bluuebunny/crossref_metadata_2025_split huggingface dataset:
p53R2 Inhibits the Proliferation of Human Cancer Cells in Association with Cell-Cycle Arrest
Authors: Zhang Keqiang , Wu Jun , Wu Xiwei , Wang Xiaochen , Wang Yan , Zhou Ning , Kuo Mei-ling , Liu Xiyong , Zhou Bingsen , Chang Lufen , Ann David , Yen Yun 
Published: January 2011

Abstract
Deregulation of the expression of p53R2, a p53-inducible homologue of the R2 subunit of ribonucleotide reductase, has been found in various human cancer tissues; however, the roles p53R2 plays in cancer progression and malignancy remain controversial. In the present study, we examined changes in gene expression profiles associated with p53R2 in cancer cells, using the analysis of cDNA microarray. Gene set enrichment analysis identified that the gene set regulating cell-cycle progression was significantly enriched in p53R2-silencing human oropharyngeal carcinoma KB cells. Attenuation of p53R2 expression significantly reduced p21 expression and moderately increased cyclin D1 expression in both wild-type p53 cancer cells (KB and MCF-7) and mutant p53 cancer cells (PC3 and MDA-MB-231). Conversely, overexpression of p53R2-GFP resulted in an increase in the expression of p21 and decrease in the expression of cyclin D1, which correlated with reduced cell population in S-phase in vitro and suppressed growth in vivo. Furthermore, the MAP/ERK kinase inhibitor PD98059 partially abolished modulation of p21 and cyclin D1 expression by p53R2. Moreover, under the conditions of nonstress and adriamycin-induced genotoxic stress, attenuation of p53R2 in KB cells significantly increased phosphorylated H2AX, which indicates that attenuation of p53R2 may enhance DNA damage induced by adriamycin. Overall, our study shows that p53R2 may suppress cancer cell proliferation partially by upregulation of p21 and downregulation of cyclin D1; p53R2 plays critical roles not only in DNA damage repair but also in proliferation of cancer cells. Mol Cancer Ther; 10(2); 269–78. ©2011 AACR.
Antisense Inhibition of Survivin Expression as a Cancer Therapeutic
Authors: Carrasco Rosa A. , Stamm Nancy B. , Marcusson Eric , Sandusky George , Iversen Philip , Patel Bharvin K.R. 
Published: January 2011

Abstract
Survivin, a family member of the inhibitor of apoptosis proteins that is expressed during mitosis in a cell cycle–dependent manner and localized to different components of the mitotic apparatus, plays an important role in both cell division and inhibition of apoptosis. Survivin is expressed in a vast majority of human cancers, but not in normal adult tissues. Survivin expression is often correlated with poor prognosis in a wide variety of cancer patients. These features make survivin an attractive target against which cancer therapeutics could be developed. We have identified a survivin antisense oligonucleotide (ASO) that potently downregulated survivin expression in human cancer cells derived from lung, colon, pancreas, liver, breast, prostate, ovary, cervix, skin, and brain as measured by quantitative RT-PCR and immunoblotting analysis. Specific inhibition of survivin expression in multiple cancer cell lines by this ASO (LY2181308) induced caspase-3–dependent apoptosis, cell cycle arrest in the G2-M phase, and multinucleated cells. We also showed that inhibition of survivin expression by LY2181308 sensitized tumor cells to chemotherapeutic-induced apoptosis. Most importantly, in an in vivo human xenograft tumor model, LY2181308 produced significant antitumor activity as compared with saline or its sequence-specific control oligonucleotide and sensitized to gemcitabine, paclitaxel, and docetaxel. Furthermore, we showed that this antitumor activity was associated with significant inhibition of survivin expression in these xenograft tumors. On the basis of these, LY2181308 is being evaluated in a clinical setting (Phase II) in combination with docetaxel for the treatment of prostate cancer. Mol Cancer Ther; 10(2); 221–32. ©2011 AACR.
Ovarian Cancer Stem Cell–Like Side Populations Are Enriched Following Chemotherapy and Overexpress EZH2
Authors: Rizzo Siân , Hersey Jenny M. , Mellor Paul , Dai Wei , Santos-Silva Alessandra , Liber Daniel , Luk Louisa , Titley Ian , Carden Craig P , Box Garry , Hudson David L. , Kaye Stanley B. , Brown Robert 
Published: January 2011

Abstract
Platinum-based chemotherapy, with cytoreductive surgery, is the cornerstone of treatment of advanced ovarian cancer; however, acquired drug resistance is a major clinical obstacle. It has been proposed that subpopulations of tumor cells with stem cell–like properties, such as so-called side populations (SP) that overexpress ABC drug transporters, can sustain the growth of drug-resistant tumor cells, leading to tumor recurrence following chemotherapy. The histone methyltransferase EZH2 is a key component of the polycomb-repressive complex 2 required for maintenance of a stem cell state, and overexpression has been implicated in drug resistance and shorter survival of ovarian cancer patients. We observed higher percentage SP in ascites from patients that have relapsed following chemotherapy compared with chemonaive patients, consistent with selection for this subpopulation during platinum-based chemotherapy. Furthermore, ABCB1 (P-glycoprotein) and EZH2 are consistently overexpressed in SP compared with non-SP from patients' tumor cells. The siRNA knockdown of EZH2 leads to loss of SP in ovarian tumor models, reduced anchorage-independent growth, and reduced tumor growth in vivo. Together, these data support a key role for EZH2 in the maintenance of a drug-resistant, tumor-sustaining subpopulation of cells in ovarian cancers undergoing chemotherapy. As such, EZH2 is an important target for anticancer drug development. Mol Cancer Ther; 10(2); 325–35. ©2010 AACR.
Pushing the Envelope in the mTOR Pathway: The Second Generation of Inhibitors
Authors: Vilar Eduardo , Perez-Garcia Jose , Tabernero Josep 
Published: January 2011

AbstractThe phosphatidylinositol-3-kinase (PI3K)/mTOR pathway has been a major focus of attention for cancer researchers in the past decade. A preliminary and incomplete understanding of the molecular biology of this complex network has importantly conditioned not only the development of the first generation of mTOR inhibitors, but also the biomarker studies designed to identify the best responders to these agents. Most recently, research in this pathway has focused on the dual nature of mTOR that is integrated by the mTOR complex 1 and complex 2. These two complexes are formed and regulated by different proteins and are also driven by multiple different compensatory feedback loops. This deeper understanding has allowed the development of a promising second generation of inhibitors, which are able to block simultaneously both complexes due to their catalytic activity over mTOR. Moreover, some of them also exert an inhibitory effect over PI3K that is a key player in the feedback loops. This article reviews the newest insights in the signaling of the mTOR pathway and then focuses on the development of the new wave of mTOR inhibitors. Mol Cancer Ther; 10(3); 395–403. ©2011 AACR.
Inhibition of Intestinal Polyp Formation by Pitavastatin, a HMG-CoA Reductase Inhibitor
Authors: Teraoka Naoya , Mutoh Michihiro , Takasu Shinji , Ueno Toshiya , Yamamoto Masafumi , Sugimura Takashi , Wakabayashi Keiji 
Published: January 2011

Abstract
It has been suggested that hyperlipidemia is positively associated with colon carcinogenesis. Statins, 3-hydroxy-3-methyl-glutaryl-coenzyme A reductase inhibitors, reduce serum lipid levels. In this study, we clarified the effects of a novel chemically synthesized statin, pitavastatin, on intestinal polyp formation in Min mice, and further examined serum lipid and adipocytokine levels, and proinflammatory and adipocytokine gene levels in intestinal mucosa of Min mice. Treatment with pitavastatin at doses of 20 and 40 ppm decreased the total number of polyps dose-dependently to 85.2% and 65.8% (P &lt; 0.05) of the untreated value, respectively. Serum levels of total cholesterol and triglyceride were slightly reduced and those of IL-6, leptin, and MCP-1 were decreased by 40-ppm pitavastatin treatment. mRNA expression levels of cyclooxygenase-2, IL-6, inducible nitric oxide (iNOS), MCP-1, and Pai-1 were significantly reduced in intestinal nonpolyp parts by pitavastatin treatment. Among them, iNOS mRNA levels were also reduced in the intestinal polyps. Moreover, oxidative stress represented by 8-nitroguanosine in the small intestinal epithelial cells was reduced by pitavastatin treatment. Related to these proinflammatory genes, PPARγ activity was activated in the intestinal nonpolyp parts and in the liver of Min mice with pitavastatin treatment. These results indicated that pitavastatin has potential benefit for the suppression of intestinal polyp development. Cancer Prev Res; 4(3); 445–53. ©2011 AACR.
Flanking Recipient Vasculature, Not Circulating Progenitor Cells, Contributes to Endothelium and Smooth Muscle in Murine Allograft Vasculopathy
Authors: Hagensen Mette K. , Shim Jeong , Falk Erling , Bentzon Jacob F. 
Published: January 2011

Objective—
The prevailing view assumes that circulating endothelial and smooth muscle progenitor cells participate in allograft vasculopathy (AV), although the seminal studies in the field were not designed to distinguish between circulating and migrating cells of recipient origin. We developed a double-transplantation technique to overcome this problem and reinvestigated the origin of endothelial cells (ECs) and smooth muscle cells (SMCs) in murine AV.

Methods and Results—

Carotid artery segments from BALB/c mice were allografted to apolipoprotein E
−/−
B6 mice with or without a “flanking” isograft interpositioned between the allograft and the recipient artery. Either recipient mice or interpositioned isografts expressed enhanced green fluorescent protein, and consequently, cells migrating into the allograft from the flanking vasculature could easily be tracked and distinguished from recruited circulating cells. Without immunosuppression, allograft donor cells vanished as expected, and AV developed by replacement and accumulation of ECs and SMCs of recipient origin. The double transplantation models revealed that all ECs and SMCs in AV had migrated into the allograft from the flanking vasculature without any contribution from putative progenitor cells in the blood.

Conclusion—
Migrating cells from the flanking vasculature, not circulating progenitor cells, are the source of recipient-derived ECs and SMCs in murine AV.
Osteoprotegerin Predicts Progression of Chronic Heart Failure: Results From CORONA
Authors: Ueland Thor , Dahl Christen P. , Kjekshus John , Hulthe Johannes , Böhm Michael , Mach François , Goudev Assen , Lindberg Magnus , Wikstrand John , Aukrust Pål , Gullestad Lars 
Published: January 2011

Background—
Osteoprotegerin (OPG) may be implicated in the pathogenesis of heart failure (HF), and circulating levels predict survival in patients with postinfarction HF. Our primary goal was to determine whether OPG provided independent prognostic information in patients with chronic HF, and to examine its potential interactions with statin therapy.

Methods and Results—

OPG as a risk factor for the primary end point (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke; n=318), all-cause mortality (n=329), and all-cause mortality/hospitalization for worsening of heart failure (WHF; n=475) was investigated in 1464 patients (≥60 years, New York Heart Association class II to IV, ischemic systolic HF, optimal pharmacological therapy) in the Controlled Rosuvastatin Multinational Trial in HF (CORONA) population, randomly assigned to 10 mg rosuvastatin or placebo. In multivariate analyses, OPG (continuous variable) added no significant predictive information for risk estimation of the primary end point (adjusting for left ventricular ejection fraction, New York Heart Association class, age, body mass index, diabetes, sex, intermittent claudication, heart rate, serum creatinine, apoA1, and N-terminal pro-B-type natriuretic peptide). However, OPG added independent predictive information for WHF hospitalization (hazard ratio [HR] 1.10 [1.04 to 1.16],
P
<0.001) and all-cause mortality/WHF hospitalization (HR 1.06 [1.01 to 1.11]). The HR indicated a reduced risk for all-cause mortality in the rosuvastatin group in those with lowest OPG values (tertile 1, HR=0.66 unadjusted [
P
=0.025]; HR=0.71 Cox adjusted [
P
=0.025]; interaction by treatment effect for the tertiles
P
=0.086).

Conclusions—
OPG added no predictive information for the primary end point, but independently predicted WHF hospitalization in older patients with advanced chronic systolic HF of ischemic etiology.

Clinical Trial Registration—

URL:
http://www.clinicaltrials.gov
. Unique identifier: NCT00206310.
Cerebral Microbleeds Are Predictive of Mortality in the Elderly
Authors: Altmann-Schneider Irmhild , Trompet Stella , de Craen Anton J.M. , van Es Adriaan C.G.M. , Jukema J. Wouter , Stott David J. , Sattar Naveed , Westendorp Rudi G.J. , van Buchem Mark A. , van der Grond Jeroen 
Published: January 2011

Background and Purpose—
To investigate the prognostic value of cerebral microbleeds (CMB) regarding overall, cardiovascular-related, and stroke-related mortality and to investigate possible differences based on a cerebral amyloid angiopathy-type and nonlobar distribution of microbleeds.

Methods—
We included 435 subjects who were participants from the nested MRI substudy of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER). Cox proportional hazard models were applied to estimate the risk of overall, cardiovascular-related, and stroke-related death associated with microbleeds in general and microbleeds with a lobar distribution suggestive of the presence of cerebral amyloid angiopathy. The corresponding Kaplan-Meier survival curves were calculated.

Results—

Subjects with >1 CMB had a 6-fold risk of stroke-related death compared to subjects without CMB (hazard ratio, 5.97; 95% CI, 1.60–22.26;
P
=0.01). The diagnosis of nonlobar microbleeds was associated with >2-fold risk of cardiovascular death compared to subjects without microbleeds (hazard ratio, 2.67; 95% CI, 1.23–5.81;
P
=0.01). Subjects with probable cerebral amyloid angiopathy-type microbleeds had >7-fold risk of stroke-related death compared to subjects without CMB (hazard ratio, 7.20; 95% CI, 1.44–36.10;
P
=0.02).

Conclusions—
This is the first study investigating the association between microbleeds and risk of overall, cardiovascular-related, and stroke-related mortality in an elderly population. Our findings indicate that the diagnosis of microbleeds is potentially of clinical relevance. Larger studies are needed to expand our observations and to address potential clinical implications and cost-benefits of such a policy.
Carotid Artery Stenting Versus Carotid Endarterectomy
Authors: Economopoulos Konstantinos P. , Sergentanis Theodoros N. , Tsivgoulis Georgios , Mariolis Anargiros D. , Stefanadis Christodoulos 
Published: January 2011

Background and Purpose—
The comparison between carotid endarterectomy and carotid artery stenting (CAS) remains a debated field, especially in the context of long-term outcomes.

Methods—
Concerning the short-term (30-day) analysis, the numbers of outcomes per arm were abstracted, whereas outcomes per arm and hazard ratios were abstracted for long-term (≥1-year) results.

Results—
Thirteen randomized trials (3723 carotid endarterectomy and 3754 CAS patients) were eligible. Regarding short-term outcomes, CAS was associated with elevated risk for stroke and “death or stroke.” CAS also exhibited a marginal trend toward higher death and “death or disabling stroke” rates. Carotid endarterectomy presented with higher rates of myocardial infarction and cranial nerve injury. Concerning long-term outcomes, CAS was associated with higher rates of stroke (pooled OR, 1.37; 95% CI, 1.13 to 1.65) and “death or stroke” (pooled OR, 1.25; 95% CI, 1.06 to 1.48). These findings were replicated at the level of pooled hazard ratios and marginally regarding secondary preventive efficacy. The difference in long-term stroke rates was particularly sizeable in patients >68 years, but little difference in rates was observed in those <68 years. No statistically significant heterogeneity became evident. Metaregression did not reveal any significant modifying effect mediated by symptomatic/asymptomatic status, distal protection, early termination of trials, area of study origin, or CAS learning curve.

Conclusions—
This meta-analysis points to the significantly less frequent stroke events after carotid endarterectomy at the long-term context. The outcomes of carotid endarterectomy seem superior to CAS, but there may be subgroups, particularly younger patients, in whom the results seem equivalent.
Differentiation of Hemicriconemoides mangiferae and H. litchi (Nematoda: Criconematina) based on morphometrics and nuclear ribosomal DNA sequences
Authors: Chen Ruey-Shyang , Ni Hui-Fang , Tsay Tung-Tsuan , Chen Diann-Yih 
Published: January 2011

Abstract
Hemicriconemoides mangiferae and H. litchi, which have been considered as
junior synonyms of H. strictathecatus, are morphologically similar, making
identification difficult. In the present study, six populations of
Hemicriconemoides spp. were collected from mango and litchi in Taiwan and
were differentiated based on morphometrics and molecular characteristics. By
comparing morphometric data from females and males, three populations
collected from mango were identified as H. mangiferae and another three
populations from litchi were identified as H. litchi. According to SEM, both
of the H. mangiferae and H. litchi males had an areolated lateral field with
four incisures; caudal alae were not found. The internal transcribed spacer
(ITS) sequences of ribosomal DNA (rDNA) from these nematode populations were
sequenced and aligned. The sequence identity of the ITS region was 89-95%
between H. mangiferae and H. litchi populations, suggesting rDNA sequence
divergence could be a taxonomic aid for species differentiation. Since H.
mangiferae and H. litchi are closely related to H. strictathecatus, more
rDNA sequence information could be valuable to deal with molecular
phylogenetic relationships of these species in depth.
Differential responses of resistant and susceptible groundnut genotypes at cellular level to Ditylenchus africanus
Authors: Steenkamp Sonia , Jordaan Anine , Mc Donald Alexander , Waele Dirk 
Published: January 2011

Abstract
Ditylenchus africanus causes cellular breakdown in pod tissue of susceptible
groundnut cultivars. The histopathology of this nematode on a resistant
genotype was studied using light microscopy and compared with the
histopathology of D. africanus on a susceptible genotype. Plants of breeding
line PC254K1 and cv. Sellie were propagated in a glasshouse, inoculated with
D. africanus at inoculum levels of 2000, 5000 and 7000 nematodes per plant
and the pods were collected at 90, 120 and 150 days after planting. In
contrast to the susceptible genotype, only a small number of nematodes were
observed in restricted areas of the pod tissue of the resistant genotype.
Furthermore, the resistant genotype showed neither external symptoms nor
cellular breakdown in reaction to D. africanus. According to results of this
study, the mechanism of resistance involved may be the inhibition of proper
development, migration and reproduction of this nematode, thus preventing it
building up to damaging population levels.
The importance of feeding status and desiccation rate in successful anhydrobiosis of Panagrolaimus detritophagus
Authors: Salehian Shakiba , Braeckman Bart P. , Beladjal Lynda , Bert Wim , Clegg James S. , Mertens Johan 
Published: January 2011

Abstract
We examined the effect of nutritional status and desiccation rate on the
ability of Panagrolaimus detritophagus to undergo anhydrobiosis, as well as
to survive high temperatures in the dried state. Both nutrition and drying
rate were found to be important, with starvation and slow drying providing
better success at anhydrobiosis. The upper temperature for survival of dried
animals in laboratory studies was 80°C. Starved worms recovered from drying
more successfully when the starvation period was followed by a smooth,
gradual dry period prior to undergoing desiccation. Thus, the ability of
these worms to enter and leave anhydrobiosis is dependent on critical stress
signals.
Associations between stress and migraine and tension-type headache: Results from a school-based study in adolescents from grammar schools in Germany
Authors: Milde-Busch Astrid , Blaschek Astrid , Heinen Florian , Borggräfe Ingo , Koerte Inga , Straube Andreas , Schankin Christoph , von Kries Rüdiger 
Published: January 2011

Introduction: Stress is considered the major contributor to migraine and tension-type headache in adolescents. Previous studies have focused on general stressors, whereas the aim of the present study was to investigate associations between individuals’ stressful experiences and different types of headache. Methods: Adolescents from 10th and 11th grades of grammar schools filled in questionnaires. Stressful experiences were measured with the Trier Inventory of Chronic Stress. Type of headache was classified according to the International Classification of Headache Disorders. Linear regressions, adjusted for sex and grade, were calculated to estimate differences in stress scores that can be attributed to migraine, tension-type headache or miscellaneous headache. Results: A total of 1260 questionnaires were analysed. Tension-type headache, migraine and co-existing migraine plus tension-type headache were found in 48.7%, 10.2% and 19.8% of the participants. In subjects with migraine or co-existing migraine plus tension-type headache, high increases in stress scores were found in all investigated dimensions, whereas much weaker and inconsistent associations were found in subjects with tension-type headache only. Conclusions: The characteristic of migraine is more associated with stressful experiences than this is the case for tension-type headache. This suggests that adolescent migraine patients might especially benefit from behavioural interventions regarding stress.
The STAT5 inhibitor pimozide decreases survival of chronic myelogenous leukemia cells resistant to kinase inhibitors
Authors: Nelson Erik A. , Walker Sarah R. , Weisberg Ellen , Bar-Natan Michal , Barrett Rosemary , Gashin Laurie B. , Terrell Shariya , Klitgaard Josephine L. , Santo Loredana , Addorio Martha R. , Ebert Benjamin L. , Griffin James D. , Frank David A. 
Published: January 2011

Abstract
The transcription factor STAT5 is an essential mediator of the pathogenesis of chronic myelogenous leukemia (CML). In CML, the BCR/ABL fusion kinase causes the constitutive activation of STAT5, thereby driving the expression of genes promoting survival. BCR/ABL kinase inhibitors have become the mainstay of therapy for CML, although CML cells can develop resistance through mutations in BCR/ABL. To overcome this problem, we used a cell-based screen to identify drugs that inhibit STAT-dependent gene expression. Using this approach, we identified the psychotropic drug pimozide as a STAT5 inhibitor. Pimozide decreases STAT5 tyrosine phosphorylation, although it does not inhibit BCR/ABL or other tyrosine kinases. Furthermore, pimozide decreases the expression of STAT5 target genes and induces cell cycle arrest and apoptosis in CML cell lines. Pimozide also selectively inhibits colony formation of CD34+ bone marrow cells from CML patients. Importantly, pimozide induces similar effects in the presence of the T315I BCR/ABL mutation that renders the kinase resistant to presently available inhibitors. Simultaneously inhibiting STAT5 with pimozide and the kinase inhibitors imatinib or nilotinib shows enhanced effects in inhibiting STAT5 phosphorylation and in inducing apoptosis. Thus, targeting STAT5 may be an effective strategy for the treatment of CML and other myeloproliferative diseases.