bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract A2: Circulating epithelial tumor cells (CETC) for molecular analysis, chemo sensitivity testing in vitro and therapy monitoring in vivo
Authors: Pachmann Katharina , Kroll Torsten , Carl Stephanie , Pachmann Ulrich 
Published: January 2011

Abstract
Most breast cancer patients do not die of their primary tumor but from metastases developing sometimes years after the primary tumor has been removed. The first spread of tumor cells detectable with conventional methods is in the lymph nodes and patients with lymph node positive disease have a poorer disease free survival than patients without affected lymph nodes. Cells from the tumor seem also to be disseminated continuously into blood during tumor growth and an increase in circulating epithelial tumor cell (CETC) numbers during adjuvant therapy is correlated with an 11- 16 fold increase in hazard of relapse. A reincrease in numbers indicates increasing resistance to the applied drugs. Therefore, it would be desirable to better characterize these cells, test them for alternative drugs and monitor the actual response to the therapy decided on.
For this purpose we have developed a method to isolate individual CETC from blood from breast cancer patients and to successfully perform molecular characterization. Cells from the same sample were subject to chemo sensitivity testing and the drugs with the highest effectivity defined. Patients were subsequently treated according to guide lines.
The molecular characteristics, sensitivity to the applied drugs and response of the CETC to these drugs were subsequently compared to clinical outcome.
The response of CETC to therapy correlated highly with the previously tested chemo sensitivity and with the reduction of an index metastasis in metastatic breast cancer patients and progression free survival. The molecular characteristics of these cells are under investigation.
Citation Information: Clin Cancer Res 2010;16(7 Suppl):A2
Abstract A30: NF1 is a tumor suppressor in neuroblastoma that determines retinoic acid response and disease outcome
Authors: Hölzel Michael , Huang Sidong , Koster Jan , Ora Ingrid , Lakeman Arjan , Caron H. N. , Callens Tom , Xie Jing , Nijkamp Wouter , Asgharzadeh Shahab , Seeger Robert C. , Messiaen Ludwine , Versteeg Rogier , Bernards Rene 
Published: January 2011

Abstract
Neuroblastoma is a malignancy of early childhood that derives from the developing neural crest and accounts for 15% of all paediatric oncology deaths. The vitamin A derivative retinoic acid (RA) controls neural development and promotes differentiation, cell cycle arrest and apoptosis of neuronal and neuroblastoma cells. These diverse effects of RA are exerted primarily through the ability to differentially regulate gene expression mediated by the retinoic acid receptors (RARs). RA is used in the clinic to treat high-risk neuroblastoma patients, however with variable success. This variability in clinical response to RA is enigmatic as no mutations in components of the RA signaling cascade have been found. By using large-scale RNAi-based genetic screens, we aimed to identify predictive biomarkers for RA sensitivity in neuroblastoma. We found an unexpected crosstalk between the tumor suppressor neurofibromin (NF1) and RA signaling. NF1 is a negative regulator of RAS signaling that promotes conversion of the active GTP bound form into the inactive GDP bound form of RAS. Activation of RAS-MEK signaling by loss of NF1 repressed ZNF423, a critical transcriptional co-activator of the retinoic acid receptors, and blocked RA induced differentiation and target gene activation. Restoration of ZNF423 levels resensitized NF1 knockdown cells to the inhibitory effect of RA. Moreover, ZNF423 and NF1 expression predicted sensitivity to RA in a large panel of neuroblastoma cell lines. Neuroblastomas with low levels of both NF1 and ZNF423 have extremely poor outcome. We found NF1 mutations in neuroblastoma cell lines and also in primary tumors. Inhibition of MEK signaling downstream of NF1 restored responsiveness to RA, suggesting a therapeutic strategy to overcome RA resistance in NF1 deficient neuroblastomas.
Citation Information: Clin Cancer Res 2010;16(7 Suppl):A30
Abstract A34: A mechanism for acquired resistance to estrogen deprivation in breast cancer cells
Authors: Aguilar Helena , Bonifaci Nuria , Sole Xavier , Musach Jordi Serra , Moreno Victor , Lazaro Conxi , Urruticoechea Ander , Pujana Miguel Angel 
Published: January 2011

Abstract
Endocrine therapies that target the proliferative effect of 17β-estradiol (17βE2) through estrogen receptor α (ERα) are the most effective form of systemic treatment of ERα-positive breast cancer. Nevertheless, through mechanisms that are not fully understood, most tumors that initially respond to therapy will recur. The long-term estrogen deprived (LTED) MCF7 cell model has been proposed to recapitulate acquired resistance to aromatase inhibition (AI) in postmenopausal women. To comprehensively elucidate this resistance, genomic, transcriptomic and molecular analyses were integrated into the time course of MCF7-LTED adaptation. Extensive and dynamic genomic changes were observed, including amplification of the ESR1 locus linked to an increase in ERα and its non-genomic role. Dynamic transcriptomic profiles were also observed that significantly correlated with genomic changes and that were influenced by transcription factors known to be involved in acquired resistance (IRF-1) and cell proliferation (E2F1) but not by canonical ERα genomic function. Evaluation of MCF7-LTED profiles association with pathological and clinical data shown consistent correlations with ERα-negative tumor status, letrozole effects and recurrence after tamoxifen treatment. This study describes the coordinated genomic, transcriptomic and molecular changes that mediate acquired resistance to endocrine therapies, suggesting a key role for the non-genomic function of ERα.
Citation Information: Clin Cancer Res 2010;16(7 Suppl):A34
Abstract A7: Combined copy number and expression analysis of formalin fixed-paraffin embedded (FFPE) tumours
Authors: Iddawela Mahesh , Rueda Oscar , Wang Yuker , Faham Malek , El-Sheemy Mohamed , Cowley Ged , Eremin Jennifer , Eremin Oleg , Earl Helena , Caldas Carlos 
Published: January 2011

Abstract
Introduction: FFPE tissues are a valuable source of tumour material for translational research that has thus far been under-used. But progress in technology has allowed the analysis of genome wide copy number and expression changes using small amounts of degraded DNA/RNA extracted from FFPE tissues. We used two platforms: molecular inversion probes assay (MIP, Affymetrix) and c-DNA mediated Annealing Selection extension and Ligation assay (DASL, Illumina™) for analysis of RNA/DNA extracted from routine core biopsies from a clinical trial to identify molecular markers of response or resistance to chemotherapy.
Method: FFPE diagnostic core biopsies of 63 patients treated with neoadjuvant adriamycin/cyclophosphamide followed by taxotere in a clinical study were used. MIP assay with 50K SNP panel was used for copy number analysis (CNA). DASL assay assessed expression of 502 genes using three probes per gene.
Results: RNA and DNA of good quality were extracted from 52/63 (82%) and 46/63 (73%) core biopsy samples, respectively. Gene expression profiling was carried out using the DASL assay and there were good correlations with IHC for ER, PR and HER-2 with area under the curve of 0.95, 0.90 and 0.96 respectively, following ROC analysis for the best transcripts. Differential expression analysis between ER+ vs. ER- cancers showed that ESR1, TFF1 and LAF4 are significantly over-expressed in ER + cancers (p&lt;0.001), while analysis of pathological complete responders vs. non responders showed over expression of CXCL9, ARHA, ARHGDIB, BCL3, ERBB2, BMYB and TGFBI among responders (p&lt;0.2). CNA showed well described aberrations in breast cancer such as high probability of gains in 1q, 8q, 11q and 20q and loss in 4q, 12q, 13q, 18q and 22q (probability of alteration ≥0.35). Samples with pathological complete response had high probability of gains in 1q (55%), 8q (40%), 17q (40%) and losses in 8p (40%) and 13q (70%). 5/46 samples were HER-2 3+ with IHC and all showed amplification around the 17q locus.
Conclusions: Reliable copy number and expression data can be generated using these assays from FFPE core biopsy samples. Role of LAF4 as an oestrogen regulated gene and roles of CXCL9, ARHA and ARHGDIB as markers of response to chemotherapy should be further investigated.
Citation Information: Clin Cancer Res 2010;16(7 Suppl):A7
Abstract B19: Pentostatin facilitates fully MHC-disparate murine mini-transplantation
Authors: Massey Paul R. , Taylor Justin , Ryan Kaitlyn , Foley Jason , Mariotti Jacopo , Fowler Daniel H. 
Published: January 2011

Abstract
Reduced-intensity conditioning regimens prior to allogeneic hematopoietic stem cell transplantation (RIC allo-HSCT) contain cytotoxic agents to create marrow space for donor cells and rely on graft-vs-leukemia effect for curative potential. Pentostatin is in the same class of chemotherapeutics as the purine analog fludarabine, which is commonly used in RIC allo-HSCT. However, pentostatin has a unique mechanism of action that targets adenosine deaminase and may allow for selective targeting of lymphocytes. We hypothesize that pentostatin can be used as an alternative to fludarabine in an MHC-disparate murine setting (stringent model).
We compared the immune effects of pentostatin (1 mg/kg/d) and fludarabine (100 mg/kg/d) alone to each in combination therapy with cyclophosphamide (50 or 100 mg/kg/d). BALB/c mice were treated with a three-day regimen followed by transplantation of B6 bone marrow. Combination PC or FC were each more effective at depleting and suppressing splenic T cells than either agent alone; however, the PC regimen was synergistic in depleting host CD4+ T cells (p&lt;0.01) and CD8+ T cells (p&lt;0.01), and suppressing their function. Immune depletion was characterized by spleen harvest followed by flow cytometry at different times during treatment, while host immune suppression was evaluated by cytokine content in multiplex bead array (Bio-Rad).
Surprisingly, recipients in both cohorts rejected the graft. We then reasoned that the rejection was mediated by host immune reconstitution. Indeed, CD4+ T cells of BALB/c mice rebounded to 22.4% (p&lt;0.0001) of pre-treatment levels 10 days after conditioning with PC, and cohorts treated with FC rebounded to 58.8% (p&lt;0.001) of pre-treatment levels (means of 26.7∗106 cells in HBSS, 6.0 ∗ 106 for P, 15.7∗106 for F, 1.9∗106 for XRT).
We successfully developed a more immunodepletive regimen by intensification of cyclophosphamide therapy to 14 days with P or F administered every 3 days. In this model, PC demonstrated approximately a 75-fold decrease in CD4+ cells two weeks after the end of treatment (8.3 × 106 v. 0.12 × 106, p&lt;0.05) and FC a 15-fold decrease (0.53 × 106, p&lt;0.05) compared to controls; granulocytes were preserved in both cases (#Gr1+ cells). The 14-day regimen also allowed for engraftment in both PC and FC, with 93% of PC–treated and 57% of FC-treated cohorts achieving &gt;5% donor chimerism (p&lt;0.0001).
In conclusion, pentostatin facilitates engraftment in stringent, fully-MHC disparate model, therefore we posit it can be used as a fludarabine alternative in a reduced-intensity human transplant setting.
Citation Information: Clin Cancer Res 2010;16(7 Suppl):B19
Abstract CN2-1: Personalized chemotherapy of cancer based on immune parameters
Authors: Zitvogel Laurence , Kroemer Guido 
Published: January 2011

Abstract
Recent data suggest that therapy-induced immunogenic cancer cell death can stimulate a therapeutic anti-cancer immune response that then contributes to the control (or even to the elimination) of residual tumor cells. Indeed, some chemotherapeutic agents (e.g. X Rays, oxaliplatin and anthracyclines) can induce immunogenic apoptosis, while others cannot (e.g. cisplatin, mitomycin C and etoposide) [Casares, 2005; Obeid, 2007; Apetoh, 2007; Obeid, 2007; Ghiringhelli, 2009]. Thus far, we know that the immunogenicity of tumor cell death is closely linked to the surface exposure of calreticuline (CRT), the secretion of ATP and the release of HMGB1 that bind to CRT receptor, P2RX7 and TLR4 on host dendritic cells respectively. Chemotherapeutic agents that fail to induce CRT exposure or HMGB1 release are unable to induce immunogenic cell death. Our published data indicate that two loss-of-function alleles (that affect toll-like receptor-4 [TLR4] and purinergic P2 receptor X7 [P2RX7] of 12 and 30% of Caucasians, respectively) reduce the efficacy of conventional anticancer therapies, for instance in anthracyline-treated breast carcinomas and in oxaliplatin-treated colon cancers. We have determined novel defects in the emission or perception of immunogenic cell death signals negatively affecting the therapeutic response of human cancers that will be presented. Mouse preclinical models allowed us to unravel novel cellular and molecular pathways involved in the immunogenicity of cell death. These data will be reviewed.
Based on this concept, which remains to be proven, one can formulate four predictions:
First, therapeutic regimens that are intrinsically unable to elicit immunogenic death should be less efficient than therapies that can trigger immunogenic cell death. Second, cancers that intrinsically lack the capacity to emit immunogenic signals during tumor cell death should fail to induce a specific immune response and have a bad prognosis. Third, immune defects that weaken the response against dying tumor cells, including defects in the perception of immunogenic signals, should worsen the prognosis of cancer and compromise the therapeutic response. Fourth, the immunogenic cell death induced by chemotherapy should influence the composition and the architecture of the immune infiltrate present in tumors, which in turn should affect the therapeutic response.
Citation Information: Clin Cancer Res 2010;16(7 Suppl):CN2-1
Abstract ED3-3: Etiological clues from breast cancer GWAS
Authors: Garcia-Closas Montserrat 
Published: January 2011

Abstract
Breast cancer is a heterogeneous disease and risk factors can be differentially associated with the development of distinct tumors subtypes that manifest different biological and clinical behavior. Tumor subtypes, such as those defined by hormone receptor expression, show different age-specific incidence rate patterns and risk factor profiles. In addition, tumors from BRCA1 and BRCA2 mutation carriers display distinct pathological characteristics. Large collaborative efforts to conduct genome-wide association studies (GWAS) have lead to recent discoveries of low penetrance, common susceptibility loci that also show distinct associations by tumor subtypes. Follow up studies are evaluating the biological mechanisms underlying the observed risk associations, as well as potential gene-gene and gene-environment interactions. The relationship between genetic variants associated with pathological subtypes of breast cancer, and the implication of discoveries of novel genetic variants to risk prediction in BRCA1/2 mutation carriers and the general population will be discussed. These discoveries might lead to improvements in our understanding of the etiology of specific tumor types, which may enable the development of targeted prevention, early detection, and treatment strategies.
Citation Information: Clin Cancer Res 2010;16(7 Suppl):ED3-3
Sorafenib Inhibits the Hepatocyte Growth Factor–Mediated Epithelial Mesenchymal Transition in Hepatocellular Carcinoma
Authors: Nagai Tomoyuki , Arao Tokuzo , Furuta Kazuyuki , Sakai Kazuko , Kudo Kanae , Kaneda Hiroyasu , Tamura Daisuke , Aomatsu Keiichi , Kimura Hideharu , Fujita Yoshihiko , Matsumoto Kazuko , Saijo Nagahiro , Kudo Masatoshi , Nishio Kazuto 
Published: January 2011

Abstract
The epithelial mesenchymal transition (EMT) has emerged as a pivotal event in the development of the invasive and metastatic potentials of cancer progression. Sorafenib, a VEGFR inhibitor with activity against RAF kinase, is active against hepatocellular carcinoma (HCC); however, the possible involvement of sorafenib in the EMT remains unclear. Here, we examined the effect of sorafenib on the EMT. Hepatocyte growth factor (HGF) induced EMT-like morphologic changes and the upregulation of SNAI1 and N-cadherin expression. The downregulation of E-cadherin expression in HepG2 and Huh7 HCC cell lines shows that HGF mediates the EMT in HCC. The knockdown of SNAI1 using siRNA canceled the HGF-mediated morphologic changes and cadherin switching, indicating that SNAI1 is required for the HGF-mediated EMT in HCC. Interestingly, sorafenib and the MEK inhibitor U0126 markedly inhibited the HGF-induced morphologic changes, SNAI1 upregulation, and cadherin switching, whereas the PI3 kinase inhibitor wortmannin did not. Collectively, these findings indicate that sorafenib downregulates SNAI1 expression by inhibiting mitogen-activated protein kinase (MAPK) signaling, thereby inhibiting the EMT in HCC cells. In fact, a wound healing and migration assay revealed that sorafenib completely canceled the HGF-mediated cellular migration in HCC cells. In conclusion, we found that sorafenib exerts a potent inhibitory activity against the EMT by inhibiting MAPK signaling and SNAI1 expression in HCC. Our findings may provide a novel insight into the anti-EMT effect of tyrosine kinase inhibitors in cancer cells. Mol Cancer Ther; 10(1); 169–77. ©2011 AACR.
Chemopreventive and Chemotherapeutic Effects of Intravesical Silibinin against Bladder Cancer by Acting on Mitochondria
Authors: Zeng Jin , Sun Yi , Wu Kaijie , Li Lei , Zhang Gang , Yang Zenglei , Wang Zhiqiang , Zhang Dong , Xue Yan , Chen Yule , Zhu Guodong , Wang Xinyang , He Dalin 
Published: January 2011

Abstract
Intravesical chemotherapy is often used to prevent the recurrence of superficial bladder cancer after transurethral resection. A search for more effective and less toxic intravesical agents is urgently needed. We previously found the in vitro apoptotic effects of silibinin, a natural flavonoid, on high-risk bladder carcinoma cells. Here, we further explored the underlying mechanisms and examined the intravesical efficacy in the prevention and treatment of bladder cancer. Human bladder carcinoma cell line 5637, which has the same molecular features of high-risk superficial bladder cancer, was used as the model system in vitro and in vivo. Autochthonous rat model of bladder cancer induced by intravesical N-methyl-N-nitrosourea (MNU) was used to investigate its intravesical efficacy. Exposure of 5637 cells to silibinin resulted in growth inhibition and induction of caspase-dependent and -independent apoptosis, which was associated with disruption of mitochondrial membrane potential and selective release of cytochrome c, Omi/HtrA2, and apoptosis-inducing factor (AIF) from mitochondria. Silibinin also downregulated survivin and caused nuclear translocation of AIF. Oral silibinin suppressed the growth of 5637 xenografts, which was accompanied with the activation of caspase-3, downregulation of survivin, and increased translocation of AIF. Furthermore, intravesical silibinin effectively inhibited the carcinogenesis and progression of bladder cancer in rats initiated by MNU by reducing the incidence of superficial and invasive bladder lesions without any side effects, which was accompanied with proapoptotic effects. These findings identify the in vitro and in vivo antitumor efficacy of silibinin, and suggest silibinin as an effective and novel intravesical agent for bladder cancer. Mol Cancer Ther; 10(1); 104–16. ©2011 AACR.
Abstract A104: 3’, 4’, 5’-Trimethoxyflavonol (TMFol), a novel putative prostate cancer chemopreventive agent: In vitro and in vivo preclinical activity
Authors: Saad Shaban , Howells Lynne , Britton Robert G. , Steward William P. , Gescher Andreas , Brown Karen , Sale Stewart 
Published: January 2011

Abstract
Flavonoids occurring in many edible fruits and vegetables, typified by fisetin and quercetin, have been suggested to prevent malignancies, including those of the prostate. Only a handful of flavonoids have thus far been subjected to exhaustive pharmacological investigation, and it is unknown whether analogues exist with pharmacological properties superior to those of flavonoids studied to date. We identified TMFol as a potent inhibitor of growth of TRAMP C2, LNCaP, and PC-3 prostate cancer cells, with IC50 values of 1.3-5µM. For comparison, the respective IC50 values for fisetin and quercetin are 8-10 fold higher. Studies in mice hint at the possibility that TMFol may be useful as prostate cancer chemopreventive agent, because TMFol levels in prostate tissue after single oral administration of 240 mg/kg reached 18 nmol/g, and steady state levels after dietary intake (0.2%) were 5 nmol/g These concentrations are consistent with those eliciting growth inhibition in prostate cells in vitro. Mechanistic studies have shown TMFol to arrest cells in the G2M phase of the cell cycle and induce apoptosis. In addition, TMFol inhibited androgen receptor signalling. When nude mice bearing the TRAMP C2 cell xenograft were exposed to TMFol (0.2% in the diet) tumor volume at termination of the experiment was significantly reduced by 41% in comparison to control (p&lt;0.001). Quercetin and fisetin had no effect, at equimolar doses, in the same mouse model. Compared to other flavonoids thus far tested as putative prostate cancer chemopreventive agents, TMFol seems superior in terms of growth-inhibitory potency, and in vivo efficacy, probably related to its metabolic stability. It therefore warrants further preclinical and clinical investigation.
Citation Information: Cancer Prev Res 2010;3(12 Suppl):A104.