bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Phase I Study of EKB-569 in Combination with Capecitabine in Patients with Advanced Colorectal Cancer
Authors: Laheru Dan , Croghan Gary , Bukowski Ronald , Rudek Michelle , Messersmith Wells , Erlichman Charles , Pelley Robert , Jimeno Antonio , Donehower Ross , Boni Joseph , Abbas Richat , Martins Patricia , Zacharchuk Charles , Hidalgo Manuel 
Published: September 2008

Abstract
Purpose: To determine the maximum tolerated dose (MTD), characterize the principal toxicities, and assess the pharmacokinetics of EKB-569, an oral selective irreversible inhibitor of the epidermal growth factor receptor tyrosine kinase, in combination with capecitabine in patients with advanced colorectal cancer.
Experimental Design: Patients were treated with EKB-569 daily for 21 days and capecitabine twice daily for 14 days of a 21-day cycle. The dose levels of EKB-569 (mg/day) and capecitabine (mg/m2 twice daily) assessed were 25/750, 50/750, 50/1,000 and 75/1,000. An expanded cohort was enrolled at the MTD to better study toxicity and efficacy. Samples of plasma were collected to characterize the pharmacokinetics of the agents. Treatment efficacy was assessed every other cycle.
Results: A total of 37 patients, the majority of whom had prior chemotherapy, received a total of 163 cycles of treatment. Twenty patients were treated at the MTD, 50 mg EKB-569, daily and 1,000 mg/m2 capecitabine twice daily. Dose-limiting toxicities were diarrhea and rash. No patients had complete or partial responses but 48% had stable disease. The conversion of capecitabine to 5-fluorouracil was higher for the combination of EKB-569 and capecitabine (321 ± 151 ng*h/mL) than for capecitabine alone (176 ± 62 ng*hours/mL; P = 0.0037).
Conclusion: In advanced colorectal cancer, 50 mg EKB-569 daily can be safely combined with 1,000 mg/m2 capecitabine twice a day. A statistically significant increase in plasma levels of 5-fluorouracil for the combination of EKB-569 and capecitabine may be due to the single-dose versus multiple-dose exposure difference, variability in exposure or a potential drug interaction.
Eradication of Ovarian Tumor Xenografts by Locoregional Administration of Targeted Immunotherapy
Authors: De Cesare Michelandrea , Calcaterra Claudia , Pratesi Graziella , Gatti Laura , Zunino Franco , Mènard Sylvie , Balsari Andrea 
Published: September 2008

AbstractPurpose: Oligodeoxynucleotides containing unmethylated CpG motifs (CpG-ODN) are potent activators of innate and adaptive immunity. Recognition of CpG-ODN is mediated by Toll-like receptor 9 expressed by immune cells, endothelial and epithelial cells, and fibroblasts. We examined the antitumor effect of CpG-ODN and the role of administration route on human ovarian cancers growing in the peritoneal cavity of nude mice.Experimental Design: Mice implanted i.p. with human ovarian carcinoma cells were treated i.p., s.c., or i.v. and assessed for survival and tumor-free incidence. Peritoneal washings were analyzed for keratinocyte chemokine production and for functional and phenotypic profiles as indicators of the cell types involved in mediating the antitumor effects.Results: IGROV-1-bearing mice treated i.p. survived significantly longer than those treated i.v. or s.c. (P = 0.0005), and nearly half of them (8 of 17) were tumor-free by the end of the experiment, a rate never achieved using a variety of chemotherapeutic drugs. High rates of tumor-free mice were observed in three other ovarian tumor xenografts treated i.p. Compared with peritoneal washings of mice treated s.c. or i.v., those from mice treated i.p. showed the highest level of serum and tissue keratinocyte chemokine, the highest number of natural killer cells and neutrophils, and the highest antiproliferative activity in vitro.Conclusions: The superior antitumor effect obtained by locoregional administration of CpG-ODN in i.p. tumor-bearing mice with a limited adaptive immune response points to the importance of innate effector cells amplification at the site of tumor growth and suggests the promise of i.p. CpG-ODN in clinical trials for ovarian cancer.
Vorinostat and Sorafenib Synergistically Kill Tumor Cells via FLIP Suppression and CD95 Activation
Authors: Zhang Guo , Park Margaret A. , Mitchell Clint , Hamed Hossein , Rahmani Mohamed , Martin Aditi Pandya , Curiel David T. , Yacoub Adly , Graf Martin , Lee Ray , Roberts John D. , Fisher Paul B. , Grant Steven , Dent Paul 
Published: September 2008

Abstract
Purpose and Design: Mechanism(s) by which the multikinase inhibitor sorafenib and the histone deacetylase inhibitor vorinostat interact to kill hepatic, renal, and pancreatic adenocarcinoma cells has been defined.
Results: Low doses of sorafenib and vorinostat interacted in vitro in a synergistic fashion to kill hepatic, renal, and pancreatic adenocarcinoma cells in multiple short-term viability (24-96 h) and in long-term colony formation assays. Cell killing was suppressed by inhibition of cathepsin proteases and caspase-8 and, to a lesser extent, by inhibition of caspase-9. Twenty-four hours after exposure, the activities of extracellular signal-regulated kinase 1/2, AKT, and nuclear factor-κB were only modestly modulated by sorafenib and vorinostat treatment. However, 24 h after exposure, sorafenib- and vorinostat-treated cells exhibited markedly diminished expression of c-FLIP-s, full-length BID, BCL-2, BCL-XL, MCL-1, XIAP, increased expression of BIM, and increased activation of BAX, BAK, and BAD. Expression of eIF2α S51A blocked sorafenib- and vorinostat-induced suppression of c-FLIP-s levels and overexpression of c-FLIP-s abolished lethality. Sorafenib and vorinostat treatment increased surface levels of CD95 and CD95 association with caspase-8. Knockdown of CD95 or FADD expression significantly reduced sorafenib/vorinostat-mediated lethality.
Conclusions: These data show that combined exposure of epithelial tumor cell types to sorafenib and vorinostat diminishes expression of multiple antiapoptotic proteins and promotes activation of the CD95 extrinsic apoptotic and the lysosomal protease pathways, and that suppression of c-FLIP-s expression represents a critical event in transduction of the proapoptotic signals from CD95 to promote mitochondrial dysfunction and death.
Postradiation Sensitization of the Histone Deacetylase Inhibitor Valproic Acid
Authors: Chinnaiyan Prakash , Cerna David , Burgan William E. , Beam Katie , Williams Eli S. , Camphausen Kevin , Tofilon Philip J. 
Published: September 2008

Abstract
Purpose: Preclinical studies evaluating histone deacetylase (HDAC) inhibitor-induced radiosensitization have largely focused on the preirradiation setting based on the assumption that enhanced radiosensitivity was mediated by changes in gene expression. Our previous investigations identified maximal radiosensitization when cells were exposed to HDAC inhibitors in both the preradiation and postradiation setting. We now expand on these studies to determine whether postirradiation exposure alone affects radiosensitivity.
Experimental Design: The effects of the HDAC inhibitor valproic acid (VA) on postirradiation sensitivity in human glioma cell lines were evaluated using a clonogenic assay, exposing cells to VA up to 24 h after irradiation. DNA damage repair was evaluated using γH2AX and 53BP1 foci and cell cycle phase distribution was analyzed by flow cytometry. Western blot of acetylated γH2AX was done following histone extraction on AUT gels.
Results: VA enhanced radiosensitivity when delivered up to 24 h after irradiation. Cells accumulated in G2-M following irradiation, although they returned to baseline at 24 h, mitigating the role of cell cycle redistribution in postirradiation sensitization by VA. At 12 h after irradiation, significant γH2AX and 53BP1 foci dispersal was shown in the control, although cells exposed to VA after irradiation maintained foci expression. VA alone had no effect on the acetylation or phosphorylation of H2AX, although it did acetylate radiation-induced γH2AX.
Conclusions: These results indicate that VA enhances radiosensitivity at times up to 24 h after irradiation, which has direct clinical application.
Gemtuzumab Ozogamicin as Part of Reduced-Intensity Conditioning for Allogeneic Hematopoietic Cell Transplantation in Patients with Relapsed Acute Myeloid Leukemia
Authors: Bornhäuser Martin , Illmer Thomas , Oelschlaegel Uta , Schetelig Johannes , Ordemann Rainer , Schaich Markus , Hänel Mathias , Schuler Ulrich , Thiede Christian , Kiani Alexander , Platzbecker Uwe , Ehninger Gerhard 
Published: September 2008

Abstract
Purpose: Gemtuzumab ozogamicin (GO) has been associated with an increased risk of liver sinusoidal obstruction syndrome (SOS) when applied within 3 months of allogeneic hematopoietic cell transplantation (HCT). We hypothesized that GO might be safe and effective as part of a reduced-intensity conditioning regimen as salvage therapy of CD33+ acute myeloid leukemia.
Experimental Design: Thirty-one patients with acute myeloid leukemia which relapsed following conventional therapy (n = 15), autologous (n = 3), or allogeneic (n = 13) HCT were included in a prospective phase I/II trial. The preparative regimen contained 6 and 3 mg/m2 of GO on days −21 and −14 before transplantation, leading to a reduction of marrow blasts in 18 patients (58%). Eight patients received further cytoreductive chemotherapy before conditioning therapy was initiated. Fludarabine-based reduced-intensity (n = 11) or nonmyelablative (n = 16) conditioning and peripheral blood stem cell infusion from related (n = 6) or unrelated (n = 21) donors could be done in 27 patients during cytopenia.
Results: Primary engraftment occurred in all evaluable patients. Only one case of reversible hepatic sinusoidal obstruction syndrome was documented. Non–relapse mortality until day 100 was 22% (n = 6). The probabilities of overall and disease-free survival at 24 months were 39% and 35%, respectively. Relapse of leukemia occurring between 2 and 24 months after transplantation (median, 8 months) was the major reason for treatment failure and death.
Conclusion: These data suggest that GO can be combined with reduced-intensity conditioning even after previous autologous or allogeneic HCT.
Expanding the Roles for Pregnane X Receptor in Cancer: Proliferation and Drug Resistance in Ovarian Cancer
Authors: Gupta Divya , Venkatesh Madhukumar , Wang Hongwei , Kim Sean , Sinz Michael , Goldberg Gary L. , Whitney Kathleen , Longley Clifford , Mani Sridhar 
Published: September 2008

Abstract
Purpose: We examined the presence of the pregnane X receptor (PXR) and its effects on ovarian cancer cells after activation by its cognate ligand.
Experimental Design: SKOV-3 and OVCAR-8 ovarian carcinoma cells were analyzed for expression of PXR by quantitative reverse transcription-PCR and Western blot. Human ovarian cancer tissue was also analyzed for PXR expression by immunochemistry. Ligand (agonist)–induced PXR target genes were analyzed in SKOV-3 cells by quantitative reverse transcription-PCR. SKOV-3 cell proliferation was assessed by MTT assay. In vivo confirmation of in vitro effects of PXR ligands were done in NOD.SCID mice carrying SKOV-3 xenografts.
Results: PXR is expressed in ovarian cancer cells. In SKOV-3 cells, PXR is functional and its activation by cognate ligands induces PXR target genes (CYP2B6, CYP3A4, and UGT1A1) but not MDR1 and MRP2. PXR activation in SKOV-3 cells induces cell proliferation and drug resistance. In mice harboring SKOV-3 xenografts, rifampicin (PXR agonist) induces cell proliferation and tumor growth.
Conclusion: PXR activation, regardless of the type of ligand agonist present, promotes the “malignant” phenotype of cancer cells. These data serve as the basis for finding novel nontoxic inhibitors of PXR activation as a method to control cell growth and prevent induction of drug resistance.
The Relationship Between Staff Members' Working Conditions and Patients' Perceptions of the Treatment Environment
Authors: Rossberg Jan Ivar , Melle Ingrid , Opjordsmoen Stein , Friis Svein 
Published: August 2008

Background: The psychosocial climate of inpatient units has proved to be related to both patient satisfaction and outcome. Aims: The aims of the study were twofold: to study the relationship between patient and staff satisfaction, and to study the relationship between the patients' perception of the treatment environment and the perceived working conditions of the staff. Method: A total of 129 different patients completed the Ward Atmosphere Scale (WAS) and a General Satisfaction Index (GSI) at 11 time points between 1981 and 2000. Staff members completed the Working Environment Scale-10 (WES-10) and the GSI. Z-scores were calculated to describe the fluctuations in the WAS, WES-10 and the GSI subscale scores. Results: The study revealed a strong correlation between patient satisfaction and staff satisfaction. Staff satisfaction correlated significantly with the WAS subscales of Practical orientation and Staff control. Furthermore, the study revealed a significant correlation between patient satisfaction and staff members' perception on the WES-10 subscale of Self-realization. Conclusion: This exploratory study revealed that the working conditions of staff are related to both patient satisfaction and the patients' perceptions of the treatment environment. A satisfactory working environment for psychiatric staff members seems important for the quality of care perceived by patients.
Genetic testing for asthma
Authors: Koppelman G. H. , te Meerman G. J. , Postma D. S. 
Published: August 2008

Asthma is a genetically complex disease caused by multiple genetic and environmental factors. An increasing number of asthma susceptibility genes are currently being identified. The present study addresses the question as to whether this genetic information can be used to predict asthma, particularly in pre-school children.The predictive value of a single gene test in a complex disease is very limited for diagnostic or preventive purposes and thus cannot be recommended. Based on data of simulation studies and other complex diseases, the use of genetic profiling that incorporates multiple genetic risk factors holds promise for clinical application. The results of genome-wide association studies will be crucial in establishing this genetic risk profile for asthma.In the future, asthma prediction may be possible, based on a prediction model that incorporates genes, personal factors and environmental risk factors. Studies in general and at-risk populations are needed to investigate and validate this approach.
Development of human antibody fragments using antibody phage display for the detection and diagnosis of Venezuelan equine encephalitis virus (VEEV)
Authors: Kirsch Martina Inga , Hülseweh Birgit , Nacke Christoph , Rülker Torsten , Schirrmann Thomas , Marschall Hans-Jürgen , Hust Michael , Dübel Stefan 
Published: September 2008

AbstractBackgroundVenezuelan equine encephalitis virus (VEEV) belongs to the Alphavirus group. Several species of this family are also pathogenic to humans and are recognized as potential agents of biological warfare and terrorism. The objective of this work was the generation of recombinant antibodies for the detection of VEEV after a potential bioterrorism assault or an natural outbreak of VEEV.ResultsIn this work, human anti-VEEV single chain Fragments variable (scFv) were isolated for the first time from a human naïve antibody gene library using optimized selection processes. In total eleven different scFvs were identified and their immunological specificity was assessed. The specific detection of the VEEV strains TC83, H12/93 and 230 by the selected antibody fragments was proved. Active as well as formalin inactivated virus particles were recognized by the selected antibody fragments which could be also used for Western blot analysis of VEEV proteins and immunohistochemistry of VEEV infected cells. The anti-VEEV scFv phage clones did not show any cross-reactivity with Alphavirus species of the Western equine encephalitis virus (WEEV) and Eastern equine encephalitis virus (EEEV) antigenic complex, nor did they react with Chikungunya virus (CHIKV), if they were used as detection reagent.ConclusionFor the first time, this study describes the selection of antibodies against a human pathogenic virus from a human naïve scFv antibody gene library using complete, active virus particles as antigen. The broad and sensitive applicability of scFv-presenting phage for the immunological detection and diagnosis of Alphavirus species was demonstrated. The selected antibody fragments will improve the fast identification of VEEV in case of a biological warfare or terroristic attack or a natural outbreak.
Quantitative real-time PCR study on persistence of pDNA vaccine pVax-Hsp60 TM814 in beef muscles
Authors: Orság Petr , Kvardová Veronika , Raška Milan , Miller Andrew D , Ledvina Miroslav , Turánek Jaroslav 
Published: September 2008

Abstract

Background
Application of plasmid DNA for immunization of food-producing animals established new standards of food safety. The addition of foreign products e.g. pDNA into the food chain should be carefully examined to ensure that neither livestock animals nor consumers develop unpredicted or undesirable side-effects.

Methods
A quantitative real-time PCR (QRTPCR) methodology was developed to study the biodistribution and persistence of plasmid DNA vaccine pDNAX (pVAX-Hsp60 TM814) in mice and beef cattle. The linear quantification range and the sensitivity of the method was found to be 10 – 109 copies per reaction (500 ng/gDNA) and 3 copies per reaction, respectively.

Results
Persistence of pDNAX in mice muscle tissue was restricted to injection site and the amount of pDNAX showed delivery formulation dependent (naked pDNA, electroporation, cationic liposome complexes) and mouse age-dependent clearance form injection site but pDNAX was still detectable even after 365 days. The QRTPCR analysis of various muscle tissue samples of vaccinated beef bulls performed 242–292 days after the last revaccination proved that residual pDNAX was found only in the injection site. The highest plasmid levels (up to 290 copies per reaction) were detected in the pDNAX:CDAN/DOPE group similarly to mice model. No pDNA was detected in the samples from distant muscles and draining lymph nodes.

Conclusion
Quantitative real-time PCR (QRTPCR) assay was developed to assess the residual pDNA vaccine pVAX-Hsp60 TM814 in mice and beef cattle. In beef cattle, ultra low residual level of pDNA vaccine was only found at the injection site. According to rough estimation, consumption of muscles from the injection site represents almost an undetectable intake of pDNA (400 fg/g muscle tissue) for consumers. Residual plasmid in native state will hardly be found at measurable level following further meat processing. This study brings supportive data for animal and food safety and hence for further approval of pDNA vaccine field trials.
Perianal squamous cell carcinoma in-situ: a report of two human papilloma virus-negative cases
Authors: Shehan James , Wang Jeff F , Repertinger Susan , Sarma Deba P 
Published: September 2008

Abstract
We are reporting two cases of perianal squamous cell carcinoma in-situ, negative for high-risk (HR) and low-risk (LR) human papilloma viruses. A brief review of anal and perianal squamous cell carcinoma and the role of HPV are presented.
Pelvic plastron secondary to acute appendicitis in a child presented as appendiceal intussusception. A case report
Authors: Christianakis Efstratios , Sakelaropoulos Anastasios , Papantzimas Constantinos , Pitiakoudis Michael , Filippou Georgios , Filippou Dimitrios , Rizos Spiros , Paschalidis Nikolaos 
Published: September 2008

Abstract
We report an unusual case of an 11-year-old Greek girl with complicated acute appendicitis. The pelvic plastron that had been formatted secondary to appendix perforation was mimicking appendiceal intussusception in the preoperative ultrasound and computed tomography images. Although acute complicated appendicitis and appendiceal intussusception may represent possible causes of acute abdomen no similar cases have reported in the literature.
Biochemical markers of bone turnover and their association with bone marrow lesions
Authors: Hunter David J , LaValley Michael , Li Jiang , Bauer Doug C , Nevitt Michael , DeGroot Jeroen , Poole Robin , Eyre David , Guermazi Ali , Gale Daniel , Totterman Saara , Felson David T 
Published: August 2008

Abstract
Introduction
Our objective was to determine whether markers of bone resorption and formation could serve as markers for the presence of bone marrow lesions (BMLs).

Methods
We conducted an analysis of data from the Boston Osteoarthritis of the Knee Study (BOKS). Knee magnetic resonance images were scored for BMLs using a semiquantitative grading scheme. In addition, a subset of persons with BMLs underwent quantitative volume measurement of their BML, using a proprietary software method. Within the BOKS population, 80 people with BMLs and 80 without BMLs were selected for the purposes of this case-control study. Bone biomarkers assayed included type I collagen N-telopeptide (NTx) corrected for urinary creatinine, bone-specific alkaline phosphatase, and osteocalcin. The same methods were used and applied to a nested case-control sample from the Framingham study, in which BMD assessments allowed evaluation of this as a covariate. Logistic regression models were fit using BML as the outcome and biomarkers, age, sex, and body mass index as predictors. An receiver operating characteristic curve was generated for each model and the area under the curve assessed.

Results
A total of 151 subjects from BOKS with knee OA were assessed. The mean (standard deviation) age was 67 (9) years and 60% were male. Sixty-nine per cent had maximum BML score above 0, and 48% had maximum BML score above 1. The only model that reached statistical significance used maximum score of BML above 0 as the outcome. Ln-NTx (Ln is the natural log) exhibited a significant association with BMLs, with the odds of a BML being present increasing by 1.4-fold (95% confidence interval = 1.0-fold to 2.0-fold) per 1 standard deviation increase in the LnNTx, and with a small partial R2 of 3.05. We also evaluated 144 participants in the Framingham Osteoarthritis Study, whose mean age was 68 years and body mass index was 29 kg/m2, and of whom 40% were male. Of these participants 55% had a maximum BML score above 0. The relationship between NTx and maximum score of BML above 0 revealed a significant association, with an odds ratio fo 1.7 (95% confidence interval = 1.1 to 2.7) after adjusting for age, sex, and body mass index.

Conclusions
Serum NTx was weakly associated with the presence of BMLs in both study samples. This relationship was not strong and we would not advocate the use of NTx as a marker of the presence of BMLs.