bluuebunny/crossref_metadata_2025 huggingface dataset:
Inverse Prognostic Impact of Angiogenic Marker Expression in Tumor Cells versus Stromal Cells in Non–Small Cell Lung Cancer
Authors: Donnem Tom , Al-Saad Samer , Al-Shibli Khalid , Delghandi Marit P. , Persson Magnus , Nilsen Marit N. , Busund Lill-Tove , Bremnes Roy M.
Published: November 2007

Purpose: The vascular endothelial growth factors (VEGF-A, -C, -D) and the VEGF receptors (VEGFR-1, -2, and -3) are important molecular markers in angiogenesis and lymphangiogenesis. This study elucidates the prognostic significance of these molecular markers in tumor cells as well as in the tumor stroma of resected non–small cell lung cancer tumors.

Experimental Design: Tumor tissue samples from 335 resected patients with stage I to IIIA disease were obtained and tissue microarrays were constructed from duplicate cores of tumor cells and surrounding stromal tissue from each resected specimen. Immunohistochemistry was used to evaluate the expression of each molecular marker. Microvessel density was assessed by CD34 immunohistochemical staining.

Results: In univariate analyses, high tumor cell expression of VEGF-A (P = 0.0005), VEGFR-1 (P = 0.013), VEGFR-2 (P = 0.006), and VEGFR-3 (P = 0.0003) were negative prognostic indicators for disease-specific survival (DSS). In tumor stroma, however, high expression of VEGF-A (P = 0.017), VEGF-C (P = 0.003), VEGF-D (P = 0.009), VEGFR-1 (P = 0.01), and VEGFR-2 (P = 0.019) correlated with good prognosis. There was no significant correlation between microvessel density and DSS. In multivariate analyses, high expression in tumor cells of VEGFR-3 (P = 0.007) was an independent negative prognostic factor for DSS, whereas in stromal cells, high VEGF-C (P = 0.004) expression had an independent positive survival impact.

Conclusion: These are the first tissue microarray data in non–small cell lung cancers showing a positive prognostic impact by highly expressed angiogenic markers in tumor stroma, with VEGF-C as a major independent prognostic indicator.
Inhibition of Protein Kinase Cβ by Enzastaurin Enhances Radiation Cytotoxicity in Pancreatic Cancer
Authors: Spalding Aaron C. , Watson Richard , Davis Mary E. , Kim Alex C. , Lawrence Theodore S. , Ben-Josef Edgar
Published: November 2007

Purpose: Aberrant activation of protein kinase Cβ (PKCβ) by pancreatic cancer cells facilitates angiogenesis and tumor cell survival. Targeting PKCβ with enzastaurin, a well-tolerated drug in clinical trials, would be expected to radiosensitize pancreatic tumors through direct antitumor and antivascular effects.

Experimental Design: We tested the hypothesis that enzastaurin radiosensitizes pancreatic cancer cells in culture and in vivo through inhibition of PKCβ. We analyzed pancreatic cancer xenografts for growth delay and microvessel density after treatment with enzastaurin, radiation, or both. We determined the effect of radiation and enzastaurin on glycogen synthase kinase 3β, a mediator of cell death in culture and in vivo.

Results: At concentrations attained in patients, enzastaurin reduced levels of active PKCβ measured by phosphorylation at Thr500 in culture and in xenografts. Enzastaurin alone did not affect pancreatic cancer cell survival, proliferation, or xenograft growth. However, enzastaurin radiosensitized pancreatic cancer cells in culture by colony formation assay. Enzastaurin alone decreased microvessel density of pancreatic cancer xenografts without appreciable effects on tumor size. When combined with radiation, enzastaurin increased radiation-induced tumor growth delay with a corresponding decrease in microvessel density. Enzastaurin inhibited radiation-induced phosphorylation of glycogen synthase kinase 3β at Ser9 in pancreatic cancer cells in culture and in tumor xenografts, suggesting a possible mechanism for the observed radiosensitization.

Conclusions: Enzastaurin inhibits PKCβ in pancreatic cancer cells in culture, enhancing radiation cytotoxicity. Additional antivascular effects of enzastaurin were observed in vivo, resulting in greater radiosensitization. These results provide the rationale for a clinical trial in locally advanced pancreatic cancer combining enzastaurin with radiation.
[18F]Galacto-RGD Positron Emission Tomography for Imaging of αvβ3 Expression on the Neovasculature in Patients with Squamous Cell Carcinoma of the Head and Neck
Authors: Beer Ambros J. , Grosu Anca-Ligia , Carlsen Janette , Kolk Andreas , Sarbia Mario , Stangier Isabelle , Watzlowik Petra , Wester Hans-Jürgen , Haubner Roland , Schwaiger Markus
Published: November 2007

Purpose: [18F]Galacto-RGD has been developed for positron emission tomography (PET)–imaging of αvβ3 expression, a receptor involved in angiogenesis and metastasis. Our aim was to study the feasibility of PET imaging with [18F]Galacto-RGD in patients with squamous cell carcinoma of the head and neck (SCCHN).

Experimental Design: Eleven patients with primary diagnosis of SCCHN were examined. After injection of 140 to 200 MBq [18F]Galacto-RGD, static emission scans 60 min post injection from the head to the abdomen (n = 11) and dynamic scans >60 min covering the tumor region (n = 6) for kinetic modeling were acquired. Standardized uptake values (SUV) were measured in tumors, muscle and oral mucosa. Immunohistochemistry was done using an αvβ3-specific antibody (n = 7). Image fusion with magnetic resonance imaging and/or computed tomography (CT) scans (n = 8) and calculation of tumor subvolumes based on SUVs was done using the iPlan software (BrainLAB).

Results: [18F]Galacto-RGD PET identified 10 of 12 tumors, with SUVs ranging from 2.2 to 5.8 (mean, 3.4 ± 1.2). Two tumors <5 mm were missed. Tumor/blood and tumor/muscle ratios were 2.8 ± 1.1 and 5.5 ± 1.6, respectively. Tumor kinetics was consistent with a two-tissue compartmental model with reversible specific binding. Immunohistochemistry confirmed αvβ3 expression in all tumors with αvβ3 being located on the microvessels in all specimens and additionally on tumor cells in one specimen. Image fusion of [18F]Galacto-RGD PET with magnetic resonance imaging/multislice CT and definition of tumor subvolumes was feasible in all cases.

Conclusions: [18F]Galacto-RGD PET allows for specific imaging of αvβ3 expression in SCCHN with good contrast. Image fusion and definition of tumor subvolumes is feasible. This technique might be used for the assessment of angiogenesis and for planning and response evaluation of αvβ3-targeted therapies.
1,1-Bis(3′-Indolyl)-1-(p-Substitutedphenyl)methanes Induce Apoptosis and Inhibit Renal Cell Carcinoma Growth
Authors: York Melissa , Abdelrahim Maen , Chintharlapalli Sudhakar , Lucero Salina D. , Safe Stephen
Published: November 2007

Purpose: 1,1-Bis(3′-indolyl)-1-(p-substitutedphenyl)methanes [methylene-substituted diindolylmethanes (C-DIM)] containing p-trifluoromethyl, p-t-butyl, and p-phenyl substituents activate peroxisome proliferator-activated receptor γ (PPARγ) and inhibit growth of several different cancer cell lines through receptor-dependent and receptor-independent pathways. The purpose of this study is to investigate the anticancer activity of these compounds in renal cell carcinoma.

Experimental Design: The anticancer activity of the p-t-butyl–substituted C-DIM compound (DIM-C-pPhtBu) was investigated in ACHN and 786-0 renal cell carcinoma cell lines and in an orthotopic model for renal carcinogenesis using ACHN cells injected directly into the kidney.

Results: PPARγ is overexpressed in ACHN cells and barely detectable in 786-0 cells, and treatment with DIM-C-pPhtBu induces proteasome-dependent degradation of cyclin D1 and variable effects on p21 and p27 expression in both cell lines. DIM-C-pPhtBu also induced several common proapoptotic responses in ACHN and 786-0 cells, including increased expression of nonsteroidal anti-inflammatory drug-activated gene-1 and endoplasmic reticulum stress, which activates death receptor 5 and the extrinsic pathway of apoptosis. Activation of these responses was PPARγ independent. In addition, DIM-C-pPhtBu (40 mg/kg/d) also inhibited tumor growth in an orthotopic mouse model for renal carcinogenesis, and this was accompanied by induction of apoptosis in renal tumors treated with DIM-C-pPhtBu but not in tumors treated with the corn oil vehicle (control).

Conclusions: DIM-C-pPhtBu and related compounds are cytotoxic to renal cancer cells and activate multiple proapoptotic and growth-inhibitory pathways. The results coupled with in vivo anticancer activity show the potential of DIM-C-pPhtBu and related C-DIMs for clinical treatment of renal adenocarcinoma.
Defective Chromosome Segregation and Telomere Dysfunction in Aggressive Wilms' Tumors
Authors: Stewénius Ylva , Jin Yuesheng , Øra Ingrid , de Kraker Jan , Bras Johannes , Frigyesi Attila , Alumets Jan , Sandstedt Bengt , Meeker Alan K. , Gisselsson David
Published: November 2007

Purpose: In many childhood neoplasms, prognostic subgroups have been defined based on specific chromosome changes. In Wilms' tumor (WT), such subclassification has been hampered by the diverse and relatively unspecific pattern of chromosomal imbalances present in these tumors. Unspecific patterns of cytogenetic imbalances in tumors are often caused by mitotic segregation errors due to short dysfunctional telomeres. As an alternative to cytogenetic classification, we therefore have evaluated whether the rate of telomere-dependent chromosomal instability could influence the clinical course in WT patients.

Experimental Design: Telomere function and mitotic segregation errors were assessed in 12 cultured tumors and in tumor tissue sections from 41 WT patients.

Results: Abnormal telomere shortening was found in cultured cells and in tissue sections from highly aggressive tumors. In vitro, dysfunctional telomeres were associated to specific cell division abnormalities, including anaphase bridges and multipolar mitoses. Assessment of mitotic figures in tissue sections revealed that anaphase bridges and multipolar mitoses were predominantly, but not exclusively, present in high-risk tumors and were predictors of poor event-free and overall survival.

Conclusions: Telomere-dependent mitotic instability is present in a subgroup of WT, predominately consisting of high-risk tumors.
Therapeutic Implications of Leukemic Stem Cell Pathways
Authors: Chumsri Saranya , Matsui William , Burger Angelika M.
Published: November 2007

An emerging concept in cancer biology is that a rare population of cancer stem cells exists among the heterogeneous cell mass that constitutes a tumor. This concept is best understood in human myeloid leukemia. Normal and malignant hematopoietic stem cell functions are defined by a common set of critical stemness genes that regulate self-renewal and developmental pathways. Several stemness factors, such as Notch or telomerase, show differential activation in normal hematopoietic versus leukemia stem cells. These differences could be exploited therapeutically even with drugs that are already in clinical use for the treatment of leukemia. The translation of novel and existing leukemic stem cell–directed therapies into clinical practice, however, will require changes in clinical trial design and the inclusion of stem cell biomarkers as correlative end points.
New Issues in Genetic Counseling of Hereditary Colon Cancer
Authors: Lynch Patrick M.
Published: November 2007

Clinicians face significant challenges in the diagnosis and management of familial colorectal cancer predisposition. Many of the challenges concern the rarity of individual conditions and their unfamiliarity to most clinicians, even those in the subspecialty areas of gastroenterology, colorectal surgery, and medical oncology. Because the World Wide Web now offers a wealth of information, familiarity with available online resources should be a minimal expectation of clinicians. Notably, these same resources are available to the lay public, so a more informed group of patients can be expected and is already being encountered. The web sites noted throughout this article are merely early examples of what should become an opportunity for instant access to the most up-to-date knowledge of rare familial colorectal cancers and their clinical features, molecular diagnostics, and clinical management and prevention. Many professional organizations have produced guidelines (in print and online) for use by practitioners in various specialties. The consistency, growing evidence base, and ready availability of these guidelines to providers and patients alike will likely foster greater recognition of the need to be in compliance with them. Finally, as investigators make progress with the genetics of these rare diseases, one can anticipate a “cooperative group” approach to clinical trials.
Radiosensitization by the Histone Deacetylase Inhibitor PCI-24781
Authors: Banuelos Carmen A. , Banáth Judit P. , MacPhail Susan H. , Zhao Jin , Reitsema Tarren , Olive Peggy L.
Published: November 2007

Purpose: PCI-24781 is a novel broad spectrum histone deacetylase inhibitor that is currently in phase I clinical trials. The ability of PCI-24781 to act as a radiation sensitizer and the mechanisms of radiosensitization were examined.

Experimental Design: Exponentially growing human SiHa cervical and WiDr colon carcinoma cells were exposed to 0.1 to 10 μmol/L PCI-24781 in vitro for 2 to 20 h before irradiation and 0 to 4 h after irradiation. Single cells and sorted populations were analyzed for histone acetylation, H2AX phosphorylation, cell cycle distribution, apoptotic fraction, and clonogenic survival.

Results: PCI-24781 treatment for 4 h increased histone H3 acetylation and produced a modest increase in γH2AX but negligible cell killing or radiosensitization. Treatment for 24 h resulted in up to 80% cell kill and depletion of cells in S phase. Toxicity reached maximum levels at a drug concentration of ∼1 μmol/L, and cells in G1 phase at the end of treatment were preferentially spared. A similar dose-modifying factor (DMF0.1 = 1.5) was observed for SiHa cells exposed for 24 h at 0.1 to 3 μmol/L, and more radioresistant WiDr cells showed less sensitization (DMF0.1 = 1.2). Limited radiosensitization and less killing were observed in noncycling human fibroblasts. Cell sorting experiments confirmed that depletion of S-phase cells was not a major mechanism of radiosensitization and that inner noncycling cells of SiHa spheroids could be sensitized by nontoxic doses. PCI-24781 pretreatment increased the fraction of cells with γH2AX foci 24 h after irradation but did not affect the initial rate of loss of radiation-induced γH2AX or the rate of rejoining of DNA double-strand breaks.

Conclusions: PCI-24781 shows promise as a radiosensitizing agent that may compromise the accuracy of repair of radiation damage.
Multidisciplinary Management of Patients with Advanced Rectal Cancer
Authors: Beart Robert W.
Published: November 2007

The chance of lymph node involvement in T3 and T4 rectal cancers is 20% to 60%, a risk sufficiently high that most clinicians favor mesorectal excision rather than less aggressive approaches. Patients who have a complete clinical response of the primary lesions to neoadjuvant therapy may represent a special case. Total mesorectal excision can be accomplished without sacrifice of the anal sphincters, and continence can be preserved. Evolving understanding of patterns of tumor spread and mechanisms of anal continence have resulted in increased use of continence-preserving procedures. Removal of the anal sphincters seems to be advantageous only if the sphincters are directly involved. A few small series suggest that a segmental sphincter resection could result in good local control and continence preservation, even if the sphincters are involved. Areas of controversy currently include the role of neoadjuvant therapy for high rectal lesions, the role of lateral lymph node dissection, and methods of improving anal continence after rectal resection.
Colon and Rectal Cancer: Laparoscopic or Open?
Authors: Boller Anne-Marie , Nelson Heidi
Published: November 2007

Early experiences with laparoscopic colectomy were unfavorable, with higher than expected rates of wound tumor implants and concerns about short and long-term compromised oncologic outcomes. Several international randomized controlled trials were initiated to address concerns regarding compromised oncologic outcomes. Each of the trials was designed to test the hypothesis that level 1 evidence supports the general feasibility and recovery advantage as well as cancer equivalence of laparoscopic colectomy in curable colon cancer. The following four phase III randomized controlled trials have completed accrual and reported early data on recovery benefits for laparoscopic colectomy: Barcelona, Clinical Outcomes of Surgical Therapy Study Group (COSTSG), Colon Cancer Laparoscopic or Open Resection (COLOR), and Conventional versus Laparoscopic-Assisted Surgery in Colorectal Cancer (CLASICC). These trials have uniformly and consistently shown a significant reduction in the use of narcotics and oral analgesics and length of hospital stay, as well as a faster return of diet and bowel function, with laparoscopic colectomy. Two of the trials, Barcelona and COSTSG, have sufficient maturation and follow-up to report recurrence and survival data, and neither has found a survival disadvantage in patients treated with laparoscopic colectomy. Results of the Barcelona trial suggest a cancer-related survival advantage in patients treated with laparoscopic colectomy, based solely on differences in patients with stage III disease; this is not confirmed by the COSTSG trial. Results of the CLASICC and COLOR trials, as well as 5-year data from the COSTSG trial, should definitively address survival results. The investigational experience with laparoscopic rectal cancer is not as mature; the subset of rectal cancer patients (n = 253) in the CLASICC trial provides the only available randomized controlled trial data. Laparoscopic colectomy in patients with curable cancer is accepted as an alternative to open colectomy, whereas the viability of laparoscopic rectal cancer resection requires further investigation.
Newer Pathologic Assessment Techniques for Colorectal Carcinoma
Authors: Turner Roderick R. , Li Carolyn , Compton Carolyn C.
Published: November 2007

The pathogenesis of colorectal carcinoma is characterized by progressive genetic abnormalities, which lead to proteomic and cellular changes that determine the cancer malignant phenotype. Phenotypic characteristics seen on histopathologic examination (e.g., tumor stage, histologic grade, and vasoinvasiveness) are essential to planning patient management and should continue to be the major focus of pathologists' efforts. Nonetheless, additional markers that improve the prognostic and predictive power of the pathologic analysis of the primary tumor have been the focus of intense research in recent years. Improved prognostic power may derive from advancements in histopathologic evaluation, more sensitive lymph node staging techniques, and specific molecular analysis methods, such as genetic tests or immunophenotypic profiles. Histopathologic improvements are needed to better standardize histologic grade determination and recognize tumor budding at the invasive front as a marker of aggressive biological behavior and an adverse parameter. Ultrastaging of mesenteric lymph nodes remains a controversial area. Genotypic studies are well developed in the areas of microsatellite instability and chromosome 18q deletion/loss of heterozygosity. Immunophenotypic studies are available in a range of areas including tumor suppressor gene/oncogene expression, proliferation/apoptosis, angiogenesis, and cell adhesion and signaling. Gene expression profiles identified by microarray techniques may help to subtype the large category of microsatellite-stable colorectal carcinoma and define immunophenotypic panels to subclassify tumors into prognostic and therapeutic groups. This brief review discusses the most promising of these approaches and evidence supporting their potential clinical utility.
New Approaches to Assessing and Treating Early-Stage Colon and Rectal Cancers: Cooperative Group Strategies for Assessing Optimal Approaches in Early-Stage Disease
Authors: Benson Al B.
Published: November 2007

The U.S. Gastrointestinal Intergroup (GI Intergroup), including the National Cancer Institute of Canada, has created a portfolio of clinical trials for patients with stage II and III colon and rectal cancer, integrating therapeutic strategies from recent advanced disease trials. Fluoropyrimidine-based combination therapy for metastatic disease, with either irinotecan or oxaliplatin plus bevacizumab, has resulted in significant improvement in response and disease-free and overall survival. Cetuximab and irinotecan have produced intriguing response and progression-free survival data from randomized phase II trials. Although patients with stage II and III rectal cancer are uniformly included in individual clinical trials, the GI Intergroup conducts separate trials in patients with stage II and III colon cancer, with the exception of the National Surgical Adjuvant Breast and Bowel Project (NSABP), which continues to merge both stages in their statistical designs. The U.S. chemotherapy platform for adjuvant therapy clinical trials is based on the positive adjuvant data from NSABP C-07 [FLOX with bolus 5-fluorouracil (5-FU)] and the MOSAIC trial (FOLFOX with infusional 5-FU). Three irinotecan-based adjuvant trials (one U.S. and two European) did not reach designated statistical end points. In addition, the GI Intergroup has consistently integrated molecular biological and other laboratory projects as important components of past and current trials. NSABP has recently completed accrual of patients to C-08, which is evaluating FOLFOX with or without bevacizumab in stage II/III colon cancer. E5202, the largest U.S. stage II colon cancer trial, determines patient risk by the initial evaluation of tumor 18q loss of heterozygosity and microsatellite instability status. Low-risk patients are observed, whereas high-risk patients are randomized to FOLFOX with or without bevacizumab. N0147 evaluates FOLFOX with or without cetuximab in patients with stage III disease. Two large rectal cancer trials have begun to accrue patients. NSABP R-04 compares neoadjuvant radiation with either continuous infusion 5-FU with or without oxaliplatin versus capecitabine with or without oxaliplatin. E5204 is the adjuvant comparison of FOLFOX with or without bevacizumab and is also available to NSABP R-04 patients.
Clinical Significance of Epidermal Growth Factor Receptor Protein Overexpression and Gene Copy Number Gains in Prostate Cancer
Authors: Schlomm Thorsten , Kirstein Patrick , Iwers Liv , Daniel Birte , Steuber Thomas , Walz Jochen , Chun Felix H.K. , Haese Alexander , Kollermann Jens , Graefen Markus , Huland Hartwig , Sauter Guido , Simon Ronald , Erbersdobler Andreas
Published: November 2007

Purpose: The epidermal growth factor receptor (EGFR) is a protein involved in the tumor progression of many cancer types and is an important therapeutic target. To determine its role in prostate cancer, we analyzed 2,497 prostate cancers on the DNA and protein level.

Experimental Design: Tissue samples from each tumor were brought into a tissue microarray and analyzed by immunohistochemistry and fluorescence in situ hybridization. A subset of cancers was also sequenced for EGFR exon 18 to 21 mutations.

Results: Detectable EGFR expression was found in 18% of cancers and was significantly associated with high grade, advanced stage, and high risk for prostate-specific antigen recurrence in univariate analysis (P < 0.0001, each). Fluorescence in situ hybridization analysis with a dual-labeling probe for centromere 7 and EGFR showed increased EGFR copy number in 3.3% of cases. EGFR copy number gains were mostly due to an overrepresentation of the entire chromosome and were associated with EGFR protein expression (P < 0.0001), high grade (P < 0.0001), and advanced stage (P = 0.0056). Only one cancer had a high-level amplification (>20 EGFR gene copies per cell). This amplification was heterogeneous, involving only ∼30% of the cancer volume. EGFR mutations were not found in 35 of the cases analyzed.

Conclusion: Increased EGFR expression is often seen in prostate cancer and is associated with poor prognosis. The significant association of EGFR copy number gains with protein expression argues for the significant role of minimal gene copy number changes for protein expression. Although EGFR expression was not an independent prognostic variable, the potential utility of anti-EGFR medications might be worth further investigation in EGFR-expressing prostate cancer.
Activation of KIF4A as a Prognostic Biomarker and Therapeutic Target for Lung Cancer
Authors: Taniwaki Masaya , Takano Atsushi , Ishikawa Nobuhisa , Yasui Wataru , Inai Kouki , Nishimura Hitoshi , Tsuchiya Eiju , Kohno Nobuoki , Nakamura Yusuke , Daigo Yataro
Published: November 2007

Purpose and Experimental Design: To identify molecules that might be useful as diagnostic/prognostic biomarkers and as targets for the development of new molecular therapies, we screened genes that were highly transactivated in a large proportion of 101 lung cancers by means of a cDNA microarray representing 27,648 genes. We found a gene encoding KIF4A, a kinesin family member 4A, as one of such candidates. Tumor tissue microarray was applied to examine the expression of KIF4A protein and its clinicopathologic significance in archival non–small cell lung cancer (NSCLC) samples from 357 patients. A role of KIF4A in cancer cell growth and/or survival was examined by small interfering RNA experiments. Cellular invasive activity of KIF4A on mammalian cells was examined using Matrigel assays.

Results: Immunohistochemical staining detected positive KIF4A staining in 127 (36%) of 357 NSCLCs and 19 (66%) of 29 small-cell lung cancers examined. Positive immunostaining of KIF4A protein was associated with male gender (P = 0.0287), nonadenocarcinoma histology (P = 0.0097), and shorter survival for patients with NSCLC (P = 0.0005), and multivariate analysis confirmed its independent prognostic value (P = 0.0012). Treatment of lung cancer cells with small interfering RNAs for KIF4A suppressed growth of the cancer cells. Furthermore, we found that induction of exogenous expression of KIF4A conferred cellular invasive activity on mammalian cells.

Conclusions: These data strongly implied that targeting the KIF4A molecule might hold a promise for the development of anticancer drugs and cancer vaccines as well as a prognostic biomarker in clinic.
Phase 2 Study of ABT-510 in Patients with Previously Untreated Advanced Renal Cell Carcinoma
Authors: Ebbinghaus Scot , Hussain Maha , Tannir Nizar , Gordon Michael , Desai Apurva A. , Knight Raymond A. , Humerickhouse Rod A. , Qian Jiang , Gordon Gary B. , Figlin Robert
Published: November 2007

Purpose: Angiogenesis is a characteristic of renal cell carcinoma. ABT-510 is an angiogenesis inhibitor that mimics the antiangiogenic properties of thrombospondin-1. This study was designed to assess the safety and efficacy of ABT-510 in patients with advanced renal cell carcinoma.

Experimental Design: Patients with previously untreated metastatic or unresectable renal cell carcinoma were randomized to treatment with one of two doses of ABT-510, self-administered s.c. twice daily in 28-day treatment periods without intervening rest periods. End points were progression-free survival (PFS), objective response rate, overall survival, and toxicity.

Results: The objective response rate was 4% in the 10 mg twice daily group, and there were two unconfirmed PRs in the 100 mg twice daily group. Respective median PFS was 4.2 and 3.3 months, with a 6-month PFS of 39% and 32%. Median overall survival was 27.8 months (10 mg twice daily) and 26.1 months (100 mg twice daily). The most frequent adverse events were injection site reactions (84%), fatigue (50%), headache (20%), and nausea (19%). The incidence of treatment-related, grade 3/4 adverse events was low and included three bleeding episodes (gastrointestinal hemorrhage, intracranial hemorrhage, and hemoptysis) and one thrombotic event (deep vein thrombosis). No deaths were attributed to ABT-510.

Conclusions: There was little evidence of clinical activity for ABT-510, and further evaluation as a single agent for treating advanced renal cell carcinoma is not warranted. The evidence of a favorable safety profile may justify further evaluation in combination therapy.
Schisandrin B Prevents Doxorubicin-Induced Cardiotoxicity via Enhancing Glutathione Redox Cycling
Authors: Li Ling , Pan Qiangrong , Han Weidong , Liu Zhen , Li Ling , Hu Xun
Published: November 2007

Purpose: The dose-cumulative cardiotoxicties and the emerging cancerous apoptotic/drug resistance are two major obstacles limiting the efficacy of anthracycline antibiotics, notably doxorubicin. We attempted to prove if schisandrin B (Sch B), a dual inhibitor of P-glycoprotein and multidrug resistance–associated protein 1, could protect against doxorubicin-induced cardiotoxicity, on the premise that Sch B is an enhancer of glutathione redox cycling that may attenuate doxorubicin-induced oxidative stress in the cardiomyocytes.

Experimental Design: Mice or rat were dosed with a single injection of doxorubicin (25 mg/kg, i.p.) with or without pretreatment of Sch B. The protective roles of Sch B against doxorubicin-induced cardiac damage were evaluated on the aspects of the release of cardiac enzymes into serum, the formation of malondialdehyde, the activation of matrix metalloproteinase, the structural damage in the left ventricles, the mortality rates, and the cardiac functions.

Results: Pretreatment of Sch B significantly attenuated doxorubicin-induced cardiotoxicities on all the aspects listed above. The underlying mechanism was associated with the effect of Sch B on maintaining the cardiomyocytic glutathione and the activities of superoxide dismutase, and the key enzymes (glutathione peroxidase, glutathione reductase, and glutathione transferase) responsible for glutathione redox cycling, which neutralized doxorubicin-induced oxidative stress.

Conclusion: To the best of our knowledge, Sch B is the only molecule ever proved to function as a cardioprotective agent as well as a dual inhibitor of P-glycoprotein and multidrug resistance–associated protein 1, which is potentially applicable to treat cancers, especially the multidrug-resistant cancers involving doxorubicin or its kin.
The Epidermal Growth Factor Receptor: A Role in Repair of Radiation-Induced DNA Damage
Authors: Chen David J. , Nirodi Chaitanya S.
Published: November 2007

The epidermal growth factor receptor (EGFR), which is frequently expressed in tumors of epithelial origin, is an important determinant of tumor responses to ionizing radiation. Elevated EGFR expression and activity frequently correlate with tumor resistance to radiotherapy in patients. EGFR is thought to confer tumor resistance to radiation through the activation of survival and cell proliferation pathways. Recent discoveries have identified a novel radioprotective function of EGFR which involves the radiation-induced nuclear translocation of the receptor and its interactions with the DNA-dependent protein kinase, a key component of the nonhomologous end-joining DNA repair pathway. Targeting the DNA repair function of EGFR may serve as a therapeutic model for sensitizing tumors to radiotherapy in patients.
Integrated Contextual Representation for Objects' Identities and Their Locations
Authors: Gronau Nurit , Neta Maital , Bar Moshe
Published: November 2007

Visual context plays a prominent role in everyday perception. Contextual information can facilitate recognition of objects within scenes by providing predictions about objects that are most likely to appear in a specific setting, along with the locations that are most likely to contain objects in the scene. Is such identity-related (“semantic”) and location-related (“spatial”) contextual knowledge represented separately or jointly as a bound representation? We conducted a functional magnetic resonance imaging (fMRI) priming experiment whereby semantic and spatial contextual relations between prime and target object pictures were independently manipulated. This method allowed us to determine whether the two contextual factors affect object recognition with or without interacting, supporting a unified versus independent representations, respectively. Results revealed a Semantic × Spatial interaction in reaction times for target object recognition. Namely, significant semantic priming was obtained when targets were positioned in expected (congruent), but not in unexpected (incongruent), locations. fMRI results showed corresponding interactive effects in brain regions associated with semantic processing (inferior prefrontal cortex), visual contextual processing (parahippocampal cortex), and object-related processing (lateral occipital complex). In addition, activation in fronto-parietal areas suggests that attention and memory-related processes might also contribute to the contextual effects observed. These findings indicate that object recognition benefits from associative representations that integrate information about objects' identities and their locations, and directly modulate activation in object-processing cortical regions. Such context frames are useful in maintaining a coherent and meaningful representation of the visual world, and in providing a platform from which predictions can be generated to facilitate perception and action.
Neurodynamics of the Prefrontal Cortex during Conditional Visuomotor Associations
Authors: Loh Marco , Pasupathy Anitha , Miller Earl K. , Deco Gustavo
Published: November 2007

The prefrontal cortex is believed to be important for cognitive control, working memory, and learning. It is known to play an important role in the learning and execution of conditional visuomotor associations, a cognitive task in which stimuli have to be associated with actions by trial-and-error learning. In our modeling study, we sought to integrate several hypotheses on the function of the prefrontal cortex using a computational model, and compare the results to experimental data. We constructed a module of prefrontal cortex neurons exposed to two different inputs, which we envision to originate from the inferotemporal cortex and the basal ganglia. We found that working memory properties do not describe the dominant dynamics in the prefrontal cortex, but the activation seems to be transient, probably progressing along a pathway from sensory to motor areas. During the presentation of the cue, the dynamics of the prefrontal cortex is bistable, yielding a distinct activation for correct and error trails. We find that a linear change in network parameters relates to the changes in neural activity in consecutive correct trials during learning, which is important evidence for the underlying learning mechanisms.
Functional Magnetic Resonance Imaging Evidence for Abnormalities in Response Selection in Attention Deficit Hyperactivity Disorder: Differences in Activation Associated with Response Inhibition but Not Habitual Motor Response
Authors: Suskauer Stacy J. , Simmonds Daniel J. , Fotedar Sunaina , Blankner Joanna G. , Pekar James J. , Denckla Martha B. , Mostofsky Stewart H.
Published: November 2007

Impaired response inhibition is thought to be a core deficit in attention deficit hyperactivity disorder (ADHD). Prior imaging studies investigating response inhibition in children with ADHD have used tasks involving different cognitive resources, thereby complicating the interpretation of their findings. In this study, a classical go/no-go task with a well-ingrained stimulus-response association (green = go; red = no-go) was used in order to minimize extraneous cognitive demands. Twenty-five children with ADHD and 25 typically developing (TD) children between the ages of 8 and 13 years and group-matched for IQ and performance on the go/no-go task were studied using event-related functional magnetic resonance imaging (fMRI). Analyses were used to examine differences in activation between the ADHD and TD groups for “go” (habitual motor response) and “no-go” (requiring inhibition of the motor response) events. Region-of-interest analyses revealed no between-group difference in activation in association with “go” events. For “no-go” events, the children with ADHD demonstrated significantly less activation than did TD controls within a network important for inhibiting a motor response to a visual stimulus, with frontal differences localized to the pre-supplementary motor area. Although blood oxygenation level-dependent fMRI data show no differences between children with ADHD and TD children in association with a habituated motor “go” response, during “no-go” events, which require selecting not to respond, children with ADHD show diminished recruitment of networks important for response inhibition. The findings suggest that abnormalities in circuits important for motor response selection contribute to deficits in response inhibition in children with ADHD and lend support to the growing awareness of ADHD-associated anomalies in medial frontal regions important for the control of voluntary actions.
Knowledge-based Correction of Flash-lag Illusion
Authors: Noguchi Yasuki , Kakigi Ryusuke
Published: November 2007

A flash is perceived to lag spatially behind a moving object even when the two retinal images are physically aligned (flash-lag effect, FLE). Here we show that this robust illusion can be diminished by a knowledge of letters in the observer's brain. When moving and flashed segments in the FLE made the shape of a Kanji letter (ideographic characters used in Japan), the magnitude of the illusory lag perceived by Japanese subjects was significantly reduced compared to when conventional geometric (nonletter) segments were used. This diminishment was not observed when a pseudo-Kanji letter was presented to Japanese subjects or when non-Japanese English-speakers (who do not have a knowledge of Kanji) saw a real Kanji letter, indicating that the reduction in the FLE was induced by a retrieval of the knowledge (shapes of letters) stored in the observer's brain. Furthermore, measurements of neural activities by magnetoencephalography showed that the initial brain response, in which the effect of the knowledge became evident, occurred as early as 160 msec after the appearance of the flashed segment. These results demonstrated a substantial influence of knowledge on the flash-lag illusion and further suggest a rapid response of the knowledge-based perceptual pathway in the human brain.
Perception and Understanding of Others' Actions and Brain Connectivity
Authors: Pavlova Marina , Sokolov Alexander N. , Birbaumer Niels , Krägeloh-Mann Ingeborg
Published: November 2007

Perception and understanding of dispositions and intentions of others through their actions are of immense importance for adaptive daily-life behavior and social communication. Here we ask whether, and, if so, how this ability is impaired in adolescents who were born premature and suffer early periventricular damage, periventricular leukomalacia (PVL) that affects brain connectivity. The visual event arrangement (EA) task was administered to PVL patients and two control groups, premature-born and term-born adolescents without brain abnormalities on a magnetic resonance imaging scan. Performance on the EA task was significantly lower in PVL patients as compared with controls. No difference was found between premature-born participants without lesions and term-born controls. Performance on the EA task was inversely related to the volumetric extent of lesions in the parieto-occipital regions of both hemispheres and, in particular, to the right temporal periventricular lesions. Whereas our earlier work reveals that compromised visual processing of biological motion, impairments in visual navigation, and other visual-perceptual disabilities in PVL patients are associated with parieto-occipital lesions, difficulties in the visual EA task solely are specifically linked to the right temporal periventricular lesions. For the first time, we show that the severity of the right temporal PVL can serve as a predictor of the ability for perception and understanding of others' actions. We assume that impairments in this ability in PVL patients are caused by disrupted brain connectivity to the right temporal cortex, a key node of the social brain.
Separable Forms of Reality Monitoring Supported by Anterior Prefrontal Cortex
Authors: Simons Jon S. , Henson Richard N. A. , Gilbert Sam J. , Fletcher Paul C.
Published: November 2007

Reality monitoring refers to the process of discriminating between internally and externally generated information. Two different tasks have often been used to assess this ability: (a) memory for perceived versus imagined stimuli; and (b) memory for participant- versus experimenter-performed operations. However, it is not known whether these two reality monitoring tasks share neural substrates. The present study involved use of a within-subjects functional magnetic resonance imaging design to examine common and distinct brain mechanisms associated with the two reality monitoring conditions. The sole difference between the two lay in greater activation in the medial anterior prefrontal cortex when recollecting whether the participant or the experimenter had carried out an operation during prior encoding as compared to recollecting whether an item had been perceived or imagined. This region has previously been linked with attending to mental states. Task differences were also reflected in the nature of functional connectivity relationships between the medial anterior and right lateral prefrontal cortex: There was a stronger correlation in activity between the two regions during recollection of self/experimenter context. This indicates a role for the medial anterior prefrontal cortex in the monitoring of retrieved information relating to internal or external aspects of context. Finally, given the importance of reality monitoring to understanding psychotic symptoms, brain activity was related to measures of proneness to psychosis and schizotypal traits. The observation of significant correlations between reduced medial anterior prefrontal signal and scores on such measures corroborates these theoretical links.
Multipoint Explicit Differencing (MED) for Time Integrations of the Wave Equation
Authors: Konor Celal S. , Arakawa Akio
Published: November 2007

For time integrations of the wave equation, it is desirable to use a scheme that is stable over a wide range of the Courant number. Implicit schemes are examples of such schemes, but they do that job at the expense of global calculation, which becomes an increasingly serious burden as the horizontal resolution becomes higher while covering a large horizontal domain. If what an implicit scheme does from the point of view of explicit differencing is looked at, it is a multipoint scheme that requires information at all grid points in space. Physically this is an overly demanding requirement because wave propagation in the real atmosphere has a finite speed. The purpose of this study is to seek the feasibility of constructing an explicit scheme that does essentially the same job as an implicit scheme with a finite number of grid points in space. In this paper, a space-centered trapezoidal implicit scheme is used as the target scheme as an example. It is shown that an explicit space-centered scheme with forward time differencing using an infinite number of grid points in space can be made equivalent to the trapezoidal implicit scheme. To avoid global calculation, a truncated version of the scheme is then introduced that only uses a finite number of grid points while maintaining stability. This approach of constructing a stable explicit scheme is called multipoint explicit differencing (MED). It is shown that the coefficients in an MED scheme can be numerically determined by single-time-step integrations of the target scheme. With this procedure, it is rather straightforward to construct an MED scheme for an arbitrarily shaped grid and/or boundaries. In an MED scheme, the number of grid points necessary to maintain stability and, therefore, the CPU time needed for each time step increase as the Courant number increases. Because of this overhead, the MED scheme with a large time step can be more efficient than a usual explicit scheme with a smaller time step only for complex multilevel models with detailed physics. The efficiency of an MED scheme also depends on how the advantage of parallel computing is taken.
The Three-Dimensional Structure and Kinematics of Drizzling Stratocumulus
Authors: Comstock Kimberly K. , Yuter Sandra E. , Wood Robert , Bretherton Christopher S.
Published: November 2007

Drizzling marine stratocumulus are examined using observations from the 2001 East Pacific Investigation of Climate Stratocumulus (EPIC Sc) field experiment. This study uses a unique combination of satellite and shipborne Doppler radar data including both horizontal and vertical cross sections through drizzle cells. Stratocumulus cloud structure was classified as closed cellular, open cellular, or unclassifiable using infrared satellite images. Distributions of drizzle cell structure, size, and intensity are similar among the cloud-structure categories, though the open-cellular distributions are shifted toward higher values. Stronger and larger drizzle cells preferentially occur when the cloud field is broken (open-cellular and unclassifiable categories). Satellite observations of cloud structure may be useful to indicate the most likely distribution of rain rates associated with a set of scenes, but infrared data alone are not sufficient to develop routine precipitation retrievals for marine stratocumulus. Individual drizzle cells about 2–20 km across usually showed precipitation growth within the cloud layer and evaporation below, divergence near echo top, and convergence below cloud base. Diverging flow near the surface was also observed beneath heavily precipitating drizzle cells. As the cloud field transitioned from a closed to an open-cellular cloud structure, shipborne radar revealed prolific development of small drizzle cells (<10 km2) that exceeded by over 5 times the number of total cells in either the preceding closed-cellular or following open-cellular periods. Peak area-average rain rates lagged by a few hours the peak in total number of drizzle cells. Based on observations from EPIC Sc, the highest stratocumulus rain rates are more likely to occur near the boundary between closed and open-cellular cloud structures.
Evaluation of Precipitation from Numerical Weather Prediction Models and Satellites Using Values Retrieved from Radars
Authors: Vasić Slavko , Lin Charles A. , Zawadzki Isztar , Bousquet Olivier , Chaumont Diane
Published: November 2007

Precipitation is evaluated from two weather prediction models and satellites, taking radar-retrieved values as a reference. The domain is over the central and eastern United States, with hourly accumulated precipitation over 21 days for the models and radar, and 13 days for satellite. Conventional statistical measures and scale decomposition methods are used. The models generally underestimate strong precipitation and show nearly constant modest skill over a 24-h forecast period. The scale decomposition results show that the effective model resolution for precipitation is many times the grid size. The model predictability extends beyond a few hours for only the largest scales.