bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Emerging Role of EpCAM in Cancer and Stem Cell Signaling
Authors: Munz Markus , Baeuerle Patrick A. , Gires Olivier 
Published: July 2009

Abstract
Initially discovered as a dominant antigen on colon carcinomas, the epithelial cell adhesion molecule (EpCAM) was considered a mere cell adhesion molecule and reliable surface-binding site for therapeutic antibodies. Recent findings can better explain the relevance of EpCAM's high-level expression on human cancers and cancer propagating cells, and its negative prognostic potential for survival of patients with certain cancers. EpCAM has oncogenic potential and is activated by release of its intracellular domain, which can signal into the cell nucleus by engagement of elements of the wnt pathway. [Cancer Res 2009;69(14):5627–9]
Prevalence of TMPRSS2-ERG Fusion Prostate Cancer among Men Undergoing Prostate Biopsy in the United States
Authors: Mosquera Juan-Miguel , Mehra Rohit , Regan Meredith M. , Perner Sven , Genega Elizabeth M. , Bueti Gerri , Shah Rajal B. , Gaston Sandra , Tomlins Scott A. , Wei John T. , Kearney Michael C. , Johnson Laura A. , Tang Jeffrey M. , Chinnaiyan Arul M. , Rubin Mark A. , Sanda Martin G. 
Published: July 2009

Abstract
Purpose: Fusion of the TMPRSS2 prostate-specific gene with the ERG transcription factor is a putatively oncogenic gene rearrangement that is commonly found in prostate cancer tissue from men undergoing prostatectomy. However, the prevalence of the fusion was less common in samples of transurethral resection of the prostate from a Swedish cohort of patients with incidental prostate cancer followed by watchful waiting, raising the question as to whether the high prevalence in prostatectomy specimens reflects selection bias. We sought to determine the prevalence of TMPRSS2-ERG gene fusion among prostate-specific antigen–screened men undergoing prostate biopsy in the United States.
Experimental Design: We studied 140 prostate biopsies from the same number of patients for TMPRSS2-ERG fusion status with a fluorescent in situ hybridization assay. One hundred and thirty-four samples (100 cancer and 34 benign) were assessable.
Results: ERG gene rearrangement was detected in 46% of prostate biopsies that were found to have prostate cancer and in 0% of benign prostate biopsies (P &lt; 0.0001). Evaluation of morphologic features showed that cribriform growth, blue-tinged mucin, macronucleoli, and collagenous micronodules were significantly more frequent in TMPRSS2-ERG fusion–positive prostate cancer biopsies than gene fusion–negative prostate cancer biopsies (P ≤ 0.04). No significant association with Gleason score was detected. In addition, non-Caucasian patients were less likely to have positive fusion status (P = 0.02).
Conclusions: This is the first prospective North American multicenter study to characterize TMPRSS2-ERG prostate cancer prevalence in a cohort of patients undergoing needle biopsy irrespective of whether or not they subsequently undergo prostatectomy. Our results show that this gene rearrangement is common among North American men who have prostate cancer on biopsy, is absent in benign prostate biopsy, and is associated with specific morphologic features. These findings indicate a need for prospective studies to evaluate the relationship of TMPRSS2-ERG rearrangement with clinical course of screening-detected prostate cancer in North American men, and a need for the development of noninvasive screening tests to detect TMPRSS2-ERG rearrangement.
Vascular Endothelial Growth Factor Polymorphisms and Esophageal Cancer Prognosis
Authors: Bradbury Penelope A. , Zhai Rihong , Ma Clement , Xu Wei , Hopkins Jessica , Kulke Matthew J. , Asomaning Kofi , Wang Zhaoxi , Su Li , Heist Rebecca S. , Lynch Thomas J. , Wain John C. , Christiani David , Liu Geoffrey 
Published: July 2009

Abstract
Purpose: Vascular endothelial growth factor (VEGF) promotes angiogenesis and vascular permeability. The VEGF gene is polymorphic. We investigated the prognostic significance of three VEGF single nucleotide polymorphisms (SNP) in esophageal cancer.
Experimental Design: Three hundred sixty-one patients were genotyped for three VEGF SNPs (−460T/C, 405G/C, and 936C/T) using DNA extracted from prospectively collected blood samples. The association of each individual SNP, and haplotypes of the three SNPs, on overall survival (OS) was investigated.
Results: The variant allele of 936C/T was associated with improved OS compared with the wild-type genotype (log-rank P &lt; 0.001). This association remained significant for OS after adjustments for age, gender, performance status, and disease stage [VEGF 936C/T: adjusted hazard ratio (AHR), 0.70; 95% confidence interval (95% CI), 0.49-0.99; P = 0.04; VEGF 936T/T: AHR, 0.11; 95% CI, 0.02-0.82; P = 0.03]. No independent associations were found for VEGF −460T/C and VEGF 405G/C. The CGC haplotype of the three VEGF SNPs (−460T/C, 405G/C, and 936C/T) combined was associated with reduced OS compared with all other patients (CGC/CGC: AHR, 1.51; 95% CI, 1.00-2.30; P = 0.05).
Conclusions: VEGF 936C/T, and a haplotype of 460T/C, 405G/C, and 936C/T combined, has potential prognostic significance in esophageal cancer.
Relationship of CDX2 Loss with Molecular Features and Prognosis in Colorectal Cancer
Authors: Baba Yoshifumi , Nosho Katsuhiko , Shima Kaori , Freed Ellen , Irahara Natsumi , Philips Juliet , Meyerhardt Jeffrey A. , Hornick Jason L. , Shivdasani Ramesh A. , Fuchs Charles S. , Ogino Shuji 
Published: July 2009

Abstract
Purpose: The homeodomain transcription factor CDX2 is a relatively specific immunohistochemical marker for gastrointestinal carcinoma. However, no study has comprehensively examined the relationship between CDX2 expression in colon cancer and clinical, pathologic, prognostic, and molecular features, including microsatellite instability and CpG island methylator phenotype (CIMP).
Experimental Design: Utilizing 621 colorectal cancers with clinical outcome and molecular data, CDX2 loss was detected in 183 (29%) tumors by immunohistochemistry.
Results: In multivariate logistic regression analysis, CDX2 loss was associated with female gender [odds ratio (OR), 3.32; P &lt; 0.0001], CIMP-high (OR, 4.42; P = 0.0003), high tumor grade (OR, 2.69; P = 0.0085), stage IV disease (OR, 2.03; P = 0.019), and inversely with LINE-1 hypomethylation (for a 30% decline; OR, 0.33; P = 0.0031), p53 expression (OR, 0.55; P = 0.011), and β-catenin activation (OR, 0.60; P = 0.037), but not with body mass index, tumor location, microsatellite instability, BRAF, KRAS, PIK3CA, p21, or cyclooxygenase-2. CDX2 loss was not independently associated with patient survival. However, the prognostic effect of CDX2 loss seemed to differ according to family history of colorectal cancer (Pinteraction = 0.0094). CDX2 loss was associated with high overall mortality (multivariate hazard ratio, 2.40; 95% CI, 1.28-4.51) among patients with a family history of colorectal cancer; no such association was present (multivariate hazard ratio, 0.97; 95% CI, 0.66-1.41) among patients without a family history of colorectal cancer.
Conclusions: CDX2 loss in colorectal cancer is independently associated with female gender, CIMP-high, high-level LINE-1 methylation, high tumor grade, and advanced stage. CDX2 loss may be associated with poor prognosis among patients with a family history of colorectal cancer.
Prevention of Radiation-Induced Oral Mucositis after Adenoviral Vector–Mediated Transfer of the Keratinocyte Growth Factor cDNA to Mouse Submandibular Glands
Authors: Zheng Changyu , Cotrim Ana P. , Sunshine Abraham N. , Sugito Takayuki , Liu Lina , Sowers Anastasia , Mitchell James B. , Baum Bruce J. 
Published: July 2009

Abstract
Purpose: The study aims to evaluate if human keratinocyte growth factor (hKGF), secreted after transduction of murine salivary glands with adenoviral vectors, can prevent oral mucositis resulting from radiation.
Experimental Design: Two serotype 5 adenoviral vectors encoding hKGF were constructed: AdEF1α-hKGF and AdLTR2EF1α-hKGF. Female C3H mice, 8 weeks old, were irradiated by single (22.5 Gy) or fractionated (5 × 8 Gy for 5 days) doses to induce oral mucositis (ulcers on tongue). One day before irradiation, the above viral vectors or an empty vector, Adcontrol, was given (1010 particles per gland) to both submandibular glands by retrograde ductal instillation. Each experiment included five groups: no irradiation and irradiation (±Adcontrol, AdEF1α-hKGF, or AdLTR2EF1α-hKGF). Blood, saliva, submandibular glands, and tongue were collected on day 7 for single-dose studies or day 10 for fractionated dosing. hKGF levels were measured by ELISA.
Results: In three separate single-dose irradiation experiments, lingual ulcers were dramatically reduced after either KGF-expressing vector. Similarly, in two separate fractionated irradiation experiments, the hKGF-expressing vectors completely prevented ulcer formation. QPCR data indicated that ∼107 to 108 particles of each vector remained in the targeted submandibular glands at the terminal time. Transgenic hKGF protein was found at high levels in saliva, serum, and submandibular gland extracts.
Conclusions: hKGF gene transfer to salivary glands prevented radiation-induced oral mucositis in mice. This proof of concept study suggests that transgenic hKGF secreted from transduced salivary glands may be useful clinically to prevent oral mucositis caused by radiation.
Response prediction to a multitargeted kinase inhibitor in cancer cell lines and xenograft tumors using high-content tyrosine peptide arrays with a kinetic readout
Authors: Versele Matthias , Talloen Willem , Rockx Cindy , Geerts Tamara , Janssen Boud , Lavrijssen Tom , King Peter , Göhlmann Hinrich W.H. , Page Martin , Perera Tim 
Published: July 2009

Abstract
Multitargeted kinase inhibitors have shown clinical efficacy in a range of cancer types. However, two major problems associated with these drugs are the low fraction of patients for which these treatments provide initial clinical benefit and the occurrence of resistance during prolonged therapy. Several types of predictive biomarkers have been suggested, such as expression level and phosphorylation status of the major targeted kinase(s), mutational status of the kinases involved and of key components of the downstream signaling cascades, and gene expression signatures. In this work, we describe the development of a response prediction platform that does not require prior knowledge of the relevant kinases targeted by the inhibitor; instead, a phosphotyrosine peptide profile using peptide arrays with a kinetic readout is derived in lysates in the presence and absence of a kinase inhibitor. We show in a range of cell lines and in xenograft tumors that this approach allows for the stratification of responders and nonresponders to a multitargeted kinase inhibitor. [Mol Cancer Ther 2009;8(7):1846–55]
Elevated Poly-(ADP-Ribose)-Polymerase Activity Sensitizes Retinoblastoma-Deficient Cells to DNA Damage–Induced Necrosis
Authors: Liu Huiping , Knabb James R. , Spike Benjamin T. , Macleod Kay F. 
Published: July 2009

Abstract
The retinoblastoma (Rb) tumor suppressor is a key regulator of cell cycle checkpoints but also protects against cell death induced by stresses such as DNA damage and death receptor ligation. We report here that cell death of Rb-deficient cells exposed to key genotoxic agents was associated with increased expression of S phase–specific E2F target genes and cell death consistently occurred in the S phase of the cell cycle. Cell cycle arrest induced by serum starvation prevented S phase entry, attenuated DNA damage, and promoted survival, suggesting that Rb-null cells die due to a failure to prevent S phase entry. DNA damage–induced death of Rb-null cells was associated with nucleotide depletion, higher activity of poly-ADP-ribose-polymerase (Parp), and cell death that was primarily necrotic. Knockdown of Parp-1 or chemical inhibition of Parp activity prevented nucleotide depletion and restored the viability of Rb-deficient cells to wild-type levels. Furthermore, chemical inhibition of Parp activity in vivo attenuated the cytotoxic effects of cisplatin against Rb-deficient tumors, arguing that Parp inhibitors should not be used therapeutically in combination with genotoxic drugs against tumors that are inactivated for the Rb tumor suppressor.(Mol Cancer Res 2009;7(7):1099–109)
p21 Expression Is Induced by Activation of Nuclear Nerve Growth Factor–Induced Bα (Nur77) in Pancreatic Cancer Cells
Authors: Lee Syng-Ook , Chintharlapalli Sudhakar , Liu Shengxi , Papineni Sabitha , Cho Sung Dae , Yoon Kyungsil , Safe Stephen 
Published: July 2009

Abstract
1,1-Bis(3′-indolyl)-1-(p-anisyl)methane (DIM-C-pPhOCH3) activates the orphan receptor nerve growth factor–induced Bα (Nur77) in cancer cells, and in this study, DIM-C-pPhOCH3 decreased Panc1 pancreatic cancer cell survival and arrested cells in G0-G1. These responses were accompanied by induction of the cyclin-dependent kinase inhibitor p21 in pancreatic cancer cells. Mechanistic studies showed that induction of p21 mRNA and protein by DIM-C-pPhOCH3 was Nur77 dependent but did not depend on Krüppel-like factor 4, which was also induced by DIM-C-pPhOCH3. Activation of p21 promoter constructs by DIM-C-pPhOCH3 required the GC-rich proximal region of the promoter, and results of RNA interference studies showed that Nur77-dependent activation of the p21 promoter involved interactions with Sp1 and Sp4 but not Sp3. Interactions of Nur77 with the p21 promoter in Panc1 cells treated with DIM-C-pPhOCH3 were also confirmed in chromatin immunoprecipitation assays. These data show that activation of nuclear Nur77 results in a novel pathway for induction of p21, which is independent of Nur77 response elements but dependent on Sp proteins bound to the GC-rich proximal region of the p21 promoter. [Mol Cancer Res 2009;7(7):1169–78]
Bleeding with anticoagulation therapy – Who is at risk, and how best to identify such patients
Authors: Cosmi Benilde , Palareti Gualtiero 
Published: July 2009

SummaryAnticoagulation with vitamin K antagonists (VKAs) has been shown to be effective in the prevention and treatment of thrombotic complications in various clinical settings, including atrial fibrillation (AF), venous thromboembolism (VTE), acute coronary syndromes and after invasive cardiac procedures. Bleeding is the most important complication of VKAs and a major concern for both physicians and patients. The occurrence of bleeding during treatment is not only important for the treated subjects, but also for a correct and complete use of this therapy in all the subjects who have a clear clinical indication for anticoagulation. This review analyses the treatment- and person- associated risk factors for bleeding during VKAs and their combination in clinical prediction rules that have been proposed in the attempt to identify those patients at higher risk for bleeding. The clinical prediction rules may help physicians stratify patients into categories of risk and thus to evaluate their individual risk/benefit ratio of starting or prolonging an anticoagulant treatment.
Heterogeneous pathogenic processes of thrombotic microangiopathies in patients with connective tissue diseases
Authors: Matsuyama Tomomi , Kuwana Masataka , Matsumoto Masanori , Isonishi Ayami , Inokuma Shigeko , Fujimura Yoshihiro 
Published: July 2009

SummaryTo clarify the pathogenic processes of thrombotic microangiopathies (TMAs) in patients with connective tissue disease (CTD), we analysed clinical characteristics and plasma ADAMTS13 levels in 127 patients with CTD-TMAs, including patients with systemic lupus erythematosus (SLE), systemic sclerosis, polymyositis/dermatomyositis, and rheumatoid arthritis (RA), and 64 patients with acquired idiopathic thrombotic thrombocytopenic purpura (ai-TTP). Plasma levels of ADAMTS13 activity, antigen, and inhibitors were determined by enzyme immunoassays. IgG type anti-ADAMTS13 antibodies were also detected by immunoblots using purified ADAMTS13. ADAMTS13 activity was significantly decreased in CTD-TMAs, regardless of the underlying disease, but the frequency of severe deficiency (defined as <0.5% of normal) was lower in CTD-TMA patients than in ai-TTP patients (16.5% vs.70.3%,p<0.01). Severe deficiency of ADAMTS13 activity was predominantly detected in patients with RA and SLE-TMAs, and was closely associated with the presence of anti-ADAMTS13 IgG antibodies. CTD-TMA patients with severe deficiency of ADAMTS13 activity appeared to have lower platelet counts and better therapeutic outcomes. At least two phenotypic TMAs occur in patients with CTDs: a minor population with deficient ADAMTS13 activity caused by neutralising autoantibodies, and a major population with normal or moderately reduced activity. Classifying CTD-TMAs by ADAMTS13 activity may be useful in predicting the clinical course and therapeutic outcomes, as patients with moderately reduced activity are likely to have more prominent renal impairment and poor prognoses.
Anti-cancer properties of low-molecular-weight heparin: Preclinical evidence
Authors: Petersen Lars , Mousa Shaker 
Published: July 2009

SummaryMalignant conditions are frequently associated with a hypercoaguable state, with recurrent thrombosis due to the impact of cancer cells and chemotherapy or radiotherapy on the coagulation cascade. Heparin and, its pharmacokinetically improved versions, low-molecular-weight heparins (LMWH) are effective in the prevention and treatment of thromboembolic events in cancer patients. There are several lines of preclinical evidence suggesting potential benefits of LMWH in hypercoagulation and thrombosis as well as in various processes involved in tumour growth and metastasis.Tinzaparin is a LMWH produced by controlled enzymatic depolymerisation of unfractionated heparin. The efficacy of tinzaparin has been documented in several clinical trials across various conditions and in special patient populations.The main objective of this review is to present the existing knowledge on the preclinical anti-cancer properties of tinzaparin and other LMWH.The evidence for tinzaparin, as well as other LMWH, regarding interference with cancer-induced hypercoagulation, cancer cell proliferation, degradation of extra-cellular matrix, angiogenesis, selectin-mediated binding of platelet and cancer cells, chemokine signalling, tumour progression, and metastasis are reviewed. Certain clinical trials suggest improved survival of cancer patients with deep venous thrombosis treated with LMWH versus unfractionated heparin and when added to the promising preclinical anti-cancer properties of LMWH this warrants further investigations in prospective, randomised, controlled clinical trials in cancer patients.The benefits of LMWH in cancer might at least in part, be independent from its anti-coagulant activities, but may still be partially dependent on its anti-coagulant activities.
Novel evaluation method for densitometric curves of von Willebrand Factor multimers and a new parameter (MMW) to describe the degree of multimersation
Authors: Udvardy Miklós , Szekeres-Csiki Katalin , Hársfalvi Jolán 
Published: July 2009

SummaryVon Willebrand factor (VWF) is built up from a varying number of subunits, of which the larger molecules have higher haemostatic activity. Von Willebrand disease (VWD) and thrombotic thrombocytopenic purpura are the best known disorders with pathognomonic changes of the highly multimerised VWF forms. There is an established method to calculate the relative amount of large oligomers. Our aim is to quantify the degree of VWF multimerisation as well, to complete the densitometric analysis of VWF electrophoresis. After optimisation, we have defined this new parameter (MMW) as the molecular weight corresponding to the lower boundary of the largest 25% of VWF protein. MMW was significantly different (p<.0001) in platelet lysate, normal samples and VWD type 2 samples (10.4, 6.3, 2.1, respectively). There was strong correlation between the MMW and the amount of large multimers in normal samples (r2=0.98) and in platelet lysate. However MMW was higher in latelet lysate, in which VWF is not cleaved by ADAMTS-13, than in healthy samples with the same amount of large multimers. Comparison of the new parameter and the collagen binding and ristocetin cofactor activity of VWF, showed that the functional tests are at least partially determined by the multimerisation; however, about 15% of VWD samples had normal activity to antigen ratios. The quantification of multimerisation aids the classification in these cases, especially at low antigen concentrations, and also might help in the detection of thrombotic conditions.
Venous thromboembolic events in hospitalised medical patients
Authors: Fanikos John , Zayaruzny Maksim , Goldhaber Samuel Z. , Piazza Gregory 
Published: July 2009

SummaryThe number of acutely ill hospitalised medical patients at risk for acute venous thromboembolism (VTE) has not been well defined. Therefore, we used the 2003 United States Healthcare Cost and Utilization Project (HCUP) Nationwide Inpatient Sample database to estimate VTE events among hospitalised medical patients. We then modeled the potential reduction in VTE with universal utilisation of appropriate pharmacological thromboprophylaxis. We calculated that 8,077,919 acutely ill hospitalised medical patients were at risk for VTE. Heart failure, respiratory failure, pneumonia, and cancer were the most common medical diagnoses. We estimated that 196,134 VTE-related events occurred in 2003, afflicting two out of every 100 acutely ill hospitalised medical patients. These VTE-related events were comprised of 122,235 symptomatic deep venous thromboses, 32,654 symptomatic episodes of pulmonary embolism, and 41,245 deaths due to VTE. In our model, rates of pharmacological thromboprophylaxis prescription were low for various acute medical illnesses, ranging from 15.3% to 49.2%. However, with universal thromboprophylaxis, 114,174 VTE-related events would have been prevented. In conclusion, acutely ill medical patients represent a large population vulnerable to the development of VTE during hospitalisation. The number of VTE-related events would be halved with universal thromboprophylaxis. Further efforts focused on improving VTE prevention strategies in hospitalised medical patients are warranted.