bluuebunny/crossref_metadata_2025 huggingface dataset:
Association of GSTP1 Polymorphism and Survival for Esophageal Cancer
Authors: Lee Jang-Ming , Wu Ming-Tsang , Lee Yung-Chie , Yang Shi-Yi , Chen Jin-Shing , Hsu Hsao-Hsun , Huang Pei-Ming , Kuo Shuenn-Wen , Lee Chun-Jean , Chen Chien-Jen
Published: September 2005

Purpose: Activity of glutathione S-transferase (GST) is associated with detoxification of xenobiotics and the maintenance of cell viability. Genetically variant GSTs produce different enzymatic activities. The clinical significance of this variation is still puzzling. We investigated whether genetic polymorphisms of GST including GSTP1, GSTM1, and GSTT1 affect survival among esophageal cancer patients.

Experimental Design: From 1996 to 2002, 233 patients with pathologically proven esophageal cancer were recruited from the Department of Surgery, National Taiwan University Hospital. GST genotypes, including GSTT1, GSTM1, and GSTP1, were determined by PCR or PCR-RFLP. The influence of the genetic polymorphisms on patient survival was estimated using the method of Kaplan-Meier survival function and Cox proportional hazards models.

Results: The mean survival times (months) of the GSTP1 Ile/Ile, Ile/Val, and Val/Val were 11, 10, and 7, respectively (P < 0.05). The more the patients carried GSTP1 variant Val alleles, the poorer the survival rate (adjusted hazard ratio, 1.36; 95% confidence interval, 1.01-1.84; Ptrend = 0.045). In contrast, no association of GSTT1 or GSTM1 genotypes with survival rate was noted.

Conclusion: The presence of the GSTP1 variant allele (Val) is associated with a poorer prognosis of esophageal cancer.
Dose-Finding Study of the Multitargeted Tyrosine Kinase Inhibitor SU6668 in Patients with Advanced Malignancies
Authors: Kuenen Bart C. , Giaccone Giuseppe , Ruijter Rita , Kok Astrid , Schalkwijk Casper , Hoekman Klaas , Pinedo Herbert M.
Published: September 2005

Purpose: SU6668 is a tyrosine kinase inhibitor which targets platelet-derived growth factor receptor-β, fibroblast growth factor receptor-1, vascular endothelial growth factor receptor-2, and KIT. We did a phase I study to define the maximum tolerated dose and to assess the pharmacokinetics of SU6668 administered orally thrice daily with food.

Patients and Methods: Patients with histologically proven, advanced, and progressive solid tumors were included at a starting dose level of 400 mg/m2 thrice daily. The early onset of dose-limiting toxicities (DLT) required dose reductions to 100 and 200 mg/m2 thrice daily. Pharmacokinetics was done on days 1, 28, and 56.

Results: Sixteen patients were included. Two of the first three patients developed DLTs, which consisted of grade 4 fatigue and grade 3 serositis-like pains. Six patients at dose level 100 mg/m2 thrice daily experienced no DLT. At dose level 200 mg/m2 thrice daily, two out of seven patients experienced DLTs consisting of grade 3 abdominal pain, grade 4 anorexia and grade 3 nausea/vomiting. Increasing doses resulted in a disproportional increase in area under the curve and Cmax (peak plasma concentration). Both variables, however, decreased significantly on days 28 and 56 compared with day 1 (P < 0.05). No objective responses were observed. Acute phase response, probably mediated by interleukin-6, was observed in serial blood samples.

Conclusions: The maximum tolerated dose of SU6668 given orally, thrice daily under fed conditions, is 100 mg/m2. Because of the low plasma levels reached at this dose level, the efficacy of SU6668 as a single agent is not to be expected.
A Predictive Model of Rectal Tumor Response to Preoperative Radiotherapy Using Classification and Regression Tree Methods
Authors: Zlobec Inti , Steele Russell , Nigam Nilima , Compton Carolyn C.
Published: September 2005

Purpose: The ability to predict rectal tumor response to preoperative radiotherapy before treatment would significantly impact patient selection. In this study, classification and regression tree (CART) methods were used to model tumor response to preoperative conformal high-dose rate brachytherapy by assessing the predictive value of vascular endothelial growth factor (VEGF), Bcl-2, p21, p53, and APAF-1.

Experimental Design: Immunohistochemistry was used to detect VEGF, Bcl-2, p21, p53, and APAF-1 from 62 pretreatment rectal tumor biopsies. Scores were assigned as percentages of positive tumor cell staining and were used in CART analysis to identify the proteins that best predicted response to radiotherapy. Ten-fold cross-validation was used to prevent overfitting and multiple cross-validation experiments were run to estimate the prediction error.

Results: Postoperative pathologic evaluation of the irradiated tumor bed revealed 43 responsive tumors [20 with complete response (T0) and 23 with partial response] and 19 nonresponsive tumors. The optimal tree resulting from CART analysis had five terminal nodes with a misclassification rate of 18%. Of the five proteins selected for their predictive value, VEGF and Bcl-2 contributed most to the classification of responsive and nonresponsive tumors. All 10 tumors with no VEGF were completely responsive (T0) to radiotherapy; 85% of those with VEGF and negative for Bcl-2 were responsive to therapy.

Conclusions: VEGF and Bcl-2 status in pretreatment rectal tumor biopsies may be predictive of response to preoperative high-dose rate brachytherapy.
Oncolytic Viral Therapy for Cervical and Ovarian Cancer Cells by Sindbis Virus AR339 Strain
Authors: Unno Youichi , Shino Yuji , Kondo Fukuo , Igarashi Natsuhiko , Wang Gang , Shimura Ryuhi , Yamaguchi Taketo , Asano Takehide , Saisho Hiromitsu , Sekiya Souei , Shirasawa Hiroshi
Published: September 2005

Purpose: Recently, the application of replication-competent viruses has been studied as anticancer agents. Sindbis virus (SIN) is an RNA virus that belongs to the Alphavirus genus in the Togaviridae virus family. The AR339 strain of SIN has not been reported to induce any serious disease to humans.

Experimental Design: In this study, we evaluated the feasibility of the replication-competent SIN AR339 strain as an agent for cervical and ovarian cancer therapy.

Results: SIN infection was able to induce cytopathic effects and apoptosis in two cervical cancer cells (HeLaS3 and C33A) and three ovarian cancer cells (HOC-1, HAC-2, and OMC-3) but not in normal human keratinocytes in vitro. The analysis of cell viability, virus protein synthesis, and viral growth showed the cancer-specific cytotoxicity and virus growth of SIN. In nude mice, i.t. and i.v. inoculation of SIN resulted in significant regression of established cervical tumors implanted at their backs. Histologic studies revealed that systemic treatment with the single injection of SIN induces necrosis within tumors at a remote site. In the metastasis model of ovarian cancer, suppression of ascites formation was observed in nude mice with i.p. SIN treatment. By using an in vivo green fluorescent protein imaging system, we also showed that systemic treatment with SIN targeted tumors specifically.

Conclusions: Our study suggested that SIN AR339 strain has a possibility as a novel agent for human cervical and ovarian cancer therapy.
Gene Expression as a Predictive Marker of Outcome in Stage IIB-IIIA-IIIB Non-Small Cell Lung Cancer After Induction Gemcitabine-Based Chemotherapy Followed By Resectional Surgery
Authors: Rosell Rafael , Felip Enriqueta , Taron Miquel , Majo Joaquim , Mendez Pedro , Sanchez-Ronco Maria , Queralt Cristina , Sanchez Jose Javier , Maestre Jose
Published: September 2005

Purpose: The first suggestions of a relationship between gene mRNA expression and differential sensitivity to gemcitabine/cisplatin are now emerging. ERCC1, RRM1, and XPD are involved in the nucleotide excision repair pathways, and tumor up-regulation of these genes leads to chemotherapy failure. In the present study, we have examined the potential correlation and predictive value of ERCC1, RRM1, and XPD mRNA expression in resected specimens from 67 stage IIB, IIIA, and IIIB non-small cell lung cancer patients treated with neoadjuvant gemcitabine/platinum followed by surgery

Experimental Design: ERCC1, RRM1, and XPD expression was quantified using real-time quantitative reverse transcription-PCR.

Results: A good correlation was found between mRNA expression levels of the three genes. For RRM1 levels, patients in the bottom quartile had a decreased risk of death compared with those in the top quartile (risk ratio = 0.30; P = 0.033). Median survival for the 17 patients in the bottom quartile was 52 months, whereas for the 15 in the top quartile, it was 26 months (P = 0.018). When the characteristics of these 17 patients were compared with all of the other 50 patients, no differences in initial staging were observed. However, the 17 patients in the bottom quartile had better outcomes, including more radiographic responses (65% versus 54%; P = 0.24), complete resections (94% versus 72%; P = 0.03), lobectomies (71% versus 34%; P = 0.004), and pathological complete responses (29% versus 0%; P = 0.00001)

Conclusions: Patients with RRM1 levels in the bottom quartile benefited significantly from gemcitabine/cisplatin neoadjuvant chemotherapy, leading us to conclude that RRM1 mRNA levels should be additionally validated to proceed with tailored chemotherapy.
Role of Mononuclear Cells and Inflammatory Cytokines in Pancreatic Cancer-Related Cachexia
Authors: Martignoni Marc E. , Kunze Phillipp , Hildebrandt Wulf , Künzli Beat , Berberat Pascal , Giese Thomas , Klöters Oliver , Hammer Jürgen , Büchler Markus W. , Giese Nathalia A. , Friess Helmut
Published: September 2005

Background and Purpose: The mechanism behind aggressive development of cachexia in patients suffering from pancreatic cancer is not well understood. In this study, we investigated which factors are associated with the cachectic status of the patients and evaluated cachexia-promoting capacity of cancer and inflammatory cells.

Experimental Design: DNA microarray analysis and quantitative reverse transcription-PCR were used to screen for cachexia-associated factors in pancreatic specimens obtained from noncachectic and cachetic patients diagnosed with pancreatic ductal adenocarcinoma. The expression pattern of the most prominently altered cachexia-associated factor, interleukin-6 (IL-6), was further analyzed in patients sera by ELISA, in pancreatic specimens by immunohistochemistry, and in a coculture system by quantitative reverse transcription-PCR using pancreatic cancer cell lines T3M4 (IL-6 positive) and Panc-1 (IL-6 negative) and peripheral blood mononuclear cells (PBMC) obtained from donors and noncachectic and cachectic patients.

Results: Among numerous analyzed factors, IL-6 was significantly overexpressed in pancreatic specimens and elevated in serum of cachectic patients. The coculture system revealed that pancreatic cancer T3M4 cells but not Panc-1 cells were able to stimulate IL-6 exclusively in cachectic PBMC (by 14-fold) and this triggering was reduced by half in the presence of IL-6-neutralizing antibodies.

Conclusion: IL-6 represents a prominent cachexia-associated factor in pancreatic cancer. IL-6 overexpression in cachectic patients is related to the ability of certain tumors to sensitize PBMC and induce cytokine expression in cachectic PBMC.
Prediction of Active Drug Plasma Concentrations Achieved in Cancer Patients by Pharmacodynamic Biomarkers Identified from the Geo Human Colon Carcinoma Xenograft Model
Authors: Luo Feng R. , Yang Zheng , Dong Huijin , Camuso Amy , McGlinchey Kelly , Fager Krista , Flefleh Christine , Kan David , Inigo Ivan , Castaneda Stephen , Wong Tai W. , Kramer Robert A. , Wild Robert , Lee Francis Y.
Published: September 2005

Purpose: Epidermal growth factor receptor (EGFR), a protein tyrosine kinase expressed in many types of human cancers, has been strongly associated with tumor progression. Cetuximab is an IgG1 anti-EGFR chimeric mouse/human monoclonal antibody that has been approved for the treatment of advanced colon cancer. Using human tumor xenografts grown in nude mice, we have determined the in vivo pharmacodynamic response of cetuximab at efficacious doses. Three pharmacodynamic end points were evaluated: tumoral phospho-EGFR, tumoral mitogen-activated protein kinase (MAPK) phosphorylation, and Ki67 expression.

Experimental Design: The pharmacodynamic study was conducted in nude mice bearing Geo tumors following a single i.p. administration of 0.25 and 0.04 mg. The tumors were analyzed by immunohistochemistry. The levels of phospho-EGFR were quantitated by an ELISA assay.

Results: At 0.25 mg, phospho-EGFR was maximally inhibited by 91% at 24 hours, whereas the level of inhibition decreased to 72% by 72 hours. At 0.04 mg, the maximum inhibition of phospho-EGFR was 53% at 24 hours, whereas the level of inhibition decreased to 37% by 72 hours. The time course of phospho-EGFR inhibition and recovery seemed to correlate with the pharmacokinetics of cetuximab. Immunohistochemical analysis showed that phospho-MAPK and Ki67 expression were inhibited between 24 and 72 hours at 0.25 and 0.04 mg. A pharmacokinetic/pharmacodynamic model was established and predicted that the plasma concentration of cetuximab required to inhibit 90% of phospho-EGFR was 67.5 μg/mL.

Conclusions: Phospho-EGFR/phospho-MAPK could be useful clinical biomarkers to assess EGFR inhibition by cetuximab.
Mammalian Target of Rapamycin Inhibition
Authors: Dutcher Janice P.
Published: September 2005

The mammalian target of rapamycin (mTOR) is a serine/threonine kinase that has been increasingly recognized as key to the regulation of cell growth and proliferation. mTOR either directly or indirectly regulates translation initiation, actin organization, tRNA synthesis, ribosome biogenesis, and many other key cell maintenance functions, including protein degradation and transcription functions. Inhibition of mTOR blocks traverse of the cell cycle from the G1 to S phase. Preclinical data show inhibition of tumor growth in a number of cell lines and xenograft models. Clinical trials are ongoing. In metastatic renal cell cancer, both tumor regression and prolonged stabilization have been noted. mTOR inhibition appears to be a key pathway that may be useful in antitumor therapy. Renal cell cancer may be particularly susceptible through both the translation inhibition pathway and pathways that enhance HIF-1α gene expression, a factor believed to stimulate growth in metastatic renal cell cancer. Additional clinical trials that use agents that inhibit mTOR are ongoing.
Telomerase Inhibition and Cell Growth Arrest After Telomestatin Treatment in Multiple Myeloma
Authors: Shammas Masood A. , Reis Robert J. Shmookler , Li Cheng , Koley Hemanta , Hurley Laurence H. , Anderson Kenneth C. , Munshi Nikhil C.
Published: September 2005

Purpose: The aim of this study was to test the efficacy of telomestatin, an intramolecular G-quadruplex intercalating drug with specificity for telomeric sequences, as a potential therapeutic agent for multiple myeloma.

Experimental Design: We treated ARD, ARP, and MM1S myeloma cells with various concentrations of telomestatin for 7 days and evaluated for telomerase activity. Myeloma cells were treated with the minimal effective telomestatin concentration for 3–5 weeks. Every 7th day the fraction of live cells was determined by trypan blue exclusion, aliquots of cells were removed for various molecular assays, and the remaining cells were replated at the same cell number and at the same concentration of telomestatin. Telomere length, apoptosis, and gene expression changes were monitored as described in detail in “Materials and Methods.”

Results: Telomestatin treatment led to inhibition of telomerase activity, reduction in telomere length, and apoptotic cell death in ARD, MM1S, and ARP myeloma cells. Gene expression profile after 1 and 7 days of telomestatin treatment revealed ≥2-fold change in only 6 (0.027%) and 51 (0.23%) of 33,000 genes surveyed, respectively. No changes were seen in expression of genes involved in cell cycle, apoptosis, DNA repair, or recombination.

Conclusions: These results demonstrate that telomestatin exerts its antiproliferative and proapoptotic effects in myeloma cells via inhibition of telomerase and subsequent reduction in telomere length. We conclude that telomerase is an important potential therapeutic target for multiple myeloma therapy, and G-quadruplex interacting agents with specificity for binding to telomeric sequences can be important agents for additional evaluation.
Gene Expression Profiling Identifies Platelet-Derived Growth Factor as a Diagnostic Molecular Marker for Papillary Thyroid Carcinoma
Authors: Yano Yukiko , Uematsu Naoya , Yashiro Tohru , Hara Hisato , Ueno Ei , Miwa Masanao , Tsujimoto Gozoh , Aiyoshi Yuji , Uchida Kazuhiko
Published: September 2005

Purpose: Cancer diagnostics and therapeutics are often based on clinically relevant markers that are expressed specifically in a malignant tissue at levels higher than in normal tissue. We examined potential markers for papillary thyroid carcinoma (PTC) by monitoring PTC-specific gene expression using cDNA microarray.

Experimental Design: Gene expression profiles for PTC tissue, normal thyroid tissue, and healthy peripheral blood cells were compared by use of a human 4000-gene cDNA microarray. Protein expressions of the up-regulated genes in PTC were examined in thyroid tissues by immunohistochemistry.

Results: Sixty-four genes were overexpressed in PTC tissue relative to normal thyroid tissue and healthy peripheral blood cells. The genes that were up-regulated in PTC were involved in cell cycle regulation, DNA damage response, angiogenesis, and oncogenesis. Among these genes, basic fibroblast growth factor and platelet-derived growth factor were identified by immunochemical methods as proteins that are specifically expressed at high levels in thyroid neoplasms. Basic fibroblast growth factor, which has been identified as a biomarker for PTC, was overexpressed in 54% of PTC cases, 67% of follicular thyroid carcinomas, and 36% of benign thyroid neoplasms. Platelet-derived growth factor was overexpressed in 81% of PTC cases and 100% of follicular carcinomas, but was immunonegative in normal thyroid tissues and benign thyroid neoplasms.

Conclusions: Platelet-derived growth factor may be a potential biomarker for PTC and follicular carcinoma. Expression profile analysis using a microarray followed by immunohistochemical study can be used to facilitate the development of molecular biomarkers for cancer.
A Phase I/II Study of Infusional Vinblastine with the P-Glycoprotein Antagonist Valspodar (PSC 833) in Renal Cell Carcinoma
Authors: Bates Susan E. , Bakke Susan , Kang Min , Robey Robert W. , Zhai Suoping , Thambi Paul , Chen Clara C. , Patil Sheela , Smith Tom , Steinberg Seth M. , Merino Maria , Goldspiel Barry , Meadows Beverly , Stein Wilfred D. , Choyke Peter , Balis Frank , Figg William D. , Fojo Tito
Published: September 2005

Purpose: P-glycoprotein (Pgp) inhibitors have been under clinical evaluation for drug resistance reversal for over a decade. Valspodar (PSC 833) inhibits Pgp-mediated efflux but delays drug clearance, requiring reduction of anticancer drug dosage. We designed an infusional schedule for valspodar and vinblastine to mimic infusional vinblastine alone. The study was designed to determine the maximally tolerated dose of vinblastine, while attempting to understand the pharmacokinetic interactions between vinblastine and valspodar and to determine the response rate in patients with metastatic renal cell cancer.

Patients and Methods: Thirty-nine patients received continuous infusion valspodar and vinblastine. Vinblastine was administered for 3 days to compensate for the expected delay in clearance and the required dose reduction. Valspodar was administered initially at a dose of 10 mg/kg/d; the dose of vinblastine varied.

Results: The maximum-tolerated dose of vinblastine was 1.3 mg/m2/d. As suggested previously, serum valspodar concentrations exceeded those needed for Pgp inhibition. Consequently, the dose of valspodar was reduced to 5 mg/kg, allowing a vinblastine dose of 2.1 mg/m2/d to be administered. Pharmacodynamic studies demonstrated continued inhibition of Pgp at lower valspodar doses by functional assay in Pgp-expressing CD56+ cells and by 99mTc-sestamibi imaging. A 15-fold range in cytochrome P450 activity was observed, as measured by midazolam clearance. No major responses were observed.

Conclusions: These results suggest that the pharmacokinetic impact of cytochrome P450 inhibition by valspodar can be reduced although not eliminated, while preserving Pgp inhibition, thus separating the pharmacokinetic and pharmacodynamic activities of valspodar.
Pretreatment with Dexamethasone Increases Antitumor Activity of Carboplatin and Gemcitabine in Mice Bearing Human Cancer Xenografts
Authors: Wang Hui , Li Mao , Rinehart John J. , Zhang Ruiwen
Published: September 2005

Purpose: The present study was undertaken to determine the effects of dexamethasone (DEX) pretreatment on antitumor activity and pharmacokinetics of the cancer chemotherapeutic agents carboplatin and gemcitabine.

Experimental Design: Antitumor activities of carboplatin and gemcitabine with or without DEX pretreatment were determined in six murine-human cancer xenograft models, including cancers of colon (LS174T), lung (A549 and H1299), and breast (MCF-7 and MDA-MB-468) and glioma (U87-MG). Effects of DEX on plasma and tissue pharmacokinetics of carboplatin and gemcitabine were also determined by using the LS174T, A549, and H1299 models.

Results: Although DEX alone showed minimal antitumor activity, DEX pretreatment significantly increased the efficacy of carboplatin, gemcitabine, or a combination of both drugs by 2–4-fold in all xenograft models tested. Without DEX treatment, the tumor exposure to carboplatin, measured by the area under the curve, was markedly lower than normal tissues. However, DEX pretreatment significantly increased tumor carboplatin levels, including 200% increase in area under the curve, 100% increase in maximum concentration, and 160% decrease in clearance. DEX pretreatment similarly increased gemcitabine uptake in tumors.

Conclusions: To our knowledge, this is the first report that DEX significantly enhances the antitumor activity of carboplatin and gemcitabine and increases their accumulation in tumors. These results provide a basis for further evaluation of DEX as a chemosensitizer in patients.
Frequency of Chromosomal Aberrations Involving
MALT1
in Mucosa-Associated Lymphoid Tissue Lymphoma in Patients with Sjögren’s Syndrome
Authors: Streubel Berthold , Huber Daniela , Wöhrer Stefan , Chott Andreas , Raderer Markus
Published: September 2005

Purpose: Mucosa-associated lymphoid tissue (MALT) lymphoma develops in the context of longstanding antigenic stimulation such as infection with Helicobacter pylori or autoimmune disease, including Sjögren’s syndrome (SS). Recently, two chromosomal aberrations involving the MALT1 gene, i.e., t(11;18)(q21;q21) and t(14;18)(q32;q21) have been reported as genetic events specific for MALT lymphoma. In view of the association between SS and the development of MALT lymphoma, we have analyzed the frequency of t(11;18)(q21;q21) and t(14;18)(q32;q21) in patients with MALT lymphomas arising in the background of SS.

Experimental Design: A retrospective analysis of patients diagnosed with MALT lymphoma and SS was performed. The t(11;18)(q21;q21) was analyzed using reverse transcriptase-PCR, whereas t(14;18)(q32;q21) was assessed by two-color interphase fluorescence in situ hybridization.

Results: Twenty-six patients (20 female and 6 male) with MALT lymphoma and SS could be identified. The lymphoma was located in the parotid (n = 14), orbit (n = 2), and submandibular gland (n = 1), whereas 9 patients had gastric MALT lymphoma. Seven of 26 patients (27%) harbored t(11;18)(q21;q21). Interestingly, only 1 of 17 patients (6%) with extragastrointestinal lymphoma was positive, as opposed to 6 of 9 patients (67%) with gastric MALT lymphoma. Four of 26 patients were positive for t(14;18)(q32;q21): 3 of 17 extragastrointestinal (18%) and 1 of 9 gastric lymphomas (11%).

Conclusions: The overall frequency of MALT1 rearrangement appears to be low in patients with extragastrointestinal MALT lymphoma associated with SS. By contrast, MALT1 rearrangement was demonstrated in 7 of 9 patients (78%) with gastric MALT lymphoma and SS. This finding may explain at least in part why gastric MALT lymphomas in patients with SS are refractory to H. pylori eradication therapy.
Therapeutic Synergy Between Irinotecan and 5-Fluorouracil against Human Tumor Xenografts
Authors: Azrak Rami G. , Cao Shousong , Slocum Harry K. , Tóth Károly , Durrani Farukh A. , Yin Ming-biao , Pendyala Lakshmi , Zhang Wanghai , McLeod Howard L. , Rustum Youcef M.
Published: September 2005

Purpose: Although the combination of irinotecan and 5-Fluorouracil is clinically active, it is associated with significant toxicity and resistance. Studies were carried out to define the optimal dosage, sequence, and timing for the combination in mice bearing xenografted human tumors.

Experimental Design: The maximum tolerated dose of irinotecan and 5-Fluorouracil in combination was determined in nude mice. Therapeutic efficacy against established human colon carcinoma xenografts, HCT-8 and HT-29, and human head and neck squamous cell carcinoma xenografts, FaDu and A253, was determined using the rugs individually, simultaneously, and in sequence with various intervals in between. Treatments were i.v. weekly × 4. Immunohistochemical and reverse transcription-PCR measurements of relevant drug-metabolizing enzymes, apoptosis-related proteins, cell cycle distribution, cyclin A, and S phase fraction expression were carried out and compared with the therapeutic outcome.

Results: The maximum tolerated dose of irinotecan resulted in cure rates of 30% or less in all xenografts. No cures were achieved with FUra alone. Concurrent administration of irinotecan and FUra, or of FUra 24 h before irinotecan, resulted in cure rates of <20%, except for FaDu (60%). Administration of irinotecan 24 h before FUra resulted in the highest cure rates, 80% in HCT-8, 0% in HT-29, 100% in FaDu, and 10% in A253.

Conclusions: The optimal therapeutic synergy was achieved when irinotecan was administered 24 h before 5-Flurouracil. Sensitivity to this combination was associated with poor differentiation status, higher cyclin A index, recruitment of cells into S phase, and induction of Bax expression and apoptosis.
Altered Expression of FAS System Is Related to Adverse Clinical Outcome in Stage I-II Breast Cancer Patients Treated with Adjuvant Anthracycline-Based Chemotherapy
Authors: Botti Claudio , Buglioni Simonetta , Benevolo Maria , Giannarelli Diana , Papaldo Paola , Cognetti Francesco , Vici Patrizia , Di Filippo Franco , Del Nonno Franca , Venanzi Franco Maria , Natali Pier Giorgio , Mottolese Marcella
Published: September 2005

Purpose: To determine the prognostic value of Fas receptor and Fas ligand (FasL) as apoptosis-related biomarkers in the context of chemoresponsiveness in breast cancer (BC) patients submitted to anthracycline-based adjuvant therapy.

Experimental Design: Fas and FasL were investigated by immunohistochemistry in surgical samples collected from 167 stage I-IIa-b BC patients enrolled in a prospective clinical trial using epirubicin plus cyclophosphamide in the adjuvant setting.

Results: Fas and FasL were significantly associated with tumor stage (P < 0.0001). Multivariate analysis indicated that stage, loss of Fas (relative risk, 8.5 and 9.12; P < 0.0001) and FasL up-regulation (relative risk, 2.38 and 2.88; P = 0.01) were independent prognostic variables influencing both disease-free survival (DFS) and overall survival (OS). A Cox analysis using a four-category Fas/FasL phenotype (+/−, +/+, −/+, −/−) as a stratification factor evidenced a highly positive association between Fas/FasL phenotype and the cumulative hazard of relapse and death in the entire series of patients. We also estimated the DFS and OS for different combinations of the pathological-tumor-node-metastasis (TNM) stage and Fas/FasL by using the K sample log-rank exact test demonstrating that significantly shorter DFS and OS were observed in Fas-negative and FasL-positive patients in both stage I-IIa and IIb.

Conclusions: Data presented herein demonstrated that, according to a number of in vitro studies, the prognosis for BC patients receiving adjuvant anthracycline-based chemotherapy strongly depends on the Fas/FasL status. Therefore, a concomitant altered pattern of Fas/FasL expression seems to configure an aggressive tumor phenotype linked to disease progression.
Pretreatment with Rituximab Does Not Inhibit the Human Immune Response against the Immunogenic Protein LMB-1
Authors: Hassan Raffit , Williams-Gould Juanita , Watson Thelma , Pai-Scherf Lee , Pastan Ira
Published: September 2005

Purpose: Rituximab, a humanized monoclonal antibody directed to the CD20 antigen present on B lymphocytes, could potentially abrogate the humoral immune response to murine monoclonal antibodies or immunotoxins by depleting antibody-producing B cells.

Experimental Design: A Phase II study of LMB-1, an immunotoxin targeting the Lewis Y tumor antigen, in combination with rituximab was conducted to test the hypothesis that rituximab could abolish or diminish the development of human antibodies to LMB-1. Five patients were treated in this study and received 375 mg/m2 rituximab on days 1 and 7 followed by 45 μg/kg/day LMB-1 on days 10, 12, and 14. The development of human antibodies against LMB-1 was detected using a serum neutralization and ELISA.

Results: All five of the patients had a total suppression of circulating CD20/CD19 B-cell population before the administration of the first dose of the immunotoxin. Before rituximab treatment, the mean percentage of CD20/CD19-positive B cells in the five treated patients was 19.8% (range, 4.5–29.8%) of the total peripheral lymphocytes. After two doses of rituximab, CD20/CD19-positive B lymphocytes constituted ≤0.1% of the total peripheral lymphocytes. Despite absent circulating antibody-producing B cells, before and during LMB-1 treatment, all of the patients developed neutralizing antibodies to the immunotoxin by day 21 of drug administration, which prevented retreatment.

Conclusions: Even though rituximab caused complete depletion of circulating CD20/CD19-positive B cells, it had no effect in suppressing the human antibody response to LMB-1 and may be of limited utility in suppressing human antibody responses to other immunogenic proteins.
Native and Nonnative Speakers' Processing of a Miniature Version of Japanese as Revealed by ERPs
Authors: Mueller Jutta L. , Hahne Anja , Fujii Yugo , Friederici Angela D.
Published: September 2005

Several event-related potential (ERP) studies in second language (L2) processing have revealed a differential vulnerability of syntax-related ERP effects in contrast to purely semantic ERP effects. However, it is still debated to what extent a potential critical period for L2 acquisition, as opposed to the attained proficiency level in the L2, contributes to the pattern of results reported in previous ERP studies. We studied L2 processing within the model of a miniature version of a natural language, namely Japanese, specifically constructed to assure high proficiency of the learners. In an auditory ERP experiment, we investigated sentence processing of the “Mini-Japanese” in Japanese native speakers and German volunteers before and after training. By making use of three different types of violation, namely, word category, case, and classifier violations, native and nonnative ERP patterns were compared. The three types of violation elicited three characteristic ERP patterns in Japanese native speakers. The word category violation elicited an anteriorly focused, broadly distributed early negativity followed by a P600, whereas the case violation evoked a P600 which was preceded by an N400. The classifier violation led solely to a late left distributed negativity with an anterior focus. Although the P600 was similar for Japanese natives and learners, the N400 and the anterior negativities were not present in the learner group. The differences across groups suggest deviant neural processes in on-line syntactic and thematic processing in the L2 learners despite high behavioral skills.
Investigating the Neural Basis of the Auditory Continuity Illusion
Authors: Husain Fatima T. , Lozito Thomas P. , Ulloa Antonio , Horwitz Barry
Published: September 2005

In this study, we investigated one type of auditory perceptual grouping phenomena—the auditory continuity illusion (also called temporal induction). We employed a previously developed, neurobiologically realistic, large-scale neural network model of the auditory processing pathway in the cortex, ranging from the primary auditory cortex to the prefrontal cortex, and simulated temporal induction without changing any model parameters. The model processes tonal contour stimuli, composed of combinations of upward and downward FM sweeps and tones, in a delayed match-to-sample task. The local electrical activities of the neuronal units of the model simulated accurately the experimentally observed electrophysiological data, where available, and the model's simulated BOLD-fMRI data were quantitatively matched with experimental fMRI data. In the present simulations, intact stimuli were matched with fragmented versions (i.e., with inserted silent gaps). The ability of the model to match fragmented stimuli declined as the duration of the gaps increased. However, when simulated broadband noise was inserted into these gaps, the matching response was restored, indicating that a continuous stimulus was perceived. The electrical activities of the neuronal units of the model agreed with electrophysiological data, and the behavioral activity of the model matched human behavioral data. In the model, the predominant mechanism implementing temporal induction is the divergence of the feedforward connections along the auditory processing pathway in the temporal cortex. These simulation results not only attest to the robustness of the model, but further predict the primary role of the anatomical connectivity of the auditory processing areas in mediating the continuity illusion.
Holistic Processing of Faces: Learning Effects with Mooney Faces
Authors: Latinus Marianne , Taylor Margot J.
Published: September 2005

The specialness of faces is seen in the face inversion effect, which disrupts the configural, but not the analytic, processing of faces. Mooney faces, which are processed holistically, allowed us to determine the contribution of holistic processing to the face inversion effect. As inverted Mooney faces are difficult to recognize as faces, we also included an intermediary training period for Mooney face recognition for half of the subjects. Early face-sensitive ERPs (N170 and P1) and P2 were measured.

Behavioral data showed an increase in correct responses to inverted and upright Mooney faces after the learning phase for the experimental group. No effects were seen on P1. N170 latency did not vary with stimulus type before the intermediary phase, however, N170 amplitude was consistently larger for upright than inverted Mooney faces. After the intermediary exercise, N170 was delayed for inverted compared to upright Mooney faces. In contrast, for both groups of subjects P2 amplitude was larger for nonface stimuli, and P2 amplitude decreased after the intermediate task only for the subjects trained to recognize Mooney faces.

As the usual inversion effect seen with photographic faces (delayed and larger N170) was not seen with Mooney faces, these data suggest that this effect on N170 is due to the recruitment of analytic processing. P2 reflected learning and a deeper processing of the stimuli that were not identifiable as faces.
Female dispersal, inbreeding avoidance and mate choice in Thomas langurs (Presbytis thomasi)
Authors: van Hooff Jan A.R.A.M , Willems Erik P. , Wich Serge A. , Sterck Elizabeth H.M.
Published: September 2005

Female social dispersal in primates differs from the general mammalian pattern of locational dispersal. Both nulliparous and parous females may disperse to another group. Several hypotheses can explain female social dispersal: reduction of predation risk, inbreeding avoidance, and offspring protection through mate choice. We tested these hypotheses with an extended data set of Thomas langurs (Presbytis thomasi) and investigated parameters of male behaviour that females may use in their dispersal decisions. Data were collected over a 12.5-year period from a wild population in Sumatra, Indonesia, allowing for some critical tests of the hypotheses. Females dispersed to a group smaller than their original one, thereby refuting the predation risk hypothesis. Maturing nulliparous females only dispersed when their father was resident. Therefore, dispersal by nulliparous females was best explained through inbreeding avoidance. Parous females transferred to young, adult males. These males provided better protection to offspring against predation and infanticide than the old, late tenure males. Therefore, females transfer to better protector males. The male behavioural cues that females use to assess male quality were unclear. Females, however, may use proxies of male age, such as group composition and acoustical characteristics of loud calls, as indicators of male quality. The results suggest that female mate choice is an important function of social dispersal by parous females. Its importance in locational dispersal remains to be investigated.
Federico García Lorca and Salāh 'Abd al-Sabūr as Composers of Modern Ballads: A Comparative Study
Authors: Azouqa Aida
Published: September 2005

As a comparative study, this paper aims at revealing the impact of Federico García Lorca's (1898-1936) collection of poems in his Gypsy Ballads (1928) on the poetry of Salāh 'Abd al-Sabūr (1931-1981), particularly on his poems in the collection of al-Nās fī Bilādī [People in My Country, 1957]. The study shows that Lorca's in fluence was both generic and stylistic, and that these elements enabled 'Abd al-Sabūr to discard his initial Romantic subjectivism, engage his poetry in the pressing issues of his age, and modernize his poetry through using appropriate modes of expression that enabled him to speak the language of his times. Through reading Lorca's work, 'Abd al-Sabūr introduced the European popular ballad into Arabic poetry (and combined it with elements from the Egyptian popular narratives); he fused the ballad with poetic devices that Lorca had applied to the ballad, so as to modernize the genre, and use it as a means for expressing his poetical concerns. To achieve its purposes, the study compares three of 'Abd al-Sabūr's poems, namely "Hajāma al-Tatār" [The Tartars Attacked], "Shanq Zahrān," [The Execution of Zahrān], and al-Nās fī Bilādī [People in My Country] with Lorca's "Ballad of the Civil Guard."
Gibran's Unpublished Letters to Archbishop Antonious Bashīr
Authors: El-Hage George
Published: September 2005

These are some of Gibran's unpublished letters to Archbishop Antonious Bashīr. They were unknown and unpublished until November 11, 2004, when they appeared in the original Arabic in the Lebanese daily newspaper, Al-Nahār (Almulhaq). According to Al-Nahār, these letters remained hidden among the archives of the Greek Orthodox Diocese in North America. It appears that Archbishop Philip Salība one day was searching in the old files of his predecessor, Antonious Bashīr, when he accidentally found these letters. Apparently, Gibran had written them to his friend, Antonious Bash¬r, who was also the translator of the Prophet into Arabic. The Lebanese newspaper adds that these letters acquire great importance as they constitute, on the one hand, a dialogue between the author and his translator, and on the other, they form part of Gibran's great literary heritage of which many hidden treasures have not yet been discovered.
Population-based laboratory surveillance for Giardia sp. and Cryptosporidium sp. infections in a large Canadian health region
Authors: Laupland Kevin B , Church Deirdre L
Published: September 2005

Background

Giardia lamblia (intestinalis) and Cryptosporidium parvum are the two most important intestinal parasites infecting North Americans but there is a paucity of active population-based surveillance data from Canada. This study determined the incidence of and demographic risk factors for developing Giardia sp. and Cryptosporidium sp. infections in a general Canadian population.

Methods

Population-based laboratory surveillance was conducted among all residents of the Calgary Health Region (CHR; population ≅ 1 million) during May 1, 1999 and April 30, 2002.

Results

Giardia sp. infection occurred at a rate of 19.6 per 100,000 populations per year. Although the yearly incidence was stable, a significant seasonal variation was observed with a peak in late summer to early fall. Males were at higher risk for development of this infection as compared to females (21.2 vs. 17.9 per 100,000/yr; relative risk (RR) 1.19; 95% confidence interval (CI), 1.00–1.40, p = 0.047), and there was a significant decrease in risk associated with an increasing age. Cryptosporidium sp. infection occurred at an overall rate of 6.0 per 100,000 populations per year although a large outbreak of Cryptosporidium sp. infections occurred in the second half of the summer of 2001. During August and September of 2001, the incidence of cryptosporidiosis was 55.1 per 100,000 per year as compared to 3.1 per 100,000 per year for the remainder of the surveillance period (p < 0.0001). Cryptosporidiosis was largely a disease of children with an incidence of 17.8 per 100,000 per year occurring among those aged < 20 years of age compared to 1.25 per 100,000 per year for adults ≥ 20 years of age (RR 14.19; 95% CI, 9.77–21.11; p < 0.0001).

Conclusion

This study provides important information on the occurrence and demographic risk groups for acquisition of giardiasis and cryptosporidiosis in a non-selected Canadian population.
Burn wounds infected with Pseudomonas aeruginosa triggers weight loss in rats
Authors: Steinstraesser Lars , Burkhard Olaf , Fan Ming H , Jacobsen Frank , Lehnhardt Marcus , Su Grace , Daigeler Adrien , Steinau Hans U , Remick Daniel , Wang Stewart C
Published: September 2005

Background

Despite dramatic improvements in the management of burns, infection still remains a serious risk for the burn patient. The aim of this study was to shed light on the impact of acute burn injury with or without infection on cytokine profiles.

Methods

Sprague-Dawley rats (n = 21) were randomized into three groups: 1) burn only 2) burn and infection or 3) sham burn. Weight was monitored and blood was collected for cytokine ELISA, LPS quantification, and peripheral blood analysis. Animals were sacrificed either after 6 or 12 days.

Results

Infected animals showed substantial weight loss until day 6 post-burn as compared to burn alone. Endotoxin and TNF-α levels were elevated early in the infected burn group within 48 hours post-burn. In contrast, significant up-regulation of the anti-inflammatory cytokine IL-10 occurred later in the clinical course and was associated with the recovery from weight loss.

Conclusion

Our results suggest that in the presence of infection, you get a SIRS response possibly due to transient endotoxemia that is only seen in the infection group. In contrast, both burn and infection get a late IL-10 (CARS) response, which is then associated with a return to normal weight in the infection group.
Evaluation of antimotility effect of Lantana camara L. var. acuelata constituents on neostigmine induced gastrointestinal transit in mice
Authors: Sagar Lenika , Sehgal Rajesh , Ojha Sudarshan
Published: September 2005

Background

Lantana camara L. (Verbenaceae), a widely growing shrub which is toxic to some animal species, has been used in the traditional medicine for treating many ailments. The purpose of the present study was to evaluate the antimotility effects of Lantana camara leaf constituents in mice intestine.

Methods

Evaluation of antimotility activity was done in intestine of mice treated with Lantana camara leaf powder, Lantana camara methanolic extract (LCME), lantadene A, neostigmine and neostigmine + LCME. Neostigmine was used as a promotility agent. Intestinal motility was assessed by charcoal meal test and gastrointestinal transit rate was expressed as the percentage of the distance traversed by the charcoal divided by the total length of the small intestine. The antidiarrheal effect of LCME was studied against castor oil induced diarrhea model in mice.

Results

The intestinal transit with LCME at a dose of 500 mg/kg was 26.46% whereas the higher dose (1 g/kg) completely inhibited the transit of charcoal in normal mice. The % intestinal transit in the neostigmine pretreated groups was 24 and 11 at the same doses respectively. When the plant extracts at 125 and 250 mg/kg doses were administered intraperitonealy, there was significant reduction in fecal output compared with castor oil treated mice. At higher doses (500 and 1000 mg/kg), the fecal output was almost completely stopped.

Conclusion

The remarkable antimotility effect of Lantana camara methanolic extract against neostigmine as promotility agent points towards an anticholinergic effect due to Lantana camara constituents and attests to its possible utility in secretory and functional diarrheas and other gastrointestinal disorders. This effect was further confirmed by significant inhibition of castor oil induced diarrhea in mice by various doses of LCME.
Phase I/IIa Study of Cisplatin and Gemcitabine As Induction Chemotherapy Followed by Concurrent Chemoradiotherapy With Gemcitabine and Paclitaxel for Locally Advanced Non–Small-Cell Lung Cancer
Authors: Divers Stephen G. , Spencer Sharon A. , Carey Delicia , Busby Elizabeth M. , Hyatt Mark D. , Robert Francisco
Published: September 2005

Purpose

This is a phase I/IIa study to assess tolerance of gemcitabine and paclitaxel with radiotherapy in locally advanced non–small-cell lung cancer after induction chemotherapy.

Patients and Methods

Fifty-seven patients with stage III non–small-cell lung cancer were treated with cisplatin 80 mg/m2 on days 1 and 22 and gemcitabine 1,250 mg/m2 on days 1, 8, 22, and 28. Chemoradiotherapy began on day 43 as follows: cohort 1 (n = 9), gemcitabine 300 mg/m2 and paclitaxel 35 mg/m2 weekly (except week 9); cohort 2 (n = 9), gemcitabine 150 mg/m2 and paclitaxel 35 mg/m2 weekly (except week 9); cohort 3 (n = 10) and the 25 phase IIa patients, gemcitabine 300 mg/m2 and paclitaxel 135 mg/m2 every 21 days. Patients were treated with three-dimensional thoracic radiotherapy concurrently to 60 Gy.

Results

Weekly chemotherapy resulted in grade 4 esophageal and grade 3 or higher pulmonary toxicities. Reduction in dose density (cohort 3) led to a tolerable toxicity profile and was chosen as the phase IIa regimen. The response rate to induction was 49%, with stable disease in 40% of the patients. The response rate after consolidation therapy was 75% (94% for weekly chemotherapy v 82% for every 3 weeks). Median survival was 23 months, and 3-year survival was 45% for eligible patients. Local relapse occurred in 20% of the patients. Performance status of more than 1 predicted for poor outcome, but baseline pulmonary function did not. Dosimetric parameters including V15, V20, V30 (percent lung volume receiving ≥ 15, ≥ 20, and ≥ 30 Gy, respectively), and mean lung dose correlated with pulmonary toxicity.

Conclusion

Additional investigation with the 3-week schedule is warranted in patients with a good performance status based on the safety profile and preliminary efficacy data observed in this study.