bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Tyrosine Kinase Inhibitor, AZD2171, Inhibits Vascular Endothelial Growth Factor Receptor Signaling and Growth of Anaplastic Thyroid Cancer in an Orthotopic Nude Mouse Model
Authors: Gomez-Rivera Fernando , Santillan-Gomez Alfredo A. , Younes Maher N. , Kim Seungwon , Fooshee David , Zhao Mei , Jasser Samar A. , Myers Jeffrey N. 
Published: August 2007

Abstract
Purpose: Anaplastic thyroid cancer (ATC) is a locally aggressive type of thyroid tumor with high rate of distant metastases. With conventional treatment, the median survival ranges from 4 to 12 months; therefore, new treatment options are needed. AZD2171 is a tyrosine kinase inhibitor of the vascular endothelial growth factor receptors (VEGFR) VEGFR-1, VEGFR-2, and VEGFR-3. The objective of the study is to determine whether AZD2171 can inhibit VEGFR-2 signaling and decrease tumor growth and prolong survival of ATC in an orthotopic nude mouse model.
Experimental Design: We examined the effects of AZD2171 on phosphorylation of VEGFR-2, mitogen-activated protein kinase, and AKT in human umbilical vascular endothelial cells. To determine the antiproliferative and antiapoptotic effects of AZD2171, we did 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide and flow cytometry assays, respectively. We assessed the antitumor effects of AZD2171 in a xenograft model of ATC using control, AZD2171, paclitaxel, and combination groups by measuring tumor size and survival.
Results: Treatment with AZD2171 led to dose-dependent inhibition of VEGFR-2 phosphorylation and its downstream signaling in human umbilical vascular endothelial cells (IC50 for cell proliferation, 500 nmol/L). In the ATC cell lines DRO and ARO, IC50 was 7.5 μmol/L. AZD2171 induced apoptosis in 50% of endothelial and ATC cells at 3 and 10 μmol/L concentrations, respectively. In vivo, AZD2171 led to a significant reduction in tumor size between control and AZD2171 (P = 0.002) or AZD2171 + paclitaxel group (P = 0.002) but not the paclitaxel alone group (P = 0.11). Survival was significantly higher among AZD2171 (P &lt; 0.001) and combination groups (P &lt; 0.001) compared with control.
Conclusions: AZD2171 effectively inhibits tumor growth and prolongs survival of ATC-bearing mice. The main effect of AZD2171 is mediated through angiogenesis inhibition.
Frequent Inactivation of RAMP2, EFEMP1 and Dutt1 in Lung Cancer by Promoter Hypermethylation
Authors: Yue Wen , Dacic Sanja , Sun Quanhong , Landreneau Rodney , Guo Mingzhou , Zhou Wei , Siegfried Jill M. , Yu Jian , Zhang Lin 
Published: August 2007

Abstract
Purpose: The goal of this study is to identify novel genes frequently silenced by promoter hypermethylation in lung cancer.
Experimental Designs: Bioinformatic analysis was done to identify candidate genes significantly down-regulated in lung cancer. The effects of DNA methyltransferase inhibitor 5-aza-2′-deoxycytidine on the expression of the candidate genes were determined. Methylated CpG sites in the promoters of the candidate genes were identified using bisulfite DNA sequencing. Methylation-specific PCR was developed and used to analyze DNA methylation in cell lines and clinical specimen. Pathologic and functional analyses were done to study the role of one candidate gene, receptor activity-modifying protein 2 (RAMP2), in suppressing lung cancer cell growth.
Results: Among 54 candidate genes down-regulated in lung cancer, 31 were found to contain CpG islands in their promoters. Six of these 31 genes could be reactivated by 5-aza-2′-deoxycytidine in at least four of six lung cancer cell lines analyzed. Promoter hypermethylation of RAMP2, epidermal growth factor–containing fibulin-like extracellular matrix protein 1, and deleted in U Twenty Twenty cells was detected in 36% to 77% of 22 lung cancer cell lines and in 38% to 50% of 32 primary lung tumors, whereas hypermethylathion of these genes was rarely found in the matched normal samples. The methylation frequencies of these genes in lung cancer were similar to those of commonly used methylation markers, such as RAS association domain family protein 1A, p16, and methylguanine-DNA methyltransferase. Immunohistochemistry showed that RAMP2 was down-regulated in a majority of lung tumors, and RAMP2 down-regulation was correlated with high tumor grade. Ectopic expression of RAMP2 inhibited lung cancer cell growth and caused apoptotic cell death. Knockdown of RAMP2 by RNA interference stimulated cell proliferation.
Conclusions: Studying the newly identified genes may provide new insight into lung tumorigenesis. These genes might be useful as molecular markers of lung cancer.
FOXA1 Expression in Breast Cancer—Correlation with Luminal Subtype A and Survival
Authors: Badve Sunil , Turbin Dmitry , Thorat Mangesh A. , Morimiya Akira , Nielsen Torsten O. , Perou Charles M. , Dunn Sandi , Huntsman David G. , Nakshatri Harikrishna 
Published: August 2007

Abstract
Purpose: FOXA1, a forkhead family transcription factor, is essential for optimum expression of ∼50% of estrogen receptor α (ERα):estrogen responsive genes. FOXA1 is expressed in breast cancer cells. It segregates with genes that characterize the luminal subtypes in DNA microarray analyses. The utility of FOXA1 as a possible independent prognostic factor has not been determined in breast cancers.
Materials and Methods: A tissue microarray comprising tumors from 438 patients with 15.4 years median follow-up was analyzed for FOXA1 expression by immunohistochemistry. Interpretable FOXA1 expression obtained in 404 patients was analyzed along with other prognostic factors like tumor grade, size, nodal status, ER, progesterone receptor (PR), and HER2/neu.
Results: FOXA1 expression (score &gt;3) was seen in 300 of 404 breast cancers and it correlated with ER (P = 0.000001), PR (P = 0.00001), and luminal A subtype (P = 0.000001). Loss of expression was noted with worsening tumor grade (P = 0.001). Univariate analysis showed nodal status (P = 0.0000012), tumor size (P = 0.00001), FOXA1 (P = 0.0004), and ER (P = 0.012) to be predictors of breast cancer–specific survival. Multivariate analysis showed only nodal status (P = 0.001) and tumor size (P = 0.039) to be significant prognostic factors, whereas FOXA1 (P = 0.060) and ER (P = 0.131) were not significant. In luminal subtype A patient subgroup, FOXA1 expression was associated with better cancer-specific survival (P = 0.024) and in ER-positive subgroup, it was better predictor of cancer-specific survival (P = 0.009) than PR (P = 0.213).
Conclusion: FOXA1 expression correlates with luminal subtype A breast cancer and it is significant predictor of cancer-specific survival in patients with ER-positive tumors. Prognostic ability of FOXA1 in these low-risk breast cancers may prove to be useful in clinical treatment decisions.
L-BLP25: A Peptide Vaccine Strategy in Non–Small Cell Lung Cancer
Authors: Sangha Randeep , Butts Charles 
Published: August 2007

Abstract
MUC1 is a mucinous glycoprotein which is overexpressed and under or aberrantly glycosylated in many human malignancies. MUC1 is associated with cellular transformation and can confer resistance to genotoxic agents. L-BLP25 is a peptide vaccine strategy that targets the exposed core peptide of MUC1. In preclinical studies, L-BLP25 induced a cellular immune response characterized by T-cell proliferation in response to MUC1 and production of IFN-γ. Phase I and II trials have established the dose and schedule of the vaccine as well as its excellent safety profile. A randomized phase II trial of maintenance L-BLP25 versus best supportive care in patients with stage IIIB/IV non–small cell lung cancer who experienced clinical benefit from initial therapy has been reported. Updated survival analysis of this trial continues to show a strong survival trend in favor of L-BLP25 (median survival, 30.6 versus 13.3 months) in a subgroup of patients with locoregional stage IIIB disease. These promising results will be tested in a phase III trial of L-BLP25 versus placebo in patients with stage III non–small cell lung cancer after response to primary chemoradiotherapy.
Corruption of the Fas Pathway Delays the Pulmonary Clearance of Murine Osteosarcoma Cells, Enhances Their Metastatic Potential, and Reduces the Effect of Aerosol Gemcitabine
Authors: Gordon Nancy , Koshkina Nadezhda V. , Jia Shu-Fang , Khanna Chand , Mendoza Arnulfo , Worth Laura L. , Kleinerman Eugenie S. 
Published: August 2007

Abstract
Purpose: Pulmonary metastases continue to be a significant problem in osteosarcoma. Apoptosis dysfunction is known to influence tumor development. Fas (CD95, APO-1)/FasL is one of the most extensively studied apoptotic pathways. Because FasL is constitutively expressed in the lung, cells that express Fas should be eliminated by lung endothelium. Cells with low or no cell surface Fas expression may be able to evade this innate defense mechanism. The purpose of these studies was to evaluate Fas expression in osteosarcoma lung metastases and the effect of gemcitabine on Fas expression and tumor growth.
Experimental Design and Results: Using the K7M2 murine osteosarcoma model, Fas expression was quantified using immunohistochemistry. High levels of Fas were present in primary tumors, but no Fas expression was present in actively growing lung metastases. Blocking the Fas pathway using Fas-associated death domain dominant-negative delayed tumor cell clearance from the lung and increased metastatic potential. Treatment of mice with aerosol gemcitabine resulted in increased Fas expression and subsequent tumor regression.
Conclusions: We conclude that corruption of the Fas pathway is critical to the ability of osteosarcoma cells to grow in the lung. Agents such as gemcitabine that up-regulate cell surface Fas expression may therefore be effective in treating osteosarcoma lung metastases. These data also suggest that an additional mechanism by which gemcitabine induces regression of osteosarcoma lung metastases is mediated by enhancing the sensitivity of the tumor cells to the constitutive FasL in the lung.
Sequential Flavopiridol, Cytosine Arabinoside, and Mitoxantrone: A Phase II Trial in Adults with Poor-Risk Acute Myelogenous Leukemia
Authors: Karp Judith E. , Smith B. Douglas , Levis Mark J. , Gore Steven D. , Greer Jacqueline , Hattenburg Catherine , Briel Janet , Jones Richard J. , Wright John J. , Colevas A. Dimitri 
Published: August 2007

Abstract
Purpose: Flavopiridol is a cyclin-dependent kinase inhibitor that is cytotoxic to leukemic blasts. In a phase I study of flavopiridol followed by 1-β-d-arabinofuranosylcytosine (ara-C) and mitoxantrone, overall response rate for adults with relapsed and refractory acute myelogenous leukemias (AML) was 31%. We have now completed a phase II study of sequential flavopiridol, ara-C, and mitoxantrone in 62 adults with poor-risk AML.
Experimental Design: Flavopiridol (50 mg/m2) was given by 1-h infusion daily × 3 beginning day 1 followed by 2 gm/m2/72 h ara-C beginning day 6 and 40 mg/m2 mitoxantrone on day 9.
Results: Flavopiridol caused a ≥50% decrease in peripheral blood blasts in 44% by median day 2 and ≥80% decrease in 26% by day 3. Self-limited tumor lysis occurred in 53%. Three (5%) died during therapy (2 multiorgan failure and 1 fungal pneumonia). Complete remissions (CR) were achieved in 12 of 15 (75%) newly diagnosed secondary AML, 18 of 24 (75%) first relapse after short CR (median CR, 9 months, including prior allotransplant), and 2 of 13 (15%) primary refractory but 0 of 10 multiply refractory AML. Disease-free survival for all CR patients is 40% at 2 years, with newly diagnosed patients having a 2-year disease-free survival of 50%.
Conclusions: Flavopiridol has anti-AML activity directly and in combination with ara-C and mitoxantrone. This timed sequential regimen induces durable CRs in a significant proportion of adults with newly diagnosed secondary AML (including complex cytogenetics) and adults with AML in first relapse after short first CR.
Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitors Vandetanib (ZD6474) and AZD2171 in Lung Cancer
Authors: Hanrahan Emer O. , Heymach John V. 
Published: August 2007

Abstract
Vascular endothelial growth factor (VEGF) is a rational target for advanced non–small cell lung cancer (NSCLC), a hypothesis validated by the recent Eastern Cooperative Oncology Group E4599 trial showing that the addition of the VEGF monoclonal antibody bevacizumab to chemotherapy prolongs overall survival. Several new tyrosine kinase inhibitors targeting the VEGF pathway are currently in advanced clinical development for NSCLC and offer several possible advantages compared with monoclonal antibodies, including oral administration, more flexible dosing, a broader spectrum of target inhibition, and different toxicity profiles. Among these agents, vandetanib (ZD6474), an inhibitor of the VEGF receptor (VEGFR)-2 and epidermal growth factor receptor tyrosine kinase, has been the most extensively studied. In a randomized phase II study of patients with platinum-refractory NSCLC, including squamous histology, vandetanib prolonged progression-free survival compared with gefitinib. In another phase II trial, an improvement in progression-free survival was observed for vandetanib in combination with docetaxel compared with docetaxel alone. AZD2171 is an inhibitor of VEGFR-1, VEGFR-2, and VEGFR-3 and other tyrosine kinases that has shown clinical activity in NSCLC in combination with carboplatin and paclitaxel. Several phase III trials are under way testing these agents either as monotherapy or in combination with chemotherapy in patients with lung cancer. Early results with these agents, and others being tested, raise the possibility that there will eventually be multiple VEGF-targeted therapies available in the clinic that can potentially benefit a broader range of patients with advanced-stage NSCLC.
Erlotinib: Recent Clinical Results and Ongoing Studies in Non–Small Cell Lung Cancer
Authors: Perez-Soler Roman 
Published: August 2007

Abstract
The epidermal growth factor receptor tyrosine kinase inhibitor erlotinib has shown to provide clinical benefit to patients with non–small cell lung cancer (NSCLC) after failure of front-line chemotherapy in a double-blind placebo-controlled clinical trial. More importantly, because of its unique mechanism of action, erlotinib seems to provide higher clinical benefit to specific subgroups of patients. The continued development of erlotinib in NSCLC is focused on the following areas: (a) validating clinical and molecular markers of clinical benefit in front-line therapy, (b) developing therapies for acquired and naturally resistant tumors, (c) revisiting combinations with chemotherapy, (d) developing combinations with antiangiogenesis agents, and (e) understanding the biological significance of the skin toxicity and developing rational approaches for its treatment. Clinical studies addressing these five areas are ongoing and are briefly described in this review.
Vascular Endothelial Growth Factor Trap in Non–Small Cell Lung Cancer
Authors: Riely Gregory J. , Miller Vincent A. 
Published: August 2007

Abstract
Several drugs currently in development target the vascular endothelial growth factor (VEGF) pathway, a validated target in the treatment of non–small cell lung cancer (NSCLC). Most clinical trial data generated to date have been with either bevacizumab, a monoclonal antibody to VEGF, or small-molecule inhibitors of VEGF receptor (VEGFR) tyrosine kinase activity (sunitinib, sorafenib, and ZD6474). VEGF Trap, an engineered soluble receptor made from extracellular domains of VEGFR1 and VEGFR2, binds to all isoforms of VEGF and to placental growth factor. VEGF Trap binds to VEGF-A and VEGF-B with markedly higher affinity than bevacizumab. The toxicities seen in phase I trials of s.c. and i.v. administration of VEGF Trap, hypertension and proteinuria, are similar to those seen with other molecules that target the VEGF pathway. In the s.c. VEGF Trap phase I trial, significant radiographic improvement was observed in a patient with heavily pretreated NSCLC. Ongoing phase I trials are evaluating combinations of VEGF Trap with platinum-based doublets and single-agent docetaxel. The activity of single-agent VEGF Trap in NSCLC is being assessed in a multicenter phase II trial.
Bevacizumab in Non–Small Cell Lung Cancer
Authors: Sandler Alan 
Published: August 2007

Abstract
Angiogenesis, the growth of new vessels from preexisting vessels, is a fundamental step in tumor growth and progression. Vascular endothelial growth factor (VEGF) is a key angiogenic factor implicated in tumor blood vessel formation and permeability. Overexpression of VEGF has been observed in a variety of cancers and has been associated with a worse relapse-free and overall survival. The antiangiogenic agent bevacizumab, a monoclonal antibody directed against VEGF, has shown clinical benefit in multiple cancers, including non–small cell lung cancer (NSCLC). Based on the favorable results of a prior randomized, phase II trial, the Eastern Cooperative Oncology Group conducted a trial (E4599) to evaluate the efficacy of bevacizumab in combination with paclitaxel and carboplatin in patients with recurrent or advanced stage IIIB or IV nonsquamous cell NSCLC. Exclusion criteria included squamous cell histology, brain metastases, significant hemoptysis, or inadequate organ function or performance status &gt;1. The primary study end point was overall survival. The median duration of survival in the chemotherapy plus bevacizumab group was 12.3 months compared with 10.3 months in the chemotherapy alone group (P = 0.003). Significant bleeding was more frequent in the chemotherapy plus bevacizumab group, 4.4% compared with 0.9% (P = 0.001). There were 15 treatment-related deaths in the chemotherapy plus bevacizumab group, including 5 due to pulmonary hemorrhage. Future and current directions include evaluation of bevacizumab in earlier stages of NSCLC, in SCLC, and in combination with other targeted agents, such as erlotinib.
Different Forms of Helper Tolerance to Carcinoembryonic Antigen: Ignorance and Regulation
Authors: Pickford Wendy J. , Watson Angus J.M. , Barker Robert N. 
Published: August 2007

Abstract
Purpose: Understanding the mechanisms of immune tolerance to tumor-associated antigens (TAA) is an important step in the design of cancer immunotherapy. The aim was to determine how T helper (Th) cell tolerance is mediated for a prototypic TAA, carcinoembryonic antigen (CEA).
Experimental Design: Peripheral blood mononuclear cells from 50 healthy volunteers were stimulated with CEA, and the type and fine specificity of any Th cell responses were identified. The inhibitory effects of T regulatory (Tr) populations were determined by depleting “natural” CD25+ Tr cells or neutralizing cytokine produced by the “induced” Tr form.
Results: Proliferative Th cell responses were consistently induced by CEA in 22 of 50 individuals. Responding cells were drawn from the CD45RA+ “naive” or quiescent population. Depleting the CD25+ fraction did not enhance CEA responsiveness. However, CEA elicited secretion of the Tr cytokine interleukin-10 (IL-10) in 23 of 50 donors, including 20 of 22 where no proliferation was induced. Neutralizing IL-10 revealed previously unseen proliferation to CEA by CD45RO+ “memory” Th cells. Epitope maps revealed differences in the fine specificities of Th cells capable of proliferating or secreting IL-10.
Conclusions: There are at least two major forms of CEA tolerance in different individuals. One is “ignorance,” a failure of specific Th cells to respond to antigen presented in vivo. The other, seen when ignorance is lost, is mediated by IL-10–secreting Tr cells that recognize CEA. TAA tolerance, for example to colorectal carcinoma cells expressing CEA, may be overcome by peptide vaccines that exploit the differences in epitopes recognized by effector and Tr responses.
Cancellation of Aerosol Indirect Effects in Marine Stratocumulus through Cloud Thinning
Authors: Wood Robert 
Published: August 2007

Abstract
Applying perturbation theory within a mixed layer framework, the response of the marine boundary layer (MBL) cloud thickness h to imposed increases of the cloud droplet concentration Nd as a surrogate for increases in cloud condensation nuclei (CCN) concentrations is examined. An analytical formulation is used to quantify the response and demonstrate theoretically that for the range of environmental conditions found over the subtropical eastern oceans, on time scales of less than a day, the cloud thickness feedback response is largely determined by a balance between the moistening/cooling of the MBL resulting from the suppression of surface precipitation, and the drying/warming resulting from enhanced entrainment resulting from increased turbulent kinetic energy. Quantifying the transient cloud response as a ratio of the second to the first indirect effects demonstrates that the nature of the feedback is critically dependent upon the nature of the unperturbed state, with the cloud-base height zcb being the single most important determinant. For zcb &lt; 400 m, increasing Nd leads to cloud thickening in accordance with the Albrecht hypothesis. However, for zcb &gt; 400 m, cloud thinning occurs, which results in a feedback effect that increasingly cancels the Twomey effect as zcb increases. The environmental conditions favoring an elevated cloud base are relatively weak lower-tropospheric stability and a dry free troposphere, although the former is probably more important over the subtropical eastern oceans. On longer time scales an invariable thickening response is found, and thus accurate quantification of the aerosol indirect effects will require a good understanding of the processes that control the time scale over which aerosol perturbations are modified.
Collisions of Cloud Droplets in a Turbulent Flow. Part IV: Droplet Hydrodynamic Interaction
Authors: Pinsky M. B. , Khain A. P. , Shapiro M. 
Published: August 2007

Abstract
The paper presents a computationally accurate and efficient method for calculation of cloud droplets’ collision efficiency in a turbulent flow with the properties typical of atmospheric clouds. According to Part III, the statistical properties of a turbulent flow are represented by a set of noncorrelated samples of turbulent velocity gradients and Lagrangian accelerations. Long series of these samples were generated for turbulent parameters typical of different atmospheric clouds. Each sample can be assigned to a certain point of the turbulent flow. Each such point can be surrounded by a small elementary volume with the linear length scale of the Kolmogorov length scale, in which the Lagrangian acceleration and the velocity gradient tensor can be considered uniform in space and invariable in time. For each sample (or an elementary volume), fluxes of droplets of one size onto droplets of another size are calculated both in the presence and absence of hydrodynamical droplet interaction (HDI). In each elementary volume, the collision efficiency is calculated as the ratio of these fluxes.
Using a set of the collision efficiency and kernels, the probability distribution functions (PDFs) and the mean values of collision efficiency and collision kernels are calculated under different dissipation rates and Reynolds numbers. It is shown that turbulence significantly increases the collision efficiency, especially for droplets of close sizes and droplet pairs containing a few-microns-radius droplet. The results suggest that the main mechanism by means of which turbulence increases the rate of cloud droplets’ collisions is its influence on HDI.