bluuebunny/crossref_metadata_2025 huggingface dataset:
Vaccination of Renal Cell Cancer Patients with Modified Vaccinia Ankara Delivering Tumor Antigen 5T4 (TroVax) Administered with Interleukin 2: A Phase II Trial
Authors: Amato Robert J. , Shingler William , Naylor Stuart , Jac Jaroslaw , Willis James , Saxena Somyata , Hernandez-McClain Joan , Harrop Richard
Published: November 2008

Purpose: The attenuated vaccinia virus modified vaccinia ankara (MVA) has been engineered to deliver the tumor antigen 5T4 (TroVax). TroVax has been evaluated in an open-label phase II trial in metastatic renal cell cancer patients in which the vaccine was administered in combination with interleukin-2 (IL-2). The safety, immunologic, and clinical efficacy of TroVax in combination with IL-2 was determined.

Experimental Design: Twenty-five patients with metastatic renal cell cancer were treated with TroVax plus IL-2. 5T4-specific cellular and humoral responses were monitored throughout the study. Clinical responses were assessed by measuring changes in tumor burden by computed tomography or magnetic resonance imaging scan.

Results: TroVax was well tolerated with no serious adverse event attributed to vaccination. Of 25 intention-to-treat patients, 21 mounted 5T4-specific antibody responses. Two patients showed a complete response for >24 months and one a partial response for >12 months. Six patients had disease stabilization from 6 to >21 months. Median progression-free survival (PFS) and overall survival (OS) were >3.37 months (range, 1.50->24.76) and >12.87 months (range, 1.90->24.76), respectively. A statistically significant relationship was detected between the magnitude of 5T4-specific antibody responses and PFS and OS.

Conclusion: TroVax in combination with IL-2 was safe and well tolerated in all patients. The high frequency of 5T4-specific immune responses and good clinical response rate are encouraging and warrant further investigation.
Irinophore C, a Novel Nanoformulation of Irinotecan, Alters Tumor Vascular Function and Enhances the Distribution of 5-Fluorouracil and Doxorubicin
Authors: Baker Jennifer H.E. , Lam Jeffrey , Kyle Alaistair H. , Sy Jonathan , Oliver Thomas , Co Steven J. , Dragowska Wieslawa H. , Ramsay Euan , Anantha Malathi , Ruth Thomas J. , Adam Michael J. , Yung Andrew , Kozlowski Piotr , Minchinton Andrew I. , Ng Sylvia S.W. , Bally Marcel B. , Yapp Donald T.T.
Published: November 2008

Purpose: To examine the antitumor effects of Irinophore C, a nanopharmaceutical formulation of irinotecan, on the tissue morphology and function of tumor vasculature in HT-29 human colorectal tumors.

Experimental Design: Fluorescence microscopy was used to map and quantify changes in tissue density, tumor vasculature, hypoxia, and the distribution of Hoechst 33342, a perfusion marker, and the anticancer drug, doxorubicin. Noninvasive magnetic resonance imaging was used to quantify Ktrans, the volume transfer constant of a solute between the blood vessels and extracellular tissue compartment of the tumor, as a measure of vascular function. Following treatment with Irinophore C, 19F magnetic resonance spectroscopy was used to monitor the delivery of 5-fluorouracil (5-FU) to the tumor tissue, whereas scintigraphy was used to quantify the presence of bound [14C]5-FU.

Results: Irinophore C decreased cell density (P = 8.42 × 10−5), the overall number of endothelial cells in the entire section (P = 0.014), tumor hypoxia (P = 5.32 × 10−9), and Ktrans (P = 0.050). However, treatment increased the ratio of endothelial cells to cell density (P = 0.00024) and the accumulation of Hoechst 33342 (P = 0.022), doxorubicin (P = 0.243 × 10−5), and 5-FU (P = 0.0002) in the tumor. Vascular endothelial growth factor and interleukin-8, two proangiogenic factors, were down-regulated, whereas the antiangiogenic factor TIMP-1 was up-regulated in Irinophore C-treated tumors.

Conclusions: Irinophore C treatment improves the vascular function of the tumor, thereby reducing tumor hypoxia and increasing the delivery and accumulation of a second drug. Reducing hypoxia would enhance radiotherapy, whereas improving delivery of a second drug to the tumor should result in higher cell kill.
Enhanced Antitumor Efficacy of Clinical-Grade Vasculature-Targeted Liposomal Doxorubicin
Authors: Pastorino Fabio , Di Paolo Daniela , Piccardi Federica , Nico Beatrice , Ribatti Domenico , Daga Antonio , Baio Gabriella , Neumaier Carlo E. , Brignole Chiara , Loi Monica , Marimpietri Danilo , Pagnan Gabriella , Cilli Michele , Lepekhin Eugene A. , Garde Seema V. , Longhi Renato , Corti Angelo , Allen Theresa M. , Wu Jinzi J. , Ponzoni Mirco
Published: November 2008

Purpose: In vivo evaluation of good manufacturing practice-grade targeted liposomal doxorubicin (TVT-DOX), bound to a CD13 isoform expressed on the vasculature of solid tumors, in human tumor xenografts of neuroblastoma, ovarian cancer, and lung cancer.

Experimental Design: Mice were implanted with lung, ovarian, or neuroblastoma tumor cells via the pulmonary, peritoneal, or orthotopic (adrenal gland) routes, respectively, and treated, at different days post inoculation, with multiple doses of doxorubicin, administered either free or encapsulated in untargeted liposomes (Caelyx) or in TVT-DOX. The effect of TVT-DOX treatment on tumor cell proliferation, viability, apoptosis, and angiogenesis was studied by immunohistochemical analyses of neoplastic tissues and using the chick embryo chorioallantoic membrane assay.

Results: Compared with the three control groups (no doxorubicin, free doxorubicin, or Caelyx), statistically significant improvements in survival was seen in all three animal models following treatment with 5 mg/kg (maximum tolerated dose) of TVT-DOX, with long-term survivors occurring in the neuroblastoma group; increased survival was also seen at a dose of 1.7 mg/kg in mice bearing neuroblastoma or ovarian cancer. Minimal residual disease after surgical removal of neuroblastoma primary mass, and the enhanced response to TVT-DOX, was visualized and quantified by bioluminescence imaging and with magnetic resonance imaging. When treated with TVT-DOX, compared with Caelyx, all three tumor models, as assayed by immunohistochemistry and chorioallantoic membrane, showed statistically significant reductions in cell proliferation, blood vessel density, and microvessel area, showing increased cell apoptosis.

Conclusion: TVT-DOX should be evaluated as a novel angiostatic strategy for adjuvant therapy of solid tumors.
Tumor Infection by Oncolytic Reovirus Primes Adaptive Antitumor Immunity
Authors: Prestwich Robin J. , Errington Fiona , Ilett Elizabeth J. , Morgan Ruth S.M. , Scott Karen J. , Kottke Timothy , Thompson Jill , Morrison Ewan E. , Harrington Kevin J. , Pandha Hardev S. , Selby Peter J. , Vile Richard G. , Melcher Alan A.
Published: November 2008

Purpose: Early clinical trials are under way exploring the direct oncolytic potential of reovirus. This study addresses whether tumor infection by reovirus is also able to generate bystander, adaptive antitumor immunity.

Experimental Design: Reovirus was delivered intravenously to C57BL/6 mice bearing lymph node metastases from the murine melanoma, B16-tk, with assessment of nodal metastatic clearance, priming of antitumor immunity against the tumor-associated antigen tyrosinase-related protein-2, and cytokine responses. In an in vitro human system, the effect of reovirus infection on the ability of Mel888 melanoma cells to activate and load dendritic cells for cytotoxic lymphocyte (CTL) priming was investigated.

Results: In the murine model, a single intravenous dose of reovirus reduced metastatic lymph node burden and induced antitumor immunity (splenocyte response to tyrosinase-related protein-2 and interleukin-12 production in disaggregated lymph nodes). In vitro human assays revealed that uninfected Mel888 cells failed to induce dendritic cell maturation or support priming of an anti-Mel888 CTL response. In contrast, reovirus-infected Mel888 cells (reo-Mel) matured dendritic cells in a reovirus dose-dependent manner. When cultured with autologous peripheral blood lymphocytes, dendritic cells loaded with reo-Mel induced lymphocyte expansion, IFN-γ production, specific anti-Mel888 cell cytotoxicity, and cross-primed CD8+ T cells specific against the human tumor-associated antigen MART-1.

Conclusion: Reovirus infection of tumor cells reduces metastatic disease burden and primes antitumor immunity. Future clinical trials should be designed to explore both direct cytotoxic and immunotherapeutic effects of reovirus.
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

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

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 >4 ng/mL and Gleason score >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

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

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

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

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

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

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

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

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

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

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 >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

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)
Luteinizing Hormone–Induced Up-Regulation of ErbB-2 Is Insufficient Stimulant of Growth and Invasion in Ovarian Cancer Cells
Authors: Warrenfeltz Susanne W. , Lott Stephen A. , Palmer Travis M. , Gray Judy C. , Puett David
Published: November 2008

The effects of luteinizing hormone (LH), a gonadotropic hormone implicated in the development of ovarian cancer, are mediated by specific binding to its G protein–coupled receptor, the LH receptor (LHR). Activated LHR initiates second messenger responses, including cyclic AMP (cAMP) and inositol phosphate. Because cAMP increases expression of ErbB-2, a receptor tyrosine kinase whose overexpression in cancers correlates with poor survival, we hypothesized that LH may regulate ErbB-2 expression. Cell surface LHR expression in stable transformants of the ErbB-2–overexpressing ovarian cancer cell line SKOV3 was confirmed by PCR and whole-cell ligand binding studies. Second messenger accumulation in the LHR-expressing cells confirmed signaling through Gs and Gq. Western blots of total protein revealed that LHR introduction up-regulated ErbB-2 protein expression 2-fold and this was further up-regulated in a time- and dose-dependent manner in response to LH. Forskolin and 8Br-cAMP also up-regulated ErbB-2 in both LHR-expressing and mock-transfected cells, indicating that regulation of ErbB-2 is a cAMP-mediated event. Kinase inhibitor studies indicated the involvement of protein kinase A–mediated, protein kinase C–mediated, epidermal growth factor receptor–mediated, and ErbB-2–mediated mechanisms. The LH-induced up-regulation of ErbB-2 was insufficient to overcome the negative effects of LH on proliferation, invasion, and migration. A molecular signature for this nonaggressive phenotype was determined by Taqman array to include increased and decreased expression of genes encoding adhesion proteins and metalloproteinases, respectively. These data establish a role for LH and LHR in the regulation of ErbB-2 expression and suggest that, in some systems, ErbB-2 up-regulation alone is insufficient in producing a more aggressive phenotype. (Mol Cancer Res 2008;6(11):1775–85)
The Emerging Role of Magnetic Resonance Imaging in the Diagnosis and Management of Pulmonary Hypertension
Authors: Kovacs Gabor , Reiter Gert , Reiter Ursula , Rienmüller Rainer , Peacock Andrew , Olschewski Horst
Published: November 2008

Pulmonary hypertension is a life-threatening chronic disorder of the pulmonary circulation. Elevated pressure and resistance in the pulmonary vessels lead to progressive right heart failure which results in functional limitations and ultimately the death of most patients. Thus, the monitoring of right ventricular (RV) function is of great importance. Cardiac magnetic resonance imaging (cardiac MRI) has several advantages over other imaging methods. The use of cine acquisition techniques allows precise description of characteristic volumetric and functional variables, such as right ventricular volumes, muscle mass, stroke volume, ejection fraction, or cardiac output. Impaired right ventricular contractility and function have also been assessed using measures like ventricular septal bowing and pressure-volume loops. MRI investigations have been performed to monitor medical treatment, and the improvement in well-established prognostic factors, such as the 6-min walk, were correlated with measures of right ventricular function. Flow-derived parameters of the pulmonary arteries (such as peak velocity, acceleration time and volume, or pulmonary flow profile) are available using velocity-encoded imaging, and may detect early signs of remodelling. Additionally, magnetic resonance angiography is a promising new tool to visualise pulmonary perfusion and to diagnose chronic thromboembolic pulmonary hypertension. The purpose of this review is to summarise recent advances of cardiovascular magnetic resonance imaging, which will play an increasing role in the comprehensive diagnostic work-up of patients with pulmonary hypertension as a tool to monitor the course of the disease and to evaluate new therapeutic approaches.
Tuberculous Duodenal Stenosis: Report of Two Cases
Authors: Benzekri O. , El Mouhadi S. , Chourak M. , Boussetta S. , El Absi M. , Echarab M. , Elouanani M. , Amraoui M. , Errougani A. , El Alami F.H. , Chkoff R.
Published: November 2008

Duodenal tuberculosis is a rare clinical entity. The authors report and emphasize the lack of special clinical, radiological and endoscopic signs of duodenal tuberculosis. The diagnosis is affirmed, at laparotomy, out of the findings of peritoneal granulations or histology of lymphatic nodes. We report our experience of two cases of duodenal tuberculosis presenting with proximal intestinal obstruction and review the available literature.
Celiac Disease and Myointimal Proliferation: A Possible Correlation?
Authors: Merra Giuseppe , Dal Lago Antonio , Roccarina Davide , Gasbarrini Giovanni , Gasbarrini Antonio , Ghirlanda Giovanni
Published: November 2008

Celiac disease (CD) is an autoimmune disorder of the small bowel that occurs in genetically predisposed people of all ages, from middle infancy, and is caused by a reaction to gliadin, a gluten protein. Some patients are diagnosed with symptoms related to the decreased absorption of nutrients or with various symptoms which, although statistically linked, have no clear relationship with the malfunctioning bowel. Classic symptoms of CD include diarrhea, weight loss, and fatigue; bowel symptoms may be limited or even absent. In this article we describe the case of a young woman with CD who presents with myointimal proliferation. However multiple cases of vessel thrombosis have been reported in patients with CD. Despite the fact that no definitive relationship between these diseases could be explained, we think this association must be remembered especially in cases of young and tenuous women with these vascular abnormalities.
Primary Aorto-Duodenal Fistula as a Late Complication of Radiotherapy: Report of a Case and Review of the Literature
Authors: Puccio Francesco , Pandolfo Gianpiero , Chiodini Stefano , Benzi Fabrizia , Solazzo Massimiliano
Published: November 2008

Primary aorto-duodenal fistula (PADF) is a rare condition that may result in rapid exsanguination if untreated. PADF due to radiotherapy appears to be extremely rare with only a few cases reported in the medical literature. We report the case of a 61-year-old man who presented with massive gastrointestinal bleeding 25 years after surgery and radiotherapy for seminoma of the testicle and was successfully treated at our institution. We also review the literature on this very uncommon condition. A Medline search was conducted for the period from 1966 to June 2006 to identify case reports of PADF following radiotherapy. Only 7 cases of PADF due to radiotherapy were identified in addition to our own, 4 males and 3 females, aged 40 to 73 years, all treated for various forms of abdominal malignancies. The latency period ranged from 2 weeks to 25 years. None of the aortas were aneurysmatic. One patient died before he could be taken to the operating room. 5 patients underwent surgical repair and 4 survived. 2 patients underwent endovascular treatment but did not survive. PADF may develop up to 25 years after radiotherapy. Diagnosis should be considered when massive upper gastrointestinal bleeding develops in a patient who had previous abdominal radiotherapy, no matter how long before the episode of bleeding. Prompt surgical repair offers a reasonable chance of cure. Endovascular procedures do not appear to be efficacious.
Mirror Syndrome Associated with Hydropic Acardius in Triplet Pregnancy
Authors: Matsubara Shigeki , Ohmaru Takako , Ohkuchi Akihide , Arai Fujimi , Kuwata Tomoyuki , Usui Rie , Takahashi Kayo , Izumi Akio , Watanabe Takashi , Suzuki Mitsuaki
Published: November 2008

Objectives: Mirror syndrome is the association of triple edema, i.e. fetal, placental and maternal edema, with maternal preeclampsia. We here report the first case of mirror syndrome resulting from hydropic acardius in triplet pregnancy. Methods/Results: A 26-year-old nulliparous woman spontaneously conceived two living fetuses and one acardius, and suffered preterm rupture of the membranes at 23 2/7 weeks of gestation. We observed triple edema, hydropic acardius, placental edema, and maternal edema, together with maternal high blood pressure, proteinuria and low hematocrit, and therefore suspected the presence of mirror syndrome. Due to the prematurity of the fetuses, we closely observed her, awaiting fetal maturity. Three days later (23 5/7 weeks), cord prolapse occurred, leading to emergent cesarean section. Female infants, weighing 492 and 554 g, respectively, were born alive; the former died on the 13th postnatal day and the latter was healthy with no sequelae. An acardius weighing 860 g had vascular communication with the 492-gram fetus. Histological examination confirmed a monochorionic, triamniotic single placenta. The mother suffered from pulmonary edema and was treated in the intensive care unit under respiratory support, but soon improved. Conclusions: When dealing with multifetal pregnancy, especially when complicated by an acardius, obstetricians must have the highest level of concern for the occurrence of mirror syndrome, a life-threatening condition both to the mother and the fetus.
Higher Implantation Rate Using Modified Quarter Laser-Assisted Zona Thinning in Repeated Implantation Failure
Authors: Debrock Sophie , Spiessens Carl , Peeraer Karen , De Loecker Peter , Willemen Dorien , D'Hooghe Thomas M.
Published: November 2008

Background/Aims: Some embryo implantation problems in patients with recurrent implantation failure may be explained by the inability of the embryo to hatch out of its zona pellucida. In this case-control study, a study group which had received modified quarter laser-assisted zona thinning (mQLAZT) was compared with a control group which had not received mQLAZT with respect to reproductive outcome. Methods: Cycles from patients with a 4th fresh embryo transfer (ET) after 3 previously failed ET cycles (no β-hCG detected) were included. Cases (group A, n = 53) included ET cycles from patients who received a 4th ET with fresh embryos after mQLAZT. Controls (group B, n = 86) included ET cycles from patients who had a 4th ET without mQLAZT. The clinical implantation rate and live birth rate per embryo transferred were measured. Results: The clinical implantation rate with positive fetal heart beat per embryo transferred was significantly higher (p = 0.035) in group A (22/107 or 21%) than in group B (18/166 or 11%). Conclusion: The data of this case-control study suggest that mQLAZT can be effective in the treatment of patients with recurrent implantation failure, but need to be confirmed by randomized trials.
Clinical Reinfarction according to Infarct Location and Reperfusion Modality in Patients with ST Elevation Myocardial Infarction
Authors: Busk Martin , Kristensen Steen D. , Rasmussen Klaus , Kelbaek Henning , Thayssen Per , Madsen Jan K. , Abildgaard Ulrik , Krusell Lars R. , Mortensen Leif S. , Thuesen Leif , Andersen Henning R. , Nielsen Torsten T.
Published: November 2008

Objectives: To evaluate clinical reinfarction during a 3-year follow-up after randomization to primary angioplasty versus fibrinolysis in anterior and non-anterior ST elevation myocardial infarction (STEMI). Methods: Clinical reinfarction was prospectively assessed by an endpoint committee blinded to the study treatment. Results: At 30 days, primary angioplasty compared with fibrinolysis reduced the reinfarction rate both in anterior STEMI patients (n = 823; 2.5 vs. 5.6%, p = 0.02) and in non-anterior STEMI patients (n = 743; 0.8 vs. 7.4%, p < 0.001). After 3 years, the reduction in reinfarction rate was no longer present in anterior STEMI patients (11.2 vs. 11.2%, p = 0.86), but persisted in non-anterior STEMI patients (5.2 vs. 13.5%, p < 0.001). Reinfarction after anterior STEMI carried a higher mortality than reinfarction after non-anterior STEMI (37.6 vs. 15.3%, p = 0.01). Independent predictors of death were: age [hazard ratio (HR) per 1-year increase in age = 1.08 (1.07–1.09)], clinical reinfarction [HR = 5.15 (3.57–7.43)], anterior index STEMI [HR = 1.65 (1.24–2.19)], and Killip class ≥2 [HR = 1.42 (1.01–2.00)]. The additional late reinfarctions after angioplasty for anterior STEMI were located within the angioplasty-treated target segment. Anterior STEMI patients had smaller mean target vessel diameter, which was associated with reinfarction. Conclusions: Clinical reinfarction is an independent predictor of death. The early superiority of primary angioplasty over fibrinolysis on reinfarction rate after anterior STEMI diminished during long-term follow-up.
The Effects of Nitric Oxide Donor Molsidomine on Skeletal Muscle Damage in a Rat Hind Limb Model of Ischemia-Reperfusion
Authors: Öztürk K. , Ozyurt H. , Somay A. , Karaca C.
Published: November 2008

Background: In this experimental study, we aimed to examine the protective effect of molsidomine (MS), a nitric oxide (NO) donor, against ischemia-reperfusion (I-R) injury in a rat skeletal muscle model. Methods: Ischemia was achieved by application of an elastic rubber band as high as possible on the left thigh of the rats. Group 1: the control group received a sham operation. Group 2: the I-R group received I-R injury to the left hind limbs. Group 3: the I-R/MS group underwent the same model of I-R injury and received MS. Group 4: the I-R/L-NAME (N-ω-nitro-L-arginine-methyl ester) group underwent the same model of I-R injury and received L-NAME, an inhibitor of NO synthase. Results: In groups 2 and 4, malondialdehyde increased significantly when compared to groups 1 and 3. Superoxide dismutase, catalase and glutathione peroxidase increased significantly in group 3 compared to groups 2 and 4. The NO levels were significantly elevated in group 3 compared to groups 2 and 4. In addition, the histopathological score was considerably lower in group 3 than in group 4. The number of necrotic muscle fibers and infiltration of neutrophils were significantly reduced in the MS-treated group. Conclusions: These findings suggest that MS can exert a protective effect against skeletal muscle injury caused by I-R in the rats.
Word Recognition following Implantation of Conventional and 10-mm Hybrid Electrodes
Authors: Dorman Michael F. , Gifford Rene , Lewis Kristen , McKarns Sharon , Ratigan Jennifer , Spahr Anthony , Shallop Jon K. , Driscoll Colin L.W. , Luetje Charles , Thedinger Bradley S. , Beatty Charles W. , Syms Mark , Novak Mike , Barrs David , Cowdrey Lisa , Black Jennifer , Loiselle Louise
Published: November 2008

We compared the effectiveness of 2 surgical interventions for improving word recognition ability in a quiet environment among patients who presented with: (1) bilateral, precipitously sloping, high-frequency hearing loss; (2) relatively good auditory thresholds at and below 500 Hz, and (3) poor speech recognition. In 1 intervention (n = 25), a conventional electrode array was inserted into 1 cochlea. As a consequence, hearing was lost in the implanted ear. In the other intervention (n = 22), a Nucleus Hybrid short-electrode array was inserted 10 mm into 1 cochlea with the aim of preserving hearing in that ear. Both groups of patients had similar low-frequency hearing and speech understanding in the ear contralateral to the implant. Following surgery, both groups had significantly higher word recognition scores than before surgery. Between-group comparisons indicated that the conventional electrode array group had higher word recognition scores than the 10-mm group when stimulation was presented to the operated ear and when stimulation was presented to both ears.