bluuebunny/crossref_metadata_2025 huggingface dataset:
Investigation of Uncoordinated Coexisting IEEE 802.15.4 Networks with Sleep Mode for Machine-to-Machine Communications
Authors: Ma Chao , He Jianhua , Tang Zuoyin , Guan Wenyang , Li Yue
Published: August 2012

The low-energy consumption of IEEE 802.15.4 networks makes it a strong candidate for machine-to-machine (M2M) communications. As multiple M2M applications with 802.15.4 networks may be deployed closely and independently in residential or enterprise areas, supporting reliable and timely M2M communications can be a big challenge especially when potential hidden terminals appear. In this paper, we investigate two scenarios of 802.15.4 network-based M2M communication. An analytic model is proposed to understand the performance of uncoordinated coexisting 802.15.4 networks. Sleep mode operations of the networks are taken into account. Simulations verified the analytic model. It is observed that reducing sleep time and overlap ratio can increase the performance of M2M communications. When the networks are uncoordinated, reducing the overlap ratio can effectively improve the network performance.
Cutaneous Neuroendocrine Carcinoma of the External Auditory Canal: A Case Report and Review of the Literature
Authors: Li Yi-Ke , Chi Fang-Lu , Wang Shu-Yi , Wang Wu-Qing , Yang Juan-Mei , Huang Yi-Bo
Published: August 2012

Cutaneous neuroendocrine carcinoma (cNEC) is rarely seen in the external ear. In this paper, we newly describe a patient with cNEC in his right external auditory canal, followed by a further discussion on the clinical features, diagnosis, and treatments of cNEC of the external ear. A review of the literature showed that cNEC of the external auditory canal generally presents as asymptomatic and that pathology yields the most confirmative diagnosis. A wide resection with adjuvant radiotherapy and chemotherapy is recommended. The overall prognosis of this condition is poor.
Rituximab-Based Treatment, HCV Replication, and Hepatic Flares
Authors: Sagnelli Evangelista , Pisaturo Mariantonietta , Sagnelli Caterina , Coppola Nicola
Published: August 2012

Rituximab, a chimeric mouse-human monoclonal antibody directed to the CD20 antigen expressed on pre-B lymphocytes and mature lymphocytes, causes a profound B-cell depletion. Due to its peculiar characteristics, this drug has been used to treat oncohaematological diseases, B cell-related autoimmune diseases, rheumatoid arthritis, and, more recently, HCV-associated mixed cryoglobulinaemic vasculitis. Rituximab-based treatment, however, may induce an increased replication of several viruses such as hepatitis B virus, cytomegalovirus, varicella-zoster virus, echovirus, and parvovirus B19. Recent data suggest that rituximab-based chemotherapy induces an increase in HCV expression in hepatic cells, which may become a target for a cell-mediated immune reaction after the withdrawal of treatment and the restoration of the immune control. Only afewsmall studies have investigated the occurrence of HCV reactivation and an associated hepatic flare in patients with oncohaematological diseases receiving R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone). These studies suggest that the hepatic flares are frequently asymptomatic, but life-threatening liver failure occurs in nearly 10% of cases.
Aortic Valvuloplasty as Bridging for TAVI in High-Risk Patients with Heyde’s Syndrome: A Case Report
Authors: Godino Cosmo , Pavon Anna Giulia , Mangieri Antonio , Margonato Alberto
Published: August 2012

There is a frequent association between aortic valve stenosis and gastrointestinal bleeding, also known as Heyde’s syndrome. In these patients, the aortic valve replacement should be recommended as “gold standard.” In high-surgical-risk patients, the Transcatheter Aortic Valve Implantation (TAVI) is an alternative option. However, the risk of bleeding recurrence, related to double antiplatelet therapy started after TAVI, cannot be excluded especially in the first months. We present a case of a patient with a severe aortic valve stenosis and a history of previously documented angiodysplasia and recurrence of gastrointestinal bleeding initially treated only with balloon aortic valvuloplasty that excluded recurrence of bleeding during the subsequent six months of followup. Therefore, a definite transfemoral Edwards XT valve implantation was planned to be performed in case of recurrence of aortic stenosis.
A New Drug Release Method in Early Development of Transdermal Drug Delivery Systems
Authors: Cai Bing , Söderkvist Karin , Engqvist Håkan , Bredenberg Susanne
Published: August 2012

In vitro drug release tests are a widely used tool to measure the variance between transdermal product performances and required by many authorities. However, the result cannot provide a good estimation of the in vivo drug release. In the present work, a new method for measuring drug release from patches has been explored and compared with the conventional USP apparatus 2 and 5 methods. Durogesic patches, here used as a model patch, were placed on synthetic skin simulator and three moisture levels (29, 57, 198 μL cm−2) were evaluated. The synthetic skin simulators were collected after 1, 2, 3, 4, 6, and 24 hours and extracted with pH 1.0 hydrochloric acid solution. The drug concentrations in the extractions were measured by isocratic reverse phase high-pressure liquid chromatography. The results showed that, with the increasing moisture level on the synthetic skin simulator, the drug release rate increased. In comparison with the conventional USP method, the drug release results performed by the new method were in more correlation to the release rate claimed in the product label. This new method could help to differentiate the drug release rates among assorted formulations of transdermal drug delivery systems in the early stage of development.
SOMO‐m Optimization Algorithm with Multiple Winners
Authors: Wu Wei , Khan Atlas
Published: August 2012

Self‐organizing map (SOM) neural networks have been widely applied in information sciences. In particular, Su and Zhao proposes in (2009) an SOM‐based optimization (SOMO) algorithm in order to find a wining neuron, through a competitive learning process, that stands for the minimum of an objective function. In this paper, we generalize the SOM‐based optimization (SOMO) algorithm to so‐called SOMO‐m algorithm with m winning neurons. Numerical experiments show that, for m > 1, SOMO‐m algorithm converges faster than SOM‐based optimization (SOMO) algorithm when used for finding the minimum of functions. More importantly, SOMO‐m algorithm with m ≥ 2 can be used to find two or more minimums simultaneously in a single learning iteration process, while the original SOM‐based optimization (SOMO) algorithm has to fulfil the same task much less efficiently by restarting the learning iteration process twice or more times.
Staphylococcus epidermidisUrinary Tract Infection in an Infant
Authors: Upadhyayula Shankar , Kambalapalli Mamatha , Asmar Basim I.
Published: August 2012

We describe the case of a previously healthy 7-month-old male infant with urinary tract infection due toStaphylococcus epidermidisgrown from two separate urine cultures. Further evaluation showed severe bilateral vesicoureteral reflux. Physicians should not assume thatS. epidermidisis always a contaminant in urine cultures.
Chemical Etching, AFM, Laser Damage Threshold, and Nonlinear Optical Studies of Potential Nonlinear Optical Crystal: Bis (L‐Glutamine) Potassium Nitrate
Authors: Hanumantharao Redrothu , Kalainathan S.
Published: August 2012

A novel semiorganic nonlinear optical crystal bis (L‐glutamine) potassium nitrate (BGPN) grown by slow evaporation technique at ambient temperature. The grown crystal surface has been analyzed by chemical etching and atomic force microscopy (AFM) studies. Amplitude parameters like area roughness, roughness average, valley height, valley depth, peak height, and peak valley height were measured successfully from AFM studies. Etching studies were carried out by various solvents like water, methanol and ethanol. The etching study indicates the occurrence of different types of etch pit patterns like striations and steplike pattern. The laser damage threshold energy has been measured by irradiating laser beam using a Q‐switched Nd: YAG laser (1064 nm). Second harmonic generation (SHG) studies have been performed by famous Kurtz powder technique with reference to standard potassium dihydrogen phosphate single crystals (KDP). It is found from this technique that SHG efficiency of BGPN is in comparison to that of standard KDP crystals.
Synthesis and Characterization of Some Novel Schiff Base Complexes of Oxovanadium(IV) Cation
Authors: Yadava A. K. , Yadav H. S. , Singh Sanjay , Yadav U. S. , Rao D. P.
Published: August 2012

A series of oxovanadium(IV) complexes of the type [VO(mac)]SO4 (where mac = tetraazamacrocyclic ligands derived from condensation of 4,4,4‐trifluro‐1‐(2‐furyl)‐1,3‐butanedione or 4,4,4‐trifluro‐1‐(2‐thenyl)‐1,3‐butanedione with p‐phenylenediamine and their reaction with β‐diketones) have been prepared using oxometal ion of vanadium as kinetic template. These complexes have been ascertained by electrical conductance, magnetic moment, elemental analyses, infrared, e.s.r. and electronic spectral data. All the oxovanadium(IV) complexes are five‐coordinate ones.
Age-Specific Effectiveness of the Finnish Cervical Cancer Screening Programme
Authors: Lönnberg Stefan , Anttila Ahti , Luostarinen Tapio , Nieminen Pekka
Published: August 2012

Background: There is currently some uncertainty about the effectiveness of screening outside the established core ages of 30 to 60. We audited the screening histories of cervical cancers and conducted a case–control evaluation of the effectiveness of organized screening in different ages.

Methods: Screening histories for 1,546 cervical cancer cases and 9,276 age-matched controls were derived by linkage to the screening register. ORs and 95% confidence intervals (CI) for the association of participation in a program screen and cervical cancer diagnosis in the following screening interval were estimated using conditional logistic regression and corrected for self-selection bias.

Results: Participation in a single screen was associated with a 47% decrease in cervical cancers, but this effect was age-dependent. Screening at 25 showed little or no impact on the risk of cervical cancer in the next interval, whereas screens at 40 to 65 showed protective effects of 51% to 66%.

Conclusions: Program screening at the age of 25 is not associated with a reduced risk of cervical cancer in the following screening interval. Additional analyses are needed that also take opportunistic screening of women during the first rounds of organized screening into consideration. In contrast, screening yields substantial risk reductions in older ages at least up to the age of 60. This study also provides moderate indication of a long-lasting risk reduction associated with screening at the age of 65.

Impact: Cervical cancer screening effectiveness is for the first time evaluated at different ages up to 65 with correction for self-selection bias of participation in organized screening. Cancer Epidemiol Biomarkers Prev; 21(8); 1354–61. ©2012 AACR.
Phase I Studies of Sirolimus Alone or in Combination with Pharmacokinetic Modulators in Advanced Cancer Patients
Authors: Cohen Ezra E.W. , Wu Kehua , Hartford Christine , Kocherginsky Masha , Eaton Kimberly Napoli , Zha Yuanyuan , Nallari Anitha , Maitland Michael L. , Fox-Kay Kammi , Moshier Kristin , House Larry , Ramirez Jacqueline , Undevia Samir D. , Fleming Gini F. , Gajewski Thomas F. , Ratain Mark J.
Published: August 2012

Purpose: Sirolimus is the eponymous inhibitor of the mTOR; however, only its analogs have been approved as cancer therapies. Nevertheless, sirolimus is readily available, has been well studied in organ transplant patients, and shows efficacy in several preclinical cancer models.

Experimental Design: Three simultaneously conducted phase I studies in advanced cancer patients used an adaptive escalation design to find the dose of oral, weekly sirolimus alone or in combination with either ketoconazole or grapefruit juice that achieves similar blood concentrations as its intravenously administered and approved prodrug, temsirolimus. In addition, the effect of sirolimus on inhibition of p70S6 kinase phosphorylation in peripheral T cells was determined.

Results: Collectively, the three studies enrolled 138 subjects. The most commonly observed toxicities were hyperglycemia, hyperlipidemia, and lymphopenia in 52%, 43%, and 41% of subjects, respectively. The target sirolimus area under the concentration curve (AUC) of 3,810 ng-h/mL was achieved at sirolimus doses of 90, 16, and 25 mg in the sirolimus alone, sirolimus plus ketoconazole, and sirolimus plus grapefruit juice studies, respectively. Ketoconazole and grapefruit juice increased sirolimus AUC approximately 500% and 350%, respectively. Inhibition of p70 S6 kinase phosphorylation was observed at all doses of sirolimus and correlated with blood concentrations. One partial response was observed in a patient with epithelioid hemangioendothelioma.

Conclusion: Sirolimus can be feasibly administered orally, once weekly with a similar toxicity and pharmacokinetic profile compared with other mTOR inhibitors and warrants further evaluation in studies of its comparative effectiveness relative to recently approved sirolimus analogs. Clin Cancer Res; 18(17); 4785–93. ©2012 AACR.
Abstract 1019: CD34+ progenitors resident in the human white adipose tissue promote tumor angiogenesis, growth and metastases in orthotopic models of breast cancer
Authors: Martin-Padura Ines , Gregato Giuliana , Marighetti Paola , Mancuso Patrizia , Calleri Angelica , Corsini Chiara , Lohririwat Visnu , Petit Jean-Yves , Bertolini Francesco
Published: August 2012

Similarly to neoplasia, the human white adipose tissue (WAT) shows in vivo a robust angiogenic switch when the growth rate exceeds a given expansion threshold. Also, anti-angiogenic drugs have been found to inhibit WAT development in postnatal mice. We have recently reported that the human WAT is very rich in CD45-CD34+ progenitors that express high levels of angiogenesis-related genes and can generate in culture endothelial cells and tubes as efficiently as mesenchymal cells (Martin-Padura et al, Cancer Res, in the press). Compared to the bone marrow, WAT contains >250 times more CD45-CD34+ progenitors with endothelial differentiation potential. The co-injection of human WAT-derived CD45-CD34+ progenitors from lipotransfer procedures contributed to tumor vascularization and significantly increased tumor growth and metastases in several orthotopic models of human breast cancer in immunodeficient NSG mice. At variance with human bone marrow-derived CD34+ progenitors, which were found to incorporate only in perivascular sites of tumor vasculature, confocal z-stack studies showed that mature endothelial cells derived from human WAT-CD34+ progenitors lined the lumen of fully functional cancer vessels where red cells were found to circulate. Transwell and 3D time-lapse studies in collagen showed that human WAT cells significantly promoted an EMT switch as well as breast cancer cell directionality, migration and invasion towards a gradient of several different chemo-attractants. Autologous lipotransfer for tissue/organ reconstruction is used in patients who had surgical removal of breast and other types of cancer. We have recently reported a study of 321 consecutive patients operated for primary breast cancer who subsequently underwent a lipotransfer procedure, compared with two matched patients with similar characteristics who did not undergo lipotransfer (Petit et al, Ann Oncol, in the press). In this study, the lipotransfer group exhibited a higher risk of local events compared to the controls when the analysis was limited to intraepithelial neoplasia. A second data revision after prolonged follow-up confirmed this significant difference. The dissection of the different roles of purified populations of WAT-derived progenitors and mature cells seems urgent to clarify which WAT cell populations can be used safely for breast reconstruction in cancer patients.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1019. doi:1538-7445.AM2012-1019
Abstract 102: Functional characterization of long noncoding RNA SPRY4-IT1 in human melanomas
Authors: Zhao Wei , Mazar Joseph , Perera Ranjan J.
Published: August 2012

Recently, we have reported that long noncoding RNA SPRY4-IT1 (Khaitan et al., Cancer Research 2011) is highly upregulated in human melanomas compared to melanocytes and keratinocytes. The elevated expression of SPRY4-IT1 in melanoma cells compared to melanocytes, its accumulation in cell cytoplasm, and effects on cell dynamics, including increased rate of wound closure upon SPRY4-IT1 overexpression, suggest that the higher expression of SPRY4-IT1 may have an important role in the molecular etiology of human melanoma. We have now engineered melanocytes to ectopically express SPRY4-IT1 and engineered cells were assayed to identify gene and protein expression changes compared to vector only cells. We observed that engineered cells show higher cell proliferation rate compared to vector only cells. Melanoma cells were treated with α-amenitin to identify the half-life of both SPRY4 and SPRY4-IT1, and our results indicate that SPRY4-IT1 has a higher RNA decay compared to its host gene SPRY4. Isolation of monosome and polysome fractions followed by qRT-PCR shows that SPRY4-IT1 is primarily transported in to the polysome fraction. Finally, we have demonstrated that SPRY4-IT1 transcriptional regulation is independent of SPRY4 gene. SPRY4-IT1 molecular function, transcriptional regulation, cellular compartmentalization, interaction with other RNAs and proteins will be discussed.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 102. doi:1538-7445.AM2012-102
Abstract 1020: Recruitment of Tie2-expressing monocytes is associated with the heightened invasive phenotype of gliomas after antiangiogenic therapies
Authors: Gabrusiewicz Konrad R. , Liu Dan , Cortes-Santiago Nahir , Hossain Mohammad B. , Piya Sujan , Conrad Charles , Marini Frank C. , Fueyo Juan , Gomez-Manzano Candelaria
Published: August 2012

Gliomas are highly vascularized tumors, and preclinical data have suggested that glioma growth critically depends on the generation of tumor associated blood vessels. Among multiple factors controlling the complex process of angiogenesis, VEGF (Vascular Endothelial Growth Factor) and its associated signaling cascade are considered of central importance. Glioma cells are a major source of VEGF, and high levels of VEGF generation have been reported to correlate with high grade malignancy and poor prognosis. Antiangiogenic therapy has been recently added to the battery of treatments to newly diagnosed malignant gliomas. However, preclinical data from our laboratory and others, as some clinical results, shown concomitantly elicit tumor adaptation and progression to stages of greater malignancy, with heightened invasiveness. These results warrant preclinical investigation. Here, we present evidence of accumulation of Tie2-expressing monocytes (TEMs) in the brain tumor/normal interphase regions in tumor-bearing animals treated with anti-VEGF agents. Immunohistochemistry using F4/80 or Iba1 antibodies revealed an increase number of microglia/macrophages in central and peripheral tumoral areas after antiangiogenesis treatment. Moreover, the recruitment of these tumor-associated microglia/macrophages (TAMs) was associated with an overrepresentation of TEMs. Almost 50% of Tie2-positive cells co-localized with microglia/macrophages after bevacizumab or prolonged VEGF-Trap/Aflibercept therapies. To determine the role of TEMs in the invasive phenotype of gliomas upon antiangiogenic therapies, we use monocytes isolated from buffy coats and sorted positively for Tie2 expression, and monocytic cultures polarized to M2 phenotype and forced to express Tie2. We found that TEMs express high level of MMP2, MMP9, CD44, and CXCR4, molecules related with extracellular matrix remodeling, using q-PCR, ELISA, FACS analysis and double immunofluorescence. Gelatin zymography, as well as collagenase assay confirmed the upregulation of MMP-2 and MMP-9 activity. Of interest, knocking down Tie2 by siRNA suppresses MMP9 activity emphasizes a role of Tie2 signaling in the regulation of MMP9. Additionally, in vitro invasion assay showed a pivotal role of TEMs in development of an invasive phenotype in glioma cells. Together, our results suggest a novel mechanism of escape of GBMs to anti-VEGF therapies and the necessity of targeting the TEM population in combination with anti-VEGF therapies to improve clinical outcome.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1020. doi:1538-7445.AM2012-1020
Abstract 1049: DNMT3b increases transformation efficiency and accelerates carcinogen induced transformation of human bronchial epithelial cells
Authors: Teneng Ivo , Telles Carmen S. , Belinsky Steven A.
Published: August 2012

Malignant tumors and cell lines are characterized by increased expression of DNMT1, DNMT3a and DNMT3b. While evidence suggests that DNMT1, DNMT3a and DNMT3b co-operate in methylation and gene silencing during carcinogenesis, very little is known regarding gene targets for DNMT3a and DNMT3b and their impact on the development of adenocarcinoma. We developed an in vitro model using human telomerase/cyclin dependent kinase 4-immortalized human bronchial epithelial cell lines (HBECs) to identify key molecular changes that drive transformation and clonal outgrowth of preneoplastic lung epithelial cells during exposure to tobacco carcinogens. Carcinogen exposure (0.5mM MNU and 0.05µM BPDE) for 12 weeks induced transformation of HBEC2 cells and transformation efficiency was associated with DNA repair capacity. A significant increase in DNMT1 protein was observed during carcinogen exposure while moderate increases in DNMT3a and DNMT3b were observed in transformed cells. Increased DNMT3a and DNMT3b levels have been reported in several cancers. We observed 5-20 fold increased expression of DNMT3a and DNMT3b in tumor derived lung cancer cell lines. Therefore we tested the hypothesis that over expressing DNMT3a and DNMT3b would accelerate transformation by targeting specific genes for methylation and promote full malignancy in carcinogen-treated HBECs. Over expression of DNMT3a or DNMT3b did not affect DNA repair capacity and was not sufficient to drive spontaneous transformation as evidenced by inability to form colonies on soft agar. Transformation efficiency was increased 2-2.5 fold in the two HBEC2 cell lines over expressing DNMT3b after 12 weeks of carcinogen treatment relative to treated parental HBEC2. In addition, after 8 weeks, colony formation was evident in the DNMT3b over expressing, but not in parental HBECs indicating that increased expression of this de novo DNMT accelerates transformation. Over expressing DNMT3a had no effect on carcinogen-induced transformation. Current studies are evaluating global re-programming of the epigenome in transformed clones using the Illumina 450k promoter array and the effect of over expression of DNMT3b on stem cell markers. This study was supported by R01 ES008801 to S.A.B. and 1F32 CA157082 to I.T.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1049. doi:1538-7445.AM2012-1049
Abstract 1064: Sloan-Kettering Institute (Ski) protein plays distant roles in activation of Smad proteins in response to nodal and TGF-β in prostate cancer cells
Authors: Vo BaoHan T. , Cody Bianca , Cao Yang , Khan Shafiq A. , Development Center for Cancer Research and Therapeutic
Published: August 2012

Transforming growth factor-β (TGF-β) acts as a tumor suppressor in the early stages of epithelial cancers by inhibiting proliferation and inducing apoptosis. However, in the later stages of the disease, TGF-β acts as a tumor promoter and is associated with aggressive forms of cancer due to its effects on angiogenesis, immune suppression, and metastasis. Previously, we have demonstrated that Nodal, another member of the TGF-β superfamily and its receptors are expressed in prostate cancer cell lines. Nodal and TGF-β exerted differential effects on prostate cancer cells; both inhibited proliferation in WPE, RWPE1, and DU145 cells while neither had effect on the proliferation of LNCaP and PC3 cells. On the other hand, Nodal and TGF-β induced migration in PC3 cells, but had no effect on cell migration in DU145 cells. Nodal primarily employs Smad2 for intracellular signaling while TGF-β is essential for both Smad2/3 phosphorylations. In the present study, we have determined the expression and role of Ski in Nodal and TGF-β signaling in prostate cancer cells. Ski is a co-repressor of the Smad-mediated TGF-β signaling. Ski was originally classified as an oncogene based on its ability to transform chicken and quail fibroblasts. RT-PCR analysis showed comparable mRNA levels of Ski in several established prostate cell lines; however, high levels of Ski protein were only detected in prostate cancer cell lines and Ski protein levels were very low or absent in normal cells. Ski protein levels were also high in prostate cancer tissue samples compared to normal prostate tissues. Treatment with Nodal and TGF-β had no effects on Ski mRNA levels; however, Nodal had no effect on Ski protein levels while TGF-β induced degradation of Ski protein levels mediated by the proteasome pathway. Reduced Ski levels correlated with increased basal and TGF-β-induced Smad2/3 phosphorylation. Knockdown of endogenous of Ski reduced proliferation in DU145 prostate cancer cells and enhanced migration of PC3 cells. We conclude that high level of Ski expression in prostate cancer cells may be responsible for repression of TGF-β and Smad2/3 signaling, but Ski protein levels do not influence Nodal effects.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1064. doi:1538-7445.AM2012-1064
Abstract 1066: Combination synergy of JAK inhibitor, BVB808, and FGFR inhibitor, BGJ398, in an FGFR3-driven multiple myeloma model
Authors: Pinzon-Ortiz Maria , Tan Lujian , Yao Yao , Schlegel Robert , Radimerski Thomas , Cao Z. Alexander
Published: August 2012

Multiple myeloma is a genetically heterogenous malignancy. Several clinical studies have indicated that the t(4:14)(p16:q32) translocation is associated with poor clinical prognosis. Two key target genes in this translocation are FGFR3 and MMSET. Additionally, activating mutations of FGFR3 have been identified, further implicating the involvement of this target in multiple myeloma. Recent advances have shed more light on the interaction between tumor cells and their microenvironment. The bone marrow stroma, endothelial cells, osteoclasts and others could promote the proliferation, survival and resistance to therapies of the malignant plasma cells. IL-6 is one of the major cytokines implicated in the tumor microenvironment. IL-6 signaling, mediated through receptor-coupled JAK-STAT pathway, has been reported to play an important role in cancer cell survival. Here we examine the combination effects of JAK inhibitor BVB808 and FGFR inhibitor BGJ398 against multiple myeloma in the preclinical setting. Combination of BVB808 and BGJ398 was tested in vitro in a panel of multiple myeloma models across broad drug concentrations. Significant synergy is noted in OPM II, a cell line harboring both t(4:14) translocation and FGFR3 K650E mutation. This combination benefit is further confirmed in the xenograft model bearing OPM II. We propose 2 hypotheses for this combination effect: 1) FGFR3 and IL-6/JAK-STAT may represent 2 parallel survival pathways in MM. When one pathway is inhibited, tumor cells would rely on the other axis as the alternative survival pathway. Synergy is noted only when both pathways are inhibited. 2) JAK-STAT may cooperate with FGFR3 to promote its activity. Synergy is achieved when potent and sustained inhibition of FGFR3 signaling is achieved with the combination of BVB808 and BGJ398. While it is an intriguing finding, the combination benefit is not observed across other MM models harboring FGFR3 lesions. Elucidation of the underlying molecular mechanism would enable more targeted therapies against two important targets in multiple myeloma.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1066. doi:1538-7445.AM2012-1066
Abstract 1069: Mutant p53 disrupts the role of ShcA in balancing the Smad-dependent and -independent signaling activity of TGF-β
Authors: Lin Shu , Yu Lan , Yang Junhua , Liu Zhao , Karia Bijal , Bishop Alexander J. R. , Jackson James , Lozano Guillermina , Copland John A. , Mu Xiaoxin , Sun Beicheng , Sun Lu-Zhe
Published: August 2012

Biomarkers are lacking for identifying the switch of transforming growth factor-beta (TGF-β) from tumor-suppressing to tumor-promoting. Mutated p53 (mp53) has been suggested to switch TGF-β to a tumor promoter. However, we found that mp53 does not always promote the oncogenic role of TGF-β. Here, we show that endogenous mp53 knockdown enhanced cell migration and phosphorylation of ERK in DU145 prostate cancer cells. Further, ectopic expression of mp53 in p53-null PC-3 prostate cancer cells enhanced Smad-dependent signaling, but inhibited TGF-β-induced cell migration by downregulating activated ERK. Reactivation of ERK by the expression of its activator, MEK-1, restored TGF-β-induced cell migration. Since TGF-β is known to activate MAPK/ERK pathway through direct phosphorylation of adaptor protein ShcA and MAPK/ERK signaling is pivotal to tumor progression, we investigated whether ShcA contributed to mp53-induced ERK inhibition and the conversion of TGF-β's role during carcinogenesis. We found that mp53 expression led to decrease of phosphorylated p52ShcA/ERK levels and increase of phosphorylated Smad levels in a panel of mp53-expressing cancer cell lines, and in mammary glands and tumors from mp53 knock-in mice. By manipulating ShcA levels to regulate ERK and Smad signaling in human untransformed and cancer cell lines, we show that TGF-β's role in regulating anchorage-dependent and -independent growth, and migration, can be shifted between growth suppression and migration promotion. Thus, our results, for the first time, suggest that mp53 disrupts ShcA's role in balancing Smad-dependent and -independent signaling activity of TGF-β and that ShcA/ERK signaling is a major pathway regulating the tumor-promoting activity of TGF-β.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1069. doi:1538-7445.AM2012-1069
Abstract 1075: Bone morphogenetic protein type I receptor antagonists decrease growth and induce cell death of lung cancer cell lines
Authors: Langenfeld John E.
Published: August 2012

Bone morphogenetic proteins (BMPs) are growth-promoting morphogens during embryonic development. BMP-2 is aberrantly expressed in 98% of non-small cell lung carcinomas (NSCLC) independent of cell type. The role the BMP signaling cascade in cancer and its effects on cell growth and survival is poorly understood. We show that in unstimulated lung cancer cell lines, that BMP signaling is basally active. Lung cancer cell lines express the BMP type I receptors alk2, alk3, and alk6. Inhibition of a single BMP type I receptor was not sufficient to decrease signaling. Inhibition of all BMP type I receptors with siRNA effectively decreased BMP signaling. BMP type I receptor antagonists, Dorsomorphin, DMH1, DMH2, and LDN decreased BMP signaling in lung cancer cell lines. BMP receptor antagonists and silencing of all BMP type I receptors with siRNA induced cell death, inhibited cell growth, and caused a significant decrease in the expression of inhibitor of differentiation (Id1, Id2, and Id3) family members, which are known to regulate cell growth and survival in many types of cancers. BMP receptor antagonists also decreased clonogenic cell growth of lung cancer cell lines. The selective antagonist, DMH2 caused the greatest reduction in the activity of the BMP type I receptors and also caused the greatest reduction in cell growth. These studies show that basally active BMP signaling in lung cancer cells regulates the expression of Id family members and promotes cell growth and survival. BMP type I receptors antagonists represents a potential means to pharmacologically treat carcinomas with an activated BMP signaling cascade.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1075. doi:1538-7445.AM2012-1075
Abstract 1190: SIRT1 links tumor suppressive NOTCH signaling to p53
Authors: Ban Jozef , Fourtouna Argyro , Machado Isidro , Aryee Dave NT , Jug Gunhild , Llombart-Bosch Antonio , Kauer Max , Kovar Heinrich
Published: August 2012

Besides its important role in organismal development, NOTCH receptor signaling exerts tissue specific proliferative or antiproliferative functions. While the oncogenic role of NOTCH has been extensively investigated due to its constitutive activation in T-cell leukemias and several epithelial cancers, little is known about NOTCH mediated tumor suppression. We have previously reported that in Ewing's sarcoma, a pediatric bone tumor driven by the chimeric ETS oncogene EWS-FLI1, auto-stimulatory NOTCH signaling is suppressed and that reactivation results in p53 and consequently growth inhibitory p21 induction via activation of the NOTCH effector HEY1. We now demonstrate that HEY1-mediated p53 stimulation is accompanied by C-terminal p53 acetylation as a consequence of downregulation of nuclear deacetylase sirtuin 1 (SIRT1). We found that both EWS-FLI1 and HEY1 bind to the SIRT1 promoter with opposite transcriptional consequences. Thus, knockdown of EWS-FLI1 and ectopic HEY1 expression resulted in similar SIRT1 modulation and p53 acetylation which could be reversed by ectopically expressed SIRT1. Consistent with these results, treatment of Ewing's sarcoma cell lines with the sirtuin inhibitor Tenovin 6 resulted in massive cell death. Immunohistochemical analysis of more than 310 Ewing's sarcoma samples identified moderate (25%-50% positive nuclei) to strong (>50% positive nuclei) SIRT1 expression in 35% of cases. Additional 20% showed sporadic positivity (between 10-25% positive nuclei). The involvement of SIRT1 in tumor suppressive NOTCH signaling is not restricted to Ewing's sarcoma, but also relevant at least to B-cell malignancies and some normal tissues, since we found that in several B-cell leukemia and lymphoma cell lines and in keratinocytes HEY1 was able to lead to activating p53 acetylation in a SIRT1 suppression-dependent manner. Supported by grants from the Austrian Science Fund (P22328-B09) and the European Comission (EU-FP7 STREP 259348).

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1190. doi:1538-7445.AM2012-1190
Abstract 1199: Sorting nexin 2 (SNX2) controls drug sensitivity to molecular targeted anticancer agents through membrane trafficking of c-Met protein in cancer cell
Authors: Ono Mayumi , Ogi Sayaka , Yamamoto Chizuko , Fujita Hideaki , Kuwano Michihiko
Published: August 2012

Various molecular targeted anticancer drugs are often developed by targeting activated growth factor receptors that are expressed on plasma membrane of cancer cells. Expression of such active receptors on the cell surface is essential to limit the drug sensitivity to molecular targeted drugs in lung cancer cells and others. The sorting nexin (SNX) family is a diverse group of cytoplasmic and membrane-associated proteins that are involved in membrane-trafficking steps within the endocytotic network. Human SNX family proteins comprise about 34 proteins with wide range of biological functions, which play specialized and/or generalized roles in the regulation of protein trafficking, including endosomal trafficking of membrane receptors and transporters. SNX1 and SNX2 are components of the mammalian retromer complex. In this study, we show that the small-interfering RNA (siRNA)-mediated knockdown of SNX2 decreased the cell-surface localization of c-Met, but not that of EGFR, resulting in degradation of the c-Met protein. Knockdown of SNX2 markedly altered sensitivity to anticancer drugs targeting c-Met and EGFR through promotion of compensatory activation of the EGFR pathway in lung cancer cells. Furthermore, SNX2 knockdown also specifically decreased c-Met expression, and altered drug sensitivity to c-Met-targeted drug in gastric cancer cells. These findings suggest that SNX2 is a key protein that regulates c-Met-driven growth-signalling pathways, affecting the therapeutic efficacy of growth factor receptor-targeted drugs in lung and gastric cancer patients.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1199. doi:1538-7445.AM2012-1199
Abstract 12: Bcr/Abl induces expression of Aurora kinase A via Akt signaling
Authors: Jang Jing , Ikezoe Takayuki , Nishioka Chie , Yokoyama Akihito
Published: August 2012

Aurora kinase A (AURKA) plays a pivotal role in the mitotic processes during cell division. We previously showed that AURKA was aberrantly expressed in hematological malignant cells including those from chronic myeloid leukemia (CML) compared to CD34+ hematopoietic stem/progenitor cells isolated from healthy volunteers. This study explored molecular mechanisms by which bcr-abl induced expression of AURKA; Lentiviral transduction of p210 bcr-abl into murine lymphoid Ba/F3 as well as human CD34+ hematopoietic stem/progenitor cells potently increased levels of AURKA in association with phosphorylation of AURKA and Akt, as assessed by real time RT-PCR and Western blot analysis. On the other hand, exposure of CML K562 cells which constitutively expressed phosphorylated forms of Akt and AURKA to imatinib, an inhibitor of bcr-abl kinase, de-phosphorylated both Akt and AURKA. In addition, the capability of bcr-abl to induce expression of AURKA in human CD34+ hematopoietic stem/progenitor cells was blunted when Akt was inactivated by a short hairpin RNA. These observations suggested that p210 bcr-abl activated AURKA at least in part via Akt signaling. Moreover, we found that lentiviral transduction of imatinib-resistant T315I mutant of bcr-abl into Ba/F3 cells also activated both Akt and AURKA. Importantly, exposure of p210 T315I bcr-abl-expressing Ba/F3 cells to a specific inhibitor of AURKA effectively inhibited their proliferation in vitro. Taken together, AURKA may be a promising molecular target in bcr-abl driven hematological malignancies and inhibition of AURKA could be useful to overcome imatinib-resistance mediated by bcr-abl mutants.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 12. doi:1538-7445.AM2012-12
Abstract 1207: Opposite effects on proliferation and bone metastasis genes by Estrogen Receptor B1 and Estrogen Receptor B2 in the prostate cancer cell line PC3
Authors: Dey Prasenjit , Jonsson Philip , Hartman Johan , Williams Cecilia , Gustafsson Jan-Åke , Ström Anders
Published: August 2012

The estrogen receptor β1 (ERα1) is successively lost during cancer progression while its splice variant estrogen receptor β2 (ERα2) is still expressed in advanced prostate cancer. The latter cancer often metastases to bone. We wanted to investigate, if the loss of ERα1 and/or expression of its splice variant ERα2 affect signaling pathways involved in bone metastasis of prostate cancer. ERα2 is a 495 amino acid long splice variant of estrogen receptor ERα1, which is 530 amino acids long. Using PC3 cells stably expressing ERα1, we found that ERα1 represses expression of the bone metastasis regulator Runx2 and its target gene Slug. On the other hand, using PC3 cells stably expressing ERα2 we found that the same factors are up-regulated. In addition, the expression of Twist1, a factor whose expression strongly correlates with high Gleason grade of prostate carcinoma is increased by ERα2. In agreement with increased Twist1 expression we find increased expression of DKK1, a factor which has been shown to increase the RANKL/OPG ratio and enhance osteoclastogenesis indicating that expression of ERα2 can cause a cancer to be osteolytic. Furthermore, we found that only ERα1 and not ERα2 inhibits proliferation and expression of the proliferation markers ki67, cyclin E, c-Myc and p45Skp2. In addition, nuclear β-catenin and its mRNA levels are reduced by ERα1 expression. In conclusion we find that ERα1 inhibits proliferation and factors known to be involved in bone metastasis while ERα2 increases proliferation and up-regulates factors involved in bone metastasis. Thus, ERα2 has oncogenic abilities in strong contrast to the tumor suppressor effect of ERα1.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1207. doi:1538-7445.AM2012-1207
Abstract 1210: Tetraspanin CD63 interacts with extranuclear estrogen receptor alpha and regulates non-genomic signaling pathways in breast cancer
Authors: Huang Jian , Mackinnon Alexander Craig , Jiang Liying
Published: August 2012

Tetraspanin is a four transmembrane protein family whose members are regarded as molecular linkers. They also serve as scaffold proteins for many signaling processes. CD63 is a member of the tetraspanin family that serves as a lysosomal protein. Estrogen receptor alpha (ERα) plays critical roles in breast carcinogenesis. Extranuclear ERα could initiate rapid estrogen responses by forming protein complexes with many signaling molecules. Here, we report a novel protein complex formed between tetraspanin CD63 and extranuclear ERα. Immunoprecepitation (IP) experiments in MCF-7 and BT474 cells showed that CD63 interacts with ERα at endogenous levels. IP experiments using extracts from different cellular compartments (nucleus, cytoplasm and plasma membrane) showed that the interaction between CD63 and ERα is mainly located on the plasma membrane. Moreover, using co-immunofluorescence (IF) staining, we found CD63 co-localized with ERα on plasma membrane and/or in the cytoplasm. To further explore the effects of CD63 on ERα signaling pathways, we stably knocked down CD63 by shRNA in MCF-7 and BT474 cells. Interestingly, the expression of ERα was increased with lower expression of CD63. We further examined ERα from extracts of nucleus, cytoplasm, and membrane by western blots, and found that ERα in cytoplasm and/or membrane was increased by knocking down CD63 whereas the ERα level in the nucleus was not changed. IF staining showed similar results. Furthermore, P-MAPK level was up-regulated in both MCF-7 and BT474 cell lines with suppressed expression of CD63. These data suggest that the tetraspanin CD63 may facilitate the transport of ERα between plasma membrane and/or cytoplasm and nucleus, an important new function. CD63 may play a key role on organizing and regulating non-genomic ERα signaling pathways in breast cancer.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1210. doi:1538-7445.AM2012-1210
Abstract 1228: Interleukin 8 (IL8) is a modulator of tumorigenicity in colon cancer initiating cells
Authors: LoGuidice Amanda , Huang Emina
Published: August 2012

Introduction: At least 20% of patients with ulcerative colitis (UC) will develop colitis associated cancer (CAC) within 30 years of disease onset. Furthermore, patients with UC have a 5 fold greater risk of developing CAC than the incidence of CRC in the general population. Recently, we isolated and propagated colon cancer initiating cells (CCICs) from UC and CRC patients, and showed that these cells generated tumors in mice and propagated as spheres in vitro. IL8 is a pro-inflammatory chemokine with known proliferation and migration properties. Previously, we showed that inhibition of IL8 inhibited the growth of CCIC-derived tumors in vivo. We hypothesize that IL8 modulates several cancer processes and potentiates the progression from colitis to cancer. Methods: Conditioned media from UC and CRC patient sphere cell isolate cultures were used for measurement of secreted IL8. Exogenous IL8 (10 ng/mL) was added to sphere cultures and proliferation was evaluated. In addition, we knocked down IL8 and IL8 receptor (CXCR1) expression in CRC cell line by short hairpin RNA (shRNA) and measured proliferation in vitro and tumor growth in vivo. We then monitored CCICs from UC or CRC patients, either in the presence or absence of IL8, for symmetric vs. asymmetric division via time lapse video. Results: The chemokine array showed an increase in IL8 in both UC and CRC spheres. Spheres treated with IL8 proliferated faster than controls. Sphere numbers increased with increased exposure to IL8 on days 5 and 7. Conditioned media concentrations of IL8 were increased in both CRC (361-2446 pg/mL) and colitic spheres (208-599 pg/mL) when compared to commercial CRC cell lines (HT29-20.8 and SW480-74.6, respectively). In vitro, knockdown of IL8 or CXCR1 decreased proliferation 1.8-fold compared to the non-targeting controls. Similarly, in vivo xenografts of IL8 or CXCR1 knockdown cells showed 80% decreased tumor growth. UC-derived CCICs exposed to exogenous IL8 exhibited an increase in proliferation starting as early as 16 hrs. We also observed that IL8 treated cells showed a higher percentage of symmetric cellular divisions (68%) when compared to untreated cells (42%). Conclusions: Our findings demonstrate that IL8 potentiates proliferation and symmetric cell division, which is thought to be associated with tumorigenicity. This indicates that IL8 may contribute to the progression of colitis-associated cancer through a modulation of tumorigenic processes.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1228. doi:1538-7445.AM2012-1228