bluuebunny/crossref_metadata_2025_split huggingface dataset:
New Strategies in Pancreatic Cancer: Emerging Epidemiologic and Therapeutic Concepts
Authors: Li Donghui , Abbruzzese James L. 
Published: July 2010

Abstract
Pancreatic cancer (PC) is a highly lethal disease with complex etiology involving both environmental and genetic factors. Although cigarette smoking is known to explain 25% of cases, data from recent studies suggest that obesity and long-term type II diabetes are two major modifiable risk factors for PC. Furthermore, obesity and diabetes seem to affect the clinical outcome of patients with PC. Understanding the mechanistic effects of obesity and diabetes on the pancreas may identify new strategies for prevention or therapy. Experimental and epidemiologic evidence suggests that the antidiabetic drug metformin has protective antitumor activity in PC. In addition to insulin resistance and inflammation as mechanisms of carcinogenesis, obesity and diabetes are linked to impairments in endothelial function and coagulation status, which increase the risks of thrombosis and angiogenesis and, in turn, the risk of PC development and progression. The associations of the ABO blood group gene and NR5A2 gene variants with PC discovered by recent genome-wide association studies may link insulin resistance, inflammation, and thrombosis to pancreatic carcinogenesis. These exciting findings open new avenues for understanding the etiology of PC and provide opportunities for developing novel strategies for prevention and treatment of this disease. Clin Cancer Res; 16(17); 4313–8. ©2010 AACR.
Targeting Cell Division Cycle 7 Kinase: A New Approach for Cancer Therapy
Authors: Montagnoli Alessia , Moll Jürgen , Colotta Francesco 
Published: July 2010

Abstract
The cell division cycle 7 (Cdc7) is a serine-threonine kinase, originally discovered in budding yeast, required to initiate DNA replication. Human Cdc7 phosphorylates the minichromosome maintenance protein 2 (Mcm2), a component of the DNA replicative helicase needed for genome duplication. Inhibition of Cdc7 in cancer cells impairs progression through S phase, inducing a p53-independent apoptotic cell death, whereas in normal cells, it does not affect cell viability. Small molecule compounds able to interfere with Cdc7 activity have been identified and shown to be effective in controlling tumor growth in animal models. Two Cdc7 inhibitors are currently in phase I clinical development. Inhibition of Cdc7 kinase activity in cancer cells restricts DNA replication and induces apoptotic cell death by an unprecedented molecular mechanism of action. Clin Cancer Res; 16(18); 4503–8. ©2010 AACR.
Immunologic Response to Xenogeneic gp100 DNA in Melanoma Patients: Comparison of Particle-Mediated Epidermal Delivery with Intramuscular Injection
Authors: Ginsberg Brian A. , Gallardo Humilidad F. , Rasalan Teresa S. , Adamow Matthew , Mu Zhenyu , Tandon Sapna , Bewkes Barrett B. , Roman Ruth-Ann , Chapman Paul B. , Schwartz Gary K. , Carvajal Richard D. , Panageas Katherine S. , Terzulli Stephanie L. , Houghton Alan N. , Yuan Jianda D. , Wolchok Jedd D. 
Published: July 2010

AbstractPurpose: Prior studies show that i.m. injection of xenogeneic orthologues of melanosomal antigens (tyrosinase, gp100) induces CD8+ T-cell responses to the syngeneic protein. To further define the optimal vaccination strategy, we conducted a pilot clinical trial comparing i.m. injection with particle-mediated epidermal delivery (PMED).Experimental Design: Human leukocyte antigen (HLA)-A*0201+ disease–free melanoma patients were randomized to the PMED or i.m. arm, receiving eight vaccinations over 4 months. Patients received 4 μg or 2,000 μg per injection, respectively, of mouse gp100 DNA. Peripheral blood mononuclear cells were collected, cultured with gp100 peptides, and analyzed by tetramer and intracellular cytokine staining for responses to HLA-A*0201–restricted gp100 epitopes [gp100209-217 (ITDQVPFSV) and gp100280-288 (YLEPGPVTA)].Results: Twenty-seven patients with stage IIB-IV melanoma were analyzable for immune response. The only common toxicity was grade 1 injection site reaction in nine patients with no intergroup difference, and one dose-limiting toxicity of acute hypersensitivity occurred in a PMED patient with undiagnosed gold allergy. Four of 27 patients produced gp100 tetramer+CD8+ T cells, all carrying the CCR7loCD45RAlo effector-memory phenotype. Five of 27 patients generated IFN-γ+CD8+ T cells, one who was also tetramer-positive. Overall, vaccination induced a response in 30% of patients, which was not significantly associated with study arm or clinical outcome. However, the PMED group showed a trend toward increased IFN-γ+CD8+ T-cell generation (P = 0.07).Conclusion: A comparable efficacy and safety profile was shown between the i.m. and PMED arms, despite a significantly decreased dose of DNA used for PMED injection. Clin Cancer Res; 16(15); 4057–65. ©2010 AACR.
Systemic Administration of Polymeric Nanoparticle-Encapsulated Curcumin (NanoCurc) Blocks Tumor Growth and Metastases in Preclinical Models of Pancreatic Cancer
Authors: Bisht Savita , Mizuma Masamichi , Feldmann Georg , Ottenhof Niki A. , Hong Seung-Mo , Pramanik Dipankar , Chenna Venugopal , Karikari Collins , Sharma Rajni , Goggins Michael G. , Rudek Michelle A. , Ravi Rajani , Maitra Amarnath , Maitra Anirban 
Published: July 2010

AbstractCurcumin or diferuloylmethane is a yellow polyphenol extracted from the rhizome of turmeric (Curcuma longa). A large volume (several hundreds) of published reports has established the anticancer and chemopreventative properties of curcumin in preclinical models of every known major cancer type. Nevertheless, the clinical translation of curcumin has been significantly hampered due to its poor systemic bioavailability, which mandates that patients consume up to 8 to 10 g of the free drug orally each day to achieve detectable levels in circulation. We have engineered a polymeric nanoparticle encapsulated curcumin formulation (NanoCurc) that shows remarkably higher systemic bioavailability in plasma and tissues compared with free curcumin upon parenteral administration. In xenograft models of human pancreatic cancer established in athymic mice, administration of parenteral NanoCurc significantly inhibits primary tumor growth in both subcutaneous and orthotopic settings. The combination of parenteral NanoCurc with gemcitabine results in enhanced tumor growth inhibition versus either single agent, suggesting an additive therapeutic influence in vivo. Furthermore, this combination completely abrogates systemic metastases in orthotopic pancreatic cancer xenograft models. Tumor growth inhibition is accompanied by significant reduction in activation of nuclear factor-κB, as well as significant reduction in expression of matrix metalloproteinase-9 and cyclin D1, in xenografts treated with NanoCurc and gemcitabine. NanoCurc is a promising new formulation that is able to overcome a major impediment for the clinical translation of curcumin to cancer patients by improving systemic bioavailability, and by extension, therapeutic efficacy. Mol Cancer Ther; 9(8); 2255–64. ©2010 AACR.
A Review of Trabectedin (ET-743): A Unique Mechanism of Action
Authors: D'Incalci Maurizio , Galmarini Carlos M. 
Published: July 2010

Abstract
Trabectedin (ET-743) is a marine alkaloid isolated from the Caribbean tunicate Ecteinascidia turbinata, with a chemical structure characterized by three fused tetrahydroisoquinoline rings. Two of these rings (subunits A and B) provide the framework for covalent interaction with the minor groove of the DNA double helix, whereas the third ring (subunit C) protrudes from the DNA duplex, apparently allowing interactions with adjacent nuclear proteins. The compound's chemical interactions trigger a cascade of events that interfere with several transcription factors, DNA binding proteins, and DNA repair pathways, likely to be different from other DNA-interacting agents. Trabectedin also causes modulation of the production of cytokines and chemokines by tumor and normal cells, suggesting that the antitumor activity could also be ascribed to changes in the tumor microenvironment. The promising data on the combination of trabectedin with other anticancer agents, observed in preclinical systems, have prompted several clinical studies that are currently ongoing. One of these combinations (trabectedin-pegylated liposomal doxorubicin) was recently authorized by the European Commission for the treatment of patients with relapsed platinum-sensitive ovarian cancer. Mol Cancer Ther; 9(8); 2157–63. ©2010 AACR.
Deletion at Fragile Sites Is a Common and Early Event in Barrett's Esophagus
Authors: Lai Lisa A. , Kostadinov Rumen , Barrett Michael T. , Peiffer Daniel A. , Pokholok Dimitry , Odze Robert , Sanchez Carissa A. , Maley Carlo C. , Reid Brian J. , Gunderson Kevin L. , Rabinovitch Peter S. 
Published: July 2010

Abstract
Barrett's esophagus (BE) is a premalignant intermediate to esophageal adenocarcinoma, which develops in the context of chronic inflammation and exposure to bile and acid. We asked whether there might be common genomic alterations that could be identified as potential clinical biomarker(s) for BE by whole genome profiling. We detected copy number alterations and/or loss of heterozygosity at 56 fragile sites in 20 patients with premalignant BE. Chromosomal fragile sites are particularly sensitive to DNA breaks and are frequent sites of rearrangement or loss in many human cancers. Seventy-eight percent of all genomic alterations detected by array-CGH were associated with fragile sites. Copy number losses in early BE were observed at particularly high frequency at FRA3B (81%), FRA9A/C (71.4%), FRA5E (52.4%), and FRA 4D (52.4%), and at lower frequencies in other fragile sites, including FRA1K (42.9%), FRAXC (42.9%), FRA 12B (33.3%), and FRA16D (33.3%). Due to the consistency of the region of copy number loss, we were able to verify these results by quantitative PCR, which detected the loss of FRA3B and FRA16D, in 83% and 40% of early molecular stage BE patients, respectively. Loss of heterozygosity in these cases was confirmed through pyrosequencing at FRA3B and FRA16D (75% and 70%, respectively). Deletion and genomic instability at FRA3B and other fragile sites could thus be a biomarker of genetic damage in BE patients and a potential biomarker of cancer risk. Mol Cancer Res; 8(8); 1084–94. ©2010 AACR.
Proteomic Profiling of Potential Molecular Targets of Methyl-Selenium Compounds in the Transgenic Adenocarcinoma of Mouse Prostate Model
Authors: Zhang Jinhui , Wang Lei , Anderson Lorraine B. , Witthuhn Bruce , Xu Yanji , Lü Junxuan 
Published: July 2010

Abstract
Because the Selenium (Se) and Vitamin E Cancer Prevention Trial (SELECT) failed to show the efficacy of selenomethionine for prostate cancer prevention, there is a critical need to identify safe and efficacious Se forms for future trials. We have recently shown significant preventive benefit of methylseleninic acid (MSeA) and Se-methylselenocysteine (MSeC) in the transgenic adenocarcinoma mouse prostate (TRAMP) model by oral administration. The present work applied iTRAQ proteomic approach to profile protein changes of the TRAMP prostate and to characterize their modulation by MSeA and MSeC to identify their potential molecular targets. Dorsolateral prostates from wild-type mice at 18 weeks of age and TRAMP mice treated with water (control), MSeA, or MSeC (3 mg Se/kg) from 8 to 18 weeks of age were pooled (9-10 mice per group) and subjected to protein extraction, followed by protein denaturation, reduction, and alkylation. After tryptic digestion, the peptides were labeled with iTRAQ reagents, mixed together, and analyzed by two-dimensional liquid chromatography/tandem mass spectrometry. Of 342 proteins identified with &gt;95% confidence, the expression of 75 proteins was significantly different between TRAMP and wild-type mice. MSeA mainly affected proteins related to prostate functional differentiation, androgen receptor signaling, protein (mis)folding, and endoplasmic reticulum–stress responses, whereas MSeC affected proteins involved in phase II detoxification or cytoprotection, and in stromal cells. Although MSeA and MSeC are presumed precursors of methylselenol and were equally effective against the TRAMP model, their distinct affected protein profiles suggest biological differences in their molecular targets outweigh similarities. Cancer Prev Res; 3(8); 994–1006. ©2010 AACR.
Vascular Endothelial Growth Factor Receptor 2–Targeted Chemoprevention of Murine Lung Tumors
Authors: Karoor Vijaya , Le Mysan , Merrick Daniel , Dempsey Edward C. , Miller York E. 
Published: July 2010

Abstract
No clinically effective chemoprevention for lung cancer has been found. Angiogenesis is an early feature of both adenocarcinoma and squamous cell lung cancer. We investigated the effects of vascular endothelial growth factor (VEGF) receptor-2 (VEGFR-2) inhibition on lung carcinogenesis in a murine model of adenocarcinoma. The VEGFR-2 tyrosine kinase inhibitor, vandetanib, was given to FVB/N mice in chow for 7 days at varying doses to show pharmacologic activity by inhibition of VEGF-mediated VEFGR-2 and ERK phosphorylation. Plasma levels corroborated adequate dosage. For chemoprevention experiments, mice were injected i.p. with 1 mg/g of urethane, a carcinogen found in tobacco smoke. Chow containing vandetanib, 75 mg/kg/d, or control chow was given to mice, starting 7 days after urethane administration. Sixteen weeks after urethane injection, mice were sacrificed, tumors enumerated and measured. Vandetanib resulted in reductions in tumor multiplicity (6.5 ± 0.86 versus 1.0 ± 0.30, P = 0.001) and average tumor volume (0.85 ± 0.10 versus 0.15 ± 0.09 mm3, P = 0.001), but not incidence (71% versus 100%, P = ns), compared with control. As vandetanib has other activities besides VEGFR-2 tyrosine kinase inhibition, we gave the anti–VEGFR-2 monoclonal antibody, DC101, for weeks 11 to 15 of a urethane carcinogenesis protocol with an arrest in tumor volume increase, but no change in multiplicity or incidence. Further investigation of the chemopreventive effect of vandetanib and other VEGF signaling inhibitors is needed. Cancer Prev Res; 3(9); 1141–7. ©2010 AACR.
A randomised determination of the Effect of Fluvastatin and Atorvastatin on top of dual antiplatelet treatment on platelet aggregation after implantation of coronary drug-eluting stents
Authors: Abrecht Linda , Zwahlen Marcel , Schmidlin Kurt , Windecker Stephan , Meier Bernhard , Haeberli Andre , Hess Otto , Wenaweser Peter , Eshtehardi Parham 
Published: July 2010

SummaryDrug-drug interaction between statins metabolised by cytochrome P450 3A4 and clopidogrel have been claimed to attenuate the inhibitory effect of clopidogrel. However, published data regarding this drug-drug interaction are controversial. We aimed to determine the effect of fluvastatin and atorvastatin on the inhibitory effect of dual anti-platelet therapy with acetylsalicylic acid (ASA) and clopidogrel. One hundred one patients with symptomatic stable coronary artery disease undergoing percutaneous coronary intervention and drug-eluting stent implantation were enrolled in this prospective randomised study. After an interval of two weeks under dual antiplatelet therapy with ASA and clopidogrel, without any lipid-lowering drug, 87 patients were randomised to receive a treatment with either fluvastatin 80 mg daily or atorvastatin 40 mg daily in addition to the dual antiplatelet therapy for one month. Platelet aggregation was assessed using light transmission aggregometry and whole blood impedance platelet aggregometry prior to randomisation and after one month of receiving assigned statin and dual antiplatelet treatment. Platelet function assessment after one month of statin and dual antiplatelet therapy did not show a significant change in platelet aggregation from 1st to 2nd assessment for either statin group. There was also no difference between atorvastatin and fluvastatin treatment arms. In conclusion, neither atorvastatin 40 mg daily nor fluvastatin 80 mg daily administered in combination with standard dual antiplatelet therapy following coronary drug-eluting stent implantation significantly interfere with the antiaggregatory effect of ASA and clopidogrel.
Risk of drug-eluting stent thrombosis in patients receiving proton pump inhibitors
Authors: Sibbing Dirk , Sonntag Ulrich , Ellert Julia , Schulz Stefanie , Byrne Robert , Mehilli Julinda , Schömig Albert , Kastrati Adnan , Sarafoff Nikolaus 
Published: July 2010

SummaryClopidogrel is a prodrug that is converted via the hepatic cytochrome P450 system into its active thiol metabolite. Evidence is accumulating that proton pump inhibitors (PPIs) inhibit this enzymatic pathway and may therefore attenuate the antiplatelet effect of clopidogrel. The objective of this study was to investigate whether patients on clopidogrel therapy after drug-eluting stent (DES) placement who also receive a PPI are at higher risk of stent thrombosis (ST). This is a retrospective analysis of patients who received dual antiplatelet treatment including clopidogrel after DES placement. Outcomes were compared according to PPI therapy. The primary endpoint was the incidence of definite ST at 30 days. Secondary endpoints were death, combined death or ST and myocardial infarction (MI). The study population included 3,338 patients and 698 patients (20.9%) received PPIs. Patients receiving a PPI had a higher risk profile at baseline. Multivariate analysis showed that PPI treatment was not independently associated with the occurrence of ST [adjusted HR 1.8 (95% CI: 0.7–4.7), p=0.23] or MI [adjusted HR 1.3 (0.8–2.3), p=0.11]. PPI treatment was significantly associated with death [adjusted HR 2.2 (1.1–4.3), p=0.02] and death or ST [adjusted HR 3.3(1.7–6.7), p=0.02]. Concomitant treatment with a PPI in patients receiving dual antiplatelet treatment after coronary stenting is not an independent predictor of ST. The higher mortality is probably due to confounding as patients on PPIs had a higher risk profile at baseline.
New insights into the structural elements involved in the skin haemorrhage induced by snake venom metalloproteinases
Authors: Oliveira Ana , Paes Leme Adriana , Asega Amanda , Camargo Antonio , Fox Jay , Serrano Solange 
Published: July 2010

SummaryHaemorrhage induced by snake venom metalloproteinases (SVMPs) is a complex phenomenon resulting in capillary disruption and extravasation. This study analysed structural elements important for the interaction of four Bothrops jararaca SVMPs of different domain organisation and glycosylation levels with plasma and extracellular matrix proteins: HF3 (P-III class) is highly glycosylated and ~80 times more haemorrhagic than bothropasin (P-III class), which has a minor carbohydrate moiety; BJ-PI (P-I class) is not haemorrhagic and the DC protein is composed of disintegrin-like/cysteine-rich domains of bothropasin. HF3, bothropasin and BJ-PI showed different degradation profiles of fibrinogen, fibronectin, vitronectin, von Willebrand factor, collagens IV and VI, laminin and Matrigel™; however, only bothropasin degraded collagen I. In solid-phase binding assays HF3 and bothropasin interacted with fibrinogen, fibronectin, laminin, collagens I and VI; the DC protein bound only to collagens I and VI; however, no binding of BJ-PI to these proteins was detected. N-deglycosylation caused loss of structural stability of bothropasin and BJ-PI but HF3 remained intact, although its haemorrhagic and fibrinogenolytic activities were partially impaired. Nevertheless, N-deglycosylated HF3 bound with higher affinity to collagens I and VI, although its proteolytic activity upon these collagens was not enhanced. This study demonstrates that features of carbohydrate moieties of haemorrhagic SVMPs may play a role in their interaction with substrates of the extracellular matrix, and the ability of SVMPs to degrade proteins in vitro does not correlate to their ability to cause haemorrhage, suggesting that novel, systemic approaches are necessary for understanding the mechanism of haemorrhage generation by SVMPs.
Recombinant activated factor VII does not reduce bleeding in rabbits treated with aspirin and clopidogrel
Authors: Hindy-François Clemence , Bachelot-Loza Christilla , Bonniec Bernard Le , Grelac Francoise , Dizier Blandine , Godier Anne , Emmerich Joseph , Gaussem Pascale , Samama Charles-Marc 
Published: July 2010

SummaryCombined antiplatelet agents (cAPA), aspirin plus clopidogrel, increase the risk of bleeding. We hypothesised that recombinant activated FVIIa (rFVIIa), which normalises thrombin generation in platelet-rich plasma from patients treated with cAPA, could limit this bleeding risk. It was the objective of this study to investigate the efficacy and safety of rFVIIa compared to placebo, in a bleeding and thrombosis model in rabbits treated with aspirin and clopidogrel. New-Zealand rabbits, randomised into two groups (Placebo1, n=36 ; cAPA, n=34), were anaesthetised, ventilated and monitored for blood pressure, temperature and carotid blood flow. The Folts model was applied to a carotid artery. Cyclic flow reductions (CFR) were recorded over a first 20-min period (Obs1). Each rabbit was then randomly assigned into one of three subgroups (Placebo2, 40 μg/kg rFVIIa, 160 μg/kg rFVIIa) and CFR were monitored for a second 20-min period (Obs2). Ear bleeding time (BT) was measured at the end of each period. Hepatosplenic (HS) section was performed at the end of the experiment and HS blood loss defines the primary endpoint. Secondary endpoints were thrombosis (CFR), prothrombin time, platelet aggregation, and thrombin generation. Non- parametric statistical tests were used (p<0.05). cAPA significantly increased HS blood loss, BT and suppressed CFR compared to Placebo1 (p<0.05). rFVIIa injection did not modify HS blood loss, BT or CFR rate in Placebo1 rabbits nor in cAPA animals. These effects were unaffected by either rFVIIa dose. rFVIIa accelerated thrombin generation but had no effect on platelet aggregation in citrated platelet-rich plasma. rFVIIa did not modify HS blood loss associated with cAPA in rabbits.
Clinical and genetic findings in five female patients with haemophilia A: Identification of a novel missense mutation, p.Phe2127Ser
Authors: Venceslá Adoración , Alvárez-Román María Teresa , Rivas Isabel , Fernández Ihosvany , Butta Nora , Baena Manel , Fuentes-Prior Pablo , Tizzano Eduardo , Jiménez-Yuste Víctor , Martín-Salces Mónica 
Published: July 2010

SummarySevere manifestations of X-linked recessive disorders such as haemophilia A (HA) are rare in females. Here we describe the clinical and genetic findings in five female HA patients from two different Spanish families. Three sisters born to consanguineous parents presented moderate bleeding due to a known mutation (p.Ser1791Pro) detected in a homozygous state. In the second family, two sisters with Morris syndrome (46,XY) and mild/moderate illness were hemizygous for a novel missense mutation, p.Phe2127Ser. The mutation is predicted to impair binding to the factor VIII (FVIII) carrier protein, von Willebrand factor, and thus increased clearance of FVIII from plasma. Clinical and molecular characterisation of these patients is essential to optimise follow-up, genetic counselling and treatment of the disease.