bluuebunny/crossref_metadata_2025 huggingface dataset:
Attenuated Salmonella Targets Prodrug Activating Enzyme Carboxypeptidase G2 to Mouse Melanoma and Human Breast and Colon Carcinomas for Effective Suicide Gene Therapy
Authors: Friedlos Frank , Lehouritis Panos , Ogilvie Lesley , Hedley Douglas , Davies Lawrence , Bermudes David , King Ivan , Martin Jan , Marais Richard , Springer Caroline J.
Published: July 2008

Purpose: We engineered the oncolytic Salmonella typhimurium–derived bacterium VNP20009 as a vector to target delivery to tumors of the prodrug-activating enzyme carboxypeptidase G2 (CPG2) and to show enhanced antitumor efficacy on administration of different prodrugs.

Experimental Design: We characterized CPG2 expression in vectors by immunoblotting, immunofluorescence, and enzyme activity. We assessed prodrug activation by high-performance liquid chromatography. Target human tumor cell and bacterial vector cell cytotoxicity was measured by flow cytometry and colony-forming assays. Therapy was shown in two human tumor xenografts and one mouse allograft with postmortem analysis of bacterial and CPG2 concentration in the tumors.

Results: CPG2 is expressed within the bacterial periplasm. It activates prodrugs and induces cytotoxicity in human tumor cells but not in host bacteria. Following systemic administration, bacteria multiply within xenografts reaching 2 × 107/g to 2 × 108/g at 40 days postinoculation. The concentration of CPG2 in these tumors increases steadily to therapeutic levels of 1 to 6 units/g. The bacteria alone reduce the growth of the tumors. Subsequent administration of prodrugs further reduces significantly the growth of the xenografts.

Conclusions: The bacteria multiply within tumors, resulting in a selective expression of CPG2. The CPG2-expressing bacteria alone reduce the growth of tumors. However, in the presence of prodrugs activated by CPG2, this oncolytic effect is greatly increased. We conclude that bacterial oncolytic therapy, combined with CPG2-mediated prodrug activation, has great potential in the treatment of a range of cancers.
Patients with ERCC1-Negative Locally Advanced Esophageal Cancers May Benefit from Preoperative Chemoradiotherapy
Authors: Kim Min Kyoung , Cho Kyung-Ja , Kwon Gui Young , Park Seung-Il , Kim Yong Hee , Kim Jong Hoon , Song Ho-Young , Shin Ji Hoon , Jung Hwoon Yong , Lee Gin Hyug , Choi Kee Don , Kim Sung-Bae
Published: July 2008

Purpose: To assess the significance of excision repair cross-complementation group 1 (ERCC1) expression as a predictive marker, we analyzed the effects of preoperative chemoradiotherapy on survival relative to ERCC1 status in patients with locally advanced operable esophageal cancer.

Experimental Design: Paraffin-embedded pretreatment tumor specimens, collected by endoscopic biopsy from patients treated with surgery alone or with preoperative chemoradiotherapy followed by surgery, were immunohistochemically assayed for ERCC1 expression.

Results: Of the 175 patients, 152 biopsy specimens were available for immunohistochemical analysis. Based on a median ERCC1 expression score of 1, we divided the samples into ERCC1-positive (score >1; 71 patients, 47%) and ERCC1-negative (score ≤1; 81 patients, 53%) groups. No differences in patient and disease characteristics were observed between the two groups. However, among patients with ERCC1-negative tumors, those who received preoperative chemoradiotherapy had longer overall survival (OS) and event-free survival (EFS) than those treated with esophagectomy alone (median OS, 59.2 versus 25.4 months, P = 0.057; median EFS, 50.7 versus 19.7 months, P = 0.042). This difference was not observed among patients with ERCC1-positive tumors. In multivariate analysis, treatment modality was the major determinant of both EFS (P = 0.006) and OS (P = 0.008) for patients with ERCC1-negative tumors, whereas Eastern Cooperative Oncology Group performance status was the only significant predictor of outcome among ERCC1-positive patients. Among patients who received esophagectomy alone, those with ERCC1-positive tumors had a tendency toward longer OS and EFS (P = 0.085 and 0.094, respectively).

Conclusions: Patients with ERCC1-negative operable esophageal tumors show a greater benefit from preoperative chemoradiotherapy followed by esophagectomy than those who undergo esophagectomy alone.
Combined Inhibition of PLCγ-1 and c-Src Abrogates Epidermal Growth Factor Receptor–Mediated Head and Neck Squamous Cell Carcinoma Invasion
Authors: Nozawa Hiroshi , Howell Gina , Suzuki Shinsuke , Zhang Qing , Qi Yanjun , Klein-Seetharaman Judith , Wells Alan , Grandis Jennifer R. , Thomas Sufi M.
Published: July 2008

Purpose: Mortality from head and neck squamous cell carcinoma (HNSCC) is usually associated with locoregional invasion of the tumor into vital organs, including the airway. Understanding the signaling mechanisms that abrogate HNSCC invasion may reveal novel therapeutic targets for intervention. The purpose of this study was to investigate the efficacy of combined inhibition of c-Src and PLCγ-1 in the abrogation of HNSCC invasion.

Experimental Design: PLCγ-1 and c-Src inhibition was achieved by a combination of small molecule inhibitors and dominant negative approaches. The effect of inhibition of PLCγ-1 and c-Src on invasion of HNSCC cells was assessed in an in vitro Matrigel-coated transwell invasion assay. In addition, the immunoprecipitation reactions and in silico database mining was used to examine the interactions between PLCγ-1 and c-Src.

Results: Here, we show that inhibition of PLCγ-1 or c-Src with the PLC inhibitor U73122 or the Src family inhibitor AZD0530 or using dominant-negative constructs attenuated epidermal growth factor (EGF)–stimulated HNSCC invasion. Furthermore, EGF stimulation increased the association between PLCγ-1 and c-Src in HNSCC cells. Combined inhibition of PLCγ-1 and c-Src resulted in further attenuation of HNSCC cell invasion in vitro.

Conclusions: These cumulative results suggest that PLCγ-1 and c-Src activation contribute to HNSCC invasion downstream of EGF receptor and that targeting these pathways may be a novel strategy to prevent tumor invasion in HNSCC.
Isopentenyl Pyrophosphate–Activated CD56+ γδ T Lymphocytes Display Potent Antitumor Activity toward Human Squamous Cell Carcinoma
Authors: Alexander Alan A.Z. , Maniar Amudhan , Cummings Jean-Saville , Hebbeler Andrew M. , Schulze Dan H. , Gastman Brian R. , Pauza C. David , Strome Scott E. , Chapoval Andrei I.
Published: July 2008

Purpose: The expression of CD56, a natural killer cell–associated molecule, on αβ T lymphocytes correlates with their increased antitumor effector function. CD56 is also expressed on a subset of γδ T cells. However, antitumor effector functions of CD56+ γδ T cells are poorly characterized.

Experimental Design: To investigate the potential effector role of CD56+ γδ T cells in tumor killing, we used isopentenyl pyrophosphate and interleukin-2–expanded γδ T cells from peripheral blood mononuclear cells of healthy donors.

Results: Thirty to 70% of expanded γδ T cells express CD56 on their surface. Interestingly, although both CD56+ and CD56− γδ T cells express comparable levels of receptors involved in the regulation of γδ T-cell cytotoxicity (e.g., NKG2D and CD94), only CD56+ γδ T lymphocytes are capable of killing squamous cell carcinoma and other solid tumor cell lines. This effect is likely mediated by the enhanced release of cytolytic granules because CD56+ γδ T lymphocytes expressed higher levels of CD107a compared with CD56− controls following exposure to tumor cell lines. Lysis of tumor cell lines is blocked by concanamycin A and a combination of anti-γδ T-cell receptor + anti-NKG2D monoclonal antibody, suggesting that the lytic activity of CD56+ γδ T cells involves the perforin-granzyme pathway and is mainly γδ T-cell receptor/NKG2D dependent. Importantly, CD56-expressing γδ T lymphocytes are resistant to Fas ligand and chemically induced apoptosis.

Conclusions: Our data indicate that CD56+ γδ T cells are potent antitumor effectors capable of killing squamous cell carcinoma and may play an important therapeutic role in patients with head and neck cancer and other malignancies.
Overexpression of Jab1 in Hepatocellular Carcinoma and Its Inhibition by Peroxisome Proliferator-Activated Receptorγ Ligands In vitro and In vivo
Authors: Hsu Ming-Chuan , Huang Chao-Cheng , Chang Hui-Chiu , Hu Tsung-Hui , Hung Wen-Chun
Published: July 2008

Purpose: Jun activation domain-binding protein 1 (Jab1) is the fifth subunit of the COP9 signalosome and exhibits oncogenic activity. We investigated Jab1 expression in hepatocellular carcinoma (HCC) tissues and cell lines and tested the effect of peroxisome proliferator-activated receptor γ (PPARγ) ligands on Jab1 expression.

Experimental Design: Jab1 expression in HCC tissues and cell lines was studied by real-time reverse transcription-PCR, immunohistochemical staining, and Western blotting. Promoter activity and chromatin immunoprecipitation assays were done to address the inhibition of Jab1 promoter by PPARγ ligands. RNA interference was used to clarify PPARγ ligand-induced inhibition of Jab1. Anticancer and Jab1-suppressing activity of PPARγ ligands was tested in nude mice.

Results: Jab1 was detected in the nucleus and cytoplasm of HCC tissues and 37% (37 of 99) of tissues exhibited Jab1 overexpression. Jab1 expression correlated with sex and hepatitis C virus infection, whereas it was negatively associated with hepatitis B virus infection. Additionally, Jab1 was overexpressed in HCC cell lines. PPARγ ligands troglitazone and rosiglitazone down-regulated Jab1 expression in HCC cells, and troglitazone directly suppressed Jab1 promoter activity by inhibiting Sp1- and Tcf4-mediated transcription. This suppression was mediated via both PPARγ-dependent and PPARγ-independent mechanisms. Ectopic expression of Jab1 counteracted troglitazone-induced growth inhibition. Animal studies verified that intratumor or i.p. injection of troglitazone attenuated HCC growth and reduced Jab1 expression in tumor tissues.

Conclusions: Our results indicate that Jab1 is overexpressed in HCC and PPARγ ligands may suppress Jab1 to inhibit the proliferation of HCC cells.
Efficacy and Safety of Two Doses of Pemetrexed Supplemented with Folic Acid and Vitamin B12 in Previously Treated Patients with Non-Small Cell Lung Cancer
Authors: Ohe Yuichiro , Ichinose Yukito , Nakagawa Kazuhiko , Tamura Tomohide , Kubota Kaoru , Yamamoto Nobuyuki , Adachi Susumu , Nambu Yoshihiro , Fujimoto Toshio , Nishiwaki Yutaka , Saijo Nagahiro , Fukuoka Masahiro
Published: July 2008

Purpose: The objective of this study was to evaluate the efficacy and safety of two doses of pemetrexed supplemented with folic acid and vitamin B12 in pretreated Japanese patients with advanced non-small cell lung cancer (NSCLC).

Experimental Design: Patients with an Eastern Cooperative Oncology Group performance status 0 to 2, stage III or IV, and who received previously one or two chemotherapy regimens were randomized to receive 500 mg/m2 pemetrexed (P500) or 1,000 mg/m2 pemetrexed (P1000) on day 1 every 3 weeks. The primary endpoint was response rate.

Results: Of the 216 patients evaluable for efficacy (108 in each arm), response rates were 18.5% (90% confidence interval, 12.6-25.8%) and 14.8% (90% confidence interval, 9.5-21.6%), median survival times were 16.0 and 12.6 months, 1-year survival rates were 59.2% and 53.7%, and median progression-free survival were 3.0 and 2.5 months for the P500 and P1000, respectively. Cox multiple regression analysis indicated that pemetrexed dose was not a significant prognostic factor. Drug-related toxicity was generally tolerable for both doses; however, the safety profile of P500 showed generally milder toxicity. Main adverse drug reactions of severity grade 3 or 4 were neutrophil count decreased (20.2%) and alanine aminotransferase (glutamine pyruvic transaminase) increased (15.8%) in P500 and neutrophil count decreased (24.3%), WBC count decreased (20.7%), and lymphocyte count decreased (18.0%) in P1000. One drug-related death from interstitial lung disease occurred in the P500.

Conclusion: P500 and P1000 are similarly active with promising efficacy and acceptable safety outcomes in pretreated patients with NSCLC. These results support the use of P500 as a second- and third-line treatment of NSCLC.
Proapoptotic Bad and Bid Protein Expression Predict Survival in Stages II and III Colon Cancers
Authors: Sinicrope Frank A. , Rego Rafaela L. , Foster Nathan R. , Thibodeau Stephen N. , Alberts Steven R. , Windschitl Harold E. , Sargent Daniel J.
Published: July 2008

Purpose: Proapoptotic BH3-only proteins Bad and Bid initiate apoptosis by binding to regulatory sites on prosurvival Bcl-2 proteins to directly neutralize their function. We determined if expression of these proteins in colon cancers may account for differences in patient survival.

Experimental Design: Tumor-node-metastasis stages II and III primary colon carcinomas from patients treated in 5-fluorouracil-based adjuvant therapy trials were studied. Immunohistochemical analysis of Bad and Bid proteins was done in tumors (n = 379) and adjacent normal mucosa. Expression was correlated with clinicopathologic variables, disease-free survival rates (DFS), and overall survival (OS) rates.

Results: High expression of the Bad protein [hazard ratio (HR), 0.64; 95% confidence interval (95% CI), 0.43-0.96; P = 0.031] in the cytoplasm of tumor cells was significantly associated with more favorable OS in a univariate analysis. The combined Bad and Bid variable was prognostic for DFS (P = 0.027) and OS (P = 0.006). Stage and histologic grade, but not DNA mismatch repair status, were also prognostic for OS. Multivariate Cox analysis showed that high expression of Bad (HR, 0.64; 95% CI, 0.43-0.97; P = 0.027) and Bid (HR, 0.68; 95% CI, 0.49-0.97; P = 0.034) were independent predictors of OS after adjustment for stage, grade, age, treatment, and study. The combined variable of Bad + Bid was independently associated with DFS (P = 0.020) and OS (P = 0.004).

Conclusion: Proapoptotic Bad and Bid proteins are independent prognostic variables in colon cancer patients receiving adjuvant treatment. If validated, Bad and Bid expression may assist in risk stratification and selection of patients to receive adjuvant chemotherapy.
Immunity Feedback and Clinical Outcome in Colon Cancer Patients Undergoing Chemoimmunotherapy with Gemcitabine + FOLFOX followed by Subcutaneous Granulocyte Macrophage Colony-Stimulating Factor and Aldesleukin (GOLFIG-1 Trial)
Authors: Correale Pierpaolo , Tagliaferri Pierosandro , Fioravanti Antonella , Del Vecchio Maria Teresa , Remondo Cinzia , Montagnani Francesco , Rotundo Maria Saveria , Ginanneschi Chiara , Martellucci Ignazio , Francini Edoardo , Cusi Maria Grazia , Tassone Pierfrancesco , Francini Guido
Published: July 2008

Purpose: GOLFIG chemoimmunotherapy regimen proved to be a safe and very active chemoimmunotherapy regimen in advanced colon cancer patients. We have thus investigated the immunobiological feedback to the treatment and its possible correlation with the clinical outcome of these patients.

Experimental Design: This clinical and immunologic study involved 46 patients, 27 males and 19 females, enrolled in the GOLFIG-1 phase II trial who received gemcitabine (1,000 mg/m2 on days 1 and 15), oxaliplatin (85 mg/m2 on days 2 and 16), levofolinic acid (100 mg/m2 on days 1, 2, 15, and 16), and 5-fluorouracil (400 mg/m2 as a bolus, and 800 mg/m2 as a 24-hour infusion on days 1, 2, 15, and 16) followed by s.c. granulocyte macrophage colony-stimulating factor (100 μg, on days 3-7) and interleukin 2 (0.5 × 106 IU twice a day on days 8-14 and 17-29).

Results: The regimen was confirmed to be safe and very active in pretreated patients with metastatic colorectal cancer. A subgroup analysis of these patients revealed a prolonged time to progression and survival in six patients who developed late signs of autoimmunity. A multivariate analysis validated the occurrence of autoimmunity signs as an independent predictor of favorable outcome. A parallel immunologic study detected in the peripheral blood mononuclear cells of these patients a progressive increase in lymphocyte and eosinophil counts, amplification in central memory, a marked depletion of immunosuppressive regulatory T cells, and activation of colon cancer–specific cytotoxic T cells.

Conclusions: Our results suggest that immunity feedback to GOLFIG regimen and its antitumor activity are tightly correlated.
Early Magnesium Reduction in Advanced Colorectal Cancer Patients Treated with Cetuximab Plus Irinotecan as Predictive Factor of Efficacy and Outcome
Authors: Vincenzi Bruno , Santini Daniele , Galluzzo Sara , Russo Antonio , Fulfaro Fabio , Silletta Marianna , Battistoni Fabrizio , Rocci Laura , Zobel Bruno Beomonte , Adamo Vincenzo , Dicuonzo Giordano , Tonini Giuseppe
Published: July 2008

Introduction: Magnesium plays a role in a large number of cellular metabolic reactions. Cetuximab is able to induce hypomagnesemia by interfering with magnesium (Mg2+) transport in the kidney. We designed this trial to investigate if Mg2+ serum level modifications may be related with clinical response and outcome in advanced colorectal cancer patients during treatment with cetuximab plus irinotecan.

Experimental Design: Sixty-eight heavily pretreated metastatic colorectal cancer patients were evaluated for Mg2+ serum levels at the following time points: before; 6 hours; and 1, 7, 14, 21, 50, and 92 days after the start of treatment.

Results: Basal Mg2+ median levels were significantly decreased just 7 days after the first anticancer infusion and progressively decreased from the 7th day onward, reaching the highest significance at the last time point (P < 0.0001). Twenty-five patients showed a reduction in median Mg2+ circulating levels of at least 20% within the 3rd week after the first infusion. Patients with this reduction showed a response rate of 64.0% versus 25.6% in the nonreduced Mg2+ group. The median time to progression was 6.0 versus 3.6 months in the reduced Mg2+ group and in that without reduction, respectively (P < 0.0001). Overall survival was longer in patients with Mg2+ reduction than in those without (10.7 versus 8.9 months).

Conclusions: Our results confirm that cetuximab treatment may induce a reduction of Mg2+ circulating levels and offer the first evidence that Mg2+ reduction may represent a new predictive factor of efficacy in advanced colorectal cancer patients treated with cetuximab plus irinotecan.
Mutations in the Nijmegen Breakage Syndrome Gene in Medulloblastomas
Authors: Huang Jian , Grotzer Michael A. , Watanabe Takuya , Hewer Ekkehard , Pietsch Torsten , Rutkowski Stefan , Ohgaki Hiroko
Published: July 2008

Purpose: Cerebellar medulloblastoma is a highly malignant, invasive embryonal tumor with preferential manifestation in children. Nijmegen breakage syndrome (NBS) with NBS1 germ-line mutations is a rare autosomal recessive disease with clinical features that include microcephaly, mental and growth retardation, immunodeficiency, increased radiosensitivity, and predisposition to cancer. There may be functional interactions between NBS1 and the TP53 pathways. The objective of the present study is to assess whether NBS1 mutations play a role in the pathogenesis of sporadic medulloblastomas.

Experimental Design: Forty-two cases of medulloblastomas were screened for mutations in the NBS1 gene (all 16 exons) and the TP53 gene (exons 5-8) by single-stranded conformational polymorphism followed by direct DNA sequencing.

Results: Seven of 42 (17%) medulloblastomas carried a total of 15 NBS1 mutations. Of these, 10 were missense point mutations and 5 were intronic splicing mutations. None of these were reported previously as germ-line mutations in NBS patients. No NBS1 mutations were detected in peritumoral brain tissues available in two patients. Of 5 medulloblastomas with TP53 mutations, 4 (80%) contained NBS1 mutations, and there was a significant association between TP53 mutations and NBS1 mutations (P = 0.001).

Conclusions: We provide evidence of medulloblastomas characterized by NBS1 mutations typically associated with mutational inactivation of the TP53 gene.
Honokiol Suppresses Survival Signals Mediated by Ras-Dependent Phospholipase D Activity in Human Cancer Cells
Authors: Garcia Avalon , Zheng Yang , Zhao Chen , Toschi Alfredo , Fan Judy , Shraibman Natalie , Brown H. Alex , Bar-Sagi Dafna , Foster David A. , Arbiser Jack L.
Published: July 2008

Purpose: Elevated phospholipase D (PLD) activity provides a survival signal in several human cancer cell lines and suppresses apoptosis when cells are subjected to the stress of serum withdrawal. Thus, targeting PLD survival signals has potential to suppress survival in cancer cells that depend on PLD for survival. Honokiol is a compound that suppresses tumor growth in mouse models. The purpose of this study was to investigate the effect of honokiol on PLD survival signals and the Ras dependence of these signals.

Experimental Design: The effect of honokiol upon PLD activity was examined in human cancer cell lines where PLD activity provides a survival signal. The dependence of PLD survival signals on Ras was investigated, as was the effect of honokiol on Ras activation.

Results: We report here that honokiol suppresses PLD activity in human cancer cells where PLD has been shown to suppress apoptosis. PLD activity is commonly elevated in response to the stress of serum withdrawal, and, importantly, the stress-induced increase in PLD activity is selectively suppressed by honokiol. The stress-induced increase in PLD activity was accompanied by increased Ras activation, and the stress-induced increase in PLD activity in MDA-MB-231 breast cancer cells was dependent on a Ras. The PLD activity was also dependent on the GTPases RalA and ADP ribosylation factor. Importantly, honokiol suppressed Ras activation.

Conclusion: The data provided here indicate that honokiol may be a valuable therapeutic reagent for targeting a large number of human cancers that depend on Ras and PLD for their survival.
EML4-ALKFusion Gene and Efficacy of an ALK Kinase Inhibitor in Lung Cancer
Authors: Koivunen Jussi P. , Mermel Craig , Zejnullahu Kreshnik , Murphy Carly , Lifshits Eugene , Holmes Alison J. , Choi Hwan Geun , Kim Jhingook , Chiang Derek , Thomas Roman , Lee Jinseon , Richards William G. , Sugarbaker David J. , Ducko Christopher , Lindeman Neal , Marcoux J. Paul , Engelman Jeffrey A. , Gray Nathanael S. , Lee Charles , Meyerson Matthew , Jänne Pasi A.
Published: July 2008

Purpose: The EML4-ALK fusion gene has been detected in ∼7% of Japanese non-small cell lung cancers (NSCLC). We determined the frequency of EML4-ALK in Caucasian NSCLC and in NSCLC cell lines. We also determined whether TAE684, a specific ALK kinase inhibitor, would inhibit the growth of EML4-ALK-containing cell lines in vitro and in vivo.

Experimental Design: We screened 305 primary NSCLC [both U.S. (n = 138) and Korean (n = 167) patients] and 83 NSCLC cell lines using reverse transcription-PCR and by exon array analyses. We evaluated the efficacy of TAE684 against NSCLC cell lines in vitro and in vivo.

Results: We detected four different variants, including two novel variants, of EML4-ALK using reverse transcription-PCR in 8 of 305 tumors (3%) and 3 of 83 (3.6%) NSCLC cell lines. All EML4-ALK-containing tumors and cell lines were adenocarcinomas. EML4-ALK was detected more frequently in NSCLC patients who were never or light (<10 pack-years) cigarette smokers compared with current/former smokers (6% versus 1%; P = 0.049). TAE684 inhibited the growth of one of three (H3122) EML4-ALK-containing cell lines in vitro and in vivo, inhibited Akt phosphorylation, and caused apoptosis. In another EML4-ALK cell line, DFCI032, TAE684 was ineffective due to coactivation of epidermal growth factor receptor and ERBB2. The combination of TAE684 and CL-387,785 (epidermal growth factor receptor/ERBB2 kinase inhibitor) inhibited growth and Akt phosphorylation and led to apoptosis in the DFCI032 cell line.

Conclusions: EML4-ALK is found in the minority of NSCLC. ALK kinase inhibitors alone or in combination may nevertheless be clinically effective treatments for NSCLC patients whose tumors contain EML4-ALK.
Persistent Aberrations in Circulating DNA Integrity after Radiotherapy Are Associated with Poor Prognosis in Nasopharyngeal Carcinoma Patients
Authors: Chan K.C. Allen , Leung Sing-Fai , Yeung Sze-Wan , Chan Anthony T.C. , Lo Y.M. Dennis
Published: July 2008

Purpose: Aberrations of circulating nucleic acid integrity have been observed in cancer patients. However, the clinical significance of such changes has not been completely elucidated. In this study, we investigated the plasma DNA integrity in nasopharyngeal carcinoma (NPC) patients and its association with patients' survival after radiotherapy.

Experimental Design: Plasma DNA integrity was analyzed for 105 NPC patients before and after curative-intent radiotherapy and for 40 healthy controls. The plasma DNA concentration of each sample was measured by two real-time PCRs targeting the leptin gene. The amplicon sizes of the two assays were 105 and 201 bp. The integrity index was calculated as the ratio of the two concentrations (201 bp/105 bp). More intact circulating DNA would give a higher integrity index.

Results: The plasma DNA integrity index of the NPC patients was significantly higher than that of the healthy controls (median, 0.356 versus 0.238; P < 0.001). After radiotherapy, a reduction in plasma DNA integrity index was observed in 70% NPC patients. Patients with persistent aberrations of plasma DNA integrity had significantly poorer survival probability than those with reduced DNA integrity after treatment (P < 0.001, Kaplan-Meier).

Conclusions: NPC is associated with disturbances in the integrity of circulating cell-free DNA. The persistence of DNA integrity aberrations after radiotherapy is associated with reduced probability of disease-free survival. Therefore, the measurement of plasma DNA integrity may serve as a useful marker for the detection and monitoring of malignant diseases.
The Use of Chelated Radionuclide (Samarium-153-Ethylenediaminetetramethylenephosphonate) to Modulate Phenotype of Tumor Cells and Enhance T Cell–Mediated Killing
Authors: Chakraborty Mala , Wansley Elizabeth K. , Carrasquillo Jorge A. , Yu Sarah , Paik Chang H. , Camphausen Kevin , Becker Michael D. , Goeckeler William F. , Schlom Jeffrey , Hodge James W.
Published: July 2008

Purpose: Exposing human tumor cells to sublethal doses of external beam radiation up-regulates expression of tumor antigen and accessory molecules, rendering tumor cells more susceptible to killing by antigen-specific CTLs. This study explored the possibility that exposure to palliative doses of a radiopharmaceutical agent could alter the phenotype of tumor cells to render them more susceptible to T cell–mediated killing.

Experimental Design: Here, 10 human tumor cell lines (4 prostate, 2 breast, and 4 lung) were exposed to increasing doses of the radiopharmaceutical samarium-153-ethylenediaminetetramethylenephosphonate (153Sm-EDTMP) used in cancer patients to treat pain due to bone metastasis. Fluorescence-activated cell sorting analysis and quantitative real-time PCR analysis for expression of five surface molecules and several tumor-associated antigens involved in prostate cancer were done. LNCaP human prostate cancer cells were exposed to 153Sm-EDTMP and incubated with tumor-associated antigen-specific CTL in a CTL killing assay to determine whether exposure to 153Sm-EDTMP rendered LNCaP cells more susceptible to T cell–mediated killing.

Results: Tumor cells up-regulated the surface molecules Fas (100% of cell lines up-regulated Fas), carcinoembryonic antigen (90%), mucin-1 (60%), MHC class I (50%), and intercellular adhesion molecule-1 (40%) in response to 153Sm-EDTMP. Quantitative real-time PCR analysis revealed additional up-regulated tumor antigens. Exposure to 153Sm-EDTMP rendered LNCaP cells more susceptible to killing by CTLs specific for prostate-specific antigen, carcinoembryonic antigen, and mucin-1.

Conclusions: Doses of 153Sm-EDTMP equivalent to palliative doses delivered to bone alter the phenotype of tumor cells, suggesting that 153Sm-EDTMP may work synergistically with immunotherapy to increase the susceptibility of tumor cells to CTL killing.
Vaccination with a Recombinant Saccharomyces cerevisiae Expressing a Tumor Antigen Breaks Immune Tolerance and Elicits Therapeutic Antitumor Responses
Authors: Wansley Elizabeth K. , Chakraborty Mala , Hance Kenneth W. , Bernstein Michael B. , Boehm Amanda L. , Guo Zhimin , Quick Deborah , Franzusoff Alex , Greiner John W. , Schlom Jeffrey , Hodge James W.
Published: July 2008

Purpose: Saccharomyces cerevisiae, a nonpathogenic yeast, has been used previously as a vehicle to elicit immune responses to foreign antigens, and tumor-associated antigens, and has been shown to reduce tumor burden in mice. Studies were designed to determine if vaccination of human carcinoembryonic antigen (CEA)-transgenic (CEA-Tg) mice (where CEA is a self-antigen) with a recombinant S. cerevisiae construct expressing human CEA (yeast-CEA) elicits CEA-specific T-cell responses and antitumor activity.

Experimental Design: CEA-Tg mice were vaccinated with yeast-CEA, and CD4+ and CD8+ T-cell responses were assessed after one and multiple administrations or vaccinations at multiple sites per administration. Antitumor activity was determined by tumor growth and overall survival in both pulmonary metastasis and s.c. pancreatic tumor models.

Results: These studies demonstrate that recombinant yeast can break tolerance and that (a) yeast-CEA constructs elicit both CEA-specific CD4+ and CD8+ T-cell responses; (b) repeated yeast-CEA administration causes increased antigen-specific T-cell responses after each vaccination; (c) vaccination with yeast-CEA at multiple sites induces a greater T-cell response than the same dose given at a single site; and (d) tumor-bearing mice vaccinated with yeast-CEA show a reduction in tumor burden and increased overall survival compared to mock-treated or control yeast-vaccinated mice in both pulmonary metastasis and s.c. pancreatic tumor models.

Conclusions: Vaccination with a heat-killed recombinant yeast expressing the tumor-associated antigen CEA induces CEA-specific immune responses, reduces tumor burden, and extends overall survival in CEA-Tg mice. These studies thus form the rationale for the incorporation of recombinant yeast-CEA and other recombinant yeast constructs in cancer immunotherapy protocols.
Osteopontin and Interleukin-8 Expression is Independently Associated with Prostate Cancer Recurrence
Authors: Caruso Daniel J. , Carmack Adrienne J.K. , Lokeshwar Vinata B. , Duncan Robert C. , Soloway Mark S. , Lokeshwar Bal L.
Published: July 2008

Purpose: Lack of reliable biomarkers limits accurate prediction of prostate-specific antigen biochemical recurrence (disease progression) in prostate cancer. The two inflammatory chemokines, osteopontin and interleukin-8 (IL-8), are associated with tumor angiogenesis and metastasis. We investigated whether osteopontin and IL-8 expression in prostate cancer correlates with disease progression.

Experimental Design: Archival prostatectomy specimens (n = 103) were obtained from patients with minimum 72-month follow-up. Osteopontin and IL-8 expression was evaluated by immunohistochemistry and graded for intensity and the area. Association of osteopontin and IL-8 staining with biochemical recurrence was evaluated by univariate and multivariate models.

Results: In tumor cells, osteopontin and IL-8 staining was higher in the recurred group (203.2 ± 78.4; 181.1 ± 89.3) than in the nonrecurred group (122.7 ± 76.6; 96.4 ± 85.6; P < 0.001). Higher osteopontin and IL-8 staining was also observed in benign areas adjacent to tumor in the recurred group, than in nonrecurred group. In univariate analysis, except age, all preoperative and postoperative variables and osteopontin and IL-8 staining scores were significantly associated with biochemical recurrence (P < 0.05). In multivariate analysis, margin status and osteopontin staining independently associated with biochemical recurrence within 72 months. Osteopontin, either alone or with IL-8 and seminal vesicle invasion, was a significant variable in predicting biochemical recurrence within 24 months. Osteopontin and IL-8 staining predicted recurrence with high sensitivity (75.5%; 73.6%) and specificity (76%; 70.6%).

Conclusion: In prostatectomy specimens, osteopontin expression is independently associated with biochemical recurrence. Both osteopontin and IL-8 may be predictors of early disease progression.
Prevalence of Urinary Incontinence in the 12-Month Postpartum Period and Related Risk Factors in Turkey
Authors: Ege Emel , Akın Belgin , Altuntuğ Kamile , Benli Saniye , Ariöz Ayten
Published: July 2008

Aim: The purpose of this study is to determine the prevalence of urinary incontinence in the 12-month postpartum period and the risk factors related to this condition. Methods: The research is a cross-sectional study of 1,749 first-year postpartum women living in the metropolis of Konya and presenting at seven city health centers. The statistical methods used were the χ2, the Student’s t test and logistic regression analysis. Results: Of the women in the study who were in their 12-month postpartum periods, 19.5% were experiencing varying degrees of urinary incontinence. While 42.2% of the women suffered from stress incontinence, 10.3% had urge incontinence, 47.5% complained of a mixed type of urinary incontinence, 7.3% reported leakage of urine during sexual intercourse and 14.4% reported the need to use protective pads. It was found that 12.3% of the women were performing pelvic floor muscle exercises and only 15.2% had consulted their doctors about urinary incontinence. Conclusion: It was seen that urinary incontinence is a serious health problem in the postpartum period, that it disrupts a woman’s daily activities, affects her sex life but that despite this, women do not receive needed medical assistance.
Nocturnal Enuresis in Turkey: Prevalence and Accompanying Factors in Different Socioeconomic Environments
Authors: Carman Kursat B. , Ceran Omer , Kaya Cevdet , Nuhoglu Cagatay , Karaman M. Ihsan
Published: July 2008

Aim: To study the prevalence of nocturnal enuresis and the impact of associated familial factors in Turkish children with a different socioeconomic status. Methods: A specific questionnaire was distributed to 3,000 parents of primary school children (6–12 years old). Of these children, 1,500 attended primary schools in Umraniye, a suburban region of Istanbul (group 1), and the other 1,500 children visited schools in Suadiye, a well-developed part of Istanbul (group 2). The first part of the survey investigated the familial conditions of the children (financial status, family history of enuresis, and family size). The second part of the questionnaire surveyed the demographic and physical characteristics of the children. The last part was designed to investigate the opinions and beliefs of the parents about nocturnal enuresis and treatment modalities. The prevalence rates of nocturnal enuresis and associated familial factors of these children from two different regions of Istanbul were compared. Results: Of the 3,000 questionnaires distributed, 2,589 (86.3%) were returned and included in the final analysis. The mean age of group 1 and 2 children was 8.88 ± 1.4 and 8.9 ± 1.5 years, respectively (p > 0.05). The gender of the subjects was equally distributed (48.6% males and 51.4% females). Enuresis was present in 334 children (25.5%) of group 1 and in 205 children (16%) of group 2. Enuresis was significantly more common in group 1 (p < 0.01). The families consisted of 4.69 ± 1.4 and 4.1 ± 1.1 persons, respectively (p < 0.01). A yearly income of USD 7,000 was achieved in group 2 by 54%, in group 1 by only 0.7% (p < 0.01). Only 26 children of group 1 (7.8%) and 22 children of group 2 (10.8%) were noted to receive medical enuresis treatments, with no statistically significant difference between the groups (p > 0.01). The parents of the enuretic children from the suburban region of Istanbul were found to consider the condition a normal developmental entity. They believed that enuresis will resolve spontaneously and that no treatment is necessary. On the contrary, the parents of the enuretic children in the well-developed region of the city believed that enuresis is a psychological problem and that intensive psychological assistance is essential for the management. Conclusions: Our study indicates that the prevalence of nocturnal enuresis in Turkey is comparable to that reported in the literature. The parents consider that enuresis nocturna is not a fatal disorder, that the drugs used in the treatment may be harmful, and that no medical assistance is required. Trained health personnel and physicians should inform the parents about enuresis in order to prevent possible behavioral and self-esteem problems.
Urodynamic Evaluation in Diabetic Patients with Prostate Enlargement and Lower Urinary Tract Symptoms
Authors: Dib Paulo Tadeu , Trigo-Rocha Flavio , Gomes Cristiano Mendes , Srougi Miguel
Published: July 2008

Introduction: Lower urinary tract symptoms (LUTS) are common in men over 50 years of age due to prostate enlargement. Diabetes mellitus is also more prevalent in this group. LUTS may result from bladder outlet obstruction (BOO) secondary to prostate enlargement or bladder dysfunction secondary to diabetes or even from a combination of both. Objectives: The objective of this study was to determine the prevalence of BOO and other urodynamic abnormalities in diabetic patients with LUTS and enlarged prostate. A secondary objective was to assess the predictive value of non-invasive tests for BOO diagnosis in this group of patients. Patients and Methods: 50 consecutive diabetic patients with enlarged prostate and LUTS were evaluated by the International Prostate Symptom Score (IPSS), ultrasonography and urodynamics. BOO diagnosis was based on pressure/flow measurements according to the International Continence Society’s standards. Results: Of the 50 patients in the study, 23 (46%) had BOO. There was no correlation between the IPSS, uroflowmetry, post-voiding residual urine or prostate volume and the presence of BOO (p > 0.05). Conclusions: There is a relatively low prevalence of BOO in diabetic patients with prostate enlargement and LUTS. Non-invasive tests did not allow the identification of these subjects. Only urodynamic evaluation is able to determine symptom etiology.
Catheter-Assisted Transurethral Resection of the Prostate: A Novel Approach
Authors: Shih Hung-Jen , Chow Yung-Chiong , Huang Chun-Jen , Su Yu-Hsien , Lin Wen-Chou , Yang Stone
Published: July 2008

Introduction: The aim of the study was to compare the safety and efficacy of catheter-assisted transurethral resection of the prostate (TURP) with traditional TURP in the treatment of benign prostatic hyperplasia. Materials and Methods: A total of 61 men were randomized to either catheter-assisted TURP (30 patients) or traditional TURP (31), both performed with a monopolar device. Measurements included the duration of Foley catheterization, length of hospital stay, symptom score and urinary flow rate. All patients were followed for at least 1 year after surgery. Results: The catheter-assisted group had a significantly shorter operative time, duration of postoperative catheterization and length of stay. There were no significant differences in changes in serum sodium and hemoglobin level on postoperative day 1. At 1 year postoperatively, none of the patients suffered from urethral stricture and the 2 groups did not differ significantly in terms of prostatic volume, peak flow rate or International Prostate Symptom Score. Conclusions: Catheter-assisted TURP is safe and produced results at 1 year similar to traditional TURP. This new method for TURP appears to be a better and more effective approach than the traditional method, although a longer period of observation is needed to assess the durability of the results.
Arsenic Methylation Capability, Heme Oxygenase-1 and NADPH Quinone Oxidoreductase-1 Genetic Polymorphisms and the Stage and Grade of Urothelial Carcinomas
Authors: Huang Steven K. , Chiu Allen Wen-Hsiang , Pu Yeong-Shiau , Huang Yung-Kai , Chung Chi-Jung , Tsai Hui-Ju , Yang Mo-Hsiung , Chen Chien-Jen , Hsueh Yu-Mei
Published: July 2008

Background: Arsenic exposure is associated with an increased risk of urothelial carcinoma (UC). To explore the distribution of the arsenic methylation capability in patients with different stages and grades of UCs, 100 UC cases were recruited between September 2002 and May 2004 for this study. Methods: Urinary arsenic species, including inorganic arsenic (AsIII + AsV), monomethylarsonic acid (MMA), and dimethylarsinic acid (DMA), were determined with a high-performance liquid chromatography-linked hydride generator and atomic absorption spectrometry. Determining the percentages of various arsenic species among the total urinary arsenic amount assessed the arsenic methylation capability. The primary methylation index (PMI) was defined as the ratio between MMA and inorganic arsenic. The secondary methylation index (SMI) was determined as the ratio between DMA and MMA. Results: Differential effects of the arsenic methylation capability were found among patients with different stages of UCs; however, none was found among different grades. Conclusion: A significantly different distribution of the HO-1 genotype was found in subjects with different-stage UCs; however, it was not related to the NAD(P)H:quinone oxidoreductase 1 genotype.
Prevalence of Prostate Cancer in End-Stage Renal Disease Patients
Authors: Kamata Toshiro , Fushimi Kiyohide
Published: July 2008

Aims: We aimed to assess the prevalence of prostate cancer in end-stage renal disease (ESRD) patients by a large-scale, multicentric and prospective study, and to show the difference between ESRD patients and normal healthy subjects. Methods: The level of serum prostate-specific antigen (PSA) was measured in 724 male ESRD patients undergoing dialysis. Those patients whose serum PSA level was over 4.0 ng/ml underwent a second screening test. After diagnosis, the prevalence of prostate cancer was subsequently calculated following adjustments by logistic-regression analysis. The prevalence of prostate cancer was also assessed in three control groups who had undergone health checks. Results: The prevalence of prostate cancer in ESRD patients was found to be 1.4%. Those of the control groups (after correction for age) were 0.4, 1.4 and 0.8%. The odds ratios were 3.49, 0.96 and 1.71. Conclusion: The prevalence of prostate cancer in ESRD patients was equal or higher compared with that of normal healthy subjects. The result strongly indicates that the use of the serum PSA assay contributes to the early detection of prostate cancer in ESRD patients.
Page Kidney Phenomenon Presenting as Acute Renal Failure after Partial Nephrectomy: A Case Report and Review of the Literature
Authors: John Jason , Allen Siân , Perry Matthew , Patel Hitendra R.H. , O’Brien Tim
Published: July 2008

Background: The Page kidney phenomenon, whilst a known condition, is in itself a rare entity. This report illustrates a case following partial nephrectomy which presented as post-operative renal failure. Case Presentation: The authors present a case of renal cell carcinoma in a solitary kidney that after partial nephrectomy resulted in a subcapsular haematoma formation and acute renal failure. Conclusion: The condition of Page kidneys are typically described in young patients after trauma. However, with the increasing usage of surgical interventions, post-operative bleeding can result in a compression-induced necrosis.
Renal Toxicity following Zoledronic Acid Reversed with Ibandronate in a Prostate Cancer Patient with Bone Metastases
Authors: Joensuu Timo K.
Published: July 2008

Bisphosphonates are a standard treatment for metastatic bone disease, although agents vary in their potential for renal toxicity. This case report describes the reversal of zoledronic acid-induced renal toxicity by switching treatment to ibandronate in a patient with hormone-refractory prostate cancer and bone metastases.
Mutational Analysis in Early-Onset Familial Dementia in the Japanese Population
Authors: Ikeuchi Takeshi , Kaneko Hiroyuki , Miyashita Akinori , Nozaki Hiroaki , Kasuga Kensaku , Tsukie Tamao , Tsuchiya Miyuki , Imamura Toru , Ishizu Hideki , Aoki Kenju , Ishikawa Atsushi , Onodera Osamu , Kuwano Ryozo , Nishizawa Masatoyo
Published: July 2008

Background: Three major causative genes have been implicated as the cause of early-onset familial Alzheimer’s disease (AD): the amyloid precursor protein gene (APP), presenilin-1 (PSEN1) and PSEN2. Although rare, a tau-related dementia with mutations in the microtubule-associated protein tau gene (MAPT) has been identified in patients showing clinical presentations similar to those of AD. Methods: We performed mutational analysis of APP, PSEN1, PSEN2, and MAPT in 10 Japanese families with early-onset dementia clinically diagnosed as probable Alzheimer’s disease. Results: In 4 index patients, we identified 4 missense PSEN1 mutations, namely, L286V, G378E, L381V, and L392V. The mean age at onset in the patients with PSEN1 mutations was 39 years. In 2 families, we found the R406W mutation in MAPT. The mean age at onset of the patients carrying the R406W mutation was 52 years, and they presented with the peculiar AD-like phenotype without apparent behavioral or language problems. Conclusion: These observations suggest that although PSEN1 mutations are the most frequent cause, the MAPT R406W mutation is an important cause of early-onset familial dementia clinically diagnosed as AD. Differentiation of patients with the MAPT mutation from AD patients by genetic testing would be meaningful, considering that a different therapeutic approach should be applied.
Construction of Armored RNA Containing Long-Size Chimeric RNA by Increasing the Number and Affinity of the Pac Site in Exogenous RNA and Sequence Coding Coat Protein of the MS2 Bacteriophage
Authors: Wei Baojun , Wei Yuxiang , Zhang Kuo , Yang Changmei , Wang Jing , Xu Ruihuan , Zhan Sien , Lin Guigao , Wang Wei , Liu Min , Wang Lunan , Zhang Rui , Li Jinming
Published: July 2008

Objectives: To construct a one-plasmid expression system of the armored RNA containing long chimeric RNA byincreasing the number and affinity of the pac site. Methods: The plasmid pET-MS2-pac was constructedwith one C-variant pac site, and then the plasmid pM-CR-2C containing 1,891-bp chimeric sequences and two C-variant pac sites was produced. Meanwhile, three plasmids (pM-CR-C, pM-CR-2W and pM-CR-W) were obtained as parallel controls with a different number and affinity of the pac site. Finally, the armored RNA was expressed and purified. Results: The armored RNA with 1,891 bases target RNA was expressed successfully by the one-plasmid expression system with two C-variant pac sites, while for one pac site, no matter whether the affinity was changed or not, only the 1,200 bases target RNA was packaged. It was also found that the C-variant pac site could increase the expression efficiency of the armored RNA. The armored RNA with 1,891-bp exogenous RNA in our study showed the characterization of ribonuclease resistance and stability at different time points and temperature conditions. Conclusions: The armored RNA with 1,891 bases exogenous RNA was constructed and the expression system can be used as a platform for preparation of the armored RNA containing long RNA sequences.