bluuebunny/crossref_metadata_2025 huggingface dataset:
Achieving a Major Molecular Response at the Time of a Complete Cytogenetic Response (CCgR) Predicts a Better Duration of CCgR in Imatinib-Treated Chronic Myeloid Leukemia Patients
Authors: Iacobucci Ilaria , Saglio Giuseppe , Rosti Gianantonio , Testoni Nicoletta , Pane Fabrizio , Amabile Marilina , Poerio Angela , Soverini Simona , Bassi Simona , Cilloni Daniela , Bassan Renato , Breccia Massimo , Lauria Francesco , Izzo Barbara , Merante Serena , Frassoni Francesco , Paolini Stefania , Montefusco Enrico , Baccarani Michele , Martinelli Giovanni ,   for the GIMEMA Working Party on Chronic Myeloid Leukemia
Published: May 2006

Purpose: Most patients with chronic-phase chronic myeloid leukemia (CML) who receive imatinib achieve a complete cytogenetic remission (CCgR) and low levels of BCR-ABL transcripts. CCgR is durable in the majority of patients but relapse occurs in a subset.

Experimental Design: To determine the potential of quantitative reverse transcription-PCR of BCR-ABL to predict cytogenetic relapse, we serially monitored residual disease in 97 CML patients with an imatinib-induced CCgR. Patients with late chronic phase CML after IFN-α failure were treated with imatinib (400 mg daily).

Results: During the imatinib median follow-up time of 36 months (range, 12-54 months), disease monitoring occurred by cytogenetics and quantitative PCR. Twenty percent of patients experienced cytogenetic relapse at a median of 18 months after CCgR and a median of 24 months after starting imatinib. None of the possible prognostic factors studied in univariate and multivariate analyses seemed to predict for loss of cytogenetic response but the reduction of BCR-ABL transcript levels at the time of CCgR is an important prognostic factor.

Conclusions: In our study, we showed not only that achieving a major molecular remission at 12 months is predictive of a durable cytogenetic remission but also that patients who achieved a major molecular remission (expressed both as the BCR-ABL/β2 microglobulin ratio % <0.0005 and as a 3-log reduction from median baseline value) already at the time of first achieving a CCgR have significantly longer cytogenetic remission durations than those without this magnitude of molecular response (P < 0.05).
Infectivity-Enhanced Adenoviruses Deliver Efficacy in Clinical Samples and Orthotopic Models of Disseminated Gastric Cancer
Authors: Kangasniemi Lotta , Kiviluoto Tuula , Kanerva Anna , Raki Mari , Ranki Tuuli , Sarkioja Merja , Wu Hongju , Marini Frank , Höckerstedt Krister , Isoniemi Helena , Alfthan Henrik , Stenman Ulf-Håkan , Curiel David T. , Hemminki Akseli
Published: May 2006

Purpose: Metastatic gastric cancer remains a common and devastating disease without curative treatment. Recent proof-of-concept clinical trials have validated gene therapy with adenoviruses as an effective and safe modality for the treatment of cancer. However, expression of the primary coxsackie-adenovirus receptor is variable in advanced cancers, and therefore, the use of heterologous receptors could be advantageous.

Experimental Design: Here, we used capsid-modified adenoviruses for increasing the transduction and subsequent antitumor efficacy. 5/3 chimeric viruses have a serotype 3 knob which allows binding to a receptor distinct from coxsackie-adenovirus receptor. The fiber of Ad5lucRGD is modified with an integrin-targeted motif. Polylysine motifs, pK7 and pK21, bind to heparan sulfates. Oncolytic adenoviruses replicate in and kill tumor cells selectively. Gastric cancer cell lines and fresh clinical samples from patients were infected with transductionally targeted viruses. Capsid-modified oncolytic adenoviruses were used in cell killing experiments. To test viral transduction and therapeutic efficacy in vivo, we developed orthotopic mouse models featuring i.p. disseminated human gastric cancer, which allowed the evaluation of biodistribution and antitumor efficacy in a system similar to humans.

Results: Capsid modifications benefited gene transfer efficiency and cell killing in gastric cancer cell lines and clinical samples in vitro and in vivo. Modified oncolytic adenoviruses significantly increased the survival of mice with orthotopic gastric cancer.

Conclusions: These preclinical data set the stage for the clinical evaluation of safety and efficacy in patients with disease refractory to current modalities.
Real-time, Image-Guided, Convection-Enhanced Delivery of Interleukin 13 Bound to Pseudomonas Exotoxin
Authors: Murad Gregory J.A. , Walbridge Stuart , Morrison Paul F. , Garmestani Kayhan , Degen Jeffrey W. , Brechbiel Martin W. , Oldfield Edward H. , Lonser Russell R.
Published: May 2006

Purpose: To determine if the tumor-targeted cytotoxin interleukin 13 bound to Pseudomonas exotoxin (IL13-PE) could be delivered to the brainstem safely at therapeutic doses while monitoring its distribution in real-time using a surrogate magnetic resonance imaging tracer, we used convection-enhanced delivery to perfuse rat and primate brainstems with IL13-PE and gadolinium-bound albumin (Gd-albumin).

Experimental Design: Thirty rats underwent convective brainstem perfusion of IL13-PE (0.25, 0.5, or 10 μg/mL) or vehicle. Twelve primates underwent convective brainstem perfusion of either IL13-PE (0.25, 0.5, or 10 μg/mL; n = 8), co-infusion of 125I-IL13-PE and Gd-albumin (n = 2), or co-infusion of IL13-PE (0.5 μg/mL) and Gd-albumin (n = 2). The animals were permitted to survive for up to 28 days before sacrifice and histologic assessment.

Results: Rats showed no evidence of toxicity at all doses. Primates showed no toxicity at 0.25 or 0.5 μg/mL but showed clinical and histologic toxicity at 10 μg/mL. Quantitative autoradiography confirmed that Gd-albumin precisely tracked IL13-PE anatomic distribution and accurately showed the volume of distribution.

Conclusions: IL13-PE can be delivered safely and effectively to the primate brainstem at therapeutic concentrations and over clinically relevant volumes using convection-enhanced delivery. Moreover, the distribution of IL13-PE can be accurately tracked by co-infusion of Gd-albumin using real-time magnetic resonance imaging.
Phase II Trial of Bevacizumab in Combination with Weekly Docetaxel in Metastatic Breast Cancer Patients
Authors: Ramaswamy Bhuvaneswari , Elias Anthony D. , Kelbick Nicole T. , Dodley Angela , Morrow Mark , Hauger Marsha , Allen Joan , Rhoades Chris , Kendra Kari , Chen Helen X. , Eckhardt S. Gail , Shapiro Charles L.
Published: May 2006

Purpose: To evaluate the safety and efficacy of bevacizumab and weekly docetaxel as first- or second-line therapy in patients with metastatic breast cancer (MBC).

Patients and Methods: Twenty-seven MBC patients received i.v. bevacizumab at 10 mg/kg on days 1 and 15 in combination with i.v. docetaxel 35 mg/m2 on days 1, 8, and 15 of a 28-day cycle. Primary end points were to assess toxicity, overall response rate, and progression-free survival. A secondary end point was to assess the relationship between plasma endothelial and cell adhesion markers and clinical outcomes.

Results: One-hundred fifty-eight treatment cycles were administered with a median of six cycles (range 1-15 cycles) per patient. The most common grade 4 toxicities per patient were as follows: 2 (7%)—pulmonary embolus, 1 (4%)—febrile neutropenia, and 1 (4%)—infection; grade 3 toxicities were 4 (15%)—neutropenia, 4 (15%)—fatigue, 2 (7%)—neuropathy, 2 (7%)—athralgias, 2 (7%)—stomatitis, 1 (7%)—pleural effusion, and 1 (4%)—hypertension. The overall response rate was 52% [95% confidence interval (95% CI), 32-71%], median response duration was 6.0 months (95% CI, 4.6-6.5 months), and the median progression-free survival was 7.5 months (95% CI, 6.2-8.3 months). In hypothesis-generating univariate and limited multivariate analyses, E-selectin was statistically significantly associated with response to the combination.

Conclusion: Bevazicumab in combination with weekly docetaxel is active with acceptable toxicities in MBC. Additional studies evaluating E-selectin as a marker of response to bevacizumab-containing chemotherapy are warranted.
Heterogeneous Nuclear Ribonucleoprotein G Shows Tumor Suppressive Effect against Oral Squamous Cell Carcinoma Cells
Authors: Shin Ki-Hyuk , Kang Mo K. , Kim Reuben H. , Christensen Russell , Park No-Hee
Published: May 2006

Purpose: Heterogeneous nuclear ribonucleoproteins (hnRNP) are nucleic acid binding proteins involved in RNA processing. We found that hnRNP G is expressed in normal human oral epithelial cells while frequently not found in the cells derived from human oral squamous cell carcinomas (HOSCC). The current study was designed to test the hypothesis that hnRNP G is a tumor suppressor.

Experimental Design: We investigated the expression levels of hnRNP G protein in normal, precancerous, and malignant oral tissues by in situ immunohistochemistry. In addition, wild-type or mutant hnRNP G was ectopically overexpressed in HOSCC cells and their effects on cellular replication kinetics, colonogenic efficiency, anchorage-independent growth, and in vivo tumorigenicity were determined.

Results: In situ immunohistochemical staining showed robust presence of hnRNP G in the basal cell layers of normal oral epithelium but the level of its staining was markedly reduced in dysplastic or cancerous tissues. Ectopic expression of wild-type hnRNP G in cancer cells lacking hnRNP G expression or containing mutant hnRNP G resulted in severe retardation of proliferation, reduction of colonogenic efficiency, loss of anchorage-independent growth, and reduction of in vivo tumorigenicity in immunocompromised mice. In addition, hnRNP G overexpression led to up-regulation of the expression of TXNIP, a cell cycle inhibitory gene, and significantly reduced the expression of the genes that promote cellular proliferation, such as EGR1, JUND, JUNB, FOS, FOSL1, ROS, and KIT.

Conclusions: These results indicate that hnRNP G is a tumor suppressor against HOSCC but its mechanisms of action remain to be further investigated.
Novel Cytosine Deaminase Fusion Gene Enhances the Effect of Radiation on Breast Cancer in Bone by Reducing Tumor Burden, Osteolysis, and Skeletal Fracture
Authors: Goblirsch Michael , Zwolak Pawel , Ramnaraine Margaret L. , Pan Weihong , Lynch Christine , Alaei Parham , Clohisy Denis R.
Published: May 2006

Background: Painful breast carcinoma metastases in bone are a common manifestation of malignant disease. Eradication of these tumors can be evasive, and as a result, skeletal morbidity increases with disease progression.

Experimental Design: The treatment potential of cytosine deaminase (CD) gene therapy combined with radiation treatment was evaluated in vitro and in vivo using a 4T1 murine breast carcinoma model. 4T1 carcinoma cells were transduced with a fusion gene encoding the extracellular and transmembrane domains of the human nerve growth factor receptor and the cytoplasmic portion of the yeast CD gene (NGFR-CDy).

Results and Conclusions: CD-expressing tumor cells (4TCDy) were highly sensitive to treatment by 5-fluorocytosine prodrug (P < 0.0001). 5-Fluorocytosine treatment of 4TCDy, but not 4T1 cells, enhanced the effects of radiation in vitro (P < 0.0001). 5-Fluorocytosine prodrug treatment also increased the therapeutic potential of radiation in vivo. Mice with 4TCDy intrafemoral tumors showed increased effectiveness of radiation based on improved reductions in tumor size, reductions in tumorigenic osteolysis, and a decrease in skeletal fractures (P < 0.01).
NOTCH1 Mutations in T-Cell Acute Lymphoblastic Leukemia: Prognostic Significance and Implication in Multifactorial Leukemogenesis
Authors: Zhu Yong-Mei , Zhao Wei-Li , Fu Jian-Fei , Shi Jing-Yi , Pan Qin , Hu Jiong , Gao Xiao-Dong , Chen Bing , Li Jun-Min , Xiong Shu-Min , Gu Long-Jun , Tang Jing-Yi , Liang Hui , Jiang Hui , Xue Yong-Quan , Shen Zhi-Xiang , Chen Zhu , Chen Sai-Juan
Published: May 2006

Purpose: NOTCH signaling pathway is essential in T-cell development and NOTCH1 mutations are frequently present in T-cell acute lymphoblastic leukemia (T-ALL). To gain insight into its clinical significance, NOTCH1 mutation was investigated in 77 patients with T-ALL.

Experimental Design: Detection of NOTCH1 mutation was done using reverse transcription-PCR amplification and direct sequencing, and thereby compared according to the clinical/biological data of the patients.

Results: Thirty-two mutations were identified in 29 patients (with dual mutations in 3 cases), involving not only the heterodimerization and proline/glutamic acid/serine/threonine domains as previously reported but also the transcription activation and ankyrin repeat domains revealed for the first time. These mutations were significantly associated with elevated WBC count at diagnosis and independently linked to short survival time. Interestingly, the statistically significant difference of survival according to NOTCH1 mutations was only observed in adult patients (>18 years) but not in pediatric patients (≤18 years), possibly due to the relatively good overall response of childhood T-ALL to the current chemotherapy. NOTCH1 mutations could coexist with HOX11, HOX11L2, or SIL-TAL1 expression. The negative effect of NOTCH1 mutation on prognosis was potentiated by HOX11L2 but was attenuated by HOX11.

Conclusion: NOTCH1 mutation is an important prognostic marker in T-ALL and its predictive value could be even further increased if coevaluated with other T-cell-related regulatory genes. NOTCH pathway thus acts combinatorially with oncogenic transcriptional factors on T-ALL pathogenesis.
Mixed Lineage Leukemia–Rearranged Childhood Pro-B and CD10-Negative Pre-B Acute Lymphoblastic Leukemia Constitute a Distinct Clinical Entity
Authors: Attarbaschi Andishe , Mann Georg , König Margit , Steiner Manuel , Strehl Sabine , Schreiberhuber Anita , Schneider Björn , Meyer Claus , Marschalek Rolf , Borkhardt Arndt , Pickl Winfried F. , Lion Thomas , Gadner Helmut , Haas Oskar A. , Dworzak Michael N. ,   on behalf of the Austrian Berlin-Frankfurt-Münster Cooperative Study Group
Published: May 2006

Purpose:Mixed lineage leukemia (MLL) abnormalities occur in ∼50% of childhood pro-B acute lymphoblastic leukemia (ALL). However, the incidence and type of MLL rearrangements have not been determined in common ALL (cALL) and CD10+ or CD10− pre-B ALL.

Experimental Design: To address this question, we analyzed 29 patients with pro-B ALL, 11 patients with CD10− pre-B ALL, 23 pre-B, and 26 cALL patients with CD10 on 20% to 80%, as well as 136 pre-B and 143 cALL patients with CD10 ≥80% of blasts. They were all enrolled in four Austrian ALL multicenter trials. Conventional cytogenetics were done to detect 11q23 abnormalities and in parallel the potential involvement of the MLL gene was evaluated with a split apart fluorescence in situ hybridization probe set.

Results: We found that 15 of 29 pro-B ALL, 7 of 11 CD10− pre-B ALL, and 1 of 2 French-American-British classification L1 mature B-cell leukemia cases had a MLL rearrangement. However, no 11q23/MLL translocation was identified among the CD10+ pre-B and cALL patients. MLL-rearranged pro-B and CD10− pre-B ALL cases had similar clinical and immunophenotypic (coexpression of CDw65 and CD15) features at initial diagnosis.

Conclusions: The striking similarities between the two CD10− ALL subsets imply that CD10− pre-B ALL variants may represent pro-B ALL cases that maintained the propensity to rearrange and express their immunoglobulin heavy chain rather than actual pre-B ALL forms transformed at this later stage of B-cell differentiation. However, direct experimental data are needed to confirm this observation.
Effective Treatment of Pancreatic Cancer Xenografts with a Conditionally Replicating Virus Derived from Type 2 Herpes Simplex Virus
Authors: Fu Xinping , Tao Lihua , Li Min , Fisher William E. , Zhang Xiaoliu
Published: May 2006

Purpose: Pancreatic cancer is a devastating disease that is almost universally fatal because of the lack of effective treatments. We recently constructed a novel oncolytic virus (FusOn-H2) from the type 2 herpes simplex virus. Because the replication potential of FusOn-H2 depends on the activation of the Ras signaling pathway, we evaluated its antitumor effect against pancreatic cancer, which often harbors K-ras gene mutations.

Experimental Design: Human pancreatic cancer xenografts were established in nude mice either s.c. or orthotopically (n = 8/group). FusOn-H2 was injected either directly (s.c. tumors) or by the i.v. or i.p. route (orthotopic tumors). Tumor volume, weight, and survival time were recorded for each animal. Statistical analyses were done by Student's t test.

Results: A single intratumor injection of FusOn-H2 completely eradicated s.c. pancreatic cancers in all animals. Systemic injection of the oncolytic virus produced clear antitumor effects but did not abolish tumors in any animal. The most striking antitumor effect was seen when the virus was given i.p. Delivery of FusOn-H2 by this route completely eradicated established orthotopic tumors in 75% of the animals and completely prevented local metastases.

Conclusions: FusOn-H2 has potent activity against human pancreatic cancer xenografts and may be a promising candidate for investigative virotherapy of this malignancy.
Epidermal Growth Factor Receptor Messenger RNA Expression, Gene Dosage, and Gefitinib Sensitivity in Non–Small Cell Lung Cancer
Authors: Dziadziuszko Rafal , Witta Samir E. , Cappuzzo Federico , Park Seongjin , Tanaka Koji , Danenberg Peter V. , Barón Anna E. , Crino Lucio , Franklin Wilbur A. , Bunn Paul A. , Varella-Garcia Marileila , Danenberg Kathleen D. , Hirsch Fred R.
Published: May 2006

Purpose: Epidermal growth factor receptor (EGFR) mRNA expression and EGFR gene dosage by quantitative PCR in tumor samples obtained from patients with gefitinib-treated non–small cell lung cancer were analyzed in order to determine the association with treatment outcome, clinical, and biological features [EGFR copy number by fluorescent in situ hybridization (FISH), EGFR tyrosine kinase mutations, and EGFR protein expression].

Experimental Design: EGFR mRNA expression was measured by real-time quantitative reverse transcription-PCR in 64 patients, and EGFR gene dosage was analyzed by real-time quantitative PCR in 82 patients from paraffin-embedded specimens.

Results: EGFR mRNA expression was higher in responders to gefitinib as compared with nonresponders (P = 0.012). Patients with high EGFR mRNA expression (>5.01) had 43% response probability, whereas patients with low EGFR mRNA expression had 8% response probability (P = 0.006). Patients with high EGFR mRNA expression had longer median progression-free (5.3 versus 2.8 months, P = 0.028) but not overall survival (13.8 versus 10.9 months, P = 0.87). EGFR mRNA expression was higher in FISH-positive patients (P = 0.001) and in patients with positive EGFR immunostaining (P < 0.001) but not in patients with EGFR mutations (P = 0.19). EGFR gene dosage did not predict response (P = 0.54), progression-free (P = 0.73), or overall survival (P = 0.89). EGFR gene dosage was not associated with FISH positivity (P = 0.15), relative mRNA expression (P = 0.27), EGFR mutation status (P = 0.39), and EGFR protein expression (P = 0.35).

Conclusion: EGFR mRNA expression is a predictive biomarker for response to gefitinib and to progression-free survival after gefitinib treatment. EGFR gene dosage is neither predictive for response nor progression-free nor overall survival.
United States Food and Drug Administration Approval Summary: Bortezomib for the Treatment of Progressive Multiple Myeloma after One Prior Therapy
Authors: Kane Robert C. , Farrell Ann T. , Sridhara Rajeshwari , Pazdur Richard
Published: May 2006

Purpose: On March 25, 2005, bortezomib (Velcade for Injection; Millennium Pharmaceuticals, Inc., Cambridge, MA, and Johnson & Johnson Pharmaceutical Research & Development, L.L.C.) received regular approval from the U.S. Food and Drug Administration (U.S. FDA) for the treatment of multiple myeloma (MM) progressing after at least one prior therapy. This approval was based on bortezomib's efficacy and safety which was shown in a single, large, comparative international open-label phase 3 trial that randomized 669 patients with MM previously treated with at least one systemic regimen to receive single-agent bortezomib or high-dose dexamethasone. The FDA analysis of the trial data and bortezomib's regulatory development are summarized here.

Experimental Design and Results: Following a preplanned interim analysis of time to disease progression (the primary end point), an independent data-monitoring committee advised the sponsor to halt the study and offer bortezomib to all dexamethasone-treated study patients. Time to progression was significantly prolonged in the bortezomib treatment arm (median, 6.2 months) compared with the dexamethasone arm (median, 3.5 months; log-rank test, P < 0.0001; hazard ratio, 0.55; 95% confidence interval, 0.44-0.69). Analysis of overall survival done on the interim database (with 20% of events) showed the superiority of bortezomib for patients (log-rank test, P < 0.05; hazard ratio, 0.57; 95% confidence interval, 0.40-0.81). Using criteria from the European Group for Blood and Marrow Transplantation, the response rate (complete plus partial response) with bortezomib was also superior to dexamethasone (38% versus 18%; P < 0.0001). Adverse events on the bortezomib arm were similar to those previously observed in phase 2 studies; some notable adverse events included asthenia, peripheral neuropathy, thrombocytopenia, and neutropenia.

Conclusions: The U.S. FDA had earlier (May 2003) granted bortezomib accelerated approval for the treatment of patients with MM progressing after two prior therapies. The results of the phase 3 trial and the FDA analysis of the data, along with the sponsor's completion of other postmarketing commitments, confirm bortezomib's benefit and support regular approval.
Effect of cA2 Anti–Tumor Necrosis Factor-α Antibody Therapy on Hematopoiesis of Patients with Myelodysplastic Syndromes
Authors: Boula Anna , Voulgarelis Michael , Giannouli Stavroula , Katrinakis George , Psyllaki Maria , Pontikoglou Charalambos , Markidou Fotini , Eliopoulos George D. , Papadaki Helen A.
Published: May 2006

Purpose: Tumor necrosis factor α (TNF-α) plays a prominent role in the pathophysiology of myelodysplastic syndromes (MDS). The aim of this study was to explore the biological and immunoregulatory effect of the treatment with the anti–tumor necrosis factor-α monoclonal antibody cA2 on bone marrow (BM) progenitor/precursor and stromal cells and lymphocyte subsets, as well as the clinical response in MDS patients.

Experimental Design: Ten low-intermediate risk MDS patients received i.v. cA2 (3 mg/kg) at weeks 0, 2, 6, and 12. The number, survival, and clonogenic potential of BM progenitor/precursor cells, the hematopoiesis-supporting capacity of BM stromal cells, and the lymphocyte activation status were investigated in the patients at baseline and following treatment using flow cytometry, clonogenic assays, and long-term BM cultures (LTBMC). Clinical response was evaluated according to standardized criteria.

Results: cA2 administration reduced the proportion of apoptotic and Fas+ cells in the CD34+ cell compartment (P = 0.0215 and P = 0.0344, respectively) and increased the clonogenic potential of BM mononuclear and CD34+ cells (P = 0.0399 and P = 0.0304, respectively) compared with baseline. The antibody reduced tumor necrosis factor-α levels in LTBMC supernatants (P = 0.0043) and significantly improved the hematopoiesis-supporting capacity of LTBMC adherent cells. The proportion of activated peripheral blood and BM T-lymphocytes decreased significantly after treatment, suggesting an immunomodulatory effect of cA2. Two patients displayed minor hematologic responses whereas the remaining patients displayed stable disease with no disease progression.

Conclusions: The encouraging biological insights from cA2 administration may be useful in conducting further clinical trials using cA2 for selected MDS patients, particularly those with evidence of immune-mediated inhibition of hematopoiesis.
Surgical Management of Late Postpneumonectomy Bronchopleural Fistula: The Transsternal, Transpericardial Route
Authors: Misthos P. , Kakaris S. , Sepsas E. , Athanassiadi K. , Skottis I.
Published: May 2006

Background: Late postpneumonectomy bronchopleural fistula (LBPF) is a serious complication. Surgical repair of the bronchial stump through a lateral thoracotomy is a dangerous attempt due to mediastinal fibrothorax and the risk of pulmonary artery stump damage. Objectives: The goal of this study was to estimate the effectiveness of the transsternal, transpericardial approach for bronchial stump repair in case of LBPF. Methods: From 1996 to 2002, 1,294 lung resections for non-small cell lung cancer were performed at our department. Out of 412 pneumonectomies, 16 patients (3.8%) presented with LBPF after right pneumonectomy for non-small cell lung cancer. Thirteen of these patients were subjected to transsternal, transpericardial bronchial stump repair. They were followed postoperatively, and morbidity and mortality rates were recorded. Results: The interval between pneumonectomy and fistula diagnosis lasted from 12 to 85 months. The estimated sizes of the fistulae ranged from 5 to 21 mm, and the length of the bronchial stump was >1 cm only in 2 patients (15.3%).Due to persistent empyema, open-window thoracostomy was performed for definite treatment immediately after the operation for bronchial stump reamputation in 6 cases (46.1%). One patient (7.6%) died 3 months postoperatively due to bronchopleural fistula recurrence. This was also the only case of fistula recurrence. Conclusion: LBPF usually needs definite management to save the patient’s life. The transsternal, transpericardial approach is a safe and effective method.
Mechanical Properties in Notched AS-4/PEEK APC-2 Composite Laminates at Elevated Temperature
Authors: Jen Ming-Hwa R. , Tseng Yu-Chung , Chang Shi-Chao , Chen Ming
Published: May 2006

The response of centrally notched AS-4/PEEK APC-2 composite laminates at elevated temperatures is investigated empirically and systematically. The failure mechanism and mechanical properties in notched cross-ply and quasi-isotropic laminates are perceived. First, the ultimate strength decreases seriously as the hole diameter increases, whereas the longitudinal stiffness changes irregularly. Next, combined with the effect of temperature elevation, the ultimate strength is accelerated to decay while the longitudinal stiffness is reduced slowly. Neglecting the increase in longitudinal stiffness, the worst case of both lay-ups as expected with the largest hole diameter and at the highest temperature still sustains at least 60% of ultimate strength. However, the reduction of strength in cross-ply laminates is more serious than that in quasi-isotropic laminates. Finally, a modified predictive model was proposed and found satisfactorily acceptable. It is also highlighted as a reliable, general, and simple model.
Damage Progression in Open-hole Tension Laminates by the SIFT-EFM Approach
Authors: Tay T. E. , Liu G. , Tan V. B. C.
Published: May 2006

Predicting and modeling progressive damage in fiber-reinforced composite structures up to and including final failure is a considerable challenge because damage in composite materials is extremely complex, involving multiple modes, such as delamination, transverse microcracking, fiber breakage, fiber pullout, etc. Indeed, damage in composites should be studied at different length scales, ranging from the micromechanical to the macromechanical specimen and structural scales. The challenge, however, is in finding theories and methodologies that will faithfully reflect the structural effects of damage progression without involving an inordinate amount of detail (and effort) in the model, so that designers and engineers will have practical tools. In this article, a novel finite element-based method for modeling progressive damage in fiber-reinforced composites is presented. The element-failure method (EFM) is based on the simple idea that the nodal forces of an element of a damaged composite material can be modified to reflect the general state of damage and loading. This has an advantage over the usual material property degradation approaches in that because the stiffness matrix of the element is not changed, computational convergence is guaranteed, resulting in a robust modeling method. When employed with a suitable micromechanics-based failure criterion, it may evolve into an engineering tool for mapping damage initiation and propagation in composite structures. Here, we have utilized the micromechanical information contained in a new strain invariant failure theory (SIFT) to guide the nodal force modification scheme to model progressive damage. As an application of the SIFT-EFM approach, we present a rational nodal force modification scheme for the modeling of progressive damage in quasi-isotropic composite laminates with open holes, subjected to remote tensile loads. The proposed nodal force modification scheme assumes loss of load-bearing capability in the direction transverse to the fibers for the case of local transverse microcracking, and assumes total loss of load-bearing capability when both transverse microcracking and fiber rupture occur. The study investigates the effect of stacking or layup sequence and shows that it is important to refine the model in the through-thickness dimension and includes nodal force modification for the out-of-plane component. It reinforces the view that damage propagation in composites is a complex three-dimensional event. When compared with experimental data, the predicted damage maps and final failure loads show correct trends and reasonable agreement.
Three-dimensional Finite Element Buckling Analysis of Debonded Sandwich Panels
Authors: Aviles Francis , Carlsson Leif A.
Published: May 2006

A three-dimensional (3D) finite element analysis has been conducted to examine the local buckling behavior of foam-cored composite sandwich panels containing a face-core debond. The influences of core stiffness and debond size and shape are examined. The core stiffness was found to have a profound influence on the local buckling load, especially for low modulus cores and smaller debonds. Panels with square debonds buckled at lower loads than those with circular debonds of the same dimension, and buckling loads for both circular and square debonds decreased with increased debond size. The results of the analysis were compared to local buckling loads determined experimentally. Reasonable agreement was found between the predicted and experimentally measured local buckling loads for both circular and square debonds.
Polypyrrole-Montmorillonite Nanocomposite: A Composite Fast Ion Conductor
Authors: Krishantha D. M. M. , Rajapakse R. M. G. , Tennakoon D. T. B. , Dias H. V. R.
Published: May 2006

Cu(II)-exchanged montmorillonite [Cu(II)-MMT] takes up pyrrolium ions by ion exchange. Two pyrrolium ions are inserted for each Cu(II) ion expelled from its interlayers. These pyrrolium ions undergo spontaneous polymerization because of the remaining Cu(II) ions present within the intergalleries to form Cu(I)-polypyrrole-MMT nanocomposite. The polypyrrole (PPY) dispels any water already present within the intergalleries and the material becomes hydrophobic and reluctant to take up water. The inherent d-spacing due to anhydrous PPY present within the intergalleries is 16.0 A, which is a 6.4 A enhancement from the situation, which contains a bare inorganic ion. The material possesses unusually high mixed electrical conductivity. The conjugation length (and hence the electronic conductivity) decreases as the temperature is increased as confirmed by the Fourier transform infrared spectroscopy. However, the ionic component of the conductivity increases with temperature. The temperature dependence of conductivity shows Arrhenius behavior but two different activation regions are clearly visible. The activation energy for Cu(I) migration within the nanocomposite is much lower than 100 C (Ea1/4 0.09 eV). At the higher temperature region, the activation energy is 0.23 eV and this value is also comparatively low suggesting the favorable motion of Cu(I) ions within the PPY-MMT nanocomposite thus making it a fast Cu(I) ion conductor. The ionic conductivities are in the range 0.66-1.15 mS cm 1 in the temperature range from 25 to 120 C.
Pharmacokinetics, Tolerability, and Performance of a Novel Matrix Transdermal Delivery System of Fentanyl Relative to the Commercially Available Reservoir Formulation in Healthy Subjects
Authors: Marier Jean‐Francois , Lor Mary , Potvin Diane , DiMarco Marika , Morelli Gaetano , Sædder Eva Aggerholm
Published: May 2006

A novel transdermal formulation of fentanyl‐containing dipropylene glycol droplets dispersed in a silicone matrix with a rate‐controlling membrane was developed. Healthy male subjects (n = 24) received repeated 72‐hour applications of fentanyl (50 μg/h) as the novel matrix and the conventional reservoir formulations in a randomized, 2‐way crossover study. Blood samples were collected, and serum concentrations of fentanyl were assayed using liquid chromatography with mass spectrometry detection. The mean area under the curve (AUCτ) and peak concentrations (Cmax) of the matrix formulation were 84 838 pg·h/mL and 1680 pg/mL, respectively. Ratio and 90% confidence intervals of AUCτ and Cmax between the 2 formulations were within 80% to 125%. Adherence of the matrix formulation was higher than the reservoir formulation (62.5 vs 56.2%, P < .0001), without affecting skin irritation. Vital signs and adverse events of the 2 formulations were similar in nature and frequency. The novel matrix formulation displayed enhanced adherence and resulted in similar pharmacokinetics and tolerability as the reservoir formulation.
Development of a Semimechanistic Model to Describe the Pharmacokinetics of Gentamicin in Patients Receiving Hemodialysis
Authors: Dang Lily , Duffull Stephen
Published: May 2006

The aim of this study was to ascertain the most suitable dosing schedule for gentamicin in patients receiving hemodialysis. We developed a model to describe the concentration‐time course of gentamicin in patients receiving hemodialysis. Using the model, an optimal dosing schedule was evaluated. Various dosing regimens were compared in their ability to achieve maximum concentration (Cmax, ≥ 8 mg/L) and area under the concentration time‐curve (AUC ≥ 70 mg·h/L and ≤ 120 mg·h/L per 24 hours). The model was evaluated by comparing model predictions against real data collected retrospectively. Simulations from the model confirmed the benefits of predialysis dosing. The mean optimal dose was 230 mg administered immediately before dialysis. The model was found to have good predictive performance when simulated data were compared to data observed in real patients. In summary, a model was developed that describes gentamicin pharmacokinetics in patients receiving hemodialysis. Predialysis dosing provided a superior pharmacokinetic profile than did postdialysis dosing.
The Effects of Ergoloid Mesylates and Ginkgo Biloba on the Pharmacokinetics of Ticlopidine
Authors: Lu Wen‐Jen , Huang Jin‐ding , Lai Ming‐Liang
Published: May 2006

Ticlopidine is sometimes coadministered with ergoloid mesylates or ginkgo biloba in clinical situations. Our objective was to examine the effect of ergoloid mesylates and ginkgo biloba on ticlopidine pharmacokinetics. Ticlopidine, ergoloid mesylates, and ginkgo biloba significantly inhibited the organic anion transporting polypeptide (OATP‐B)–mediated uptake of [3H]‐estrone‐3‐sulfate in a concentration‐dependent manner. When ergoloid mesylates was coadministered with ticlopidine, the ticlopidine area under the plasma drug concentration‐time profile (AUC) from 0 to 12 hours was decreased 30% and the peak plasma drug concentration (Cmax) was decreased 29%, compared with ticlopidine administration alone. There were no significant changes in the pharmacokinetic parameters of ticlopidine when it was coadministered with ginkgo biloba. In summary, ergoloid mesylates is a more potent inhibitor of OATP‐B than is ginkgo biloba, and it can reduce the oral bioavailability of drugs transported by OATP‐B. Ergoloid mesylates markedly decreased the AUC and Cmax of ticlopidine, probably by inhibiting the OATP‐B‐mediated uptake of ticlopidine during the intestinal absorption phase. The results support a new model of intestinal drug‐drug interaction.
Bioequivalence of Liquid and Reconstituted Lyophilized Etanercept Subcutaneous Injections
Authors: Sullivan John T. , Ni Liyun , Sheelo Claudia , Salfi Margaret , Peloso Paul M.
Published: May 2006

The objective of this study was to compare the pharmacokinetics of liquid and reconstituted lyophilized etanercept. This single‐center, open‐label study had a 2‐period crossover design in which 36 healthy subjects were randomly assigned in a 1:1 ratio to etanercept (liquid/lyo or lyo/liquid). The treatments were separated by 28 days. Blood samples were obtained predose and at 10 predetermined time points postdose. Serum concentrations were determined by enzyme‐linked immunosorbent assay. Noncompartmental pharmacokinetic parameters were analyzed using a standard crossover analysis of variance model. Thirty‐three subjects completed both treatment periods. Geometric mean values (adjusted) of area under the serum drug concentration‐time curve from time zero to the time of the final quantifiable sample, area under the serum drug concentration‐time curve from time zero to infinity, and maximum concentration obtained with the 50‐mg/mL liquid etanercept injection were 93.0%, 90.7%, and 98.5% of the respective parameters for 2 injections of 25 mg/mL reconstituted formulation. All associated confidence intervals were within the predefined equivalence interval of 80% to 125%. No differences in safety profiles of the 2 formulations were apparent. Liquid etanercept was bioequivalent to the reconstituted lyophilized etanercept formulation.
Comparison of Maximum Drug Concentration and Area Under the Time‐Concentration Curve Between Humans and Animals for Oral and Intravenous Investigational Drugs
Authors: Fujita Tomoe , Matsumoto Yoshiaki , Ozaki Machiko , Majima Masataka , Kumagai Yuji , Ohtani Yoshio
Published: May 2006

The study compared maximum drug concentration (Cmax) and area under the time‐concentration curve (AUC) after normalization of doses to body weight and to body surface area and developed relationships for Cmaxand AUC between humans and animals for 75 oral and 10 intravenous investigational drugs. For the oral drugs, animal‐human ratios of Cmaxwere different among animals in both normalizations. Surface area‐normalized AUC ratios were not different, whereas weight‐normalized ones were different. For both normalizations for intravenous drugs, AUC ratios were not different. Drugs exhibiting 1/10 or smaller ratios tended to have low bioavailability. Regression of the relationships for dose‐normalized Cmaxand AUC transformed logarithmically between humans and animals were significant for the drugs with relatively high bioavailability. As approaches for predicting human Cmaxand AUC from animals, surface area normalization seems to surpass weight normalization, and the equation obtained can be applied to drugs with high bioavailability.
An Open‐Label, Parallel Group Study Investigating the Effects of Age and Gender on the Pharmacokinetics of the Once‐Daily Glucagon‐Like Peptide‐1 Analogue Liraglutide
Authors: Damholt Birgitte , Golor Georg , Wierich Werner , Pedersen Poul , Ekblom Marianne , Zdravkovic Milan
Published: May 2006

Liraglutide is a once‐daily glucagon‐like peptide‐1 analogue being developed for the treatment of type 2 diabetes. The aim of this study was to investigate the effect of age and gender on the pharmacokinetics of liraglutide. Eight male and 8 female subjects were recruited from an 18‐ to 45‐year‐old group and an over‐65‐year‐old group, respectively. All subjects received a single subcutaneous dose of 1.0 mg liraglutide. The area under the liraglutide plasma concentration curve from time 0 to last quantifiable concentration adjusted for body weight (significant covariate; P = .001) was found to be equivalent in young and elderly subjects (primary end point), with an estimated ratio of 0.94 (90% confidence interval, 0.84–1.06; P = .39). No significant impact of gender was observed (P = .38; estimated ratio, 1.08; 90% confidence interval, 0.93–1.26). Adverse events were of mild or moderate severity. The most frequently reported events were headache, vomiting, and nausea. When adjusted for body weight, no effect of gender or age was found on the pharmacokinetics of liraglutide.
National Veterans Health Administration Hospitalizations for Syncope Compared to Acute Myocardial Infarction, Fracture, or Pneumonia in Community‐Dwelling Elders: Outpatient Medication and Comorbidity Profiles
Authors: French Dustin D. , Campbell Robert , Spehar Andrea , Rubenstein Laurence Z. , Accomando John , Cunningham Francesca
Published: May 2006

The authors used 2 national Veterans Health Administration databases to identify outpatient medications and all 30 Elixhauser comorbidities for 2579 unique patients, age 65+ years, hospitalized for syncope in fiscal year 2004. For comparison, we identified other elderly patients hospitalized with acute myocardial infarction (N = 4491), fracture (N = 2797), or pneumonia (N = 9473). The categories of medications included drugs that affect the cardiovascular, central nervous, or the muscular skeletal system. The most notable differences between syncope compared to acute myocardial infarction patients occurred in central nervous system drugs in anticonvulsants/barbiturates, antidepressants, antihistamine/antinauseants, antipsychotics, and cholinesterase inhibitors (P < .0018). Comparing syncope patients with fracture patients, the central nervous medication profile was similar, but the cardiovascular medication profile differed (P < .0018); their hypertension comorbidities also differed (60.45% vs 46.34%); (P < .0016). These findings indicate significant potential associations that warrant further study. Studies linking national outpatient medications to hospitalizations for specific conditions can foster the development of more proactive pharmacovigilance systems.
Testosterone and conflict tactics within late-adolescent couples: A dyadic predictive model
Authors: Kaiser Heidemarie , Powers Sally
Published: May 2006

This study examined predictive relations between testosterone levels and conflict tactics in late adolescent heterosexual couples. It was hypothesized that testosterone (T) levels within the couple would predict aggressive conflict tactics, with the link between testosterone and aggression expected to be stronger for males. Results of hierarchical linear modeling analyses showed that the interaction of his and her T levels predicted the male's frequency of both psychological aggression and physical assault within the relationship; when both he and she were concordant for higher or lower levels of T for their gender group, he was more aggressive than if they had complementary levels. There was also a trend toward this same synergistic interaction in predicting females' physical assault. Possible explanations from primate research and evolutionary theory, as well as how these findings fit with previous indications from marital research, are discussed.
Are cognitive representations of friends' request refusals implemented in the orbitofrontal and dorsolateral prefrontal cortices? A cognitive neuroscience approach to ‘theory of mind’ in relationships
Authors: Heisel Alan D. , Beatty Michael J.
Published: May 2006

Formulating cognitive representations of others' mental states when interpreting behavior (i.e., ‘theory of mind’) rather than merely focusing on the behavior is considered a distinctly human trait which both interpersonal scholars and cognitive neuroscientists agree plays a critical role in the development and maintenance of social relationships. Although brain-imaging studies have led to huge advances in the understanding of memory and language, theories of social relationships remain relatively uninformed by cognitive neuroscience. In the present study, hypotheses regarding the implementation of theory of mind in a relationship context are (a) derived from extant theory and research, and (b) tested via brain-imaging technology. Specifically, spectrum analyses were conducted using brain wave recordings collected by an electroencephalograph (EEG) monitoring oscillations in the gamma range for the orbitofrontal and dorsolateral prefrontal cortices while participants attempted to construct cognitive representations regarding a friend's request refusal. Results indicated statistically greater electrical activity in both cortical regions for participants engaged in the task than for participants in the control condition. The implications of the findings for building a fully elaborated sequential process model of cognitive representations in interpersonal contexts, among other theoretical endeavors, are discussed.
Thermo Gravimetric Analysis of Ridge Gourd Natural Fabric Reinforcement
Authors: Rajulu A. Varada , Devi R. Rama , Venunadhan A.
Published: May 2006

The natural bilayer fabric of ridge gourd vegetable belonging to the Cucurbitaceae family is treated with 2% aqueous NaOH solution. The primary thermograms of the fibers from this natural fabric of both the layers (top and bottom) before and after alkali treatment are recorded in an inert atmosphere at a heating rate of 10C/min. Using these thermograms, the initial and final degradation temperatures and inflection points are found. Employing the Doyle method, the integral procedural degradation temperature is also determined. The thermal stability of fabric for both layers is found to increase on alkali treatment.
Report: Transboundary hazardous waste management. Part II: performance auditing of treatment facilities in importing countries
Authors: Chang Tien-Chin , Ni Shih-Piao , Fan Kuo-Shuh , Lee Ching-Hwa
Published: May 2006

Before implementing the self-monitoring model programme of the Basel Convention in the Asia, Taiwan has conducted a comprehensive 4-year follow-up project to visit the governmental authorities and waste-disposal facilities in the countries that import waste from Taiwan. A total of nine treatment facilities, six of which are reported in this paper, and the five countries where the plants are located were visited in 2001-2002. France, Belgium and Finland primarily handled polychlorinated biphenyl capacitors, steel mill dust and metal waste. The United States accepted metal sludge, mainly electroplating sludge, from Taiwan. Waste printed circuit boards, waste wires and cables, and a mixture of waste metals and electronics were the major items exported to China. Relatively speaking, most treatment plants for hazardous waste paid close attention to environmental management, such as pollution control and monitoring, site zoning, system management regarding occupational safety and hygiene, data management, permits application, and image promotion. Under the tight restrictions formulated by the central environment agency, waste treatment plants in China managed the environmental issues seriously. For example, one of the treatment plants had ISO 14001 certification. It is believed that with continuous implementation of regulations, more improvement is foreseeable. Meanwhile, Taiwan and China should also continuously enhance their collaboration regarding the transboundary management of hazardous waste.