bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Novel Role of Tyrosine Kinase Inhibitor in the Reversal of Immune Suppression and Modulation of Tumor Microenvironment for Immune-Based Cancer Therapies
Authors: Ozao-Choy Junko , Ma Ge , Kao Johnny , Wang George X. , Meseck Marcia , Sung Max , Schwartz Myron , Divino Celia M. , Pan Ping-Ying , Chen Shu-Hsia 
Published: March 2009

AbstractIn tumor-bearing hosts, myeloid-derived suppressor cells (MDSC) and T regulatory cells (Treg) play important roles in immune suppression, the reversal of which is vitally important for the success of immune therapy. We have shown that ckit ligand is required for MDSC accumulation and Treg development. We hypothesized that sunitinib malate, a receptor tyrosine kinase inhibitor, could reverse MDSC-mediated immune suppression and modulate the tumor microenvironment, thereby improving the efficacy of immune-based therapies. Treatment with sunitinib decreased the number of MDSC and Treg in advanced tumor-bearing animals. Furthermore, it not only reduced the suppressive function of MDSCs but also prevented tumor-specific T-cell anergy and Treg development. Interestingly, sunitinib treatment resulted in reduced expression of interleukin (IL)-10, transforming growth factor-β, and Foxp3 but enhanced expression of Th1 cytokine IFN-γ and increased CTL responses in isolated tumor-infiltrating leukocytes. A significantly higher percentage and infiltration of CD8 and CD4 cells was detected in tumors of sunitinib-treated mice when compared with control-treated mice. More importantly, the expression of negative costimulatory molecules CTLA4 and PD-1 in both CD4 and CD8 T cells, and PDL-1 expression on MDSC and plasmacytoid dendritic cells, was also significantly decreased by sunitinib treatment. Finally, sunitinib in combination with our immune therapy protocol (IL-12 and 4-1BB activation) significantly improves the long-term survival rate of large tumor-bearing mice. These data suggest that sunitinib can be used to reverse immune suppression and as a potentially useful adjunct for enhancing the efficacy of immune-based cancer therapy for advanced malignancies. [Cancer Res 2009;69(6):2514–22]
Tumor-Initiating Cells of HER2-Positive Carcinoma Cell Lines Express the Highest Oncoprotein Levels and Are Sensitive to Trastuzumab
Authors: Magnifico Alessandra , Albano Luisa , Campaner Stefano , Delia Domenico , Castiglioni Fabio , Gasparini Patrizia , Sozzi Gabriella , Fontanella Enrico , Menard Sylvie , Tagliabue Elda 
Published: March 2009

Abstract
Purpose: The existence of tumor-initiating cells in breast cancer has profound implications for cancer therapy. In this study, we investigated the sensitivity of tumor-initiating cells isolated from human epidermal growth factor receptor type 2 (HER2)-overexpressing carcinoma cell lines to trastuzumab, a compound used for the targeted therapy of breast cancer.
Experimental Design: Spheres were analyzed by indirect immunofluorescence for HER2 cell surface expression and by real-time PCR for HER2 mRNA expression in the presence or absence of the Notch1 signaling inhibitor (GSI) or Notch1 small interfering RNA. Xenografts of HER2-overexpressing breast tumor cells were treated with trastuzumab or doxorubicin. The sphere-forming efficiency (SFE) and serial transplantability of tumors were assessed.
Results: In HER2-overexpressing carcinoma cell lines, cells with tumor-initiating cell properties presented increased HER2 levels compared with the bulk cell population without modification in HER2 gene amplification. HER2 levels were controlled by Notch1 signaling, as shown by the reduction of HER2 cell surface expression and lower SFE following γ-secretase inhibition or Notch1 specific silencing. We also show that trastuzumab was able to effectively target tumor-initiating cells of HER2-positive carcinoma cell lines, as indicated by the significant decrease in SFE and the loss of serial transplantability, following treatment of HER2-overexpressing xenotransplants.
Conclusions: Here, we provide evidence for the therapeutic efficacy of trastuzumab in debulking and in targeting tumor-initiating cells of HER2-overexpressing tumors. We also propose that Notch signaling regulates HER2 expression, thereby representing a critical survival pathway of tumor-initiating cells.
Coassociation of Estrogen Receptor and p160 Proteins Predicts Resistance to Endocrine Treatment; SRC-1 is an Independent Predictor of Breast Cancer Recurrence
Authors: Redmond Aisling M. , Bane Fiona T. , Stafford Anthony T. , McIlroy Marie , Dillon Mary F. , Crotty Thomas B. , Hill Arnold D. , Young Leonie S. 
Published: March 2009

Abstract
Purpose: This study investigates the role of the p160 coactivators AIB1 and SRC-1 independently, and their interactions with the estrogen receptor, in the development of resistance to endocrine treatments.
Experimental Design: The expression of the p160s and the estrogen receptor, and their interactions, was analyzed by immunohistochemistry and quantitative coassociation immunofluorescent microscopy, using cell lines, primary breast tumor cell cultures, and a tissue microarray with breast cancer samples from 560 patients.
Results: Coassociation of the p160s and estrogen receptor α was increased in the LY2 endocrine-resistant cell line following treatment with tamoxifen in comparison with endocrine-sensitive MCF-7 cells. In primary cultures, there was an increase in association of the coactivators with estrogen receptor α following estrogen treatment but dissociation was evident with tamoxifen. Immunohistochemical staining of the tissue microarray revealed that SRC-1 was a strong predictor of reduced disease-free survival (DFS), both in patients receiving adjuvant tamoxifen treatment and untreated patients (P &lt; 0.0001 and P = 0.0111, respectively). SRC-1 was assigned a hazard ratio of 2.12 using a Cox proportional hazards model. Endocrine-treated patients who coexpressed AIB1 with human epidermal growth factor receptor 2 had a significantly shorter DFS compared with all other patients (P = 0.03). Quantitative coassociation analysis in the patient tissue microarray revealed significantly stronger colocalization of AIB1 and SRC-1 with estrogen receptor α in patients who have relapsed in comparison with those patients who did not recur (P = 0.026 and P = 0.00001, respectively).
Conclusions: SRC-1 is a strong independent predictor of reduced DFS, whereas the interactions of the p160 proteins with estrogen receptor α can predict the response of patients to endocrine treatment.
The Antitumor and Immunoadjuvant Effects of IFN-α in Combination with Recombinant Poxvirus Vaccines
Authors: Hance Kenneth W. , Rogers Connie J. , Zaharoff David A. , Canter Daniel , Schlom Jeffrey , Greiner John W. 
Published: March 2009

AbstractPurpose: IFN-α is a pleiotropic cytokine possessing immunomodulatory properties that may improve the efficacy of therapeutic cancer vaccines. The aim of this study was to evaluate the effectiveness and compatibility of combining recombinant IFN-α with poxvirus vaccines targeting the human carcinoembryonic antigen (CEA) in murine models of colorectal and pancreatic adenocarcinomas, where CEA is a self-antigen.Experimental Design: The phenotypic and functional effects of IFN-α were evaluated in the draining inguinal lymph nodes of tumor-free mice. We studied the effect of the site of IFN-α administration (local versus distal) on antigen-specific immune responses to poxvirus vaccination. Mechanistic studies were conducted to assess the efficacy of IFN-α and CEA-directed poxvirus vaccines in tumor-bearing CEA transgenic mice.Results: We identified a dose and schedule of IFN-α that induced a locoregional expansion of the draining inguinal lymph nodes and improved cellular cytotoxicity (natural killer and CD8+) and antigen presentation. Suppression of the vaccinia virus was avoided by administering IFN-α distal to the site of vaccination. The combination of IFN-α and vaccine inhibited tumor growth, improved survival, and elicited CEA-specific CTL responses in mice with CEA+ adenocarcinomas. In mice with pancreatic tumors, IFN-α slowed tumor growth, induced CTL activity, and increased CD8+ tumor-infiltrating lymphocytes.Conclusions: These data suggest that IFN-α can be used as a biological response modifier with antigen-directed poxvirus vaccines to yield significant therapeutic antitumor immune responses. This study provides the rationale and mechanistic insights to support a clinical trial of this immunotherapeutic strategy in patients with CEA-expressing carcinomas.
Androgen Receptor Levels and Association with PIK3CA Mutations and Prognosis in Breast Cancer
Authors: Gonzalez-Angulo Ana M. , Stemke-Hale Katherine , Palla Shana L. , Carey Mark , Agarwal Roshan , Meric-Berstam Funda , Traina Tiffany A. , Hudis Clifford , Hortobagyi Gabriel N. , Gerald William L. , Mills Gordon B. , Hennessy Bryan T. 
Published: March 2009

Abstract
Purpose: To examine the androgen receptor (AR) levels in breast cancer and to assess the impact of AR expression on patient outcomes.
Experimental Design: Reverse-phase protein arrays were used to measure AR levels and a mass spectroscopy–based approach was used to detect PIK3CA mutations. Means and SDs were generated for AR levels. Linear regression models were used to determine if AR levels differed by tumor subtype and PIK3CA mutation status. Two-sample t tests were used to identify pair-wise differences. Survival probabilities were estimated with the use of the Kaplan-Meier product and log-rank test.
Results: The median age was 59 years (23-89 years). Significant differences in AR levels existed among different breast tumor subtypes (highest in estrogen receptor–positive and/or progesterone receptor–positive tumors) as well as by PIK3CA mutation status (P &lt; 0.0001 for both). AR levels were significantly higher in breast tumors with kinase domain PIK3CA mutations versus tumors that are wild type or with PIK3CA helical mutations (P = 0.017 and P &lt; 0.0001, respectively). In 347 patients, dichotomized AR level by the median was a significant prognostic factor of recurrence-free survival (P = 0.0002) and overall survival (P = 0.004). High AR levels were associated with a significantly improved recurrence-free survival in 207 patients with early-stage estrogen/progesterone receptor–positive tumors after adjuvant hormonal therapy. A trend (P = 0.07) was found toward higher AR expression in PIK3CA mutant versus PIK3CA wild-type triple-negative breast tumors.
Conclusions: AR levels may represent a prognostic marker in breast cancers and may provide a valuable tool for selecting treatment. There was an association of PIK3CA mutation (kinase domain) with increased AR levels.
Considerations for the Use of Imaging Tools for Phase II Treatment Trials in Oncology
Authors: Shankar Lalitha K. , Van den Abbeele Annick , Yap Jeff , Benjamin Robert , Scheutze Scott , FitzGerald T.J. 
Published: March 2009

Abstract
In the context of assessing tumor response, imaging tools have the potential to play a vital role in phase II and III treatment trials. If the imaging test is able to predict potential phase III success in a reliable fashion, it would be a useful tool in phase II trial design as it may provide for a more rapid and timely response assessment. The benefits and challenges of using anatomic imaging measures as well as the promising molecular imaging measures, primarily fluorodeoxyglucose-positron emission tomography, are discussed here. The general issues related to successful implementation of advanced imaging in the context of phase II treatment trials are discussed.
Combining Radiotherapy with APO010 in Cancer Treatment
Authors: Verbrugge Inge , Wissink Esther H.J. , Rooswinkel Rogier W. , Jongsma Johan , Beltraminelli Nicola , Dupuis Marc , Borst Jannie , Verheij Marcel 
Published: March 2009

Abstract
Purpose: Various proapoptotic agents are currently being explored to improve the outcome of radiotherapy. We have evaluated whether APO010—a novel recombinant ligand of the Fas/CD95 death receptor—enhanced the cytotoxic effect of radiation on lymphoid and solid tumor cell types.
Experimental Design: A Bcl-2–overexpressing T-leukemic cell line (Jurkat), a colon carcinoma cell line (HCT116), and a mesothelioma cell line were used as model systems in vitro and in a subcutaneous transplant setting in immunodeficient mice. Sensitivity to single and combined treatment was read out by apoptosis hallmarks and clonogenic survival in vitro, and by tumor growth delay using bioluminescence and palpation in vivo.
Results: Whereas the three cell lines resisted apoptosis induction by irradiation and APO010 alone, combined treatment greatly enhanced their apoptotic response. In clonogenic survival assays, APO010 reduced the outgrowth of Jurkat-Bcl-2 and HCT116 cells and sensitized the mesothelioma cell line to radiation. In vivo, systemic treatment with APO010 alone caused tumor growth delay in Jurkat-Bcl-2 and HCT116 cells. However, APO010 did not improve the efficacy of radiotherapy in any of the model systems at the selected single dose, which had moderate and reversible systemic toxicity.
Conclusions: Although APO010 and radiation had a clear combined cytotoxic effect on tumor cells in vitro, a combined therapeutic effect was not achieved on the same cells subcutaneously grafted in mice, at APO010 doses approximating the maximally tolerable level. These findings suggest that it will be difficult to identify a therapeutic window for this combined modality approach in a clinical setting.
Parthenolide promotes the ubiquitination of MDM2 and activates p53 cellular functions
Authors: Gopal Y.N. Vashisht , Chanchorn Ekkawit , Van Dyke Michael W. 
Published: March 2009

AbstractMDM2 belongs to a class of ring-finger domain–containing ubiquitin ligases that mediate the proteasomal degradation of numerous proteins, including themselves. Arguably, the most important substrate of MDM2 is p53, which controls cell cycle progression and apoptosis. MDM2 and p53 are parts of a feedback regulatory loop whose perturbations are often present in cancer and are targets for anticancer drug development. We found that the natural product, small-molecule anti-inflammatory agent parthenolide (PN), which is actively being investigated as a potential therapeutic for many human cancers, induces ubiquitination of MDM2 in treated cells, resulting in the activation of p53 and other MDM2-regulated tumor-suppressor proteins. Using cells with functional gene deletions and small interfering RNA knockdown studies, we found that these effects required the DNA damage transducer ataxia telangiectasia mutated. The effects of PN on tumor suppressor activation were comparable with that of nutlin-3a, a recently developed small molecule that was designed to interfere with the interaction between MDM2 and p53 but does not promote MDM2 ubiquitination. Our study illustrates an alternative approach for controlling MDM2 and p53 activities and identifies an additional critically important cancer pathway affected by PN. [Mol Cancer Ther 2009;8(3):552–62]
Gravity Waves in Shear and Implications for Organized Convection
Authors: Stechmann Samuel N. , Majda Andrew J. 
Published: March 2009

AbstractIt is known that gravity waves in the troposphere, which are often excited by preexisting convection, can favor or suppress the formation of new convection. Here it is shown that in the presence of wind shear or barotropic wind, the gravity waves can create a more favorable environment on one side of preexisting convection than the other side.Both the nonlinear and linear analytic models developed here show that the greatest difference in favorability between the two sides is created by jet shears, and little or no difference in favorability is created by wind profiles with shear at low levels and no shear in the upper troposphere. A nonzero barotropic wind (or, equivalently, a propagating heat source) is shown to also affect the favorability on each side of the preexisting convection. It is shown that these main features are captured by linear theory, and advection by the background wind is the main physical mechanism at work. These processes should play an important role in the organization of wave trains of convective systems (i.e., convectively coupled waves); if one side of preexisting convection is repeatedly more favorable in a particular background wind shear, then this should determine the preferred propagation direction of convectively coupled waves in this wind shear.In addition, these processes are also relevant to individual convective systems: it is shown that a barotropic wind can lead to near-resonant forcing that amplifies the strength of upstream gravity waves, which are known to trigger new convective cells within a single convective system. The barotropic wind is also important in confining the upstream waves to the vicinity of the source, which can help ensure that any new convective cells triggered by the upstream waves are able to merge with the convective system.All of these effects are captured in a two-dimensional model that is further simplified by including only the first two vertical baroclinic modes. Numerical results are shown with a nonlinear model, and linear theory results are in good agreement with the nonlinear model for most cases.
Correction of Humidity Biases in Vaisala RS80-H Sondes during NAME
Authors: Ciesielski Paul E. , Johnson Richard H. , Wang Junhong 
Published: March 2009

Abstract
Examination of the upper-air sonde data taken in conjunction with the North American Monsoon Experiment (NAME) revealed that data at several sites in the core monsoon region exhibited a significant dry bias. In this study, a simple, yet effective, statistical correction technique is applied to correct this dry bias. In addition, a second correction is applied to all Vaisala RS80-H sondes to remove a daytime dry bias resulting from solar heating of the humidity sensor. Moisture analyses computed from the corrected sondes compare favorably to those from independent satellite and aircraft estimates. The corrections led to significant improvement in the description of the humidity field and in several convective parameters, such as precipitable water (PW), CAPE, convective inhibition (CIN), and in the diurnal cycle of apparent drying Q2.
Reply
Authors: Kellenbenz David J. , Grafenauer Thomas J. , Davies Jonathan M. 
Published: March 2009

Abstract
Edwards and Thompson have made comprehensive and thorough comments concerning the methods, accuracy, and results in a case study by Kellenbenz et al. These comments questioned the representativeness of model-derived soundings and graphics used, as well as the modification methods employed with soundings presented in the 18 July 2004 case study. Other issues included the application of previous database studies to lifting condensation level (LCL) values found in the 18 July 2004 examination, as well as a focus that emphasized a single tornadic storm. In this response, the authors address problems and oversights with the 18 July 2004 case study, using new data to conduct a reanalysis of the environment on that evening. Additionally, a large independent database of Rapid Update Cycle (RUC) analysis soundings associated with supercell tornadoes is used to provide the context from which to carefully evaluate LCL results from the 18 July 2004 case relative to significant and violent tornadoes. Results indicate that although the LCL height associated with the F4 tornadic supercell in the original case study was probably overestimated, the background LCL environment was still unusually high for a violent tornado. New material presented in this response reinforces the conclusion that, when LCL heights are at the far upper end of empirical study distributions associated with significant tornadoes, undue weight should not be given to LCL as a tornado probability reduction factor when CAPE–storm relative helicity (SRH) combinations and deep-layer shear are also strong.
Is parental coping associated with quality of life in juvenile idiopathic arthritis?
Authors: Cavallo Sabrina , Feldman Debbie Ehrmann , Swaine Bonnie , Meshefedjian Garbis , Malleson Peter N , Duffy Ciarán M 
Published: March 2009

Abstract
Parents of children with a chronic condition such as juvenile arthritis must cope with greater demands than those living with a healthy child. They must adopt different behaviours in order to lessen the impact on the family structure. Parental coping refers to the parent's specific cognitive and behavioural efforts to reduce or manage a demand on the family system. The aims of this study were: to describe coping in a cohort of parents of children with JIA; to determine whether quality of life is associated with parental coping; to explore whether socio-demographic factors such as child's age, family socioeconomic status and family structure are associated with parental coping. One hundred eighty-two parents caring for a child with JIA completed a postal survey at three times over a one-year period, which included the Juvenile Arthritis Quality of Life Questionnaire (JAQQ), the Coping Health Inventory for Parents (CHIP) and questionnaires describing socio-demographic characteristics. Linear mixed models were employed to analyse the association between the child's quality of life and parental coping. Mean total QoL scores (JAQQ) showed that children experienced difficulty in completing specified activities at most just below 25% of the time and results fall off slightly following the 6 month time point. Mean parental coping scores for the CHIP subscales at baseline were 38.4 ± 9.0, 33.4 ± 11.6, 16.5 ± 6.1, for Maintaining Family Integration (maximum score 57), Maintaining Social Support (maximum score 54) and Understanding the Medical Situation (maximum score 24), respectively. Understanding the Medical Situation was deemed most useful. The child's QoL was associated with parental coping. Parents of children with greater psychosocial dysfunction used more coping behaviours related to Understanding the Medical Situation (β coefficient, 0.73; 95% CI, 0.01, 1.45). These findings underscore the importance of helping parents of children with JIA better understand their child's medical situation.
An Ultrasonogram Reporting System for Thyroid Nodules Stratifying Cancer Risk for Clinical Management
Authors: Horvath Eleonora , Majlis Sergio , Rossi Ricardo , Franco Carmen , Niedmann Juan P. , Castro Alex , Dominguez Miguel 
Published: March 2009

Abstract
Context: There is a high prevalence of thyroid nodules on ultrasonographic (US) examination. However, most of them are benign. US criteria may help to decide cost-effective management.
Objective: Our objective was to develop a standardized US characterization and reporting data system of thyroid lesions for clinical management: the Thyroid Imaging Reporting and Data System (TIRADS).
Design: This was a prospective study using the TIRADS, which is based on the concepts of the Breast Imaging Reporting Data System of the American College of Radiology.
Materials: A correlation of the US findings and fine needle aspiration biopsy (FNAB) results in 1959 lesions biopsied under US guidance and studied histologically during an 8-yr period was divided into three stages. In the first stage, 10 US patterns were defined. In the second stage, four TIRADS groups were defined according to risk. The percentages of malignancy defined in the Breast Imaging Reporting and Data System were followed: TIRADS 2 (0% malignancy), TIRADS 3 (&lt;5% malignancy), TIRADS 4 (5–80% malignancy), and TIRADS 5 (&gt;80% malignancy).
Results: The TIRADS classification was evaluated at the third stage of the study in a sample of 1097 nodules (benign: 703; follicular lesions: 238; and carcinoma: 156). Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy were 88, 49, 49, 88, and 94%, respectively. The ratio of benign to malignant or follicular FNAB results currently is 1.8.
Conclusions: The TIRADS has allowed us to improve patient management and cost-effectiveness, avoiding unnecessary FNAB. In addition, we have established standard codes to be used both for radiologists and endocrinologists.