bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Phase I Trial of Twice-Weekly 17-Allylamino-Demethoxy-Geldanamycin in Patients with Advanced Cancer
Authors: Nowakowski Grzegorz S. , McCollum Andrea K. , Ames Matthew M. , Mandrekar Sumithra J. , Reid Joel M. , Adjei Alex A. , Toft David O. , Safgren Stephanie L. , Erlichman Charles 
Published: October 2006

Abstract
Purpose: To determine the maximum tolerated dose (MTD), dose-limiting toxicity, and pharmacokinetics of 17-allylamino-demethoxy-geldanamycin (17-AAG) administered on days 1, 4, 8, and 11 every 21 days and to examine the effect of 17-AAG on the levels of chaperone and client proteins.
Experimental Design: A phase I dose escalating trial in patients with advanced solid tumors was done. Toxicity and tumor responses were evaluated by standard criteria. Pharmacokinetics were done and level of target proteins was measured at various points during cycle one.
Results: Thirteen patients were enrolled in the study. MTD was defined as 220 mg/m2. Dose-limiting toxicities were as follows: dehydration, diarrhea, hyperglycemia, and liver toxicity. At the MTD, the mean clearance of 17-AAG was 18.7 L/h/m2. There was a significant decrease in integrin-linked kinase at 6 hours after infusion on day 1 but not at 25 hours in peripheral blood mononuclear cells. Treatment with 17-AAG on day 1 significantly increased pretreatment levels of heat shock protein (HSP) 70 on day 4, which is consistent with the induction of a stress response. In vitro induction of a stress response and up-regulation of HSP70 resulted in an increased resistance to HSP90-targeted therapy in A549 cells.
Conclusions: The MTD of 17-AAG on a twice-weekly schedule was 220 mg/m2. Treatment at this dose level resulted in significant changes of target proteins and also resulted in a prolonged increase in HSP70. This raises the possibility that HSP70 induction as part of the stress response may contribute to resistance to 17-AAG.
Piroxicam and Cisplatin in a Mouse Model of Peritoneal Mesothelioma
Authors: Spugnini Enrico P. , Cardillo Irene , Verdina Alessandra , Crispi Stefania , Saviozzi Silvia , Calogero Raffaele , Nebbioso Angela , Altucci Lucia , Cortese Giancarlo , Galati Rossella , Chien Jeremy , Shridhar Viji , Vincenzi Bruno , Citro Gennaro , Cognetti Francesco , Sacchi Ada , Baldi Alfonso 
Published: October 2006

AbstractPurpose: The aim of the present study was to evaluate the effects of piroxicam, a widely used nonsteroidal anti-inflammatory drug, alone and in combination with cisplatin (CDDP), on cell growth of mesothelioma cells.Experimental Design: Cell proliferation, cell cycle analysis, and microarray technology were done on MSTO-211H and NCI-H2452 cells treated with piroxicam. Moreover, the effects of piroxicam and CDDP on tumor growth and survival of mouse xenograft models of mesothelioma were determined.Results: Piroxicam treatment of MSTO-211H and NCI-H2452 cells resulted in a significant inhibition of proliferation. Cell cycle analysis revealed that there was an increase in the rate of apoptosis in MSTO-211H cells and an increase in the cells accumulating in G2-M in NCI-H2452. Moreover, a marked tumor growth inhibition and an extended survival of mice treated with a combination of piroxicam and CDDP in MSTO-211H cell–induced peritoneal mesotheliomas was observed. Last, GeneChip array analysis of MSTO-211H mesothelioma cell line revealed that piroxicam treatment caused up-regulation of metabolic pathway–associated genes and down-regulation of genes related to RNA processing apparatus. Of note, epidermal growth factor receptor, one of the new biological targets of chemotherapy for mesothelioma, was down-regulated and HtrA1, a serine protease recently shown to be an endogenous mediator of CDDP cytotoxicity, was up-regulated following piroxicam treatment both in vitro and in vivo.Conclusion: These data suggest that piroxicam sensitizes mesothelioma cells to CDDP-induced cytotoxicity by modulating the expression of several target genes. Therefore, piroxicam in combination with CDDP might potentially be useful in the treatment of patients with mesothelioma.
A Phase I Study on Adoptive Immunotherapy Using Gene-Modified T Cells for Ovarian Cancer
Authors: Kershaw Michael H. , Westwood Jennifer A. , Parker Linda L. , Wang Gang , Eshhar Zelig , Mavroukakis Sharon A. , White Donald E. , Wunderlich John R. , Canevari Silvana , Rogers-Freezer Linda , Chen Clara C. , Yang James C. , Rosenberg Steven A. , Hwu Patrick 
Published: October 2006

Abstract
Purpose: A phase I study was conducted to assess the safety of adoptive immunotherapy using gene-modified autologous T cells for the treatment of metastatic ovarian cancer.
Experimental Design: T cells with reactivity against the ovarian cancer–associated antigen α-folate receptor (FR) were generated by genetic modification of autologous T cells with a chimeric gene incorporating an anti-FR single-chain antibody linked to the signaling domain of the Fc receptor γ chain. Patients were assigned to one of two cohorts in the study. Eight patients in cohort 1 received a dose escalation of T cells in combination with high-dose interleukin-2, and six patients in cohort 2 received dual-specific T cells (reactive with both FR and allogeneic cells) followed by immunization with allogeneic peripheral blood mononuclear cells.
Results: Five patients in cohort 1 experienced some grade 3 to 4 treatment-related toxicity that was probably due to interleukin-2 administration, which could be managed using standard measures. Patients in cohort 2 experienced relatively mild side effects with grade 1 to 2 symptoms. No reduction in tumor burden was seen in any patient. Tracking 111In-labeled adoptively transferred T cells in cohort 1 revealed a lack of specific localization of T cells to tumor except in one patient where some signal was detected in a peritoneal deposit. PCR analysis showed that gene-modified T cells were present in the circulation in large numbers for the first 2 days after transfer, but these quickly declined to be barely detectable 1 month later in most patients. An inhibitory factor developed in the serum of three of six patients tested over the period of treatment, which significantly reduced the ability of gene-modified T cells to respond against FR+ tumor cells.
Conclusions: Large numbers of gene-modified tumor-reactive T cells can be safely given to patients, but these cells do not persist in large numbers long term. Future studies need to employ strategies to extend T cell persistence. This report is the first to document the use of genetically redirected T cells for the treatment of ovarian cancer.
Met Receptor Signaling: A Key Effector in Esophageal Adenocarcinoma
Authors: Anderson Mark R. , Harrison Rebecca , Atherfold Paul A. , Campbell Moray J. , Darnton S. Jane , Obszynska Jolanta , Jankowski Janusz A.Z 
Published: October 2006

Abstract
Purpose: The incidence of esophageal adenocarcinoma is rising, and survival rates remain poor. The hepatocyte growth factor (HGF) receptor Met has been detected in esophageal cancer. The perturbation of cadherin/catenin complexes has also been shown. We sought to investigate a link among Met expression, cadherin/catenin biology, and cell growth. We assessed the prognostic significance of Met expression in esophageal adenocarcinoma.
Experimental Design: Met and HGF expression in esophageal tissues were assessed using immunohistochemistry and ELISA. Met-positive cell lines (OE33 and SEG1) and a Met-negative cell line (TE7) were incubated with HGF. Real-time reverse transcription-PCR and Western blotting were used to assess levels of E-cadherin expression. Nuclear TCF/β-catenin signaling was assessed following reporter construct transfection. Agar colony formation was used to assess anchorage-independent growth. A panel of 72 resected esophageal adenocarcinomas were assessed for Met expression by immunohistochemistry and correlated to survival data.
Results: An increased expression of Met was seen along the metaplasia- adenocarcinoma sequence. Met-positive cells showed reductions in E-cadherin mRNA (37% and 69%) and protein expression following stimulation with HGF (P &lt; 0.01). OE33 and SEG-1 showed up to a 2-fold increase in the levels of β-catenin nuclear signaling (P &lt; 0.01). TE7 only responded when transfected to express Met; E-cadherin expression decreased by 64% (P &lt; 0.01). HGF stimulation led to increased agar colony formation (P &lt; 0.01). Patients with Met-positive tumors showed lower 6-month survival rates after surgical resection than those with Met-negative tumors (P &lt; 0.05).
Conclusions: Met activation induces changes consistent with early invasion, such as down-regulation of E-cadherin, increased nuclear TCF/β-catenin signaling, and anchorage-independent growth. This is supported by ex vivo data associating Met with reduced short-term survival. Inhibitors of Met may be effective treatment for esophageal adenocarcinoma.
Randomized Phase II Study of Interleukin-12 in Combination with Rituximab in Previously Treated Non-Hodgkin's Lymphoma Patients
Authors: Ansell Stephen M. , Geyer Susan M. , Maurer Matthew J. , Kurtin Paul J. , Micallef Ivana N.M. , Stella Philip , Etzell Paul , Novak Anne J. , Erlichman Charles , Witzig Thomas E. 
Published: October 2006

Abstract
Purpose: Rituximab is a chimeric antibody that induces B-cell apoptosis and recruits immune effector cells to mediate cell lysis. Interleukin-12 (IL-12) facilitates cytolytic responses by T cells and natural killer cells. This phase II study was done to determine the efficacy and toxicity of IL-12 in combination with rituximab in patients with B-cell non-Hodgkin's lymphoma (NHL).
Experimental Design: Fifty-eight patients with histologically confirmed relapsed B-cell NHL were randomized to receive concurrent treatment with rituximab and IL-12 (arm A) or rituximab with subsequent treatment with IL-12 after documented nonresponse or progression after rituximab (arm B). Treatment consisted of 375 mg/m2 rituximab on days 1, 8, 15, and 22 and 300 ng/kg IL-12 given s.c. twice weekly starting on day 2 for arm A or upon progression for arm B.
Results: The overall response rate was 37% (11 of 30) in arm A and 52% (13 of 25) in arm B. All of the responses seen in arm B occurred while patients received rituximab, and no responses occurred during treatment with subsequent IL-12. The median duration of response was 16 months for arm A and 12 months for arm B. Biopsy specimens were serially obtained in a subset of patients and showed that changes in gene expression were different when cells from the peripheral blood were compared with cells from lymph node biopsies.
Conclusions: The concomitant use of IL-12 and rituximab had modest disease activity in patients with B-cell NHL, but the sequential administration of IL-12 after rituximab did not result in additional clinical responses.
Biological Role of Estrogen Receptor β in Salivary Gland Adenocarcinoma Cells
Authors: Ohshiro Kazufumi , Rayala Suresh K. , Williams Michelle D. , Kumar Rakesh , El-Naggar Adel K. 
Published: October 2006

Abstract
Purpose: This study is intended to investigate the biological role of estrogen receptor (ER) nongenomic signaling in salivary gland adenocarcinoma cells that predominantly express ERβ.
Experimental Design: Salivary gland adenocarcinoma cell lines HSG and HSY were used to study the effect of diarylpropionitrile and estrogen on the nongenomic signaling of ERβ, cytoskeletal remodeling, and cell motility.
Results: We found that diarylpropionitrile and estrogen triggered rapid activation of the extracellular signal-regulated kinase 1/2 (ERK), Src, and focal adhesion kinase signaling pathways. Estrogen stimulation also induced long cytoplasmic extensions, filopodia formation, and abnormal outgrowths in both HSG and HSY cells. We further observed that ligand-induced migration of these cells was blocked by the pure antiestrogen ICI 182780 and the mitogen-activated protein/ERK kinase inhibitor PD98059, indicating that estrogen-induced cell migration is mediated by the activation of ERβ nongenomic signaling.
Conclusion: These results clearly showed that ERβ nongenomic signaling is active in salivary gland cells and has a biological role in migration, presumably via the stimulation of ERK1/2. In future, the findings of this study might have clinical importance as several ERβ-selective agonists are currently being available, and these could potentially be used for therapeutic targeting of ERβ-positive salivary tumors.
Grape Seed Extract Inhibits In vitro and In vivo Growth of Human Colorectal Carcinoma Cells
Authors: Kaur Manjinder , Singh Rana P. , Gu Mallikarjuna , Agarwal Rajesh , Agarwal Chapla 
Published: October 2006

Abstract
Purpose: Accumulating evidences suggest the beneficial effects of fruit-and-vegetable consumption in lowering the risk of various cancers, including colorectal cancer. Herein, we investigated the in vitro and in vivo anticancer effects and associated mechanisms of grape seed extract (GSE), a rich source of proanthocyanidins, against colorectal cancer.
Experimental Design: Effects of GSE were examined on human colorectal cancer HT29 and LoVo cells in culture for proliferation, cell cycle progression, and apoptosis. The in vivo effect of oral GSE was examined on HT29 tumor xenograft growth in athymic nude mice. Xenografts were analyzed by immunohistochemistry for proliferation and apoptosis. The molecular changes associated with the biological effects of GSE were analyzed by Western blot analysis.
Results: GSE (25-100 μg/mL) causes a significant dose- and time-dependent inhibition of cell growth with concomitant increase in cell death. GSE induced G1 phase cell cycle arrest along with a marked increase in Cip1/p21 protein level and a decrease in G1 phase–associated cyclins and cyclin-dependent kinases. GSE-induced cell death was apoptotic and accompanied by caspase-3 activation. GSE feeding to mice at 200 mg/kg dose showed time-dependent inhibition of tumor growth without any toxicity and accounted for 44% decrease in tumor volume per mouse after 8 weeks of treatment. GSE inhibited cell proliferation but increased apoptotic cell death in tumors. GSE-treated tumors also showed enhanced Cip1/p21 protein levels and poly(ADP-ribose) polymerase cleavage.
Conclusions: GSE may be an effective chemopreventive agent against colorectal cancer, and that growth inhibitory and apoptotic effects of GSE against colorectal cancer could be mediated via an up-regulation of Cip1/p21.
A systematic review of the relationship between socio-economic position and physical activity
Authors: Gidlow Christopher , Johnston Lynne Halley , Crone Diane , Ellis Naomi , James David 
Published: October 2006

Objective The aim of the present review was to examine epidemiological evidence to determine if there is strong evidence of a positive gradient of increasing physical activity across the socio-economic strata, and how relationships are affected by socio-economic measurement. Design Systematic review. Method A search of major databases was conducted to identify published studies that reported physical activity in relation to socio-economic position (SEP) in adults. Results Twenty-eight cross-sectional and five longitudinal studies met the inclusion criteria. Approximately half of these were American. Consequently education and income were most commonly used to represent SEP. The majority of studies were secondary analyses of existing health survey data, which could explain the generally large sample sizes and methodological weaknesses in physical activity and SEP measurement. There was consistent evidence of a higher prevalence or higher levels of leisure-time or moderate-vigorous intensity physical activity in those at the top of the socio-economic strata compared with those at the bottom. Evidence for positive gradients across the socio-economic strata was less consistent. Education produced the most stable relationships, less susceptible to confounding effects of ethnicity and the environment. Conclusion Those at the top of the socio-economic scale appear to perform more leisure-time activity than those at the bottom. Diverse and often crude physical activity and socio-economic measurement made it difficult to distinguish between artefact and true effect in a relationship with so many potential confounding influences. Further studies using up-to-date methods of socio-economic and physical activity measurement are necessary to further explore this relationship and its confounders.
Analysing sequential events in clinical trials
Authors: Salter A , Raab G , Day S 
Published: October 2006

Background Data from clinical trials where the endpoint is a single survival time are readily analysed by standard methods, most commonly using a semi-parametric proportional hazards approach. However, when the outcome involves two sequential survival times, standard methods may not be applicable. Methods We consider methods appropriate for the analysis of survival data in clinical trials where there are two distinct, sequential and opposing survival endpoints and where inferences about the second event are of particular interest. Two motivating examples of randomized clinical trials with different designs provide important illustrations of the methodology in practice. Results Bivariate log-normal survival models are proposed as useful way of modeling such data. These models can be simply implemented in two stages, each of which is a univariate log-normal survival analysis. Different approaches to the analyses are described according to whether a second randomized treatment assignment is made at the time when the first event occurs and the second phase of the study commences. In the absence of a second randomization, the bivariate log-normal model adjusts for selection into the second phase of the study. Conclusions The investigation of ‘treatment sequences’ should, wherever possible, be handled by repeat randomization, which can then be followed by valid, unbiased analyses. However, in many clinical trial scenarios, this is simply not possible. In this case, the best approach is to consider the data as arising from an observational study, whilst controlling for all appropriate covariates. Limitations The approach we describe is appropriate for log-normally distributed data but could be generalised to handle other distributions, although the process of model fitting would be less straight-forward.
REEzoning in allanite related to changing partition coefficients during crystallization: implications for REE behaviour in an epidote-bearing tonalite
Authors: Beard J. S. , Sorensen S. S. , Gieré B. 
Published: October 2006

AbstractAllanite is present in most samples of the tonalitic Bell Island Pluton, with an average mode near 0.05 wt.%. Allanite occurs as cores in igneous epidote-clinozoisite and exhibits characteristic and consistent zoning patterns.REE-rich cores (All40-70) grade out towards epidote-clinozoisite withREEbelow electron microprobe detection limits. La, Ce and Pr contents are highest in theREE-richcores of zoned crystals. Nd and Sm contents both initially increase as totalREEdecreases and are highest in intermediate zones. Y contents are generally low throughout, but tend to be highest in analyses with A115-20.The zoning behaviour exhibited by the allanite, specifically the rimward increases in Nd, Sm, and Y, cannot be accounted for by simple fractionation and are best explained by increases in allanite/ melt partition coefficients (Kdvalues) for these elements during crystallization. We propose that the variation inKdvalues reflects modification of the allanite structure with changingREEcontent. These modifications are manifested by changes in colour, extinction, and pleochroism within the zoned crystals and include changes in unit-cell volume and dimensions. The changes inKdvalues are large enough to result in crossingREEpatterns within single allanite crystals. Fractional crystallization of zoned allanite can have noticeable effects onLREEcontents and La/Sm (and almost certainly La/Lu) in magmas. In the Bell Island pluton, 80% of La, but <3% of Y is contained in allanite. Although some of the variation in theLREEchemistry of the pluton is attributable to statistical sampling error, much of it appears to reflect petrogenetic processes that controlledLREEabundance and, ultimately, allanite mode. One sample of Bell Island tonalite is depleted inLREEand has low La/Lu and La/Sm. These chemical features can be modelled by fractionation of zoned allanite.
Thermal expansion of highly silicic nepheline-kalsilite crystalline solutions
Authors: Hovis G. L. , Person E. , Spooner A. , Roux J. 
Published: October 2006

AbstractWe have investigated the thermal expansion of nepheline-kalsilite crystalline solutions having 12.5% excess silicon relative to the stoichiometric composition. It is proposed that differences in the thermal expansion among various members of the series, and also between this series and a previously studied low-Si series, can be explained by three factors: (1) shrinkage of the tetrahedral rings caused by the substitution of Na for K, especially in the case of kalsilite, allows for greater expansion from the increased vibrational amplitude of Na ions with increasing temperature. (2) The occupancy of alkali sites by ions rather than vacancies draws tetrahedral rings inward via electrical attraction to these ions, providing the potential for greater expansion with ionic vibration as temperature increases. (3) Structural differences between nepheline and kalsilite, in particular the existence of two alkali sites in nepheline, account for the increased thermal expansion of K-enriched nepheline relative to Na-nepheline, as the occupation of the larger alkali position by K+ results in greater thermal expansion than is the case with Na+ occupancy of the same sites.
Compositional evolution and cryptic variation in pyroxenes of the peralkaline Lovozero intrusion, Kola Peninsula, Russia
Authors: Kogarko L. N. , Williams C. T. , Woolley A. R. 
Published: October 2006

AbstractThe Lovozero alkaline massif is the largest of the world's layered peralkaline intrusions (∼650 km2). We describe the evolution of clinopyroxene from the liquidus to the late residual stage throughout the whole vertical section (2.5 km thick) of the Lovozero Complex. Microprobe data (∼990 analyses) of the clinopyroxenes define a relatively continuous trend from diopside containing 15–20% hedenbergite and 10–12% aegirine components, to pure aegirine. The main substitutions during the evolution of the Lovozero pyroxenes are (Na,Fe3+,Ti) for (Ca,Mg,Fe2+). The composition of the pyroxene changes systematically upwards through the intrusion with an increase in Na, Fe3+ and Ti and decrease in Ca and Mg.The compositional evolution of the Lovozero pyroxene reflects primary fractionation processes in the alkaline magma that differentiated in situ from the bottom to the top of the magma chamber as a result of magmatic convection, coupled with the sedimentation of minerals with different settling velocities.The temperature interval of pyroxene crystallization is very wide and probably extends from 970 to 450°C. The redox conditions of pyroxene crystallization in the Lovozero intrusion were relatively low, approximating the QFM buffer.