bluuebunny/crossref_metadata_2025_split huggingface dataset:
Chemoresistance of lung cancer stemlike cells depends on activation of Hsp27
Authors: Hsu Han‐Shui , Lin Jiun‐Han , Huang Wen‐Chien , Hsu Tien‐Wei , Su Kelly , Chiou Shih‐Hwa , Tsai Yo‐Ting , Hung Shih‐Chieh 
Published: November 2010

AbstractBACKGROUND:In the current study, the authors sought to identify the molecular mechanisms underlying the chemoresistance of lung cancer stem or initiation cells (cancer stem cells).METHODS:A549 lung cancer cells before and after selective enrichment of a subpopulation of cancer stem cells were treated with superoxide and traditional chemotherapeutics to determine their sensitivity or resistance to these cytotoxic agents. Apoptotic activity was measured using a variety of fluorescence‐based and biochemical techniques. Specific pathways involved in the chemoresistance of cancer stem cell‐enriched lung cancer cells were analyzed with Western blotting and pharmacologic targeting therapy in a xenograft model.RESULTS:Lung cancer stem cells exhibited significantly decreased apoptotic response to treatment with superoxide, cisplatin, gemcitabine, or a combination of cisplatin and gemcitabine compared with control A549 cells. Apoptotic resistance was mediated through the inactivation of caspase‐9 and caspase‐3. Increased activation of p38MAPK, MAPKAPK2, and Hsp27 was observed in lung cancer stem cells compared with control A549 cells both before and after exposure to superoxide and chemotoxic agents. In a mouse model of lung cancer, chemotherapy‐induced cells increased in the antiapoptosis pathway, and quercetin, an inhibitor of Hsp27, combined with traditional chemotherapy was effective in blocking the pathway and in the treatment of lung tumors in vivo.CONCLUSIONS:The authors' data demonstrate that lung cancer stem cells have elevated levels of activated Hsp27 upon treatment with superoxide and traditional chemotherapy. When combined with chemotoxic agents, blockage of Hsp27 decreased the survival of lung cancer stem cells, which otherwise were resistant to traditional chemotherapy. Cancer 2011. © 2010 American Cancer Society.
A prognostic model for soft tissue sarcoma of the extremities and trunk wall based on size, vascular invasion, necrosis, and growth pattern
Authors: Carneiro Ana , Bendahl Par‐Ola , Engellau Jacob , Domanski Henryk A. , Fletcher Christopher D. , Rissler Pehr , Rydholm Anders , Nilbert Mef 
Published: November 2010

AbstractBACKGROUND:In soft tissue sarcoma, better distinction of high‐risk and low‐risk patients is needed to individualize treatment and improve survival. Prognostic systems used in clinical practice identify high‐risk patients based on various factors, including age, tumor size and depth, histological type, necrosis, and grade.METHODS:Whole‐tumor sections from 239 soft tissue sarcomas of the extremities were reviewed for the following prognostic factors: size, vascular invasion, necrosis, and growth pattern. A new prognostic model, referred to as SING (Size, Invasion, Necrosis, Growth), was established and compared with other clinically applied systems.RESULTS:Size, vascular invasion, necrosis, and peripheral tumor growth pattern provided independent prognostic information with hazard ratios of 2.2‐2.6 for development of metastases in multivariate analysis. When these factors were combined into the prognostic model SING, high risk of metastasis was predicted with a sensitivity of 74% and a specificity of 85%. Moreover, the prognostic performance of SING compared favorably with other widely used systems.CONCLUSIONS:SING represents a promising prognostic model, and vascular invasion and tumor growth pattern should be considered in soft tissue sarcoma prognostication. Cancer 2011. © 2010 American Cancer Society.
Benefits of interferon‐β and temozolomide combination therapy for newly diagnosed primary glioblastoma with the unmethylated MGMT promoter
Authors: Motomura Kazuya , Natsume Atsushi , Kishida Yugo , Higashi Hiroyuki , Kondo Yutaka , Nakasu Yoko , Abe Tatsuya , Namba Hiroki , Wakai Kenji , Wakabayashi Toshihiko 
Published: November 2010

AbstractBACKGROUND:The aim of the current study was to catalog genomic and epigenomic abnormalities in newly diagnosed glioblastoma patients and determine the correlation among clinical, genetic, and epigenetic profiles and clinical outcome.METHODS:This study retrospectively included 68 consecutive patients who underwent surgical treatment and received standard radiotherapy with temozolomide (TMZ)‐based chemotherapy. Of a total of 68 patients, 39 patients (57.4%) received interferon (IFN)‐β in combination of TMZ.RESULTS:The genetic and epigenetic alterations frequently observed were EGFR amplification (51.5%), TP53 mutation (33.8%), CDKN2A loss (32.4%), TP53 loss (16.2%), methylation of the MGMT promoter (33.8%) and IDH1 mutation (5.9%). Multivariate analysis revealed that methylated MGMT promoter and the combination of TMZ and IFN‐β were independent prognostic factors associated with survival. The median survival time (MST) of the patients who received the combination of IFN‐β and TMZ was significantly greater with 19.9 months as compared to the TMZ alone group (12.7 months). Notably, in even patients whose tumors had unmethylated MGMT promoter, the MST prolonged to 17.2 months when receiving TMZ with IFN‐β, compared to 12.5 months in those receiving TMZ without IFN‐β.CONCLUSIONS:Taken together, addition of IFN‐β for newly diagnosed primary GBM achieved a favorable outcome, particularly in patients with unmethylated MGMT promoter. Cancer 2011. © 2010 American Cancer Society.
Clinical variables and primary tumor characteristics predictive of the development of melanoma brain metastases and post‐brain metastases survival
Authors: Zakrzewski Jan , Geraghty Laurel N. , Rose Amy E. , Christos Paul J. , Mazumdar Madhu , Polsky David , Shapiro Richard , Berman Russell , Darvishian Farbod , Hernando Eva , Pavlick Anna , Osman Iman 
Published: November 2010

AbstractBACKGROUND:Melanoma patients who develop brain metastases (B‐Met) have limited survival and are excluded from most clinical trials. In the current study, the authors attempted to identify primary tumor characteristics and clinical features predictive of B‐Met development and post‐B–Met survival.METHODS:A prospectively accrued cohort of 900 melanoma patients was studied to identify clinicopathologic features of primary melanoma (eg, thickness, ulceration, mitotic index, and lymphovascular invasion) that are predictive of B‐Met development and survival after a diagnosis of B‐Met. Associations between clinical variables present at the time of B‐Met diagnosis (eg, extracranial metastases, B‐Met location, and the presence of neurological symptoms) and post‐B–Met survival were also assessed. Univariate associations were analyzed using Kaplan‐Meier survival analysis, and the effect of independent predictors was assessed using multivariate Cox proportional hazards regression analysis.RESULTS:Of the 900 melanoma patients studied, 89 (10%) developed B‐Met. Ulceration and site of the primary tumor on the head and neck were found to be independent predictors of B‐Met development on multivariate analysis (P = .001 and P = .003, respectively). Clinical variables found to be predictive of post‐B–Met survival on multivariate analysis included the presence of neurological symptoms (P = .008) and extracranial metastases (P = .04). Ulceration was the only primary tumor characteristic that remained a significant predictor of post‐B–Met survival on multivariate analysis (P = .04).CONCLUSIONS:Primary tumor ulceration was found to be the strongest predictor of B‐Met development and remained an independent predictor of decreased post‐B–Met survival in a multivariate analysis inclusive of primary tumor characteristics and clinical variables. The results of the current study suggest that patients with ulcerated primary tumors should be prospectively studied to determine whether heightened surveillance for B‐Met can improve clinical outcome. Cancer 2011. © 2010 American Cancer Society.
Identification and validation of Notch pathway activating compounds through a novel high‐throughput screening method
Authors: Pinchot Scott N. , Jaskula‐Sztul Renata , Ning Li , Peters Noel R. , Cook Mackenzie R. , Kunnimalaiyaan Muthusamy , Chen Herbert 
Published: November 2010

AbstractBACKGROUND:Carcinoids are neuroendocrine (NE) tumors with limited treatment options. Notch activation has been shown to suppress growth and hormone production in carcinoid cells.METHODS:The purpose of this study was to provide a process for identifying Notch activating compounds via high‐throughput screening (HTS) and to validate the effects of the strongest hit from the 7264 compounds analyzed: resveratrol (RESV).RESULTS:Treatment of carcinoid cells with RESV resulted in up‐regulation of the Notch signaling pathway as measured by suppression of its downstream target achaete‐scute complex‐like 1. Luciferase reporter assays incorporating the centromere‐binding factor 1 binding site also confirmed the functional activity of RESV‐induced Notch. Because activation of the Notch pathway has been shown to suppress carcinoid proliferation, RESV treatment of carcinoid cells led to a dose‐dependent inhibition of cellular growth. Immunoblotting revealed phosphorylation of cdc2 (Tyr15) and up‐regulation of p21Cip1/Waf, markers of cell cycle arrest, with RESV treatment. Flow cytometry confirmed the mechanism of RESV‐induced growth inhibition is S phase cell cycle arrest. Furthermore, because Notch has been shown to inhibit bioactive hormone production from NE tumors, RESV also suppressed expression of the NE peptides/hormones chromogranin A and serotonin. RNA interference assays demonstrated that the hormone suppressing capacity of RESV was due to up‐regulation of the Notch2 isoform.CONCLUSIONS:HTS can be used to identify novel Notch activating compounds, which may have the potential to suppress carcinoid tumor growth and the associated endocrinopathies. Cancer 2011. © 2010 American Cancer Society.
Racial disparities in the use of hospice services according to geographic residence and socioeconomic status in an elderly cohort with nonsmall cell lung cancer
Authors: Hardy Dale , Chan Wenyaw , Liu Chih‐Chin , Cormier Janice N. , Xia Rui , Bruera Eduardo , Du Xianglin L. 
Published: November 2010

AbstractBACKGROUND:The authors investigated whether there were racial disparities in the receipt of hospice services within geographic residence and socioeconomic status (SES) levels.METHODS:In total, 117,894 patients aged ≥66 years with nonsmall cell lung cancer (NSCLC) were identified from the Surveillance, Epidemiology, and End Results‐Medicare linked database who had received hospice services in the last 6 months before death and who died between January 1, 1991 and December 31, 2005. Multivariate odds ratios (ORs) with 95% confidence intervals (CIs) using mixed‐effects logistic regression models were used to describe relations.RESULTS:In urban areas, there were significant disparity trends in age/sex‐adjusted rates for blacks and Asians/Pacific Islanders compared with whites (P = .003 and P = .036, respectively). Blacks (OR, 0.79; 95% CI, 0.75‐0.82), Asians/Pacific Islanders (OR, 0.42; 95% CI, 0.39‐0.46), and Hispanics (OR, 0.81; 95% CI, 0.73‐0.91) were less likely to receive hospice services. In rural areas, blacks were 21% less likely to receive hospice services (OR, 0.79; 95% CI, 0.63‐0.98). Patients in the poorest socioeconomic status (SES) quartile were 7% less likely to receive hospice services (OR, 0.93; 95% CI, 0.86‐1.00). Moreover, within stratified SES quartiles, blacks and Asians/Pacific Islanders had lower receipt of hospice services, and Asians/Pacific Islanders were the least likely to receive hospice services, particularly those in the poorest SES quartile. In general, older patients and women were more likely to receive hospice services.CONCLUSIONS:There were substantial disparities in the receipt of hospice services among ethnic minorities within urban and rural areas and within SES levels. The results indicated that efforts are needed to identify barriers, enhance support, and educate patients on the benefits of hospice services. Cancer 2010. © 2010 American Cancer Society.
Considering temozolomide as a novel potential treatment for esophageal cancer
Authors: Bruyère Céline , Lonez Caroline , Duray Anaelle , Cludts Stéphanie , Ruysschaert Jean‐Marie , Saussez Sven , Yeaton Paul , Kiss Robert , Mijatovic Tatjana 
Published: November 2010

AbstractBACKGROUND:C‐X‐C ligand (CXCL) chemokines exert major roles in the biologic aggressiveness of esophageal cancer. In the current study, the authors investigated temozolomide (TMZ)‐induced effects on activity of the CXCL chemokine network in human esophageal cancer cells. To the authors' knowledge, TMZ has not been investigated previously in experimental or clinical esophageal cancers.METHODS:A complete mapping of CXCL chemokines and their receptor messenger RNA was performed in 2 established human esophageal cancer cell lines (OE21 and OE33) and in 4 surgical samples from patients with esophageal carcinoma. The analyses pointed out the potential importance of CXCL2, and monitoring CXCL2 with quantitative videomicroscopy indicated that its biologic activity was silenced in OE21 esophageal cancer cells. TMZ‐mediated antitumor activity was determined in vivo in an OE21 metastatic nude mice xenograft model.RESULTS:The messenger RNA levels of CXC chemokines and their receptors were similar in both cell lines and in the 4 surgical specimens. CXCL2 depletion by small interfering RNA (siRNA) displayed marked effects on the proliferation of transfected OE21 cells. Chronic in vitro TMZ treatment of OE21 and OE33 cells markedly decreased CXCL2 and CXCL3 secretion. In vivo, TMZ induced significant delays in OE21 xenograft tumor development and improved the survival of OE21 xenograft‐bearing mice, whereas cisplatin did not. Analyses performed on tissue samples from in vivo experiments revealed that TMZ also impaired tumor angiogenesis.CONCLUSIONS:The current study emphasized the role of proangiogenic chemokines in esophageal cancer biology and indicated the possibility of using TMZ as a clinically compatible drug to impair the actions of the CXCL chemokine network in esophageal cancers. Cancer 2011. © 2010 American Cancer Society.
Systemic administration of reovirus (Reolysin) inhibits growth of human sarcoma xenografts
Authors: Hingorani Pooja , Zhang Wendong , Lin Juan , Liu Laibin , Guha Chandan , Kolb E. Anders 
Published: November 2010

AbstractBACKGROUND:Despite advancement in therapies, overall survival rates for relapsed pediatric sarcomas are dismal. Newer therapies are needed to effectively salvage these patients. Oncolytic viruses (such as reovirus) and other genetically altered viruses (such as herpes simplex viruses and adenoviruses) have shown efficacy in a variety of solid tumors including sarcomas. Reolysin is an unmodified oncolytic reovirus that selectively replicates in Ras‐activated cancer cells while not causing any significant human illness in its wild form.METHODS:By using a panel of pediatric sarcoma cell lines in vitro and flank xenografts in vivo, Reolysin was evaluated as a single agent and in combination with cisplatin and radiation therapy. Electron microscopy and immunohistochemistry was used to demonstrated a cytopathic effect in treated tumors.RESULTS:Reolysin inhibited the proliferation and viability of sarcoma cell lines at a dose of 1 to 10 virus particles per cell. In vivo, 5 × 109 plaque‐forming units (PFU) administered via the tail vein every other day for 3 doses every 21 days inhibited the growth of tumor xenografts with improvement in event‐free survival. In the SKES1 Ewing sarcoma line, there was therapeutic enhancement when reovirus was administered in combination with radiation or cisplatin. In the RH30 line and the OS33 line, therapeutic enhancement was demonstrated with radiation and cisplatin, respectively.CONCLUSIONS:These results suggest that Reolysin alone or in combination with other cytotoxic agents may be effective therapy in pediatric sarcomas. Cancer 2011. © 2010 American Cancer Society.
On the decay and stability of global solutions to the 3‐D inhomogeneous Navier‐Stokes equations
Authors: Abidi Hammadi , Gui Guilong , Zhang Ping 
Published: November 2010

AbstractIn this paper, we investigate the large‐time decay and stability to any given global smooth solutions of the 3‐D incompressible inhomogeneous Navier‐Stokes equations. In particular, we prove that given any global smooth solution (a,u) of (1.2), the velocity fieldudecays to 0 with an explicit rate, which coincides with theL2norm decay for the weak solutions of the 3‐D classical Navier‐Stokes system [26,29] astgoes to ∞. Moreover, a small perturbation to the initial data of (a,u) still generates a unique global smooth solution to (1.2), and this solution keeps close to the reference solution (a,u) fort> 0. We should point out that the main results in this paper work for large solutions of (1.2). © 2010 Wiley Periodicals, Inc.
Separating early sensory neuron and blood vessel patterning
Authors: Miller Laura C. , Freter Sabine , Liu Feng , Taylor Jeremy S.H. , Patient Roger , Begbie Jo 
Published: November 2010

AbstractThe anatomical association between sensory nerves and blood vessels is well recognised in the adult, and interactions between the two are important during development. Here we have examined the relationship between developing blood vessels and sensory neuronal cell bodies, which is less well understood. We show in the chick that the nascent dorsal root ganglia (DRG) lie dorsal to the longitudinal anastomosis, adjacent to the developing neural tube at the level of the sulcus limitans. Furthermore, the blood vessel is present prior to the neurons suggesting that it may play a role in positioning the DRG. We use the zebrafish cloche mutation to analyse DRG formation in the absence of blood vessels and show that the DRG are positioned normally. Thus, despite their close anatomical relationship, the patterning of the blood vessel and DRG alongside the neural tube is separable rather than interdependent. Developmental Dynamics 239:3297–3302, 2010. © 2010 Wiley‐Liss, Inc.
MESD is essential for apical localization of megalin/LRP2 in the visceral endoderm
Authors: Lighthouse Janet K. , Zhang Liqun , Hsieh Jen‐Chih , Rosenquist Thomas , Holdener Bernadette C. 
Published: November 2010

AbstractDeletion of the Mesd gene region blocks gastrulation and mesoderm differentiation in mice. MESD is a chaperone for the Wnt co‐receptors: low‐density lipoprotein receptor‐related protein (LRP) 5 and 6 (LRP5/6). We hypothesized that loss of Wnt signaling is responsible for the polarity defects observed in Mesd‐deficient embryos. However, because the Mesd‐deficient embryo is considerably smaller than Lrp5/6 or Wnt3 mutants, we predicted that MESD function extends more broadly to the LRP family of receptors. Consistent with this prediction, we demonstrated that MESD function in vitro was essential for maturation of the β‐propeller/EGF domain common to LRPs. To begin to understand the role of MESD in LRP maturation in vivo, we generated a targeted Mesd knockout and verified that loss of Mesd blocks WNT signaling in vivo. Mesd mutants continue to express the pluripotency markers Oct4, Nanog, and Sox2, suggesting that Wnt signaling is essential for differentiation of the epiblast. Moreover, we demonstrated that MESD was essential for the apical localization of the related LRP2 (Megalin/MEG) in the visceral endoderm, resulting in impaired endocytic function. Combined, our results provide evidence that MESD functions as a general LRP chaperone and suggest that the Mesd phenotype results from both signaling and endocytic defects resulting from misfolding of multiple LRP receptors. Developmental Dynamics 240:577–588, 2011. © 2010 Wiley‐Liss, Inc.
Nitrogen loadings to two small estuaries, Prince Edward Island, Canada: a 2‐year investigation of precipitation, surface water and groundwater contributions
Authors: Danielescu Serban , MacQuarrie Kerry T. B. 
Published: November 2010

AbstractIn this research the dissolved inorganic nitrogen (DIN) loadings from direct precipitation, stream flow and groundwater discharge to two small estuaries located in Prince Edward Island (PEI), Canada, were quantified over a 2‐year period. The two estuaries, like many around the world, exhibit deteriorating conditions that are believed to be related to excessive nitrogen transport from adjacent catchments. The significance of the groundwater transport pathway and the temporal variability of the loadings have not been previously investigated. The wet fraction of the atmospheric loading was quantified using available precipitation and DIN concentration records. Stream water entering the estuaries and the discharge from numerous shoreline springs, the predominate form of groundwater discharge, were monitored periodically during the study. The annual DIN loads delivered to both estuaries were dominated by streams, although groundwater discharge provided significant contributions of approximately 15–18%. Temporal variability of DIN loading was large, with monthly loads varying by a factor of 5; this variability was found to be primarily related to the variability of freshwater discharge. Concentrations of nitrate in stream water discharging to the estuaries and shoreline groundwater springs were similar in each catchment, suggesting that there was minimal differential attenuation during transport via these two pathways. The McIntyre Creek estuary had one of the highest normalized loads reported in the literature (1700 kg NO3‐N/ha estuary/year), more than four‐fold that of the Trout River estuary, and this result appears to be related to the larger percentage of land area used for potato production in the catchment. This study demonstrates that direct groundwater discharge to estuaries in PEI should not be ignored and that seasonal variations in loading may be important for managing DIN delivery to such estuaries. Copyright © 2010 John Wiley & Sons, Ltd.
Gemcitabine depletes regulatory T‐cells in human and mice and enhances triggering of vaccine‐specific cytotoxic T‐cells
Authors: Rettig Lorna , Seidenberg Samuel , Parvanova Iana , Samaras Panagiotis , Knuth Alexander , Pascolo Steve 
Published: November 2010

AbstractParticle‐mediated epidermal delivery (PMED) is a potent genetic vaccination method. However, a recent report found PMED only poorly and infrequently triggered antigen‐specific cytotoxic T‐cells in cancer patients. Here, we show that injection of the chemotherapeutic drug Gemcitabine in mice results in improvement of the efficacy of subsequent PMED vaccination against NY‐ESO‐1. We found in mice and in cancer patients that administration of Gemcitabine induces a transient reduction in the percentage of regulatory T‐cells among CD4‐positive cells. The higher relative sensitivity of regulatory T‐cells compared to other CD4‐positive T‐cells toward cytostatic drugs can be linked to the higher frequency of proliferating cells in the regulatory compartment compared to the nonregulatory CD4‐compartment in healthy people and cancer patients. Thus, by affecting regulatory T‐cells more than other lymphocyte subsets, chemotherapeutic agents can create a transient hyperimmunoreactive window. Such a window would provide an ideal timepoint to administer a vaccine expected to induce a therapeutically relevant anticancer cytotoxic T‐cell response.