bluuebunny/crossref_metadata_2025_split huggingface dataset:
Cooperative Activity of Cytotoxic Chemotherapy with Antiangiogenic Thrombospondin-I Peptides, ABT-526 in Pet Dogs with Relapsed Lymphoma
Authors: Rusk Anthony , Cozzi Elizabeth , Stebbins Marty , Vail David , Graham Joanne , Valli Victor , Henkin Jack , Sharpee Rick , Khanna Chand 
Published: December 2006

AbstractPurpose: Thrombospondin-I (TSP-I) is a natural antiangiogenic protein that enhances apoptosis of activated endothelial cells. A modified nonapeptide from TSP-I, ABT-526, has been found to be active in mouse cancer models and in dogs with naturally occurring cancers. To further assist in the development of ABT-526, we report herein on its evaluation in combination with cytotoxic chemotherapy in pet dogs with relapsed non-Hodgkin's lymphoma (NHL).Experimental Design: Ninety-four pet dogs with naturally occurring first-relapse NHL were entered into a prospective randomized placebo controlled double-blinded trial of ABT-526 plus CeeNu (Bristol-Myers Squibb, New York, NY) versus CeeNu alone. Endpoints included response rate, duration of response, time to progression, and incidence of toxicoses.Results: No significant ABT-526-specific toxicities were seen. CeeNu-associated toxicities, including neutropenia, thrombocytopenia, gastroenteritis, and elevated alanine transaminase, were similar. No significant difference in objective response rate was seen (ABT-526 + CeeNu versus placebo + CeeNu, 23/49 versus 23/37; P &gt; 0.25). Cooperative activity between ABT-526 and CeeNu chemotherapy was evident based on a significant increase in the median response duration of dogs receiving ABT-526 plus CeeNu compared with placebo plus CeeNu (35 versus 15 days; P &lt; 0.05). The time to progression for responding cases was also significantly greater in dogs receiving ABT-526 plus CeeNu compared with placebo plus CeeNu (41 versus 21 days; P &lt; 0.05).Conclusions: Results of this preclinical trial suggest that the activity of ABT-526 is sustained when combined with cytotoxic chemotherapy; furthermore, the activity seems to be associated with the maintenance of CeeNu-induced treatment responses. Further studies of TSP-I peptide antiangiogenic therapy in pet dogs and humans with NHL are warranted.
Epidermal Growth Factor Receptor Activation: How Exon 19 and 21 Mutations Changed Our Understanding of the Pathway
Authors: Rosell Rafael , Taron Miquel , Reguart Noemi , Isla Dolores , Moran Teresa 
Published: December 2006

AbstractThe discovery of epidermal growth factor receptor (EGFR) mutations in never-smokers has been the most relevant finding ever in non–small cell lung cancer. When patients whose tumors bear the sensitizing mutations are treated with the tyrosine kinase inhibitors gefitinib or erlotinib, we witness response rates and durations never before reported, including complete responses. At the same time, the presence of EGFR mutations has raised numerous new questions, tantalizing data, and new challenges for treatment. This is particularly true as we try to generalize the findings in lung cancer to other malignancies. The indiscriminate use of gefitinib or erlotinib in the general lung cancer population results in meager survival benefit for patients. Similarly, the tyrosine kinase inhibitors have limited activity in a variety of tumor types with EGFR overexpression. This has led to the question of whether EGFR remains a viable target in patients other than those whose tumors contain mutations, and whether the modest activity of cetuximab in colorectal cancer and head and neck cancer represents all that we can expect from inhibition of this pathway in the absence of mutation. Mechanisms of pathway activation other than mutation have been discovered in recent years, and include overexpression mediated by gene amplification or by amplification of a dinucleotide repeat in the EGFR promoter, mutation of an extracellular region on EGFR generating a mutant protein termed EGFRvIII, and enhanced signaling due to heterodimerization with other members of the EGFR family, particularly overexpression of HER2/HER3. The extent to which these paths to EGFR activation will confer sensitivity to the tyrosine kinase inhibitors or to EGFR monoclonal antibodies is being explored. Thus far, published clinical data suggest that there is little room for the administration of gefitinib or erlotinib in the absence of EGFR mutations. The five articles in this edition of CCR Focus will address the various mechanisms of EGFR pathway activation and provide insight into the potential for translation into clinical relevance.
The Coamplification Pattern of the MYCN Amplicon Is an Invariable Attribute of Most MYCN-Amplified Human Neuroblastomas
Authors: Weber Axel , Starke Sven , Bergmann Eckhard , Christiansen Holger 
Published: December 2006

Abstract
Purpose: Fifteen percent to 20% of human neuroblastomas show amplification of the MYCN oncogene physiologically located at chromosome 2p24-25, indicating an aggressive subtype of human neuroblastoma with a poor clinical outcome. Recent findings revealed that the structure of the amplicon differs interindividually and that coamplification of genes in telomeric proximity to MYCN might play a relevant role in neuroblastoma development and response to treatment, respectively. We now asked if the amplicon structure is an invariable attribute of an individual tumor or if the coamplification pattern could change during progress or in case of recurrent disease.
Experimental Design: We used a previously described multiplex PCR approach to analyze the coamplification status of MYCN-amplified human neuroblastomas (n = 33) in tumor tissue at the time of initial diagnosis and in consecutive tissue specimens at later time points after initial treatment or from relapsing disease. The MYCN copy number per haploid genome (Mcn/hg) in these specimens was determined in a separate duplex PCR.
Results: In 32 of the 33 investigated tumors, the amplicon structure showed no changes after initial chemotherapy and in recurrent disease. Mcn/hg showed a decrease after initial treatment (n = 23), whereas we found a significant increase in recurrent disease (n = 10).
Conclusion: Our data indicate that the initial determined structure of the 2p24-25 amplicon is a consistent attribute in the great majority of the individual MYCN-amplified neuroblastomas and shows no plasticity during or after chemotherapy. Observed changes in the Mcn/hg over the course of disease are in line with preexisting cell culture findings.
Sorafenib for the Treatment of Advanced Renal Cell Carcinoma
Authors: Kane Robert C. , Farrell Ann T. , Saber Haleh , Tang Shenghui , Williams Gene , Jee Josephine M. , Liang Chengyi , Booth Brian , Chidambaram Nallaperumal , Morse David , Sridhara Rajeshwari , Garvey Patricia , Justice Robert , Pazdur Richard 
Published: December 2006

Abstract
Purpose: This report describes the U.S. Food and Drug Administration (FDA) review and approval of sorafenib (Nexavar, BAY43-9006), a new small-molecule, oral, multi-kinase inhibitor for the treatment of patients with advanced renal cell carcinoma (RCC).
Experimental Design: After meeting with sponsors during development studies of sorafenib, the FDA reviewed the phase 3 protocol under the Special Protocol Assessment mechanism. Following new drug application submission, FDA independently analyzed the results of two studies in advanced RCC: a large, randomized, double-blinded, phase 3 international trial of single-agent sorafenib and a supportive phase 2 study.
Results: In the phase 3 trial, 902 patients with advanced progressive RCC after one prior systemic therapy were randomized to 400 mg sorafenib twice daily plus best supportive care or to a matching placebo plus best supportive care. Primary study end points included overall survival and progression-free survival (PFS). A PFS analysis, pre-specified and conducted after a total of 342 events, showed statistically significant superiority for the sorafenib group (median = 167 days) compared with that for the controls (median = 84 days, log-rank P &lt; 0.000001); the sorafenib/placebo hazard ratio was 0.44 (95% confidence interval, 0.35-0.55). Results were similar regardless of patient risk score, performance status, age, or prior therapy. The (partial) response rate to sorafenib was 2.1%. Overall survival results are preliminary. The principal toxicities in the sorafenib patients included reversible skin rashes in 40% and hand-foot skin reaction in 30%; diarrhea was reported in 43%, treatment-emergent hypertension was reported in 17%, and sensory neuropathic changes were reported in 13%. Grade 4 adverse events were uncommon. Grade 3 adverse events were hand-foot skin reaction (6%), fatigue (5%), and hypertension (3%). Laboratory findings included asymptomatic hypophosphatemia in 45% of sorafenib patients versus 11% in the placebo arm and elevation of serum lipase in 41% of sorafenib patients versus 30% in the placebo arm. Grade 4 pancreatitis was reported in two sorafenib patients, although both patients subsequently resumed sorafenib, with one at full dose.
Conclusions: Sorafenib received FDA regular approval on December 20, 2005 for the treatment of advanced RCC based on the persuasive magnitude of improvement in PFS with acceptable safety. The recommended dose is 400 mg (two 200-mg tablets) twice daily taken either 1 h before or 2 h after meals. Adverse events were accommodated by temporary dose interruptions or reductions.
Methylation of Serum DNA Is an Independent Prognostic Marker in Colorectal Cancer
Authors: Wallner Maike , Herbst Andreas , Behrens Andrea , Crispin Alexander , Stieber Petra , Göke Burkhard , Lamerz Rolf , Kolligs Frank T. 
Published: December 2006

Abstract
Purpose: Aberrant CpG island hypermethylation is a feature of a subgroup of colorectal cancers, which can be detected in the serum of affected patients. This study was designed to identify methylation targets with prognostic significance in the serum of patients with colorectal cancer.
Experimental Design: In a gene evaluation set consisting of sera from 24 patients with local colorectal cancers, 14 with metastasized disease, and 20 healthy controls, the genes HPP1/TPEF, HLTF, and hMLH1 were identified as potential serum DNA methylation markers. These genes were further analyzed in a test set of sera of 104 patients with colorectal cancer.
Results: Methylation of HLTF, HPP1/TPEF, and hMLH1 was found to be significantly correlated with tumor size, and methylation of HLTF and HPP1/TPEF was significantly associated with metastatic disease and tumor stage. Moreover, methylation of HPP1/TPEF was also associated with serum carcinoembryonic antigen. The prognostic relevance of methylation of these genes was tested in pretherapeutic sera of 77 patients with known follow-up. Patients with methylation of HPP1/TPEF or HLTF were found to have unfavorable prognosis (P = 0.001 and 0.008). In contrast, serum methylation of hMLH1 was not associated with a higher risk of death. Multivariate analysis showed methylated HPP1 and/or HLTF serum DNA to be independently associated with poor outcome and a relative risk of death of 3.4 (95% confidence interval, 1.4-8.1; P = 0.007).
Conclusions: These data show that the methylation status of specific genes in the serum of patients with colorectal cancer has the potential to become a pretherapeutic predictor of outcome.
Amplification and Overexpression of CACNA1E Correlates with Relapse in Favorable Histology Wilms' Tumors
Authors: Natrajan Rachael , Little Suzanne E. , Reis-Filho Jorge S. , Hing Lara , Messahel Boo , Grundy Paul E. , Dome Jeffrey S. , Schneider Toni , Vujanic Gordan M. , Pritchard-Jones Kathy , Jones Chris 
Published: December 2006

Abstract
Purpose: The most well established molecular markers of poor outcome in Wilms' tumor are loss of heterozygosity at chromosomes 1p and/or 16q, although to date no specific genes at these loci have been identified. We have previously shown a link between genomic gain of chromosome 1q and tumor relapse and sought to further elucidate the role of genes on 1q in treatment failure.
Experimental Design: Microarray-based comparative genomic hybridization identified a microamplification harboring a single gene (CACNA1E) at 1q25.3 in 6 of 76 (7.9%) Wilms' tumors, correlating with a shorter relapse-free survival (P = 0.0044, log-rank test). Further characterization of this gene was carried out by measuring mRNA and protein expression as well as stable transfection of HEK293 cells.
Results: Overexpression of the CACNA1E transcript was associated with DNA copy number (P = 0.0204, ANOVA) and tumor relapse (P = 0.0851, log-rank test). Immunohistochemistry against the protein product CaV2.3 revealed expression localized to the apical membrane in the distal tubules of normal kidney but not to the metanephric blastemal cells of fetal kidney from which Wilms' tumors arise. Nuclear localization in 99 of 160 (61.9%) Wilms' tumor cases correlated with a reduced relapse-free survival, particularly in cases treated with preoperative chemotherapy (P = 0.009, log-rank test). Expression profiling of stably transfected HEK293 cells revealed specific up-regulation of the immediate early response genes EGR1/EGR2/EGR3 and FOS/FOSB, mediated by activation of the MEK/ERK5/Nur77 pathway.
Conclusions: These data identify a unique genetic aberration with direct clinical relevance in Wilms' tumor relapse and provide evidence for a potential novel mechanism of treatment resistance in these tumors.
β2-Microglobulin Promotes the Growth of Human Renal Cell Carcinoma through the Activation of the Protein Kinase A, Cyclic AMP–Responsive Element-Binding Protein, and Vascular Endothelial Growth Factor Axis
Authors: Nomura Takeo , Huang Wen-Chin , Zhau Haiyen E. , Wu Daqing , Xie Zhihui , Mimata Hiromitsu , Zayzafoon Majd , Young Andrew N. , Marshall Fray F. , Weitzmann M. Neale , Chung Leland W.K. 
Published: December 2006

Abstract
Purpose: β2-Microglobulin (β2M), a soluble protein secreted by cancer and host inflammatory cells, has various biological functions, including antigen presentation. Because aberrant expression of β2M has been reported in human renal cell carcinoma, we investigated the effects of β2M overexpression on cancer cell growth and analyzed its molecular signaling pathway.
Experimental Design: We established clonal cell lines that overexpressed β2M in human renal cell carcinoma (SN12C) cells and then examined cell growth in vitro and in vivo and studied the β2M-mediated downstream cell signaling pathway.
Results: Our results showed that β2M expression positively correlates with (a) in vitro growth on plastic dishes and as Matrigel colonies, (b) cell invasion and migration in Boyden chambers, and (c) vascular endothelial growth factor (VEGF) expression and secretion by cells. We found, in addition, that β2M mediates its action through increased phosphorylation of cyclic AMP–responsive element-binding protein (CREB) via the protein kinase A-CREB axis, resulting in increased VEGF expression and secretion. In convergence with this signal axis, β2M overexpression also activated both phosphatidylinositol 3-kinase/Akt and mitogen-activated protein kinase pathways. β2M overexpression induced accelerated growth of SN12C in mouse subcutis and bone. Interrupting the β2M signaling pathway using small interfering RNA led to apoptosis with increased activation of caspase-3 and caspase-9 and cleaved poly(ADP-ribose) polymerase.
Conclusions: Our results showed for the first time that the β2M-protein kinase A-CREB-VEGF signaling axis plays a crucial role in support of renal cell carcinoma growth and progression and reveals a novel therapeutic target.
Effect of an Epidermal Growth Factor Receptor Inhibitor in Mouse Models of Lung Cancer
Authors: Yan Ying , Lu Yan , Wang Min , Vikis Haris , Yao Ruisheng , Wang Yian , Lubet Ronald A. , You Ming 
Published: December 2006

Abstract
Gefitinib (Iressa, ZD1839) is a potent high-affinity competitive tyrosine kinase inhibitor aimed primarily at epidermal growth factor receptor (EGFR). Inhibitors in this class have recently been approved for clinical use in the treatment of advanced non–small cell lung cancer as monotherapy following failure of chemotherapy. We examined the efficacy of gefitinib on lung tumorigenesis in mouse models using both postinitiation and progression protocols. Gefitinib was given at a dose of 200 mg/kg body weight (i.g.) beginning either 2 or 12 weeks following carcinogen initiation. In the postinitiation protocol, gefitinib significantly inhibited both tumor multiplicity (∼70%) and tumor load (∼90%) in A/J or p53-mutant mice (P &lt; 0.0001). Interestingly, gefitinib was also highly effective against lung carcinogenesis in the progression protocol when individual animals already have multiple preinvasive lesions in the lung. Gefitinib exhibited ∼60% inhibition of tumor multiplicity and ∼80% inhibition of tumor load when compared with control mice (both P &lt; 0.0001). These data show that gefitinib is a potent chemopreventive agent in both wild-type and p53-mutant mice and that a delayed administration was still highly effective. Analyses of mutations in the EGFR and K-ras genes in lung tumors from either control or treatment groups showed no mutations in EGFR and consistent mutation in K-ras. Using an oligonucleotide array on control and gefitinib-treated lesions showed that gefitinib treatment failed to alter the activity or the expression level of EGFR. In contrast, gefitinib treatment significantly altered the expression of a series of genes involved in cell cycle, cell proliferation, cell transformation, angiogenesis, DNA synthesis, cell migration, immune responses, and apoptosis. Thus, gefitinib showed highly promising chemopreventive and chemotherapeutic activity in this mouse model of lung carcinogenesis. (Mol Cancer Res 2006;4(12):971–81)
Children’s Production of Word Accents in Swedish Revisited
Authors: Ota Mitsuhiko 
Published: December 2006

AbstractThe two word accents in Stockholm Swedish (Accent I and Accent II) are distinguishedby a consistent falling pitch contour on the stressed syllable of AccentII words. The current study presents new types of evidence that this feature ofword accent can be systematically found in words produced by 16- to 18-montholdSwedish-speaking children. Compared to other disyllabic productions, thestressed syllable in Accent II words have a larger F0 decline, more sequences ofhigh-low turning points identified by a stylized contour algorithm and an earlier F0peak. In addition, a negative correlation is found between the value of F0 peak andF0 change in the stressed syllable. Taken together, these findings indicate that childrenlearning Swedish have internalized a subtle but lexically relevant pitch contourby a very early stage of word production.
II.—On the Critical Point in the Consolidation of Granitic Rocks
Authors: Sorby H. C. 
Published: December 2006

In carefully reviewing the various facts which I have been able to collect since the publication of my paper on the microscopical Structure of Crystals, I have been led to believe that many peculiarities in the structure of granitic rocks may be explained by a principle, which, as far as I am aware, has not hitherto attracted attention. It appears to me extremely probable that the critical point in the consolidation of granitic rocks is very closely connected with the critical temperature at which highly heated and compressed steam would condense into an equal volume of highly heated and expanded liquid water.As I pointed out in the paper already mentioned, rocks melted under great pressure probably contain water either dissolved as a gas in a liquid, or in the state of a fused hydrate. On cooling down to a lower temperature, the crystallizing out of anhydrous minerals would almost necessarily set free this previously combined water. As long as the temperature was above the critical point it would necessarily remain more or less disseminated in the rock as highly compressed steam, but as soon as the temperature fell below the critical point, it would condense into highly expanded liquid water.
On a new form of Phosphorite
Authors: Gunn Henry Hamilton 
Published: December 2006

In making an examination of some samples of Phosphorite, recently discovered in Southern Russia, I was much struck by the unusual appearance of the substance, and after a closer examination came to the conclusion that it was a new form of the mineral, and ought to be brought before the notice of this society, in order that its occurrence and physical structure might be recorded and discussed.The mineral which forms the subject of this paper occurs in rounded masses, varying in size from 5 to 9 inches in diameter. The outer surface is smooth and presents an appearance highly suggestive of the form being due to the action of running water, but upon fracturing several of these balls I found in every instance that they were c6mposed of a number of fibres radiating from the centre, of small size, and of a blueish grey colour, having a hardness of about 4.
IV.—Further Notes on Mineral “growth”
Authors: Readwin T. A. 
Published: December 2006

AbstractMr. Readwin stated that since reading his former paper (Mill Mag., No. 5), he had visited the museums of Copenhagen, Stockholm, Christiania, Kongsberg, and London, in search of corroborative evidences of “Recent Mineral-growth at ordinary temperatures, under ordinary conditions,” and that he was satisfied that mineral “growth under ordinary conditions,” is not of unusual occurrence, .although, hitherto, neither generally observed, nor believed.Mr. Readwin also stated that several of the specimens referred to in his former paper, some of which he took on his journey, exhibited changes and developments during his absence.In conclusion, Mr. Readwin submitted an idea of Metal-growth more closely at home.
I.—On the Non-Meteoric Origin of the Masses of Metallic Iron in the Basalt of Disko in Greenland. Selected and translated from the original Danish paper of K. J. V. Steenstrup
Authors: Rohde J. G. 
Published: December 2006

Scarcely in any case has the meteoric origin of any iron been more doubtful than that of the Greenland masses found by Professor Nordenskjòld in 1870, for although they contain about 2 per cent. of nickel, and, when etched, show the Widmanstätt’s figures, the fact that iron is imbedded in the basalt, on which the so-called meteorites were lying, bespeaks that the loose masses of iron originally belonged to the basalt.“The Blue Rocks” (Danish, Blaafjeld, Greenland, Ovifak), on the southern coast of Disko, where the iron was found, are about 1800 feet high; the foot up to 600 or 700 feet is covered by loose stones forming a slant of 30 or 40° above which, in the almost perpendicular rock, 13 or 14 horizontal seams of trap are seen.
IV.—On Mineral growth, at ordinary temperatures, and under ordinary conditions
Authors: Readwin T. A. 
Published: December 2006

“Plants live, and grow ; Animals live, grow, and move; Minerals, neither live, grow, nor move.”For so long a time, has this been an article of almost universal belief, that any nonconformity therewith, is looked upon with more or less of grave suspicion.In what follows, it is proposed to show that there is a rather more natural order in which the aphorism may appropriately run; namely :—Minerals grow, Plants live and grow, Animals live, grow, and move at will. “The three kingdoms of nature,” as they are not at all inconveniently called, exist in close relationship; so very close, indeed, that some naturalists think they are not really apart from each other.
VII. Note on the mode of occurrence and localities of Abriachanite
Authors: Aitkin Thomas 
Published: December 2006

The blue substance first came under my observation many years ago in one of the Slickensides, in the first quarry opened for the supply of Abriachan granite, and situated by the side of the road leading to Abriachan,-a somewhat isolated district amongst the hills overlooking Lock Ness.It was then seen in purplish-blue spots, dotting here and there the surface of the rocks which had been exposed to considerable weathering, and over which water had poured freely.