bluuebunny/crossref_metadata_2025 huggingface dataset:
Tactical supply chain planning in the forest products industry through optimization and scenario-based analysis
Authors: Beaudoin Daniel , LeBel Luc , Frayret Jean-Marc
Published: May 2007

A mixed integer programming model that aims at supporting the tactical wood procurement decisions of a multifacility company is presented. This model allows for wood exchanges between companies. Furthermore, the material flow through the supply chain is driven by both a demand to satisfy ("pull" strategy) and a market mechanism ("push" strategy), enabling the planner to take into consideration both wood freshness and the notion of quality linked to the age of harvested wood into log, chips, and end-product demands. An inability to consider alternative plans for implementation, and the difficulty of assessing the performance of these plans in an uncertain environment, are two shortcomings of the manual planning process. A planning process, based on human planner – decision support system interactions that allows a company to overcome these shortcomings is therefore presented. The process combines Monte Carlo methods and an anticipation mechanism that will, in the long term, enable the company to take into account equipment transportation costs. The proposed planning process leads to a multicriteria decision-making problem where the human planner has to select a plan to implement from a set of candidate plans. A hypothetical test case shows that it is possible to manage the wood flow from stump to end market in such a way as to preserve freshness and extract higher value from the logs processed in the mills. The test case also shows that the proposed planning process achieves an average profitability increase of 8.8% compared with an approach based on a deterministic model using average parameter values. Finally, a sensitivity analysis reveals that the accuracy of standing inventory on harvest blocks and the anticipated market conditions are the most important parameters to consider in selecting a good wood procurement plan.
Blood-Based Biomarkers of SU11248 Activity and Clinical Outcome in Patients with Metastatic Imatinib-Resistant Gastrointestinal Stromal Tumor
Authors: Norden-Zfoni Anat , Desai Jayesh , Manola Judith , Beaudry Paul , Force Jeremy , Maki Robert , Folkman Judah , Bello Carlo , Baum Charles , DePrimo Sam E. , Shalinsky David R. , Demetri Goerge D. , Heymach John V.
Published: May 2007

Purpose: There is an unmet need for noninvasive markers to measure the biological effects of targeted agents, particularly those inhibiting the vascular endothelial growth factor (VEGF) receptor (VEGFR) pathway, and identify patients most likely to benefit from treatment. In this study, we investigated potential blood-based biomarkers for SU11248 (sunitinib malate), a multitargeted tyrosine kinase inhibitor, in patients with metastatic imatinib-refractory gastrointestinal stromal tumors.

Experimental Design: Patients (n = 73) enrolled in a phase I/II trial received SU11248 daily for 14 or 28 days followed by 14 days without treatment per cycle. Clinical benefit was defined as progression-free survival of >6 months. We assessed plasma markers, including VEGF and soluble VEGFR-2 (sVEGFR-2), and two cellular populations bearing VEGF receptors: monocytes and, in a subset of patients, mature circulating endothelial cells (CEC).

Results: Compared to patients with progressive disease, patients with clinical benefit had significantly greater increases in CECs (0.52 versus −−0.01 CEC/μL/d, P = 0.03) and smaller decreases in monocyte levels (47% versus 60%, P = 0.007) during cycle 1. VEGF increased by 2.2-fold and sVEGFR-2 decreased 25% during the first 2 weeks of treatment. Neither plasma marker correlated with clinical outcome although a modest inverse correlation was observed between sVEGFR-2 changes and plasma drug levels. Monocytes, VEGF, and sVEGFR-2 all rebounded towards baseline off treatment.

Conclusions: Monocytes, VEGF, and sVEGFR-2 were consistently modulated by treatment, suggesting that they may serve as pharmacodynamic markers for SU11248. Changes in CECs and monocytes, but not the plasma markers, differed between the patients with clinical benefit and those with progressive disease. These end points merit further investigation in future trials to determine their utility as markers of SU11248 activity and clinical benefit in gastrointestinal stromal tumors and other tumor types.
A Phase 1 Study of Pralatrexate in Combination with Paclitaxel or Docetaxel in Patients with Advanced Solid Tumors
Authors: Azzoli Christopher G. , Krug Lee M. , Gomez Jorge , Miller Vincent A. , Kris Mark G. , Ginsberg Michelle S. , Henry Roxanne , Jones Jessica , Tyson Leslie , Dunne Megan , Pizzo Barbara , Farmer Amy , Venkatraman Ennapadam , Steffen Robert , Sirotnak F.M.
Published: May 2007

Purpose: Pralatrexate is a rationally designed antifolate with greater preclinical antitumor activity than methotrexate. Pralatrexate was synergistic with paclitaxel and with docetaxel in mouse xenograft experiments. This phase 1 study was designed to determine the maximum tolerated dose and toxicity of pralatrexate plus paclitaxel or docetaxel in patients with advanced cancer.

Experimental Design: Pralatrexate was administered i.v. every 2 weeks (days 1 and 15) in a 4-week cycle. Depending on the taxane used and dose being tested, the taxane was administered on days 1 and 15; days 2 and 16; or days 1, 8, and 15. In the latter part of the study, patients in the docetaxel arm were treated with vitamin B12 and folic acid supplementation to mitigate toxicity and allow pralatrexate dose escalation.

Results: For the combination of pralatrexate plus paclitaxel without vitamin supplementation, dose-limiting stomatitis and peripheral neuropathy were encountered at the lowest dose levels tested. For pralatrexate plus docetaxel plus vitamin supplementation, pralatrexate 120 mg/m2 plus docetaxel 35 mg/m2 administered on the same day every other week was defined as the maximum tolerated dose and schedule, with dose-limiting toxicities at higher dose combinations including stomatitis and asthenia. Significant antitumor activity was observed for this combination in patients with non–small-cell lung cancer.

Conclusions: Pralatrexate (120 mg/m2) plus docetaxel (35 mg/m2) plus vitamin supplementation is well tolerated with signs of efficacy against non–small-cell lung cancer that merit phase 2 testing.
Prognostic Relevance of Clinical and Biological Risk Factors in Childhood Medulloblastoma: Results of Patients Treated in the Prospective Multicenter Trial HIT'91
Authors: Rutkowski Stefan , von Bueren André , von Hoff Katja , Hartmann Wolfgang , Shalaby Tarek , Deinlein Frank , Warmuth-Metz Monika , Soerensen Niels , Emser Angela , Bode Udo , Mittler Uwe , Urban Christian , Benesch Martin , Kortmann Rolf D. , Schlegel Paul G. , Kuehl Joachim , Pietsch Torsten , Grotzer Michael
Published: May 2007

Purpose: To identify better risk stratification systems in childhood medulloblastoma based on clinical factors and analysis of routinely processed formalin-fixed tumor material.

Experimental Design: Formalin-fixed paraffin-embedded tumor samples from well-documented patients treated within the prospective randomized multicenter trial HIT'91 were analyzed for DNA amplification of c-myc and N-myc (n = 133) and mRNA expression of c-myc and trkC (n = 104; compared with human cerebellum) using validated methods of quantitative PCR and reverse transcription-PCR. Results were related to clinical data and outcome.

Results: TrkC and c-myc mRNA expression were identified as independent prognostic factors by multivariate analysis. Three risk groups were identified. (a) Favorable risk group: all 8 patients (2 metastatic) with high trkC (>1× human cerebellum) and low c-myc mRNA expression (≤1× human cerebellum) remained relapse-free [7-year event-free survival (EFS), 100%]. (b) Poor risk group: 10 of 15 patients with metastatic disease and high c-myc and low trkC mRNA expression relapsed (7-year EFS, 33%). (c) Intermediate risk group: the 7-year EFS of the remaining 78 patients was 65%. Among 47 M0 stage patients, all 10 patients with high trkC mRNA expression remained relapse-free compared with 15 events in 37 patients with low trkC mRNA expression levels (7-year EFS, 100% versus 62%; P = 0.056).

Conclusions: Whereas the collection of fresh-frozen tumor samples remains a major challenge in large clinical trials, routinely processed paraffin-embedded tissue samples can be used to quantitate the prognostic biological markers trkC and c-myc. On prospective validation of cutoff levels, this may lead to improved stratification of treatment for children with medulloblastoma.
Clinical Significance of CD99 Down-Regulation in Gastric Adenocarcinoma
Authors: Lee Jung Hyun , Kim Seok-Hyung , Wang Li-Hui , Choi Yoon-La , Kim Young Chul , Kim Jin Hee , Park Tae Sung , Hong Yun-Chul , Shin Young Kee
Published: May 2007

Purpose: CD99 is a cell adhesion molecule associated with human tumors. The aim of the present study was to characterize its role in the development and progression of human gastric adenocarcinoma.

Experimental Design: The expression of CD99 was investigated in 283 gastric adenocarcinomas and related lesions and 9 gastric carcinoma cell lines. We also analyzed the methylation status of CD99 gene by using methylation-specific PCR and examined loss of heterozygosity (LOH) of this gene locus by using an intragenic marker. Moreover, we assessed whether SP1, a positive transcription factor for CD99, is expressed in these samples.

Results: We found that the decreased expression of CD99 was strongly associated with poor survival and unfavorable clinicopathologic variables. Promoter region methylation (15 of 89, 16.9%) and LOH (21 of 74, 28.4%) were observed and significantly associated with CD99 down-regulation (P < 0.05). In addition, most of the gastric adenocarcinoma cases with CD99 down-regulation had reduced expression of SP1 (47 of 103, 45.6%; P < 0.01). This relationship between CD99 and SP1 was consolidated by using SP1 small interfering RNA transfection experiment and CD99 promoter luciferase assay. Furthermore, we showed that CD99 down-regulation was associated with proliferation and migration in gastric carcinoma cell line.

Conclusion: These observations suggest that CD99 down-regulation is a critical event in the progression of gastric adenocarcinoma, and CD99 promoter methylation, CD99 LOH, and SP1 down-regulation were responsible for the down-regulation of CD99.
c-Myc–Induced Chemosensitization Is Mediated by Suppression of Cyclin D1 Expression and Nuclear Factor-κB Activity in Pancreatic Cancer Cells
Authors: Biliran Hector , Banerjee Sanjeev , Thakur Archana , Sarkar Fazlul H. , Bollig Aliccia , Ahmed Fakhara , Wu Jiusheng , Sun Yuan , Liao Joshua D.
Published: May 2007

Purpose: Pancreatic cancer is a highly aggressive disease that remains refractory to various chemotherapeutic agents. Because the proto-oncogene c-myc can modulate apoptosis in response to cytotoxic insults and is commonly overexpressed in pancreatic cancer, we investigated the value of c-myc as a potential modulator of cellular response to various chemotherapeutic agents.

Experimental Design: Stable overexpression or small interfering RNA (siRNA)–mediated knockdown of c-myc and restoration of cyclin D1 were done in the Ela-myc pancreatic tumor cell line. Cell viability after cisplatin treatment of c-myc–overexpressing, control, and siRNA-transfected cells was determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay and drug-induced apoptosis was measured by DNA fragmentation, sub-G1, and poly(ADP-ribose) polymerase cleavage analyses. Protein expression profile after cisplatin treatment was determined by Western blotting and DNA binding activity of nuclear factor-κB was examined by electrophoretic mobility shift assay.

Results: Ectopic overexpression of c-myc in murine and human pancreatic cancer cell lines, Ela-myc and L3.6pl, respectively, resulted in increased sensitivity to cisplatin and other chemotherapeutic drugs. Increased sensitivity to cisplatin in c-myc–overexpressing cells was due, in part, to the marked increase in cisplatin-induced apoptosis. Conversely, down-regulation of c-myc expression in stable c-myc–overexpressing cells by c-myc siRNA resulted in decreased sensitivity to cisplatin-induced cell death. These results indicate an important role of c-myc in chemosensitivity of pancreatic cancer cells. The c-myc–induced cisplatin sensitivity correlated with inhibition of nuclear factor κB activity, which was partially restored by ectopic cyclin D1 overexpression.

Conclusions: Our results suggest that the c-myc–dependent sensitization to chemotherapy-induced apoptosis involves suppression of cyclin D1 expression and nuclear factor κB activity.
Implication of the Insulin-like Growth Factor-IR Pathway in the Resistance of Non–small Cell Lung Cancer Cells to Treatment with Gefitinib
Authors: Morgillo Floriana , Kim Woo-Young , Kim Edward S. , Ciardiello Fortunato , Hong Waun Ki , Lee Ho-Young
Published: May 2007

Purpose: Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors have been found to be effective against lung cancer in vitro, but clinical resistance to these agents has developed as their usage has increased. In this study, we determined whether the insulin-like growth factor I (IGF-I) signaling pathway induces resistance of non–small cell lung cancer (NSCLC) cells to the EGFR tyrosine kinase inhibitor gefitinib.

Experimental Design: The effects of gefitinib and cetuximab on NSCLC cells, alone or with an IGF-I receptor (IGF-IR) inhibitor, were assessed using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay, the flow cytometry–based terminal nucleotidyl transferase–mediated nick end labeling assay, coimmunoprecipitation, and Western blot analysis. EGFR and IGFR expression in NSCLC tissues were examined by Western blot analysis.

Results: Gefitinib inhibited NSCLC cell proliferation by inducing apoptosis when IGF-IR signaling was suppressed. Treatment with gefitinib, but not cetuximab, induced EGFR:IGF-IR heterodimerization and activation of IGF-IR and its downstream signaling mediators, resulting in increased survivin expression in NSCLC cell lines with high levels of IGF-IR expression. Inhibition of IGF-IR activation and knockdown of survivin expression led to increased apoptosis. In contrast, overexpression of survivin protected cells with low IGF-IR expression from gefitinib-induced apoptosis. Most NSCLC tissues with EGFR overexpression had associated high levels of IGF-IR expression.

Conclusions: IGF-IR expression may be useful as a predictive marker for gefitinib treatment of NSCLC. Suppression of IGF-IR signaling pathways may prevent or delay development of gefitinib resistance in patients with NSCLC.
The Unfolded Protein Response and Integrated Stress Response to Anoxia
Authors: Rzymski Tomasz , Harris Adrian L.
Published: May 2007

The lack of oxygen delivery to tumor cells has profound consequences for tumor growth and correlates with poor prognosis. Some tumors contain regions of very severe hypoxia called anoxia, which constitutes a functionally different state to hypoxia. In response to anoxia, mammalian cells induce coordinated cytoprotective programs that are critical for tumor survival: the unfolded protein response and integrated stress response. Therefore, targeting additional components of anoxic pathways, besides the hypoxia-inducible response, may be effective for future anticancer therapies.
Collagen XXIII Expression Is Associated with Prostate Cancer Recurrence and Distant Metastases
Authors: Banyard Jacqueline , Bao Lere , Hofer Matthias D. , Zurakowski David , Spivey Kristin A. , Feldman Adam S. , Hutchinson Lloyd M. , Kuefer Rainer , Rubin Mark A. , Zetter Bruce R.
Published: May 2007

Purpose: We had previously identified a new transmembrane collagen, type XXIII, in metastatic rat prostate carcinoma cells. The purpose of this study was to determine the expression of collagen XXIII in human prostate cancer and investigate its relationship with disease progression.

Experimental Design: We investigated collagen XXIII expression in prostate cancer tissue and did a retrospective analysis of association with prostate-specific antigen (PSA)–defined disease recurrence. The presence of collagen XXIII in prostate cancer patient urine was also assessed before and after prostatectomy.

Results: Collagen XXIII protein was detected at very low levels in benign prostate tissue and was significantly increased in prostate cancer. Distant metastases exhibited significantly higher collagen XXIII levels compared with either localized prostate cancer or regional (lymph node) metastases. Patients with high collagen XXIII levels had a 2.8-fold higher risk of PSA failure with median time to failure of 8.1 months, compared with low collagen XXIII patients with a median time to failure of 5 years. Multivariate Cox regression showed that the presence of collagen XXIII was significantly associated with time to PSA recurrence, independent of other clinical variables. Collagen XXIII was also detected in prostate cancer patient urine, with reduced levels after prostatectomy, indicating potential as a noninvasive fluid biomarker.

Conclusions: We present the first report demonstrating increased collagen XXIII expression in prostate cancer tissue. We show that collagen XXIII level is a significant independent predictor of PSA-defined disease recurrence, suggesting a potential role as a molecular biomarker of prostate cancer progression and metastasis.
Pulsed-High Intensity Focused Ultrasound and Low Temperature–Sensitive Liposomes for Enhanced Targeted Drug Delivery and Antitumor Effect
Authors: Dromi Sergio , Frenkel Victor , Luk Alfred , Traughber Bryan , Angstadt Mary , Bur Monica , Poff Jason , Xie Jianwu , Libutti Steven K. , Li King C.P. , Wood Bradford J.
Published: May 2007

Purpose: To determine if pulsed-high intensity focused ultrasound (HIFU) could effectively serve as a source of hyperthermia with thermosensitive liposomes to enhance delivery and efficacy of doxorubicin in tumors.

Experimental Design: Comparisons in vitro and in vivo were carried out between non–thermosensitive liposomes (NTSL) and low temperature–sensitive liposomes (LTSL). Liposomes were incubated in vitro over a range of temperatures and durations, and the amount of doxorubicin released was measured. For in vivo experiments, liposomes and free doxorubicin were injected i.v. in mice followed by pulsed-HIFU exposures in s.c. murine adenocarcinoma tumors at 0 and 24 h after administration. Combinations of the exposures and drug formulations were evaluated for doxorubicin concentration and growth inhibition in the tumors.

Results: In vitro incubations simulating the pulsed-HIFU thermal dose (42°C for 2 min) triggered release of 50% of doxorubicin from the LTSLs; however, no detectable release from the NTSLs was observed. Similarly, in vivo experiments showed that pulsed-HIFU exposures combined with the LTSLs resulted in more rapid delivery of doxorubicin as well as significantly higher i.t. concentration when compared with LTSLs alone or NTSLs, with or without exposures. Combining the exposures with the LTSLs also significantly reduced tumor growth compared with all other groups.

Conclusions: Combining low-temperature heat-sensitive liposomes with noninvasive and nondestructive pulsed-HIFU exposures enhanced the delivery of doxorubicin and, consequently, its antitumor effects. This combination therapy could potentially produce viable clinical strategies for improved targeting and delivery of drugs for treatment of cancer and other diseases.
T-Cell Distribution and Adhesion Receptor Expression in Metastatic Melanoma
Authors: Weishaupt Carsten , Munoz Karla N. , Buzney Elizabeth , Kupper Thomas S. , Fuhlbrigge Robert C.
Published: May 2007

Purpose: Metastatic malignant melanoma is a devastating disease with a poor prognosis. Recent therapeutic trials have focused on immunotherapy to induce development of endogenous antitumor immune responses. To date, such protocols have shown success in activation of tumor-specific CTL but no overall improvement in survival. To kill tumor, antigen-specific CTL must efficiently target and enter tumor tissue. The purpose of this study was to examine the pathway of leukocyte migration to metastatic melanoma.

Experimental design: Peripheral blood and metastatic melanoma tissues (n = 65) were evaluated for expression of adhesion molecules using immunohistochemistry of tumor sections and flow cytometry of tumor-associated and peripheral blood CTL and compared with healthy controls. CTL expressing T-cell receptors for the melanoma antigen MART-1 were identified in a subset of samples by reactivity with HLA-A2 tetramers loaded with MART-1 peptide.

Results: Results show that the majority of metastatic melanoma samples examined do not express the vascular adhesion receptors E-selectin (CD62E), P-selectin (CD62P), and intercellular adhesion molecule-1 (CD54) on vessels within the tumor boundaries. Strong adhesion receptor expression was noted on vessels within adjacent tissue. Tumor-associated T lymphocytes accumulate preferentially in these adjacent areas and are not enriched for skin- or lymph node–homing receptor phenotype.

Conclusion: Expression of leukocyte homing receptors is dysregulated on the vasculature of metastatic melanoma. This results in a block to recruitment of activated tumor-specific CTL to melanoma metastases and is a likely factor limiting the effectiveness of current immunotherapy protocols.
Inhibition of the Phosphatidylinositol 3-Kinase/Akt Pathway Improves Response of Long-term Estrogen-Deprived Breast Cancer Xenografts to Antiestrogens
Authors: Sabnis Gauri , Goloubeva Olga , Jelovac Danijela , Schayowitz Adam , Brodie Angela
Published: May 2007

Purpose: Aromatase inhibitors that block the synthesis of estrogen are proving to be superior to antiestrogens and may replace tamoxifen as first-line treatment for postmenopausal estrogen receptor (ER)–positive breast cancer patients. However, acquisition of resistance to all forms of treatments is inevitable and a major clinical concern. In this study, we have investigated the effects of long-term estrogen deprivation in the breast cancer xenograft model and whether sensitivity to antiestrogens can be restored in vivo. We also compared whether combining wortmannin with tamoxifen or fulvestrant inhibited tumor growth better than either drug alone.

Experimental Design: Long-term estrogen-deprived aromatase-transfected human ER-positive breast cancer cells (UMB-1Ca) were grown as tumors in ovariectomized athymic nude mice. Twelve weeks after inoculation, when tumors reached 300 mm3, animals were grouped and injected with vehicle, Δ4A, letrozole, tamoxifen, fulvestrant, wortmannin, tamoxifen plus wortmannin, and wortmannin plus fulvestrant. Tumor volumes were measured weekly.

Results: Tumors of UMB-1Ca cells grew equally well with and without androstenedione, indicating the ability of the cells to proliferate in the absence of estrogen. The combination of wortmannin with tamoxifen or fulvestrant inhibited tumor growth better than either drug alone. The combination of wortmannin plus fulvestrant was the most effective treatment that maintained tumor regression for a prolonged time.

Conclusion: These results suggest that blocking both ER and growth factor receptor pathways could provide effective control over tumor growth of long-term estrogen-deprived human breast cancers.
A Cross-sectional Study of a Prototype Carcinogenic Human Papillomavirus E6/E7 Messenger RNA Assay for Detection of Cervical Precancer and Cancer
Authors: Castle Philip E. , Dockter Janel , Giachetti Cristina , Garcia Francisco A.R. , McCormick Mary Kay , Mitchell Amy L. , Holladay E. Blair , Kolk Daniel P.
Published: May 2007

Purpose: To evaluate carcinogenic human papillomavirus (HPV) mRNA for E6 and E7 mRNA detection on clinical specimens to identify women with cervical precancer and cancer.

Experimental Design: We evaluated a prototype assay that collectively detects oncogenes E6/E7 mRNA for 14 carcinogenic HPV genotypes on a sample of liquid cytology specimens (n = 531), masked to clinical data and to the presence of HPV genotypes detected by PGMY09/11 L1 consensus primer PCR assay.

Results: We found an increasing likelihood of testing positive for carcinogenic HPV E6/E7 mRNA with increasing severity of cytology (PTrend < 0.0001) and histology (PTrend < 0.0001), with 94% of cervical intraepithelial neoplasia grade 3 (CIN3) histology cases (46 of 49) and all five cancer cases testing positive for carcinogenic HPV E6/E7 mRNA. Overall, fewer specimens tested positive for carcinogenic HPV E6/E7 mRNA than for carcinogenic HPV DNA (P < 0.0001, McNemar's χ2 test), especially in women with <CIN1 (P < 0.0001). We also found that using a higher positive cutpoint for detection of carcinogenic HPV E6/E7 mRNA improved the association of positive test results with cervical precancer and cancer by reducing the number of test positives in women without precancer without reducing clinical sensitivity for cervical precancer and cancer compared with detection of carcinogenic HPV E6/E7 mRNA using a lower positive cutpoint by the same assay and with detection of carcinogenic HPV DNA.

Conclusions: We found that carcinogenic HPV E6/E7 mRNA is a potentially useful biomarker for detection of cervical precancer and cancer and warrants further evaluation.
Phase I Trial of Sorafenib in Combination with Gefitinib in Patients with Refractory or Recurrent Non–Small Cell Lung Cancer
Authors: Adjei Alex A. , Molina Julian R. , Mandrekar Sumithra J. , Marks Randolph , Reid Joel R. , Croghan Gary , Hanson Lorelei J. , Jett James R. , Xia Chenghua , Lathia Chetan , Simantov Ronit
Published: May 2007

Purpose: To evaluate the combination of sorafenib and gefitinib in patients with advanced non–small cell lung cancer.

Experimental Design: In this dose-escalation trial, patients received oral sorafenib (200-400 mg) twice daily with gefitinib (250 mg orally) once daily to identify the recommended dose for phase II trials (RDP; part A). The pharmacokinetics of the RDP were characterized further in additional patients (part B) receiving single-agent gefitinib or sorafenib for 21 days followed by a 7-day washout with crossover to the other agent for an additional 21 days. Patients then received the combination of sorafenib plus gefitinib in 28-day cycles. Safety, pharmacokinetics, and antitumor efficacy were evaluated. Potential drug-drug interactions and the relationship between pharmacokinetics and toxicity were also assessed.

Results: Thirty-one patients were treated (n = 12, part A; n = 19, part B). Most adverse events were grade 1/2. The most frequent grade 3/4 events included diarrhea and elevated alanine aminotransferase (both 9.7%). One dose-limiting toxicity occurred (part A: elevated alanine aminotransferase at 400 mg twice daily). Gefitinib had no effect on sorafenib pharmacokinetics. However, gefitinib Cmax (26%) and area under the curve (38%) were reduced by concomitant sorafenib. One patient had a partial response; 20 (65%; n = 8, part A; n = 12, part B) had stable disease ≥4 months. The RDP was sorafenib 400 mg twice daily with gefitinib 250 mg once daily.

Conclusions: Sorafenib combined with gefitinib is well tolerated, with promising efficacy in patients with advanced non–small cell lung cancer. Studies to further investigate the significance of the reduction in gefitinib exposure by sorafenib are warranted.
Recombinant Human Hexamer-Dominant IgM Monoclonal Antibody to Ganglioside GM3 for Treatment of Melanoma
Authors: Azuma Yumiko , Ishikawa Yuji , Kawai Shigeto , Tsunenari Toshiaki , Tsunoda Hiroyuki , Igawa Tomoyuki , Iida Shin-ichiro , Nanami Masahiko , Suzuki Masami , Irie Reiko F. , Tsuchiya Masayuki , Yamada-Okabe Hisafumi
Published: May 2007

Purpose: L612, a human IgM monoclonal antibody produced by an EBV-transformed human B-cell line, binds to ganglioside GM3 and kills GM3-positive human melanoma cells in the presence of complement. It has been shown to be effective in some patients with late-stage melanoma. L612 consists of hexameric IgM (about 20%), pentameric IgM (about 74%), and other minor IgM molecules. Because hexameric IgM activates complement more effectively than pentameric IgM, we developed and evaluated a hexamer-dominant recombinant IgM for clinical applications.

Experimental Design: Chinese hamster ovary (CHO) cells were transfected with heavy- and light-chain genes of L612, with or without the joining-chain gene. Antitumor effects of the recombinant IgM secreted from CHO cells were evaluated in vitro and in vivo.

Results: Recombinant IgM secreted from CHO cells without the joining chain (designated CA19) was ∼80% hexameric, whereas recombinant IgM from CHO cells transfected with heavy-, light-, and joining-chain genes (designated CJ45) was about 90% pentameric. Both CA19 and CJ45 recombinant IgMs caused complement-dependent cytotoxicity against human and mouse melanoma cell lines, but the amount of CA19 required for 50% specific cytotoxicity was 5 to 10 times smaller. I.v. injection of CA19 compared with CJ45 or native L612 elicited more profound antitumor activity in nude rats bearing a GM3-positive mouse melanoma xenograft.

Conclusions: A hexamer-dominant human IgM against GM3 may provide a more potent treatment option for patients with GM3-positive melanoma.
Phase I Evaluation of J591 as a Vascular Targeting Agent in Progressive Solid Tumors
Authors: Morris Michael J. , Pandit-Taskar Neeta , Divgi Chaitanya R. , Bender Samantha , O'Donoghue Joseph A. , Nacca Angelo , Smith-Jones Peter , Schwartz Lawrence , Slovin Susan , Finn Ronald , Larson Steven , Scher Howard I.
Published: May 2007

Purpose: The antibody J591 targets the external domain of prostate-specific membrane antigen, which is expressed in the neovasculature of nonprostate solid tumors. This phase I trial tested the hypothesis that J591 could be used as a vascular targeting platform for patients with nonprostate solid tumors.

Experimental Design: Patients with progressive solid tumors were eligible. Twenty patients, divided into six dosage cohorts of 3 to 6 patients each, were treated every 3 weeks to a maximum of four doses using either 5, 10, 20, 40, 60, or 100 mg of J591 antibody. Two milligrams of antibody were labeled with 10 mCi of indium-111.

Results: Patients with a wide variety of solid tumors were tested; all had good tumor localization. No dose-limiting toxicities were observed. The serum clearance rate decreased with increasing antibody mass, likely a result of early hepatic uptake of antibody. Half-life for each successive cohort was 0.71, 0.84, 1.86, 1.83, 3.32, and 3.56 days. Hepatic saturation seemed to occur by 60 mg. Seventeen of 18 (94%) patients with soft tissue disease on standard scans showed uptake in the soft tissues on antibody scans as did 6 of 6 patients with bone disease.

Conclusions: The tumoral neovasculature of a variety of solid tumors can be selectively and safely targeted using J591. In planning for future studies using J591 as a radiation delivery platform, an antibody mass of 60 mg should be considered, as it would seem to minimize the radiation delivered to the liver while minimizing the radiation dose to bone.
ABT-888, an Orally Active Poly(ADP-Ribose) Polymerase Inhibitor that Potentiates DNA-Damaging Agents in Preclinical Tumor Models
Authors: Donawho Cherrie K. , Luo Yan , Luo Yanping , Penning Thomas D. , Bauch Joy L. , Bouska Jennifer J. , Bontcheva-Diaz Velitchka D. , Cox Bryan F. , DeWeese Theodore L. , Dillehay Larry E. , Ferguson Debra C. , Ghoreishi-Haack Nayereh S. , Grimm David R. , Guan Ran , Han Edward K. , Holley-Shanks Rhonda R. , Hristov Boris , Idler Kenneth B. , Jarvis Ken , Johnson Eric F. , Kleinberg Lawrence R. , Klinghofer Vered , Lasko Loren M. , Liu Xuesong , Marsh Kennan C. , McGonigal Thomas P. , Meulbroek Jonathan A. , Olson Amanda M. , Palma Joann P. , Rodriguez Luis E. , Shi Yan , Stavropoulos Jason A. , Tsurutani Alan C. , Zhu Gui-Dong , Rosenberg Saul H. , Giranda Vincent L. , Frost David J.
Published: May 2007

Purpose: To evaluate the preclinical pharmacokinetics and antitumor efficacy of a novel orally bioavailable poly(ADP-ribose) polymerase (PARP) inhibitor, ABT-888.

Experimental Design: In vitro potency was determined in a PARP-1 and PARP-2 enzyme assay. In vivo efficacy was evaluated in syngeneic and xenograft models in combination with temozolomide, platinums, cyclophosphamide, and ionizing radiation.

Results: ABT-888 is a potent inhibitor of both PARP-1 and PARP-2 with Kis of 5.2 and 2.9 nmol/L, respectively. The compound has good oral bioavailability and crosses the blood-brain barrier. ABT-888 strongly potentiated temozolomide in the B16F10 s.c. murine melanoma model. PARP inhibition dramatically increased the efficacy of temozolomide at ABT-888 doses as low as 3.1 mg/kg/d and a maximal efficacy achieved at 25 mg/kg/d. In the 9L orthotopic rat glioma model, temozolomide alone exhibited minimal efficacy, whereas ABT-888, when combined with temozolomide, significantly slowed tumor progression. In the MX-1 breast xenograft model (BRCA1 deletion and BRCA2 mutation), ABT-888 potentiated cisplatin, carboplatin, and cyclophosphamide, causing regression of established tumors, whereas with comparable doses of cytotoxic agents alone, only modest tumor inhibition was exhibited. Finally, ABT-888 potentiated radiation (2 Gy/d × 10) in an HCT-116 colon carcinoma model. In each model, ABT-888 did not display single-agent activity.

Conclusions: ABT-888 is a potent inhibitor of PARP, has good oral bioavailability, can cross the blood-brain barrier, and potentiates temozolomide, platinums, cyclophosphamide, and radiation in syngeneic and xenograft tumor models. This broad spectrum of chemopotentiation and radiopotentiation makes this compound an attractive candidate for clinical evaluation.
Stable Myocardial-Specific AAV6-S100A1 Gene Therapy Results in Chronic Functional Heart Failure Rescue
Authors: Pleger Sven T. , Most Patrick , Boucher Matthieu , Soltys Stephen , Chuprun J. Kurt , Pleger Wiebke , Gao Erhe , Dasgupta Abhijit , Rengo Giuseppe , Remppis Andrew , Katus Hugo A. , Eckhart Andrea D. , Rabinowitz Joseph E. , Koch Walter J.
Published: May 2007

Background—

The incidence of heart failure is ever-growing, and it is urgent to develop improved treatments. An attractive approach is gene therapy; however, the clinical barrier has yet to be broken because of several issues, including the lack of an ideal vector supporting safe and long-term myocardial transgene expression.

Methods and Results—

Here, we show that the use of a recombinant adeno-associated viral (rAAV6) vector containing a novel cardiac-selective enhancer/promoter element can direct stable cardiac expression of a therapeutic transgene, the calcium (Ca
2+
)-sensing S100A1, in a rat model of heart failure. The chronic heart failure–rescuing properties of myocardial S100A1 expression, the result of improved sarcoplasmic reticulum Ca
2+
handling, included improved contractile function and left ventricular remodeling. Adding to the clinical relevance, long-term S100A1 therapy had unique and additive beneficial effects over β-adrenergic receptor blockade, a current pharmacological heart failure treatment.

Conclusions—

These findings demonstrate that stable increased expression of S100A1 in the failing heart can be used for long-term reversal of LV dysfunction and remodeling. Thus, long-term, cardiac-targeted rAAV6-S100A1 gene therapy may be of potential clinical utility in human heart failure.
Distinct Roles of Estrogen Receptors α and β Mediating Acute Vasodilation of Epicardial Coronary Arteries
Authors: Traupe Tobias , Stettler Christoph D. , Li Huige , Haas Elvira , Bhattacharya Indranil , Minotti Roberta , Barton Matthias
Published: May 2007

This study investigated the contribution of estrogen receptors (ERs) α and β for epicardial coronary artery function, vascular NO bioactivity, and superoxide (O
2
−
) formation. Porcine coronary rings were suspended in organ chambers and precontracted with prostaglandin F
2α
to determine direct effects of the selective ER agonists 4,4′,4″-(4-propyl-[
1
H]pyrazole-1,3,5-triyl)tris-phenol (PPT) or 2,3-bis(4-hydroxyphenyl)-propionitrile (DPN) or the nonselective ER agonist 17β-estradiol. Indirect effects on contractility to U46619 and relaxation to bradykinin were assessed and effects on NO, nitrite, and O
2
−
formation were measured in cultured cells. Within 5 minutes, selective ERα activation by PPT, but not 17β-estradiol or the ERβ agonist DPN, caused rapid, NO-dependent, and endothelium-dependent relaxation (49±5%;
P
<0.001 versus ethanol). PPT also caused sustained endothelium- and NO-independent vasodilation similar to 17β-estradiol after 60 minutes (72±3%;
P
<0.001 versus ethanol). DPN induced endothelium-dependent NO-independent relaxation via endothelium-dependent hyperpolarization (40±4%;
P
<0.01 versus ethanol). 17β-Estradiol and PPT, but not DPN, attenuated the responses to U46619 and bradykinin. All of the ER agonists increased NO and nitrite formation in vascular endothelial but not smooth muscle cells and attenuated vascular smooth muscle cell O
2
−
formation (
P
<0.001). ERα activation had the most potent effects on both nitrite formation and inhibiting O
2
−
(
P
<0.05). These data demonstrate novel and differential mechanisms by which ERα and ERβ activation control coronary artery vasoreactivity in males and females and regulate vascular NO and O
2
−
formation. The findings indicate that coronary vascular effects of sex hormones differ with regard to affinity to ERα and ERβ, which will contribute to beneficial and adverse effects of hormone replacement therapy.
Purinergic P2X Receptors Mediate Excitatory Transmission to Cardiac Vagal Neurons in the Nucleus Ambiguus After Hypoxia
Authors: Griffioen Kathleen J. , Gorini Christopher , Jameson Heather , Mendelowitz David
Published: May 2007

Challenges such as hypoxia elicit a powerful response from both the central cardiovascular and respiratory neuronal networks. Recent work indicates that purinergic neurotransmission in the brain stem is an important modulator of central respiratory network responses to hypoxia. This study tests whether alterations in purinergic neurotransmission extend beyond respiratory responses to hypoxia and also mediates respiratory inputs to cardiac vagal neurons. To examine central cardiorespiratory responses to hypoxia, we used an in vitro medullary slice that allows simultaneous examination of rhythmic respiratory-related activity and synaptic neurotransmission to cardioinhibitory vagal neurons. Here we show that P2X receptor activation mediates respiratory-related excitatory neurotransmission to parasympathetic cardiac vagal neurons, the dominant control of heart rate. These data demonstrate a critical functional role for adenosine 5′-triphosphate–mediated purinergic signaling in facilitating respiratory-related excitatory neurotransmission to cardiac vagal neurons after hypoxia.
Plasma Osteoprotegerin Levels in the General Population
Authors: Omland Torbjørn , Drazner Mark H. , Ueland Thor , Abedin Moeen , Murphy Sabina A. , Aukrust Pål , de Lemos James A.
Published: May 2007

Osteoprotegerin, a member of the tumor necrosis factor receptor superfamily, has pleiotropic effects on bone metabolism, endocrine function, and the immune system. Myocardial expression and circulating levels of osteoprotegerin are increased in heart failure. The relationship between osteoprotegerin levels in the general population and indices of left ventricular structure and function is unknown. Plasma osteoprotegerin levels and cardiac MRI indices of left ventricular structure and function were available in 2715 subjects (median age: 44 years; 45% male) enrolled in the Dallas Heart Study. The associations between osteoprotegerin concentration and indices of left ventricular structure and function were assessed by linear regression analysis, adjusting for possible confounders. By gender-specific linear regression analysis, higher osteoprotegerin levels were significantly associated with higher left ventricular mass, left ventricular wall thickness, left ventricular concentricity index, and lower left ventricular ejection fraction (
P
<0.001 for all). After adjustment for age, race, fat-free mass, fat mass, hypertension, diabetes, coronary artery disease, estimated glomerular filtration rate, hypercholesterolemia, smoking status, hormone replacement therapy, coronary artery calcium score >10, and presence of aortic plaque, osteoprotegerin remained significantly associated with each of these left ventricular indices among male subjects (
P
<0.05 for each). Among female subjects, higher osteoprotegerin was independently associated with higher left ventricular end-systolic volume and lower ejection fraction (
P
<0.0001 for each) but not with indices of left ventricular hypertrophy. These findings are compatible with the theory that osteoprotegerin may play a pathophysiological role in the development of left ventricular hypertrophy and systolic dysfunction.
A Correction for Land Contamination of Atmospheric Variables near Land–Sea Boundaries*
Authors: Kara A. Birol , Wallcraft Alan J. , Hurlburt Harley E.
Published: May 2007

Ocean models need over-ocean atmospheric forcing. However, such forcing is not necessarily provided near the land–sea boundary because 1) the atmospheric model grid used for forcing is frequently much coarser than the ocean model grid, and 2) some of the atmospheric model grid over the ocean includes land values near coastal regions. This paper presents a creeping sea-fill methodology to reduce the improper representation of scalar atmospheric forcing variables near coastal regions, a problem that compromises the usefulness of the fields for ocean model simulations and other offshore applications. For demonstration, atmospheric forcing variables from archived coarse-resolution gridded products—the 1.125° × 1.125° 15-yr European Centre for Medium-Range Weather Forecasts (ECMWF) Re-Analysis (ERA-15) and 1.0° × 1.0° Navy Operational Global Atmospheric Prediction System (NOGAPS)—are used here. A fine-resolution [1/25° × 1/25° cos(lat)], (longitude × latitude) (∼3.2 km) eddy-resolving Black Sea Hybrid Coordinate Ocean Model (HYCOM) is then forced with/without sea-filled atmospheric variables from these gridded products to simulate monthly mean climatological sea surface temperature (SST). Using only over-ocean values from atmospheric forcing fields in the ocean model simulations significantly reduces the climatological mean SST bias (by ∼1°–3°C) and rms SST difference over the seasonal cycle (by ∼2°–3°C) in coastal regions. Performance of the creeping sea-fill methodology is also directly evaluated using measurements of wind speed at 10 m above the surface from the SeaWinds scatterometer on the NASA Quick Scatterometer (QuikSCAT) satellite. Comparisons of original monthly mean wind speeds from operational ECMWF and NOGAPS products with those from QuikSCAT give basin-averaged rms differences of 1.6 and 1.4 m s−1, respectively, during 2000–03. Similar comparisons performed with sea-filled monthly mean wind speeds result in a much lower rms difference (0.7 m s−1 for both products) during the same time period, clearly confirming the accuracy of the methodology even on interannual time scales. Most of the unrealistically low wind speeds from ECMWF and NOGAPS near coastal boundaries are appropriately corrected with the use of the creeping sea fill. Wind speed errors for ECWMF and NOGAPS (mean bias of ≥ 2.5 m s−1 with respect to QuikSCAT during 2000–03) are substantially eliminated (e.g., almost no bias) near most of the land–sea boundaries. Finally, ocean, atmosphere, and coupled atmospheric–oceanic modelers need to be aware that the creeping sea fill is a promising methodology in significantly reducing the land contamination resulting from an improper land–sea mask existing in gridded coarse-resolution atmospheric products (e.g., ECMWF).
Scale Evolution of Finite-Amplitude Instabilities on a Coastal Upwelling Front
Authors: Durski Scott M. , Allen J. S. , Egbert G. D. , Samelson R. M.
Published: May 2007

Nonlinear model simulations of a coastal upwelling system show frontal instabilities that initiate at short alongshore scales but rapidly evolve to longer wavelengths. Several factors associated with the nonstationarity of this basic state contribute to the progression in scale. A portion of the system evolution is associated with the external forcing. Another portion is associated with the alteration of the alongshore mean flow resulting from wave growth. Direct interactions between the finite-amplitude disturbances also promote emergence of new scales. The relative role of each of these mechanisms is isolated through tangent linear simulations about basic states that approximate the nonlinear system to differing degrees. The basic states include an alongshore uniform time-evolving upwelling solution, the alongshore average of a three-dimensionally evolving upwelling solution, and the full three-dimensional nonlinear solution. Disturbance growth about a frozen-field upwelling state is also examined. Perturbation experiments are performed for persistent and relaxed wind forcing. Although the frontal disturbances in the nonlinear model exhibit a progression to larger scale over the full range of forcing scenarios considered, the mechanisms most responsible for the process differ between wind-forced and unforced cases. Under relaxed wind conditions, the perturbation growth experiments indicate that the scale evolution over the first four days is reflected in the way linear disturbances respond to the adjustment of an alongshore uniform upwelling front to wind cessation. The continued increase in scale between days 4 and 7 is related to the linear disturbance evolution on the alongshore average of a flow state that has been altered by wave–mean flow interaction. Past day 7, the observed scale change is not captured in the linear growth experiments and evidently results largely from nonlinear wave–wave interaction processes. Under sustained upwelling winds, the linear growth experiments fail to describe even the earliest scale change in the nonlinear solutions, indicating that nonlinear wave–wave effects are significant from very near the start of the simulations.
Eddy Amplitudes in Baroclinic Turbulence Driven by Nonzonal Mean Flow: Shear Dispersion of Potential Vorticity
Authors: Smith K. Shafer
Published: May 2007

As in the midlatitude atmosphere, midocean eddies are primarily generated by baroclinically unstable mean currents. In contrast to the atmosphere, however, oceanic currents are significantly nonzonal. Even weak nonzonal currents are linearly unstable since β does not suppress growing meridional waves. Theories for the nonlinear equilibration of baroclinic instability, and hence theories for the amplitudes of midocean eddies, must therefore take into account the different dynamics of nonzonal flow. It is shown here that the amplitude of fully developed baroclinic turbulence due to nonzonal shears differs from that due to zonal shears primarily in the nature of the eddy generation. Since β will act to create large-scale zonal jet structures regardless of the generation source, the nature of eddy fluxes of potential vorticity (the source of eddy energy) in the zonal and meridional directions are fundamentally different. The cross-jet mixing has been shown previously to obey a mixing-length scaling, and this corresponds to the generation due to unstable zonal flow. The along-jet mixing, which corresponds to the generation due to the meridional shear, is shown here to be best described by a shear dispersion model. The resulting flux is orders of magnitude higher than in the cross-jet direction, and thus eddy energies driven by baroclinically unstable mean flows with a nonzero meridional component are much larger. This provides an explanation for recently reported results. Moreover, given recent observational and modeling studies showing the ubiquitous presence of zonal jets in the oceans, the results presented here indicate a powerful source of eddy energy.