bluuebunny/crossref_metadata_2025_split huggingface dataset:
Expression of EBV Latent Antigens, Mammalian Target of Rapamycin, and Tumor Suppression Genes in EBV-Positive Smooth Muscle Tumors: Clinical and Therapeutic Implications
Authors: Ong Kong Wee , Teo Marissa , Lee Victor , Ong Danny , Lee Ann , Tan Chieh Suai , Vathsala A. , Toh Han Chong 
Published: August 2009

Abstract
Purpose: EBV-positive smooth muscle tumor (EBV+SMT) is a rare disease with no established therapy. We describe the largest single institution analysis in renal transplant recipients. It aims to define its clinical features and determine the expression of EBV latent genes as well as key molecular pathways.
Experimental Design: Patients with EBV+SMT were identified from the Singapore General Hospital Renal Transplant Registry database. These tumors were investigated for expression of EBV latent genes with Southern blots, EBV latent antigens, mammalian target of rapamycin (mTOR), Akt, p70 S6 kinase, and vascular endothelial growth factor using immunohistochemistry, as well as methylation status of cancer-related genes using methylation-specific PCR.
Results: Eight were found to be EBV+SMT in 1,123 transplant patients. All displayed indolent clinical courses and were unresponsive to immunosuppression reduction. Complete tumor regression was seen in one patient following administration of sirolimus. These tumors display the full range of known EBV latent genes. Immunohistochemistry with total and phosphorylated mTOR and Akt were positive for all patients, and vascular endothelial growth factor was positive in 25% of patients, suggesting activation of the mTOR/Akt pathway. Methylation of RASSF1A was found in all tissue samples, whereas promoter hypermethylation of RARβ, GSTP1, DAPK, and p14 was observed in some samples.
Conclusions: Our results suggest that these tumors display a EBV type III latency pattern. The mTOR pathway is also activated. EBV may play a role in silencing RASSF1A. EBV-specific immunotherapy, mTOR inhibitors, and demethylating agents are possible therapeutic options in this disease. (Clin Cancer Res 2009;15(17):5350–8)
Erythropoietin Receptor Expression and Correlation to Tamoxifen Response and Prognosis in Breast Cancer
Authors: Larsson Anna-Maria , Jirström Karin , Fredlund Erik , Nilsson Sofie , Rydén Lisa , Landberg Göran , Påhlman Sven 
Published: August 2009

Abstract
Purpose: The main function of erythropoietin (EPO) is to stimulate erythropoiesis. EPO receptors (EPOR) are expressed in other cell types, including tumor cells, suggesting that the EPO/EPOR pathway governs additional cellular processes besides erythropoiesis. Recombinant EPO (rhEPO) is frequently given to anemic cancer patients, although data on clinical outcome are conflicting. In an attempt to understand these clinical data, we analyzed EPO and EPOR expression in breast cancer and evaluated EPOR as a putative prognostic and predictive marker in breast cancer patients treated with tamoxifen.
Experimental Design: EPO mRNA/protein and EPOR mRNA were quantified by PCR and ELISA, respectively. Tissue microarrays containing 500 breast tumors from premenopausal women randomized to tamoxifen or no adjuvant treatment were evaluated for EPOR expression by immunohistochemistry. Predictive and prognostic information was evaluated using Kaplan-Meier curves and log-rank tests to estimate recurrence-free survival (RFS).
Results: EPO and EPOR were expressed in cultured cells, and breast tumor specimens expressed EPOR at varying levels. Tamoxifen treatment significantly increased RFS in patients with estrogen receptor–positive/progesterone receptor–positive (ER+/PR+) tumors with low EPOR expression (P = 0.001) but had no effect on RFS in patients with tumors with high EPOR expression (P = 0.98). In the untreated cohort, RFS was significantly improved for patients with ER+ tumors with high EPOR expression.
Conclusion: EPOR is abundantly expressed in breast cancer specimens. The fact that high expression of EPOR is related to an impaired tamoxifen response in ER+/PR+ tumors and to improved survival in untreated patients suggests that EPOR expression in breast cancer affects tumor behavior. (Clin Cancer Res 2009;15(17):5552–9)
A New Immunostain Algorithm Classifies Diffuse Large B-Cell Lymphoma into Molecular Subtypes with High Accuracy
Authors: Choi William W.L. , Weisenburger Dennis D. , Greiner Timothy C. , Piris Miguel A. , Banham Alison H. , Delabie Jan , Braziel Rita M. , Geng Huimin , Iqbal Javeed , Lenz Georg , Vose Julie M. , Hans Christine P. , Fu Kai , Smith Lynette M. , Li Min , Liu Zhongfeng , Gascoyne Randy D. , Rosenwald Andreas , Ott German , Rimsza Lisa M. , Campo Elias , Jaffe Elaine S. , Jaye David L. , Staudt Louis M. , Chan Wing C. 
Published: August 2009

AbstractPurpose: Hans and coworkers previously developed an immunohistochemical algorithm with ∼80% concordance with the gene expression profiling (GEP) classification of diffuse large B-cell lymphoma (DLBCL) into the germinal center B-cell–like (GCB) and activated B-cell–like (ABC) subtypes. Since then, new antibodies specific to germinal center B-cells have been developed, which might improve the performance of an immunostain algorithm.Experimental Design: We studied 84 cases of cyclophosphamide-doxorubicin-vincristine-prednisone (CHOP)–treated DLBCL (47 GCB, 37 ABC) with GCET1, CD10, BCL6, MUM1, FOXP1, BCL2, MTA3, and cyclin D2 immunostains, and compared different combinations of the immunostaining results with the GEP classification. A perturbation analysis was also applied to eliminate the possible effects of interobserver or intraobserver variations. A separate set of 63 DLBCL cases treated with rituximab plus CHOP (37 GCB, 26 ABC) was used to validate the new algorithm.Results: A new algorithm using GCET1, CD10, BCL6, MUM1, and FOXP1 was derived that closely approximated the GEP classification with 93% concordance. Perturbation analysis indicated that the algorithm was robust within the range of observer variance. The new algorithm predicted 3-year overall survival of the validation set [GCB (87%) versus ABC (44%); P &lt; 0.001], simulating the predictive power of the GEP classification. For a group of seven primary mediastinal large B-cell lymphoma, the new algorithm is a better prognostic classifier (all “GCB”) than the Hans' algorithm (two GCB, five non-GCB).Conclusion: Our new algorithm is significantly more accurate than the Hans' algorithm and will facilitate risk stratification of DLBCL patients and future DLBCL research using archival materials. (Clin Cancer Res 2009;15(17):5494–502)
CD24 Is a Novel Predictor for Poor Prognosis of Hepatocellular Carcinoma after Surgery
Authors: Yang Xin-Rong , Xu Yang , Yu Bin , Zhou Jian , Li Jia-Chu , Qiu Shuang-Jian , Shi Ying-Hong , Wang Xiao-Ying , Dai Zhi , Shi Guo-Ming , Wu Bin , Wu Li-Ming , Yang Guo-Huan , Zhang Bo-Heng , Qin Wen-Xin , Fan Jia 
Published: August 2009

Abstract
Purpose: To investigate the role of CD24 in tumor invasion and prognostic significance in hepatocellular carcinoma (HCC).
Experimental Design: CD24 expression was measured in stepwise metastatic HCC cell lines, tumor, peritumoral tissues, and normal liver tissues by quantitative real-time PCR and Western blot. The role of CD24 in HCC was investigated by CD24 depletion using small interfering RNA. Tumor tissue microarrays of 314 HCC patients who underwent resection between 1997 and 2000 were used to detect expression of CD24, β-catenin, and proliferating cell nuclear antigen. Prognostic significance was assessed using Kaplan-Meier survival estimates and log-rank tests.
Results: CD24 was overexpressed in the highly metastatic HCC cell line and in tumor tissues of patients with recurrent HCC. Depletion of CD24 caused a notable decrease in cell proliferation, migration, and invasiveness in vitro. Univariate and multivariate analyses revealed that CD24 was a significant predictor for overall survival and relapse-free survival. CD24 expression was correlated with poor prognosis independent of α-fetoprotein, tumor-node-metastasis stage, and Edmondson stage. High CD24 expression was significantly associated with cytoplasmic and nuclear accumulation of β-catenin (P = 0.023), high tumor proliferative status (P = 0.018), and diffused intrahepatic recurrence and distant metastasis (P = 0.026). Adjuvant transcatheter arterial chemoembolization after surgery reduced the rate of early recurrence (≤1 year) in CD24+ HCC patients (P = 0.024) but had no significant effect in CD24− patients (P = 0.284).
Conclusions: Overexpression of CD24 in HCC was associated with high invasiveness and metastatic potential, high tumor proliferation status, and activation of the Wnt/β-catenin pathway. CD24 may be a novel predictor for poor prognosis of HCC patients after surgery. (Clin Cancer Res 2009;15(17):5518–27)
Salivary microRNA: Discovery, Characterization, and Clinical Utility for Oral Cancer Detection
Authors: Park Noh Jin , Zhou Hui , Elashoff David , Henson Bradley S. , Kastratovic Dragana A. , Abemayor Elliot , Wong David T. 
Published: August 2009

Abstract
Purpose: We have previously shown that a transcriptome is found in saliva and subpanels of these mRNAs can be used as oral cancer biomarkers. In this study, we measured the presence of microRNAs (miRNA) in saliva and determined their potential as an additional set of oral cancer biomarkers.
Experimental Design: A total of 314 miRNAs were measured using reverse transcriptase-preamplification-quantitative PCR in 12 healthy controls. Degradation pattern of endogenous and exogenous saliva miRNAs were measured at room temperature over time. Selected miRNAs were validated in saliva of 50 oral squamous cell carcinoma patients and 50 healthy matched control subjects.
Results: We detected ∼50 miRNAs in both the whole and supernatant saliva. Endogenous saliva miRNA degraded much slower compared with exogenous miRNA. Two miRNAs, miR-125a and miR-200a, were present in significantly lower levels (P &lt; 0.05) in the saliva of oral squamous cell carcinoma patients than in control subjects.
Conclusions: Both whole and supernatant saliva of healthy controls contained dozens of miRNAs, and similar to saliva mRNAs, these miRNAs are stable. Saliva miRNAs can be used for oral cancer detection. (Clin Cancer Res 2009;15(17):5473–7)
Integration of Molecular Profiling into the Lung Cancer Clinic
Authors: Pao William , Kris Mark G. , Iafrate A. John , Ladanyi Marc , Jänne Pasi A. , Wistuba Ignacio I. , Miake-Lye Ryn , Herbst Roy S. , Carbone David P. , Johnson Bruce E. , Lynch Thomas J. 
Published: August 2009

Abstract
Individuals from five thoracic oncology centers in the United States recently met to discuss how to integrate molecular profiling into the care of all patients with carcinoma of the lung. Lung cancer is an area of medical oncology in which clinicians are beginning to use specific tumor-associated molecular aberrations to assign and/or prioritize targeted therapies for patients. At this early stage, multiple hurdles remain before molecular profiling becomes a routine part of thoracic oncology practice. Concrete collaborative next steps were discussed that could help lead to standardized methods across institutions. In particular, to develop specific targeted therapies for patients whose tumors harbor rare mutations, it will be important for multiple institutions to work together to identify appropriate candidates, design the appropriate trials, and execute the trials with adequate numbers to achieve the necessary end points. Implementation will facilitate realization of the promise of molecularly tailored therapy, which could lead to more effective treatments with fewer side effects. (Clin Cancer Res 2009;15(17):5317–22)
Blood Flow-Metabolism Mismatch: Good for the Tumor, Bad for the Patient
Authors: Mankoff David A. , Dunnwald Lisa K. , Partridge Savannah C. , Specht Jennifer M. 
Published: August 2009

Abstract
Although tightly coupled in most normal tissues, blood flow and metabolism are often not well matched in tumors. A flow-metabolism mismatch, specifically, high metabolism relative to blood flow, can be recognized in tumors by functional and molecular imaging and is associated with poor response to treatment and early relapse or disease progression. (Clin Cancer Res 2009;15(17):5294–6)
Impacts of Evaporation from Raindrops on Tropical Cyclones. Part II: Features of Rainbands and Asymmetric Structure
Authors: Sawada Masahiro , Iwasaki Toshiki 
Published: August 2009

Abstract
In this study, the impacts of evaporative cooling from raindrops on a tropical cyclone (TC) are examined using cloud-resolving simulations under an idealized condition. Part I of this study showed that evaporative cooling greatly increases the kinetic energy of a TC and its size because rainbands provide a large amount of condensation heating outside the eyewall. Part II investigates characteristics of simulated rainbands in detail. Rainbands are actively formed, even outside the eyewall, in the experiment including evaporative cooling, whereas they are absent in the experiment without evaporative cooling. Rainbands propagate in the counterclockwise and radially outward direction, and such behaviors are closely related to cold pools. New convective cells are successively generated at the upstream end of a cold pool, which is referred to here as the upstream development. The upstream development organizes spiral-shaped rainbands along a low-level streamline that is azimuthally averaged and propagates them radially outward. Asymmetric flows from azimuthally averaged low-level wind advance cold pool fronts in the normal direction to rainbands, which are referred to here as cross-band propagation. The cross-band propagation deflects the movement of each cell away from the low-level streamlines and rotates it in the counterclockwise direction. Cross-band propagation plays an essential role in the maintenance of rainbands. Advancement of cold pool fronts lifts up the warm and moist air mass slantwise and induces heavy precipitation. Evaporative cooling from raindrops induces downdrafts and gives feedback to the enhancement of cold pools.
Seasonal Influences on Coupled Ocean–Atmosphere Variability in the Tropical Atlantic Ocean
Authors: Bates Susan C. 
Published: August 2009

Abstract
Numerous studies and observational analyses point to a connection between the annual cycle and tropical Atlantic variability, specifically the influence of the seasons. Although a previous study has shown that the annual cycle is not necessary for the generation of this variability, this study demonstrates that the annual cycle provides particular conditions that modulate this variability. Particular seasons are investigated through the use of a coupled ocean–atmosphere model using anomaly coupling as the coupling strategy in order to control the mean state of the system. To isolate the influence of each season, the model is integrated in perpetuated mean states that simulate perpetual boreal spring, summer, fall, and winter seasonal mean states. These are compared to a control simulation that contains an annual cycle. Evidence is shown that the annual cycle modulates tropical Atlantic variability in the following three ways: 1) the background mean state for some seasons provides favorable conditions for the growth of particular patterns through regional air–sea feedback mechanisms, 2) mechanisms that excite the variability are seasonally dependent, and 3) the progression through the annual cycle is important for certain variabilities to be excited and grow.
Sensitivity of Climate Change Induced by the Weakening of the Atlantic Meridional Overturning Circulation to Cloud Feedback
Authors: Zhang Rong , Kang Sarah M. , Held Isaac M. 
Published: August 2009

Abstract
A variety of observational and modeling studies show that changes in the Atlantic meridional overturning circulation (AMOC) can induce rapid global-scale climate change. In particular, a substantially weakened AMOC leads to a southward shift of the intertropical convergence zone (ITCZ) in both the Atlantic and the Pacific Oceans. However, the simulated amplitudes of the AMOC-induced tropical climate change differ substantially among different models. In this paper, the sensitivity to cloud feedback of the climate response to a change in the AMOC is studied using a coupled ocean–atmosphere model [the GFDL Coupled Model, version 2.1 (CM2.1)]. Without cloud feedback, the simulated AMOC-induced climate change in this model is weakened substantially. Low-cloud feedback has a strong amplifying impact on the tropical ITCZ shift in this model, whereas the effects of high-cloud feedback are weaker. It is concluded that cloud feedback is an important contributor to the uncertainty in the global response to AMOC changes.
Acute dasatinib exposure commits Bcr-Abl–dependent cells to apoptosis
Authors: Snead Jennifer L. , O'Hare Thomas , Adrian Lauren T. , Eide Christopher A. , Lange Thoralf , Druker Brian J. , Deininger Michael W. 
Published: August 2009

AbstractPioneering work with the Bcr-Abl inhibitor, imatinib, demonstrated a requirement for constant Bcr-Abl inhibition to achieve maximal therapeutic benefit in treating chronic myeloid leukemia (CML), establishing a paradigm that has guided further drug development for this disease. Surprisingly, the second-generation Bcr-Abl inhibitor, dasatinib, was reported to be clinically effective with once-daily dosing, despite a short (3- to 5-hour) plasma half-life. Consistent with this observation, dasatinib treatment of progenitor cells from chronic-phase CML patients for 4 hours, followed by washout, or continuously for 72 hours both resulted in an induction of apoptosis and a reduction in the number of clonogenic cells. Such acute treatments with clinically achievable dasatinib concentrations also irreversibly committed Bcr-Abl+ CML cell lines to apoptotic cell death. Potent transient Bcr-Abl inhibition using the alternative inhibitor, nilotinib, also resulted in cell death. These findings demonstrate that in vitro assays designed to model in vivo pharmacokinetics can predict clinical efficacy. Furthermore, they challenge the widely held notion that continuous target inhibition is required for optimal efficacy of kinase inhibitors.
Association between beta2-glycoprotein I plasma levels and the risk of myocardial infarction in older men
Authors: de Laat Bas , de Groot Philip G. , Derksen Ronald H. W. M. , Urbanus Rolf T. , Mertens Koen , Rosendaal Frits R. , Doggen Carine J. M. 
Published: August 2009

Abstract
von Willebrand factor (VWF) serves as adhesive surface for platelets to adhere to the vessel wall. We have recently found that beta2-glycoprotein I is able to inhibit platelet binding to VWF, indicating a role in the pathophysiology of arterial thrombosis. In the present study, we investigated whether differences in beta2-glycoprotein I plasma levels influence the risk of myocardial infarction. We have measured beta2-glycoprotein I and VWF antigen levels in 539 men with a first myocardial infarction and in 611 control subjects. Although we did not find a profound effect of beta2-glycoprotein I plasma levels on myocardial infarction in the overall population, we found a dose-dependent protective effect of increasing beta2-glycoprotein I plasma levels on myocardial infarction in men 60 years and older. In this age group, we found an odds ratio of 0.41 (95% confidence interval, 0.22-0.74) for high beta2-glycoprotein I levels compared with low levels. High plasma levels of beta2-glycoprotein I remained protective for myocardial infarction despite high levels of VWF. To conclude, high circulating levels of beta2-glycoprotein I appeared to be associated with a reduced risk of myocardial infarction in elderly men. In vivo experiments are needed to investigate the exact contribution of beta2-glycoprotein I on the pathophysiology of myocardial infarction.
Macrophages are an abundant component of myeloma microenvironment and protect myeloma cells from chemotherapy drug–induced apoptosis
Authors: Zheng Yuhuan , Cai Zhen , Wang Siqing , Zhang Xiang , Qian Jianfei , Hong Sungyoul , Li Haiyan , Wang Michael , Yang Jing , Yi Qing 
Published: August 2009

Abstract
Multiple myeloma remains an incurable disease. One of the major problems is that myeloma cells develop drug resistance on interaction with bone marrow stromal cells. In this study, we examined the effects of macrophages (Mφs), a type of stromal cells, on myeloma cell survival and response to chemotherapy. We showed that Mφ, in particular tumor-associated Mφ, is a protector of myeloma cells. The protective effect was dependent on direct contact between Mφs and myeloma cells. Mφs protected both myeloma cell lines and primary myeloma cells from spontaneous and chemotherapy drug-induced apoptosis by attenuating the activation and cleavage of caspase-dependent apoptotic signaling. These findings are clinically relevant because we found that CD68+ Mφs heavily infiltrate the bone marrow of patients with myeloma but not the bone marrow of control patients. Thus, our results indicate that Mφs may contribute to myeloma cell survival and resistance to chemotherapeutic treatment in vivo.
Phase 3 randomized, placebo-controlled, double-blind study of high-dose continuous infusion cytarabine alone or with laromustine (VNP40101M) in patients with acute myeloid leukemia in first relapse
Authors: Giles Francis , Vey Norbert , DeAngelo Daniel , Seiter Karen , Stock Wendy , Stuart Robert , Boskovic Darinka , Pigneux Arnaud , Tallman Martin , Brandwein Joseph , Kell Jonathan , Robak Tadeusz , Staib Peter , Thomas Xavier , Cahill Ann , Albitar Maher , O'Brien Susan 
Published: August 2009

Abstract
Laromustine is a sulfonylhdrazine alkylator with significant antileukemia activity. An international, randomized (2:1), double-blind, placebo-controlled study was conducted to compare complete remission (CR) rates and overall survival (OS) in patients with first relapse acute myeloid leukemia (AML) treated with laromustine and high-dose cytarabine (HDAC) versus HDAC/placebo. Patients received 1.5 g/m2 per day cytarabine continuous infusion for 3 days and laromustine 600 mg/m2 (n = 177) or placebo (n = 86) on day 2. Patients in CR received consolidation with laromustine/HDAC or HDAC/placebo as per initial randomization. After interim analysis at 50% enrollment, the Data Safety Monitoring Board (DSMB) expressed concern that any advantage in CR would be compromised by the observed on-study mortality, and enrollment was held. The CR rate was significantly higher for the laromustine/HDAC group (35% vs 19%, P = .005). However, the 30-day mortality rate and median progression-free survival were significantly worse in this group compared with HDAC/placebo (11% vs 2%; P = .016; 54 days vs 34; P = .002). OS and median response durations were similar in both groups. Laromustine/HDAC induced significantly more CR than HDAC/placebo, but OS was not improved due to mortality associated with myelosuppression and its sequelae. The DSMB subsequently approved a revised protocol with laromustine dose reduction and recombinant growth factor support. The study was registered as NCT00112554 at http://www.clinicaltrials.gov.