bluuebunny/crossref_metadata_2025_split huggingface dataset:
Enhancing Mammalian Target of Rapamycin (mTOR)–Targeted Cancer Therapy by Preventing mTOR/Raptor Inhibition-Initiated, mTOR/Rictor-Independent Akt Activation
Authors: Wang Xuerong , Yue Ping , Kim Young Ae , Fu Haian , Khuri Fadlo R. , Sun Shi-Yong 
Published: September 2008

Abstract
It has been shown that mammalian target of rapamycin (mTOR) inhibitors activate Akt while inhibiting mTOR signaling. However, the underlying mechanisms and the effect of the Akt activation on mTOR-targeted cancer therapy are unclear. The present work focused on addressing the role of mTOR/rictor in mTOR inhibitor-induced Akt activation and the effect of sustained Akt activation on mTOR-targeted cancer therapy. Thus, we have shown that mTOR inhibitors increase Akt phosphorylation through a mechanism independent of mTOR/rictor because the assembly of mTOR/rictor was inhibited by mTOR inhibitors and the silencing of rictor did not abrogate mTOR inhibitor-induced Akt activation. Moreover, Akt activation during mTOR inhibition is tightly associated with development of cell resistance to mTOR inhibitors. Accordingly, cotargeting mTOR and phosphatidylinositol 3-kinase/Akt signaling prevents mTOR inhibition-initiated Akt activation and enhances antitumor effects both in cell cultures and in animal xenograft models, suggesting an effective cancer therapeutic strategy. Collectively, we conclude that inhibition of the mTOR/raptor complex initiates Akt activation independent of mTOR/rictor. Consequently, the sustained Akt activation during mTOR inhibition will counteract the anticancer efficacy of the mTOR inhibitors. [Cancer Res 2008;68(18):7409–18]
Glucocorticoids Antagonize Estrogens by Glucocorticoid Receptor–Mediated Activation of Estrogen Sulfotransferase
Authors: Gong Haibiao , Jarzynka Michael J. , Cole Timothy J. , Lee Jung Hoon , Wada Taira , Zhang Bin , Gao Jie , Song Wen-Chao , DeFranco Donald B. , Cheng Shi-Yuan , Xie Wen 
Published: September 2008

AbstractGlucocorticoids and estrogens are two classes of steroid hormones that have essential but distinct physiologic functions. Estrogens also represent a risk factor for breast cancer. It has been suggested that glucocorticoids can attenuate estrogen responses, but the mechanism by which glucocorticoids inhibit estrogenic activity is unknown. In this study, we show that activation of glucocorticoid receptor (GR) by dexamethasone (DEX) induced the expression and activity of estrogen sulfotransferase (SULT1E1 or EST), an enzyme important for the metabolic deactivation of estrogens, because sulfonated estrogens fail to activate the estrogen receptor. Treatment with DEX lowered circulating estrogens, compromised uterine estrogen responses, and inhibited estrogen-dependent breast cancer growth in vitro and in a xenograft model. We further showed that the mouse and human SULT1E1 genes are transcriptional targets of GR and deletion of Sult1e1/Est in mice abolished the DEX effect on estrogen responses. These findings have revealed a novel nuclear receptor–mediated and metabolism-based mechanism of estrogen deprivation, which may have implications in therapeutic development for breast cancers. Because glucocorticoids and estrogens are widely prescribed drugs, our results also urge caution in avoiding glucocorticoid-estrogen interactions in patients. [Cancer Res 2008;68(18):7386–93]
Systemic Targeting of CpG-ODN to the Tumor Microenvironment with Anti–neu-CpG Hybrid Molecule and T Regulatory Cell Depletion Induces Memory Responses in BALB-neuT Tolerant Mice
Authors: Sharma Sanjay , Dominguez Ana Lucia , Manrique Soraya Zorro , Cavallo Federica , Sakaguchi Shimon , Lustgarten Joseph 
Published: September 2008

AbstractWe have shown that neu transgenic mice are immunotolerant and that immunizations with dendritic cells (DC) pulsed with neu-derived antigens were not able to control tumor growth in these animals. We tested whether, by modulating the tumor microenvironment with Toll-like receptor ligands, it could be possible to induce the activation of antitumor responses in neu mice. Our results indicate that only intratumoral (i.t.) injections of CpG-ODN induce an antitumor response in neu mice. To target the CpG-ODN to the tumor site anywhere within the body, we chemically conjugated an anti–Her-2/neu monoclonal antibody (mAb) with CpG-ODN. The anti–neu-CpG hybrid molecule retained its ability to bind to Her-2/neu+ tumors, activate DCs, and induce antitumor responses. Our results indicated that injections of anti–neu-CpG induced the rejection of primary tumors in 100% of BALB/c mice and only in ∼30% of BALB-neuT mice. After challenging the BALB/c and BALB-neuT mice, we observed that BALB/c mice developed a protective memory response; in contrast, BALB-neuT mice succumbed to the challenge. After injections of anti–neu-CpG, T regulatory cells (T-reg) were drastically reduced at the tumor site, but a large number were still present in the lymphoid organs. When BALB-neuT mice were treated with anti–neu-CpG plus anti-GITR mAb, but not with anti-CD25 mAb, 100% of the BALB-neuT mice rejected the primary tumor and developed a protective memory response indicating the critical role of T-regs in regulating the repertoire against self antigens. Taken together, these results indicate that CpG-ODN–targeted therapy and depletion of T-regs optimally activate a primary response and generate a protective memory response against self-tumor antigens. [Cancer Res 2008;68(18):7530–40]
A Fluorescence In situ Hybridization Screen for E26 Transformation–Specific Aberrations: Identification of DDX5-ETV4 Fusion Protein in Prostate Cancer
Authors: Han Bo , Mehra Rohit , Dhanasekaran Saravana M. , Yu Jindan , Menon Anjana , Lonigro Robert J. , Wang Xiaosong , Gong Yusong , Wang Lei , Shankar Sunita , Laxman Bharathi , Shah Rajal B. , Varambally Sooryanarayana , Palanisamy Nallasivam , Tomlins Scott A. , Kumar-Sinha Chandan , Chinnaiyan Arul M. 
Published: September 2008

Abstract
Recurrent gene fusions involving E26 transformation–specific (ETS) transcription factors ERG, ETV1, ETV4, or ETV5 have been identified in 40% to 70% of prostate cancers. Here, we used a comprehensive fluorescence in situ hybridization (FISH) split probe strategy interrogating all 27 ETS family members and their five known 5′ fusion partners in a cohort of 110 clinically localized prostate cancer patients. Gene rearrangements were only identified in ETS genes that were previously implicated in prostate cancer gene fusions including ERG, ETV1, and ETV4 (43%, 5%, and 5%, respectively), suggesting that a substantial fraction of prostate cancers (estimated at 30–60%) cannot be attributed to an ETS gene fusion. Among the known 5′ gene fusion partners, TMPRSS2 was rearranged in 47% of cases followed by SLC45A3, HNRPA2B1, and C15ORF21 in 2%, 1%, and 1% of cases, respectively. Based on this comprehensive FISH screen, we have made four noteworthy observations. First, by screening the entire ETS transcription factor family for rearrangements, we found that a large fraction of prostate cancers (44%) cannot be ascribed to an ETS gene fusion, an observation which will stimulate research into identifying recurrent non-ETS aberrations in prostate cancers. Second, we identified SLC45A3 as a novel 5′ fusion partner of ERG; previously, TMPRSS2 was the only described 5′ partner of ERG. Third, we identified two prostate-specific, androgen-induced genes, FLJ35294 and CANT1, as 5′ partners to ETV1 and ETV4. Fourth, we identified a ubiquitously expressed, androgen-insensitive gene, DDX5, fused in frame with ETV4, leading to the expression of a DDX5-ETV4 fusion protein. [Cancer Res 2008;68(18):7629–37]
Gene Expression Profile and Angiogenic Markers Correlate with Response to Neoadjuvant Bevacizumab Followed by Bevacizumab plus Chemotherapy in Breast Cancer
Authors: Yang Sherry X. , Steinberg Seth M. , Nguyen Dat , Wu Thomas D. , Modrusan Zora , Swain Sandra M. 
Published: September 2008

Abstract
Purpose: To identify biomarkers and gene expression profile signatures to distinguish patients with partial response (PR) from those with stable disease (SD) and progressive disease (PD).
Experimental Design: Twenty patients with inflammatory breast cancer and one patient with locally advanced breast cancer received one cycle of bevacizumab followed by six cycles of bevacizumab plus docetaxel-doxorubicin before surgery. Baseline angiogenic/tumor markers were examined by immunohistochemistry and gene expression profiles were measured by Agilent Whole Human Genome arrays. All were assessed for clinical response.
Results: Fourteen patients (67%, 95% confidence interval, 43-85.4%) had PR, five had SD, and two had PD. Expression of CD31 and platelet-derived growth factor receptor-β (PDGFR-β) in the tumor vasculature by immunohistochemistry was significantly associated with response (PR versus SD/PD; CD31 median, 33.5 versus 13.2; P = 0.0004; PDGFR-β median, 5.9 versus 0.6; P = 0.01). Tumor VEGF-A showed a trend towards association with response (2.65 versus 0.25; P = 0.04). pVEGFR2(Y996), pVEGFR2(Y951), MVD, Ki67, apoptosis, grade, ER, HER-2/neu, and p53 were not associated with response. Twenty-six of 1,339 Gene Ontology (GO) classes at the gene transcriptional level were differentially expressed between patients with PR and SD/PD (P &lt; 0.005). Representative significant GO classes include spindle (11 genes; P = 0.001), vascular endothelial growth factor receptor activity including PDGFR-β (5 genes; P = 0.002), and cell motility including CD31 (80 genes; P = 0.005).
Conclusions: Baseline CD31, PDGFR-β, and GO classes for vascular endothelial growth factor receptor activity and mitosis were significantly associated with response to bevacizumab followed by bevacizumab plus chemotherapy.
Impaired Tamoxifen Metabolism Reduces Survival in Familial Breast Cancer Patients
Authors: Newman William G. , Hadfield Kristen D. , Latif Ayshe , Roberts Stephen A. , Shenton Andrew , McHague Christopher , Lalloo Fiona , Howell Sacha , Evans D. Gareth 
Published: September 2008

Abstract
Purpose: Tamoxifen has been the mainstay adjuvant hormonal treatment for breast cancer for many years. Conversion of tamoxifen to its active metabolite, endoxifen, is reduced by low activity of the cytochrome P450 enzyme, CYP2D6. We examined the effect of reduced CYP2D6 activity on the response to tamoxifen in patients with familial early-onset breast cancer.
Experimental Design: We conducted a case note review and genotyping for the CYP2D6*3, CYP2D6*4, CYP2D6*5, and CYP2D6*41 alleles in 115 patients (47 BRCA1, 68 BRCA2) with familial breast cancer who had been treated with 20-mg tamoxifen following surgery.
Results: Eight (7%) individuals had genotypes consistent with poor metabolizer status, and 4 (3.5%) individuals took CYP2D6 inhibitor drugs concomitant with their tamoxifen and were also considered poor metabolizer. Time to tumor recurrence, disease-free survival, and overall survival were reduced in the patient group with poor metabolizer CYP2D6 activity. However, a significant effect was confined to patients with BRCA2 mutations with a worse overall survival (median survival, 7 versus 28 years; P = 0.008; adjusted hazard ratio, 9.7).
Conclusions: Poor metabolizer status for CYP2D6 predicts worse overall survival in patients with familial breast cancer. Therefore, CYP2D6 inhibitor drugs should not be prescribed concomitantly with tamoxifen. Prospective studies should be undertaken to establish the effect of CYP2D6 status on outcome in familial breast cancer patients treated with tamoxifen.
Monitoring Caspase-3 Activation with a Multimodality Imaging Sensor in Living Subjects
Authors: Ray Pritha , De Abhijit , Patel Manishkumar , Gambhir Sanjiv Sam 
Published: September 2008

Abstract
Purpose: Capsase-3 plays an important role in chemotherapy-induced apoptosis in many cancers. Herein, we applied a multimodality reporter vector to monitor caspase-3 activation indirectly in live cells and tumors of living animals undergoing apoptosis.
Experimental Design: A fusion protein (MTF) was constructed by combining three different reporter proteins, red fluorescent protein (mRFP1), firefly luciferase (FL), and HSV1-sr39 truncated thymidine kinase (TK), linked through a caspase-3 recognizable polypeptide linker. After cleavage by caspase-3, a significant gain in mRFP1, FL, and TK activity are observed by fluorescence-activated cell sorting and enzyme-based assays. A melanoma cell line (B16F10-mtf-hrl) stably expressing mtf (to measure caspase-3 activation) and hrl-IRES-gfp (to determine the decrease in a number of viable cells) vectors was generated to measure two independent molecular events upon treatment.
Results: Upon induction with 8 μmol/L staurosporine, the fusion protein showed a 2.8-fold increase in FL (P = 0.03), a 1.5-fold increase in TK (P = not significant), and a 2-fold increase in mRFP1 (P = 0.05) activity in 293T cells. Bioluminescence and micropositron emission tomography imaging of the apoptotic B16F10-mtf-hrl tumors showed a 2-fold higher FL activity (897 versus 416) and a 2-fold higher TK activity (10.3 versus 3.87) than control tumors when normalized with RL activity. Using a similar normalization approach, the time kinetics of caspase-3 activation by two protein kinase-C inhibitors was noninvasively monitored in living mice.
Conclusion: This multimodality caspase sensor vector could effectively and noninvasively monitor caspase-3 activation from single live cells to a multicellular tumor environment and, thus, would be a valuable tool for drug screening in preclinical models and future patient cell based therapy.
Randomized Study of Intravenous versus Subcutaneous Interleukin-2, and IFNα in Patients with Good Prognosis Metastatic Renal Cancer
Authors: Négrier Sylvie , Perol David , Ravaud Alain , Bay Jacques O. , Oudard Stéphane , Chabaud Sylvie , Fargeot Pierre , Delva Remy , Deplanque Gael , Gravis Gwenaelle , Escudier Bernard ,   for the French Immunotherapy Group
Published: September 2008

Abstract
Purpose: Metastatic renal cancer patients with a single metastatic site are potentially amenable to interleukin 2 (IL-2) + IFN-α. A French immunotherapy intergroup multicenter trial assessed the potential benefit of i.v. over s.c. administration of IL-2 in this combination.
Experimental Design: Untreated patients with one metastatic site were randomized to continuous i.v. infusion (18 × 106 IU/m2/d; arm A) or twice daily s.c. injections (9 × 106 or 18 × 106 IU; arm B) of IL-2, associated with s.c. IFN-α (6 × 106 IU) 3 days per week in both arms. Tumor response was assessed (WHO criteria) at weeks 12 and 24 to 26. The primary end point was overall survival, with an expected 15% improvement at 4 years with i.v. IL-2. The planned sample size was 220 (80% power, 5% significance, one-sided test). Intent-to-treat analysis was done and survivals were compared using log-rank tests.
Results: From January 2000 to January 2005, 80 and 75 patients were randomized to arms A and B, respectively. Enrollment was stopped early because of low accrual; analysis was done at 42.5 months median follow-up. Patient characteristics were well balanced between groups. Response rates were 17.9% versus 21.3% in arms A and B. Progression-free survival rates were not significantly different. Overall survival difference was not significant: median 33 months (95% confidence interval, 27.0-40.2; P = 0.202).
Conclusions: In combination with IFN-α in selected, good prognosis metastatic renal cell carcinoma patients, i.v. IL-2 offers no significant advantage over s.c. IL-2 and induces higher toxicity. Although i.v. IL-2 induced longer responses, it seems unreasonable to continue recommending this regimen after the recent introduction of more effective therapies.
Predicting Clinical Outcome in Patients Diagnosed with Synchronous Ovarian and Endometrial Cancer
Authors: Ramus Susan J. , Elmasry Karim , Luo Zhiyuan , Gammerman Alex , Lu Karen , Ayhan Ayse , Singh Naveena , McCluggage W. Glenn , Jacobs Ian J. , Whittaker John C. , Gayther Simon A. 
Published: September 2008

Abstract
Purpose: Patients with synchronous ovarian and endometrial cancers may represent cases of a single primary tumor with metastasis (SPM) or dual primary tumors (DP). The diagnosis given will influence the patient's treatment and prognosis. Currently, a diagnosis of SPM or DP is made using histologic criteria, which are frequently unable to make a definitive diagnosis.
Experimental Design: In this study, we used genetic profiling to make a genetic diagnosis of SPM or DP in 90 patients with synchronous ovarian/endometrial cancers. We compared genetic diagnoses in these patients with the original histologic diagnoses and evaluated the clinical outcome in this series of patients based on their diagnoses.
Results: Combining genetic and histologic approaches, we were able make a diagnosis in 88 of 90 cases, whereas histology alone was able to make a diagnosis in only 64 cases. Patients diagnosed with SPM had a significantly worse survival than patients with DP (P = 0.002). Patients in which both tumors were of endometrioid histology survived longer than patients of other histologic subtypes (P = 0.025), and patients diagnosed with SPM had a worse survival if the mode of spread was from ovary to endometrium rather than from endometrium to ovary (P = 0.019).
Conclusions: Genetic analysis may represent a powerful tool for use in clinical practice for distinguishing between SPM and DP in patients with synchronous ovarian/endometrial cancer and predicting disease outcome. The data also suggest a hitherto uncharacterized level of heterogeneity in these cases, which, if accurately defined, could lead to improved treatment and survival.
A Novel Inhibitor of Signal Transducers And Activators Of Transcription 3 Activation Is Efficacious Against Established Central Nervous System Melanoma and Inhibits Regulatory T Cells
Authors: Kong Ling-Yuan , Abou-Ghazal Mohamed K. , Wei Jun , Chakraborty Arup , Sun Wei , Qiao Wei , Fuller Gregory N. , Fokt Izabela , Grimm Elizabeth A. , Schmittling Robert J. , Archer Gary E. , Sampson John H. , Priebe Waldemar , Heimberger Amy B. 
Published: September 2008

Abstract
Purpose: Activation of signal transducers and activators of transcription 3 (STAT3) has been identified as a central mediator of melanoma growth and metastasis. We hypothesized that WP1066, a novel STAT3 blockade agent, has marked antitumor activity, even against the melanoma metastasis to brain, a site typically refractory to therapies.
Experimental Design: The antitumor activities and related mechanisms of WP1066 were investigated both in vitro on melanoma cell lines and in vivo on mice with subcutaneously syngeneic melanoma or with intracerebral melanoma tumors.
Results: WP1066 achieved an IC50 of 1.6, 2.3, and 1.5 μmol/L against melanoma cell line A375, B16, and B16EGFRvIII, respectively. WP1066 suppressed the phosphorylation of Janus-activated kinase 2 and STAT3 (Tyr705) in these cells. Tumor growth in mice with subcutaneously established syngeneic melanoma was markedly inhibited by WP1066 compared with that in controls. Long-term survival (&gt;78 days) was observed in 80% of mice with established intracerebral syngeneic melanoma treated with 40 mg/kg of WP1066 in contrast to control mice who survived for a median of 15 days. Although WP1066 did not induce immunologic memory or enhance humoral responses to EGFRvIII, this compound reduced the production of immunosuppressive cytokines and chemokines (transforming growth factor-β, RANTES, MCP-1, vascular endothelial growth factor), markedly inhibited natural and inducible Treg proliferation, and significantly increased cytotoxic immune responses of T cells.
Conclusions: The antitumor cytotoxic effects of WP1066 and its ability to induce antitumor immune responses suggest that this compound has potential for the effective treatment of melanoma metastatic to brain.
Association of Common PALB2 Polymorphisms with Breast Cancer Risk: A Case-Control Study
Authors: Chen Peizhan , Liang Jie , Wang Zhanwei , Zhou Xiaoyi , Chen Lu , Li Mian , Xie Dong , Hu Zhibin , Shen Hongbing , Wang Hui 
Published: September 2008

Abstract
Purpose: The PALB2 gene has an essential role in BRCA2-mediated DNA double-strand break repair and intra–S phase DNA damage checkpoint control, and its mutations are moderately associated with breast cancer susceptibility. This study was designed to investigate the common variants of PALB2 and their association with breast cancer risk.
Experimental Design: Four single nucleotide polymorphisms (SNP; rs249954, rs249935, rs120963, and rs16940342) which tagged all 19 of the reported SNPs (minor allele frequency &gt;0.05) covering PALB2 were selected and genotyped in 1,049 patients with breast cancer and 1,073 cancer-free controls in a female Chinese population.
Results: Based on the multiple hypothesis testing with the Benjamini-Hochberg method, tagging SNPs (tSNP) rs249954, rs120963, and rs16940342 were found to be associated with an increase of breast cancer risk (false discovery rate–adjusted P values of 0.004, 0.028, and 0.049, respectively) under the dominant model. tSNP rs249954 was associated with a 36% increase of breast cancer risk [adjusted odds ratio (OR), 1.36; 95% confidence intervals (CI), 1.13-1.64; P = 0.001; TT/TC versus CC genotypes]. The adjusted OR for rs120963 was 1.25 (95% CI, 1.04-1.49; P = 0.014; CC/CT versus TT genotypes). For rs16940342, the adjusted OR was 1.21 (95% CI, 1.02-1.45; P = 0.037; GG/GA versus AA genotypes). Based on an additive model, tSNPs rs249954 and rs120963 were associated with an increase of breast cancer risk (P = 0.005 and 0.019; respectively), with the false discovery rate–adjusted P values being 0.020 and 0.038, respectively.
Conclusions: Our data suggest that the variants of PALB2 confer low-penetrance breast cancer susceptibility in a Chinese population.
Clinical Usefulness of EGFR Gene Copy Number as a Predictive Marker in Colorectal Cancer Patients Treated with Cetuximab: A Fluorescent In situ Hybridization Study
Authors: Personeni Nicola , Fieuws Steffen , Piessevaux Hubert , De Hertogh Gert , De Schutter Jef , Biesmans Bart , De Roock Wendy , Capoen An , Debiec-Rychter Maria , Van Laethem Jean-Luc , Peeters Marc , Humblet Yves , Van Cutsem Eric , Tejpar Sabine 
Published: September 2008

Abstract
Purpose: To evaluate the usefulness and the pitfalls inherent to the assessment of the epidermal growth factor receptor (EGFR) gene copy number (GCN) by fluorescence in situ hybridization (FISH) for outcome prediction to cetuximab in metastatic colorectal cancer. The value of testing KRAS mutation status, in addition to EGFR GCN, was also explored.
Experimental Design: FISH analysis of 87 metastatic colorectal cancer patients treated with cetuximab was done, recording individual GCN per cell and using different samples per tumor. Performances of published cutoff points and different summaries of EGFR GCN distribution were assessed for response prediction.
Results: In our data set, two published cutoff points performed less well than in their training set, yielding positive predictive values and negative predictive values between 40.0% and 48.3% and between 81.0% and 86.5%, respectively. Among summaries of GCN distribution explored, mean and right-tailed distribution of GCN yielded the highest performances. A mean EGFR GCN ≥2.83 provided an area under the curve of 0.71. Important heterogeneity of repeated measures of mean EGFR GCN was observed within tumors (intraclass correlation, 0.61; within-class SD, 0.40), leading to potential misclassifications of FISH status in 7 of 18 (38.8%) patients if a cutoff point were used. In multivariable analysis, EGFR GCN testing provided significant information independent of the KRAS status to predict response (P = 0.016) and overall survival (P = 0.005).
Conclusions: We confirm the association between increased EGFR GCN and outcome after cetuximab. However, because of reproducibility concerns, any decision making based on published cutoff points is not warranted.