G. , Odorico Dimitri M. , Clements Judith A. 
Published: January 2009

Abstract
Kallikrein 4 (KLK4) is a member of the human KLK gene family of serine proteases, many of which are implicated in hormone-dependent cancers. Like other KLKs, such as KLK3/PSA and KLK2, KLK4 gene expression is also regulated by steroid hormones in hormone-dependent cancers, although the transcriptional mechanisms are ill defined. Here, we have investigated the mechanisms mediating the hormonal regulation of KLK4 in breast (T47D) and prostate (LNCaP and 22Rv1) cancer cells. We have shown that KLK4 is only expressed in breast and prostate cancers that express the progesterone receptor (PR) and androgen receptor (AR), respectively. Expression analysis in PR- and AR-positive cells showed that the two predominant KLK4 variants that use either TIS1 or TIS2a/b are both up-regulated by progesterone in T47D cells and androgens in LNCaP cells. Two putative hormone response elements, K4.pPRE and K4.pARE at −2419 bp and −1005 bp, respectively, were identified in silico. Electrophoretic mobility shift assays and luciferase reporter experiments suggest that neither K4.pARE nor ∼2.8 kb of the KLK4 promoter interacts directly with the AR to mediate KLK4 expression in LNCaP and 22Rv1 cells. However, we have shown that K4.pPRE interacts directly with the PR to up-regulate KLK4 gene expression in T47D cells. Further, chromatin immunoprecipitation experiments showed a time-dependent recruitment of the PR to the KLK4 promoter (−2496 to −2283), which harbors K4.pPRE. This is the first study to show that progesterone-regulated KLK4 expression in T47D cells is mediated partly by a hormone response element (K4.pPRE) at −2419 bp. (Mol Cancer Res 2009;7(1):129–41)
Mutual Regulation of Hypoxia-Inducible Factor and Mammalian Target of Rapamycin as a Function of Oxygen Availability
Authors: Knaup Karl X. , Jozefowski Katrin , Schmidt Regina , Bernhardt Wanja M. , Weidemann Alexander , Juergensen Jan Steffen , Warnecke Christina , Eckardt Kai-Uwe , Wiesener Michael S. 
Published: January 2009

Abstract
The mammalian target of rapamycin (mTOR) regulates cellular growth and proliferation, mainly by controlling cellular translation. Most tumors show constitutive activation of the mTOR pathway. In hypoxia, mTOR is inactivated, which is believed to be part of the program of the cell to maintain energy homeostasis. However, certain proteins are believed to be preferentially translated during hypoxia via 5′ terminal oligopyrimidine tract mechanisms with controversial discussion about the involvement of the mTOR-dependent ribosomal protein S6 (rpS6). The hypoxia-inducible transcription factor (HIF) is the master regulator of hypoxic adaptation and itself strongly implicated in tumor growth. HIF is translationally regulated by mTOR. The regulatory features and the involvement of molecular oxygen itself in this regulation of HIF by mTOR are poorly understood. mTOR inhibition leads to profound attenuation of HIFα protein in the majority of primary and cancer cells studied. Under severe hypoxia, no influence of mTOR inhibitors was observed; thus, stimulation of HIFα by mTOR may only be relevant under mild hypoxia or even normoxia. HIF expression and phosphorylated rpS6 negatively correlate in experimental tumors. In cell culture, prolonged hypoxia abolishes rpS6 phosphorylation, which seems to be partly independent of the upstream p70S6 kinase. We show that hypoxic repression of rpS6 is largely dependent on HIF, implicating a negative feedback loop, which may influence cellular translational rates and metabolic homeostasis. These data implicate that the hypoxic microenvironment renders tumor cells resistant to mTOR inhibition, at least concerning hypoxic gene activation, which would add to the difficulties of other established therapeutic strategies in hypoxic cancer tissues. (Mol Cancer Res 2009;7(1):88–98)
Focused PCR Screen Reveals p53 Dependence of Nitric Oxide-Induced Apoptosis and Up-Regulation of Maspin and Plasminogen Activator Inhibitor-1 in Tumor Cells
Authors: Lim Shuhui , Hung Amos C. , Porter Alan G. 
Published: January 2009

Abstract
We investigated p53-dependent gene expression in nitric oxide (NO)-induced apoptosis of two tumor cell types. Seventy-seven putative p53-regulated genes were screened for NO-mediated expression changes. Twenty-four genes were up-regulated and three genes were down-regulated significantly by NO in human neuroblastoma cells. Genes known to be involved in apoptosis, which were up-regulated by ≥2-fold, included FAS, CASP-1, BIK, PUMA, DR4 and the serpins maspin (SERPINB5), and plasminogen activator inhibitor-1 (PAI-1). Real-time PCR confirmed maspin and PAI-1 mRNAs exhibited the greatest NO-induced induction, which occurred in a p53-dependent manner. The substantial NO-mediated up-regulation of these serpins mRNAs correlated with large increases in their protein levels, which occurred before or coinciding with apoptosis. p53-deficient neuroblastoma cells were largely resistant to NO killing and showed much reduced maspin and PAI-1 mRNA and protein levels after NO treatment. p53 was activated by NO mainly in the nuclei of neuroblastoma cells. p53−/− HCT116 colon carcinoma cells were strongly resistant to NO-induced apoptosis and failed to up-regulate maspin and PAI-1 (in contrast to p53+/+ HCT116 cells). Our results suggest that both apoptosis and induction of the two serpins by NO require the transcriptional activity of p53. Because maspin is a tumor suppressor and PAI-1 can promote senescence and regulate cell death, it will now be worth investigating whether their p53-mediated expression contributes to the NO-induced p53-dependent death of tumor cells. (Mol Cancer Res 2009;7(1):55–66)
The Role of Automated External Defibrillators in Athletics
Authors: Rothmier Justin D. , Drezner Jonathan A. 
Published: January 2009

Context: Sudden cardiac arrest is the leading cause of death in young athletes. The purpose of this review is to summarize the role of automated external defibrillators and emergency planning for sudden cardiac arrest in the athletic setting. Evidence Acquisition: Relevant studies on automated external defibrillators, early defibrillation, and public-access defibrillation programs were reviewed. Recommendations from consensus guidelines and position statements applicable to automated external defibrillators in athletics were also considered. Results: Early defibrillation programs involving access to automated external defibrillators by targeted local responders have demonstrated a survival benefit for sudden cardiac arrest in many public and athletic settings. Conclusion: Schools and organizations sponsoring athletic programs should implement automated external defibrillators as part of a comprehensive emergency action plan for sudden cardiac arrest. In a collapsed and unresponsive athlete, sudden cardiac arrest should be suspected and an automated external defibrillator applied as soon as possible, as decreasing the time interval to defibrillation is the most important priority to improve survival in sudden cardiac arrest.
The Use of Eccentrically Biased Resistance Exercise to Mitigate Muscle Impairments Following Anterior Cruciate Ligament Reconstruction: A Short Review
Authors: Gerber J. Parry , Marcus Robin L. , Dibble Leland E. , LaStayo Paul C. 
Published: January 2009

Background: Novel interventions that can safely and effectively overload muscle early following anterior cruciate ligament reconstruction are needed to minimize atrophy and weakness that often becomes longstanding. Evidence Acquisition: Eccentrically induced forces can be safely applied during the early stages of rehabilitation following surgery and serve as a potent stimulus for increasing muscle size and strength. Results: Compared to a standard rehabilitation program, adding an early 12-week eccentric resistance-training program 3 weeks after anterior cruciate ligament reconstruction induces improvement in quadriceps and gluteus maximus volume at 15 weeks and at 1 year after surgery. Likewise, those who performed an eccentrically biased rehabilitation program also achieved greater improvements in quadriceps strength and hopping ability measured at 15 weeks and at 1 year after surgery. Clinical Relevance: There is potential to safely and feasibly perform eccentric contractions as part of a formal rehabilitation program following anterior cruciate ligament reconstruction.
A novel molecular mechanism of primary resistance to FLT3-kinase inhibitors in AML
Authors: Breitenbuecher Frank , Markova Boyka , Kasper Stefan , Carius Birgit , Stauder Torsten , Böhmer Frank D. , Masson Kristina , Rönnstrand Lars , Huber Christoph , Kindler Thomas , Fischer Thomas 
Published: January 2009

Abstract
Currently, FLT3 tyrosine kinase inhibitors (TKIs) are emerging as the most promising drug therapy to overcome the dismal prognosis of acute myelogenous leukemia (AML) patients harboring internal tandem duplications (ITDs) of FLT3. However, up-front drug resistance occurs in approximately 30% of patients, and molecular mechanisms of resistance are poorly understood. Here, we have uncovered a novel mechanism of primary resistance to FLT3 TKIs in AML: an FLT3 receptor harboring a nonjuxtamembrane ITD atypically integrating into the β-2 sheet of the first kinase domain (FLT3_ITD627E) induces dramatic up-regulation of the anti-apoptotic myeloid cell leukemia 1 protein (MCL-1). Using RNA interference technology, deregulated MCL-1 protein expression was shown to play a major role in conferring the resistance phenotype of 32D_ITD627E cells. Enhanced and sustained binding of the adaptor protein GRB-2 to the FLT3_ITD627E receptor is involved in MCL-1 up-regulation and is independent from TKI (PKC412)–induced inhibition of the receptor kinase. Thus, we describe a new mechanism of primary resistance to TKIs, which operates by reprogramming local and distant signal transduction events of the FLT3 tyrosine kinase. The data presented suggest that particular ITDs of FLT3 may be associated with rewired signaling and differential responsiveness to TKIs.
How I treat and monitor viral hepatitis B infection in patients receiving intensive immunosuppressive therapies or undergoing hematopoietic stem cell transplantation
Authors: Liang Raymond 
Published: January 2009

AbstractHepatitis B virus (HBV) reactivation is a serious but preventable complication of immunosuppression. Full HBV serologic profile must be obtained from all patients receiving intensive immunosuppressive therapy. In general, preemptive anti-HBV therapy is more effective than giving treatment after development of reactivation. Prompt lamivudine therapy should be given to at-risk patients who are hepatitis B surface antigen (HBsAg)–positive. It is recommended that lamivudine be continued until at least 6 months after the cessation of immunosuppression. Some patients requiring a longer duration of lamivudine therapy are at risk of developing drug resistance. The newer anti-HBV agents are effective in overcoming lamivudine resistance. Early use of these agents may be considered. HBV reactivation was observed in HBsAg-negative patients with occult HBV infection (HBV DNA-positive) who are on heavy immunosuppression. The optimal management of this group of patients is unclear. For patients receiving allogeneic HSC transplants, the HBV status of the donors requires special attention. To minimize the risk of transmission of infection to recipients, HBsAg-positive donors should receive adequate anti-HBV therapy before HSC donation. As the result of adoptive immune transfer, clearance of HBsAg is observed in HBsAg-positive patients receiving HSC transplants from donors who are positive for hepatitis B surface and core antibodies.
CNS events in elderly patients with aggressive lymphoma treated with modern chemotherapy (CHOP-14) with or without rituximab: an analysis of patients treated in the RICOVER-60 trial of the German High-Grade Non-Hodgkin Lymphoma Study Group (DSHNHL)
Authors: Boehme Volkmar , Schmitz Norbert , Zeynalova Samira , Loeffler Markus , Pfreundschuh Michael 
Published: January 2009

AbstractOne thousand two hundred twenty-two patients treated in the Rituximab with CHOP over age 60 years (RICOVER-60) trial were examined for central nervous system (CNS) disease developing during first-line therapy or after a complete or partial remission had been achieved. Patients received 6 or 8 courses of CHOP (cyclophosphamide, adriamycin, vincristine, prednisone) administered every 2 weeks (CHOP-14) with or without rituximab. CNS prophylaxis for patients with involvement of bone marrow, testes, upper neck, or head consisted of intrathecal (i.th.) methotrexate (days 1 and 5 of first 2 courses). Fifty-eight cases of lymphoma in the CNS were observed (36/609 patients in the CHOP-14 and 22/608 patients in the arituximab–CHOP-14 [R-CHOP–14] arm). The estimated 2-year incidence of CNS disease was 6.9% (confidence interval [CI] 4.5; 9.3) after CHOP-14 and 4.1% (CI 2.3; 5.9) after R-CHOP–14. R-CHOP reduced the relative risk for CNS disease to 0.58 (95% CI 0.3; 1.0, P = .046). Cox regression analysis identified “involvement of more than 1 extranodal site” and “B-symptoms” as significant risk factors for CNS disease. Patients treated with R-CHOP–14 did not show any benefit from i.th. methotrexate. We conclude that elderly patients with aggressive CD20-positive lymphoma show a significantly lower incidence of CNS disease if treated with R-CHOP–14 instead of CHOP-14. Intrathecal methotrexate has no role in preventing CNS disease for patients treated with combined immunochemotherapy (R-CHOP–14)—with the possible exception of patients with testicular involvement. The original clinical trials are registered on www.clinicaltrials.gov as NCT000052936.
microRNA-29c and microRNA-223 down-regulation has in vivo significance in chronic lymphocytic leukemia and improves disease risk stratification
Authors: Stamatopoulos Basile , Meuleman Nathalie , Haibe-Kains Benjamin , Saussoy Pascale , Van Den Neste Eric , Michaux Lucienne , Heimann Pierre , Martiat Philippe , Bron Dominique , Lagneaux Laurence 
Published: January 2009

Abstract
Aberrant expression of microRNAs has been recently associated with chronic lymphocytic leukemia (CLL) outcome. Although disease evolution can be predicted by several prognostic factors, a better outcome individualization in a given patient is still of utmost interest. Here, we showed that miR-29c and miR-223 expression levels decreased significantly with progression from Binet stage A to C were significantly lower in poor prognostic subgroups (defined by several prognostic factors) and could significantly predict treatment-free survival (TFS) and overall survival (OS). Furthermore, we developed a quantitative real-time polymerase chain reaction (qPCR) score combining miR-29c, miR-223, ZAP70, and LPL (from 0 to 4 poor prognostic markers) to stratify treatment and death risk in a cohort of 110 patients with a median follow-up of 72 months (range, 2-312). Patients with a score of 0/4, 1/4, 2/4, 3/4, and 4/4 had a median TFS of greater than 312, of 129, 80, 36, and 19 months, respectively (hazard ratio, HR0/4 < 1/4 < 2/4 < 3/4 < 4/4 = 17.00, P < .001). Patients with a score of 0-1/4, 2-3/4, and 4/4 had a median OS of greater than 312, of 183 and 106 months, respectively (HR0/4 < 1/4 < 2/4 < 3/4 < 4/4 = 13.69, P = .001). This score will help to identify, among the good and poor prognosis subgroups, patients who will need early therapy and thus will require a closer follow-up.
The G protein-coupled receptor subset of the dog genome is more similar to that in humans than rodents
Authors: Haitina Tatjana , Fredriksson Robert , Foord Steven M , Schiöth Helgi B , Gloriam David E 
Published: January 2009

Abstract

Background
The dog is an important model organism and it is considered to be closer to humans than rodents regarding metabolism and responses to drugs. The close relationship between humans and dogs over many centuries has lead to the diversity of the canine species, important genetic discoveries and an appreciation of the effects of old age in another species. The superfamily of G protein-coupled receptors (GPCRs) is one of the largest gene families in most mammals and the most exploited in terms of drug discovery. An accurate comparison of the GPCR repertoires in dog and human is valuable for the prediction of functional similarities and differences between the species.

Results
We searched the dog genome for non-olfactory GPCRs and obtained 353 full-length GPCR gene sequences, 18 incomplete sequences and 13 pseudogenes. We established relationships between human, dog, rat and mouse GPCRs resolving orthologous pairs and species-specific duplicates. We found that 12 dog GPCR genes are missing in humans while 24 human GPCR genes are not part of the dog GPCR repertoire. There is a higher number of orthologous pairs between dog and human that are conserved as compared with either mouse or rat. In almost all cases the differences observed between the dog and human genomes coincide with other variations in the rodent species. Several GPCR gene expansions characteristic for rodents are not found in dog.

Conclusion
The repertoire of dog non-olfactory GPCRs is more similar to the repertoire in humans as compared with the one in rodents. The comparison of the dog, human and rodent repertoires revealed several examples of species-specific gene duplications and deletions. This information is useful in the selection of model organisms for pharmacological experiments.
The genome sequence of the fish pathogen Aliivibrio salmonicida strain LFI1238 shows extensive evidence of gene decay
Authors: Hjerde Erik , Lorentzen Marit Sjo , Holden Matthew TG , Seeger Kathy , Paulsen Steinar , Bason Nathalie , Churcher Carol , Harris David , Norbertczak Halina , Quail Michael A , Sanders Suzanne , Thurston Scott , Parkhill Julian , Willassen Nils Peder , Thomson Nicholas R 
Published: January 2009

Abstract

Background
The fish pathogen Aliivibrio salmonicida is the causative agent of cold-water vibriosis in marine aquaculture. The Gram-negative bacterium causes tissue degradation, hemolysis and sepsis in vivo.

Results
In total, 4 286 protein coding sequences were identified, and the 4.6 Mb genome of A. salmonicida has a six partite architecture with two chromosomes and four plasmids. Sequence analysis revealed a highly fragmented genome structure caused by the insertion of an extensive number of insertion sequence (IS) elements. The IS elements can be related to important evolutionary events such as gene acquisition, gene loss and chromosomal rearrangements. New A. salmonicida functional capabilities that may have been aquired through horizontal DNA transfer include genes involved in iron-acquisition, and protein secretion and play potential roles in pathogenicity. On the other hand, the degeneration of 370 genes and consequent loss of specific functions suggest that A. salmonicida has a reduced metabolic and physiological capacity in comparison to related Vibrionaceae species.

Conclusion
Most prominent is the loss of several genes involved in the utilisation of the polysaccharide chitin. In particular, the disruption of three extracellular chitinases responsible for enzymatic breakdown of chitin makes A. salmonicida unable to grow on the polymer form of chitin. These, and other losses could restrict the variety of carrier organisms A. salmonicida can attach to, and associate with. Gene acquisition and gene loss may be related to the emergence of A. salmonicida as a fish pathogen.