bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bortezomib-Mediated Inhibition of Steroid Receptor Coactivator-3 Degradation Leads to Activated Akt
Authors: Ayala Gustavo , Yan Jun , Li Rile , Ding Yi , Thompson Timothy C. , Mims Martha P. , Hayes Teresa G. , MacDonnell Vivian , Lynch R. Garret , Frolov Anna , Miles Brian J. , Wheeler Thomas M. , Harper J. Wade , Tsai Ming-Jer , Ittmann Michael M. , Kadmon Dov 
Published: November 2008

Abstract
Purpose: To assess the safety of administering bortezomib to patients undergoing a radical prostatectomy, to assess pathologic changes induced by bortezomib in prostate cancer specimen, and to verify alterations by the drug in proteasome protein targets.
Experimental Design: Bortezomib is a proteasome inhibitor that has shown activity in vitro and in vivo in prostate cancer. We performed a neoadjuvant clinical trial of bortezomib in men with prostate cancer at high risk of recurrence. The primary endpoints were to evaluate safety and biological activity.
Results: Bortezomib is generally safe in the preoperative setting. Antitumor activity was manifested by tumor cytopathic effect, drops in serum prostate-specific antigen in some patients, and increases in tumor apoptosis. This was associated with cytoplasmic entrapment of nuclear factor-κB. We found an unexpected increase in proliferation in treated tissues and in vitro. Bortezomib also increased SRC-3 levels and phosphorylated Akt, both in vitro and in treated prostate cancer tissues. Knockdown of SRC-3 blocked the increase in activated Akt in vitro. Combined treatment with bortezomib and the Akt inhibitor perifosine was more effective than either agent alone in vitro.
Conclusion: These data suggest that combined therapies targeting the proteasome and the Akt pathway may have increased efficacy.
Activation of the Osteopontin/Matrix Metalloproteinase-9 Pathway Correlates with Prostate Cancer Progression
Authors: Castellano Giancarlo , Malaponte Grazia , Mazzarino Maria C. , Figini Mariangela , Marchese Francesco , Gangemi Pietro , Travali Salvatore , Stivala Franca , Canevari Silvana , Libra Massimo 
Published: November 2008

Abstract
Purpose: Prostate cancer remains the second most frequent cause of tumor-related deaths in the Western world. Additional markers for the identification of prostate cancer development and progression are needed. Osteopontin (OPN), which activates matrix metalloproteinases (MMP), is considered a prognostic biomarker in several cancers. “In silico” and experimental approaches were used to determine whether OPN-mediated MMP activation may be a signal of prostate cancer progression.
Experimental Design: Pearson correlation coefficients were computed for each OPN/MMP pair across seven publicly available prostate cancer gene expression data sets. Using Gene Set Enrichment Analysis, 101 cancer-related gene sets were analyzed for association with OPN and MMP-9 expression. OPN, MMP-9, MMP-2 tissue inhibitor of metalloproteinase-1 plasma levels, and MMP gelatinase activity were measured by ELISA and zymography in 96 and 92 patients with prostate cancer and benign prostatic hyperplasia, respectively, and 125 age-matched healthy men.
Results: Computational analyses identified a significant correlation only between MMP-9 and OPN, and showed significant enrichment scores in “cell proliferation”, “genes constituting the phosphoinositide-3-kinase predictor”, “proliferation signature”, and “tumor metastasis” gene sets in association with both OPN and MMP-9. Plasma analyses revealed a significant increase in OPN and MMP-9 levels and activity in patients with prostate cancer in association with clinical variables (prostate-specific antigen &gt;4 ng/mL and Gleason score &gt;7). Significant correlation between OPN and MMP-9 levels were also observed. Mean plasma levels of OPN and MMP-9 decreased in patients with prostate cancer within 6 months after prostatectomy.
Conclusions: The concordant computational and experimental data indicate that the extent of OPN pathway activation correlates with prostate cancer progression.
G-Quadruplex Ligand RHPS4 Potentiates the Antitumor Activity of Camptothecins in Preclinical Models of Solid Tumors
Authors: Leonetti Carlo , Scarsella Marco , Riggio Giuseppe , Rizzo Angela , Salvati Erica , D'Incalci Maurizio , Staszewsky Lidia , Frapolli Roberta , Stevens Malcolm F. , Stoppacciaro Antonella , Mottolese Marcella , Antoniani Barbara , Gilson Eric , Zupi Gabriella , Biroccio Annamaria 
Published: November 2008

Abstract
Purpose: The formation of G-quadruplex structures at telomeric DNA sequences blocks telomerase activity, offering an original strategy to design and develop new antitumor agents. The pentacyclic acridinium salt RHPS4 is one of the most effective and selective G4 ligands able to rapidly disrupt telomere architecture, resulting in apoptosis of cancer cells. Here, we studied the therapeutic index of RHPS4 and its integration with chemotherapeutics in preclinical model of solid tumors.
Experimental Design: The antitumoral activity of RHPS4 was evaluated on human xenografts of different histotypes and compared with that of standard antineoplastic agents. Moreover, the effect of RHPS4/chemotherapeutics combinations on cell survival was studied and the most favorable combination was evaluated on tumor-bearing mice.
Results: RHPS4 was active in vivo as single agent and showed a high therapeutic efficacy when compared with conventional drugs. Moreover, RHPS4 had antitumoral activity in human melanoma xenografts inherently resistant to chemotherapy and exhibited antimetastatic activity. RHPS4 also showed a strong synergistic interaction with camptothecins and this effect was strictly dependent on the drug sequence employed. Treatment of mice with irinotecan followed by RHPS4 was able to inhibit and delay tumor growth and to increase mice survival.
Conclusions: Our data show that RHPS4 has a good pharmacodynamic profile and in combination therapy produces a strong antitumoral activity, identifying this drug as promising agent for clinical development.
An Orthotopic Murine Model of Sinonasal Malignancy
Authors: Gelbard Alexander , Kupferman Michael E. , Jasser Samar A. , Chen Wantao , El-Naggar Adel K. , Myers Jeffrey N. , Hanna Ehab Y. 
Published: November 2008

Abstract
Purpose: Malignant sinonasal tumors are clinically challenging due to their proximity to vital structures and their diverse histogenesis and biological behavior. To date, no animal models accurately reflect the clinical behavior of these malignancies. We developed an orthotopic murine model of sinonasal malignancy that reproduces the intracranial extension, bony destruction, and spread along neural fascial planes seen in patients with aggressive sinonasal malignancies of various histologies.
Experimental Design: Human squamous cell carcinoma line (DM14) and adenoid cystic carcinoma line (ACC-3) were implanted in the right maxillary sinus or soft palate in male nude mice. Animals were monitored for tumor growth and survival. Tumor specimens were removed for histopathologic evaluation to assess for intracranial extension, orbital invasion, bony invasion, perineural invasion, and distant metastasis. Statistical analysis was done to calculate P values with the Student's t test for individual tumor volumes. Differences in survival times were assessed using the log-rank test.
Results: Mice with DM14 or ACC-3 implanted in either the maxillary sinus or the soft palate developed large primary tumors. A statistically significant inverse correlation between survival and the number of tumor cells implanted was found. Histopathologic evaluation revealed orbital invasion, intracranial extension, pulmonary metastasis, lymph node metastasis, and perineural invasion.
Conclusions: We describe the first orthotopic model for sinonasal malignancy. Our model faithfully recapitulates the phenotype and malignant behavior of the aggressive tumor types seen in patients. This model offers an opportunity to identify and specifically target the aberrant molecular mechanisms underlying this heterogeneous group of malignancies.
Overexpression of Indoleamine 2,3-Dioxygenase in Human Endometrial Carcinoma Cells Induces Rapid Tumor Growth in a Mouse Xenograft Model
Authors: Yoshida Norio , Ino Kazuhiko , Ishida Yoshiyuki , Kajiyama Hiroaki , Yamamoto Eiko , Shibata Kiyosumi , Terauchi Mikio , Nawa Akihiro , Akimoto Hidetoshi , Takikawa Osamu , Isobe Ken-ichi , Kikkawa Fumitaka 
Published: November 2008

Abstract
Purpose: Indoleamine 2,3-dioxygenase (IDO) is a tryptophan-catabolizing enzyme that induces immune tolerance in mice. Our prior study showed that high tumoral IDO expression in endometrial cancer tissues correlates with disease progression and impaired patient survival. The purpose of the present study was to clarify the functional role of IDO in human endometrial cancer cells and to investigate the therapeutic potential of IDO inhibitors.
Experimental Design: IDO cDNA was transfected into the human endometrial carcinoma cell line AMEC, resulting in the establishment of stable clones of IDO-overexpressing AMEC cells (AMEC-IDO). AMEC-IDO cells were characterized in vitro as well as in vivo using a mouse xenograft model.
Results: There was no significant difference in in vitro cell proliferation, migration, or chemosensitivity to paclitaxel between AMEC-IDO and control vector–transfected cells (AMEC-pcDNA). However, in vivo tumor growth was markedly enhanced in AMEC-IDO–xenografted nude mice when compared with AMEC-pcDNA–xenografted mice. Splenic natural killer (NK) cell counts in AMEC-IDO–xenografted mice were significantly decreased when compared with control mice. Furthermore, conditioned medium obtained from AMEC-IDO cell cultures markedly reduced the NK lysis activity of nude mice. Finally, oral administration of the IDO inhibitor 1-methyl-d-tryptophan in combination with paclitaxel in AMEC-IDO–xenografted mice strongly potentiated the antitumor effect of paclitaxel, resulting in significantly prolonged survival.
Conclusions: This is the first evidence showing that IDO overexpression in human cancer cells contributes to tumor progression in vivo with suppression of NK cells. Our data suggest that targeting IDO may be a novel therapeutic strategy for endometrial cancer.
Diabodies Targeting Epithelial Membrane Protein 2 Reduce Tumorigenicity of Human Endometrial Cancer Cell Lines
Authors: Shimazaki Kaori , Lepin Eric J. , Wei Bo , Nagy Agnes K. , Coulam Catherine P. , Mareninov Sergey , Fu Maoyong , Wu Anna M. , Marks James D. , Braun Jonathan , Gordon Lynn K. , Wadehra Madhuri 
Published: November 2008

Abstract
Purpose: Endometrial cancer is the most common gynecologic malignancy. One promising biomarker is epithelial membrane protein 2 (EMP2), and its expression is an independent prognostic indicator for tumors with poor clinical outcome expression. The present study assesses the suitability of EMP2 as a therapeutic target.
Experimental Design: Human monovalent anti-EMP2 antibody fragments were isolated from a human phage display library and engineered as bivalent antibody fragments (diabodies) with specificity and avidity to both EMP2 peptides and native cell-surface EMP2 protein. Diabodies were assessed using cell death and apoptosis assays. In addition, the efficacy of EMP2 diabodies on endometrial cancer tumors was determined using mouse xenograft models.
Results: Treatment of human endometrial adenocarcinoma cell lines with anti-EMP2 diabodies induced significant cell death and caspase-3 cleavage in vitro. These responses correlated with cellular EMP2 expression and were augmented by progesterone, which physiologically induces EMP2 expression. In vivo, treatment of subcutaneous human xenografts of HEC-1A cell lines with anti-EMP2 diabodies suppressed tumor growth and induced cell death in the xenograft.
Conclusions: These findings suggest that EMP2 may be a potential pharmacologic target for human endometrial cancer.
Leukemia-Associated Antigens Are Critical for the Proliferation of Acute Myeloid Leukemia Cells
Authors: Greiner Jochen , Bullinger Lars , Guinn Barbara-ann , Döhner Hartmut , Schmitt Michael 
Published: November 2008

Abstract
Acute myeloid leukemia (AML) is the most common acute leukemia in adults. With intensive induction therapy, most patients younger than 60 years achieve complete remission. However, even if these younger patients were treated intensively, more than 50% will relapse. Clinical results of patients older than 60 years are more unfavorable. Therefore, in all patients with AML, the overall survival is still low. In the past decade, several leukemia-associated antigens (LAA) have been identified in patients with acute myeloid leukemia. BAGE, BCL-2, OFA-iLRP, FLT3-ITD, G250, hTERT, PRAME, proteinase 3, RHAMM, survivin, and WT-1 are all LAAs that have been shown to induce CD8+ T-cell recognition and for some antigens also humoral immune responses. Interestingly, most of these LAAs are linked to cell cycle or proliferation. This article discusses the balance between LAA-driven leukemia cell expansion and the elimination of these cells through attacks on LAAs by the immune system. Current knowledge of the function and CD8+ T-cell recognition of LAAs is reviewed and an outlook is given on how to improve T-cell responses to LAAs in acute myeloid leukemia cells.
Genetic Analysis of Cancer-Implicated MicroRNA in Ovarian Cancer
Authors: Bearfoot Jennifer L. , Choong David Y.H. , Gorringe Kylie L. , Campbell Ian G. 
Published: November 2008

Abstract
Purpose: There is accumulating evidence that microRNAs may function like classic tumor suppressor genes but little is known about their mechanism of inactivation in cancer cells. We investigated whether somatic mutations are a common mechanism of inactivation of microRNA genes in ovarian cancer.
Experimental Design: Ten cancer-implicated microRNA genes were analyzed for somatic mutations in 90 ovarian epithelial cancers and matching normal DNA. High-resolution melt analysis and bidirectional sequencing was used to detect sequence variations.
Results: High-resolution melt analysis and direct sequencing did not identify any somatic mutations but did reveal numerous novel and previously reported germ line base substitutions, deletions, and insertions surrounding the mature microRNA sequences. The majority of variants were detected in the same proportion of non–cancer control individuals suggesting that they do not represent ovarian cancer–predisposing alleles.
Conclusion: The absence of somatic mutations in any of the 10 cancer-implicated microRNAs in our large cohort of ovarian tumors suggests that this may be an uncommon mechanism of inactivation of microRNAs in ovarian cancer.
Nuclear Factor-κB Modulation in Patients Undergoing Induction Chemotherapy for Acute Myelogenous Leukemia
Authors: Strair Roger K. , Gharibo Mecide , Schaar Dale , Rubin Arnold , Harrison Jonathan , Aisner Joseph , Lin Hsin-Ching , Lin Yong , Goodell Lauri , Anand Monika , Balsara Binaifer , Dudek Liesel , Rabson Arnold , Medina Daniel J. 
Published: November 2008

Abstract
Purpose: Nuclear factor-κB (NF-κB) is constitutively expressed in many acute myelogenous leukemia (AML) cells and AML stem cells. Ex vivo treatment of AML cells with inhibitors of NF-κB results in diminished AML cell survival and enhances the cytotoxic effects of chemotherapeutic agents. The purpose of this study was to determine if standard anti-inflammatory agents modulate AML cell nuclear NF-κB when administered in conjunction with induction chemotherapy.
Experimental Design: Patients with newly diagnosed AML were treated with dexamethasone, choline magnesium trisalicylate, or both for 24 hours prior to and 24 hours following initiation of standard induction chemotherapy. AML cell nuclear NF-κB was measured at baseline, 24, and 48 hours.
Results: Choline magnesium trisalicylate ± dexamethasone decreased nuclear NF-κB, whereas dexamethasone alone was associated with an increase in nuclear NF-κB in AML cells.
Conclusions: These results show the feasibility of NF-κB modulation in conjunction with induction chemotherapy for patients with AML using inexpensive readily available medications. A follow-up study to determine the effects of NF-κB modulation on clinical end points is warranted.
Proliferation Imaging to Measure Early Cancer Response to Targeted Therapy
Authors: Mankoff David A. , Eary Janet F. 
Published: November 2008

Abstract
Positron emission tomography imaging using thymidine and analogues labeled with positron emitters provides noninvasive and quantitative estimates of regional cellular proliferation. This CCR Translations summary reviews the biological basis for proliferation imaging and discusses recent results using 18F-fluorothymidine-positron emission tomography to measure response to targeted therapy in the context of prior studies and potential future applications.
Antisense MDM2 Enhances E2F1-Induced Apoptosis and the Combination Sensitizes Androgen-Dependent and Androgen-Independent Prostate Cancer Cells to Radiation
Authors: Udayakumar Thirupandiyur S. , Hachem Paul , Ahmed Mansoor M. , Agrawal Sudhir , Pollack Alan 
Published: November 2008

Abstract
We have previously shown in separate studies that MDM2 knockdown via antisense MDM2 (AS-MDM2) and E2F1 overexpression via adenoviral-mediated E2F1 (Ad-E2F1) sensitized prostate cancer cells to radiation. Because E2F1 and MDM2 affect apoptosis through both common and independent pathways, we hypothesized that coupling these two treatments would result in increased killing of prostate cancer cells. In this study, the effect of Ad-E2F1 and AS-MDM2 in combination with radiation was investigated in three prostate cancer cell lines: LNCaP cells, LNCaP-Res cells [androgen insensitive with functional p53 and androgen receptor (AR)], and PC3 cells (androgen insensitive, p53null, and ARnull). A supra-additive radiosensitizing effect was observed in terms of clonogenic inhibition and induction of apoptosis (caspase-3 + caspase-7 activity) in response to Ad-E2F1 plus AS-MDM2 treatments in all three cell lines. In LNCaP and LNCaP-Res, these combination treatments elevated the levels of phospho-Ser15 p53 with significant induction of p21waf1/cip1, phospho-γH2AX, PUMA, and Bax levels and reduction of AR and bcl-2 expression. Similarly, ARnull and p53null PC-3 cells showed elevated levels of Bax and phospho-γH2AX expression. These findings show that the combination of Ad-E2F1 and AS-MDM2 significantly increases cell death in prostate cancer cells exposed to radiation and that this effect occurs in the presence or absence of AR and p53. (Mol Cancer Res 2008;6(11):1742–54)
Mutation of ERBB2 Provides a Novel Alternative Mechanism for the Ubiquitous Activation of RAS-MAPK in Ovarian Serous Low Malignant Potential Tumors
Authors: Anglesio Michael S. , Arnold Jeremy M. , George Joshy , Tinker Anna V. , Tothill Richard , Waddell Nic , Simms Lisa , Locandro Bianca , Fereday Sian , Traficante Nadia , Russell Peter , Sharma Raghwa , Birrer Michael J. ,   AOCS Study Group, deFazio Anna , Chenevix-Trench Georgia , Bowtell David D.L. 
Published: November 2008

Abstract
Approximately, 10% to 15% of serous ovarian tumors fall into the category designated as tumors of low malignant potential (LMP). Like their invasive counterparts, LMP tumors may be associated with extraovarian disease, for example, in the peritoneal cavity and regional lymph nodes. However, unlike typical invasive carcinomas, patients generally have a favorable prognosis. The mutational profile also differs markedly from that seen in most serous carcinomas. Typically, LMP tumors are associated with KRAS and BRAF mutations. Interrogation of expression profiles in serous LMP tumors suggested overall redundancy of RAS-MAPK pathway mutations and a distinct mechanism of oncogenesis compared with high-grade ovarian carcinomas. Our findings indicate that activating mutation of the RAS-MAPK pathway in serous LMP may be present in &gt;70% of cases compared with ∼12.5% in serous ovarian carcinomas. In addition to mutations of KRAS (18%) and BRAF (48%) mutations, ERBB2 mutations (6%), but not EGFR, are prevalent among serous LMP tumors. Based on the expression profile signature observed throughout our serous LMP cohort, we propose that RAS-MAPK pathway activation is a requirement of serous LMP tumor development and that other activators of this pathway are yet to be defined. Importantly, as few nonsurgical options exist for treatment of recurrent LMP tumors, therapeutic targeting of this pathway may prove beneficial, especially in younger patients where maintaining fertility is important. (Mol Cancer Res 2008;6(11):1678–90)
Period 2 Mutation Accelerates ApcMin/+ Tumorigenesis
Authors: Wood Patricia A. , Yang Xiaoming , Taber Andrew , Oh Eun-Young , Ansell Christine , Ayers Stacy E. , Al-Assaad Ziad , Carnevale Kevin , Berger Franklin G. , Peña Maria Marjorette O. , Hrushesky William J.M. 
Published: November 2008

Abstract
Colorectal cancer risk is increased in shift workers with presumed circadian disruption. Intestinal epithelial cell proliferation is gated throughout each day by the circadian clock. Period 2 (Per2) is a key circadian clock gene. Per2 mutant (Per2m/m) mice show an increase in lymphomas and deregulated expression of cyclin D and c-Myc genes that are key to proliferation control. We asked whether Per2 clock gene inactivation would accelerate intestinal and colonic tumorigenesis. The effects of PER2 on cell proliferation and β-catenin were studied in colon cancer cell lines by its down-regulation following RNA interference. The effects of Per2 inactivation in vivo on β-catenin and on intestinal and colonic polyp formation were studied in mice with Per2 mutation alone and in combination with an Apc mutation using polyp-prone ApcMin/+ mice. Down-regulation of PER2 in colon cell lines (HCT116 and SW480) increases β-catenin, cyclin D, and cell proliferation. Down-regulation of β-catenin along with Per2 blocks the increase in cyclin D and cell proliferation. Per2m/m mice develop colonic polyps and show an increase in small intestinal mucosa β-catenin and cyclin D protein levels compared with wild-type mice. ApcMin/+Per2m/m mice develop twice the number of small intestinal and colonic polyps, with more severe anemia and splenomegaly, compared with ApcMin/+ mice. These data suggest that Per2 gene product suppresses tumorigenesis in the small intestine and colon by down-regulation of β-catenin and β-catenin target genes, and this circadian core clock gene may represent a novel target for colorectal cancer prevention and control. (Mol Cancer Res 2008;6(11):1786–93)