bluuebunny/crossref_metadata_2025 huggingface dataset:
Protein sequences classification by means of feature extraction with substitution matrices
Authors: Saidi Rabie , Maddouri Mondher , Mephu Nguifo Engelbert
Published: May 2010

Background

This paper deals with the preprocessing of protein sequences for supervised classification. Motif extraction is one way to address that task. It has been largely used to encode biological sequences into feature vectors to enable using well-known machine-learning classifiers which require this format. However, designing a suitable feature space, for a set of proteins, is not a trivial task. For this purpose, we propose a novel encoding method that uses amino-acid substitution matrices to define similarity between motifs during the extraction step.

Results

In order to demonstrate the efficiency of such approach, we compare several encoding methods using some machine learning classifiers. The experimental results showed that our encoding method outperforms other ones in terms of classification accuracy and number of generated attributes. We also compared the classifiers in term of accuracy. Results indicated that SVM generally outperforms the other classifiers with any encoding method. We showed that SVM, coupled with our encoding method, can be an efficient protein classification system. In addition, we studied the effect of the substitution matrices variation on the quality of our method and hence on the classification quality. We noticed that our method enables good classification accuracies with all the substitution matrices and that the variances of the obtained accuracies using various substitution matrices are slight. However, the number of generated features varies from a substitution matrix to another. Furthermore, the use of already published datasets allowed us to carry out a comparison with several related works.

Conclusions

The outcomes of our comparative experiments confirm the efficiency of our encoding method to represent protein sequences in classification tasks.
Core promoter structure and genomic context reflect histone 3 lysine 9 acetylation patterns
Authors: Kratz Anton , Arner Erik , Saito Rintaro , Kubosaki Atsutaka , Kawai Jun , Suzuki Harukazu , Carninci Piero , Arakawa Takahiro , Tomita Masaru , Hayashizaki Yoshihide , Daub Carsten O
Published: May 2010

Background

Histone modifications play an important role in gene regulation. Acetylation of histone 3 lysine 9 (H3K9ac) is generally associated with transcription initiation and unfolded chromatin, thereby positively influencing gene expression. Deep sequencing of the 5' ends of gene transcripts using DeepCAGE delivers detailed information about the architecture and expression level of gene promoters. The combination of H3K9ac ChIP-chip and DeepCAGE in a myeloid leukemia cell line (THP-1) allowed us to study the spatial distribution of H3K9ac around promoters using a novel clustering approach. The promoter classes were analyzed for association with relevant genomic sequence features.

Results

We performed a clustering of 4,481 promoters according to their surrounding H3K9ac signal and analyzed the clustered promoters for association with different sequence features. The clustering revealed three groups with major H3K9ac signal upstream, centered and downstream of the promoter. Narrow single peak promoters tend to have a concentrated activity of H3K9ac in the upstream region, while broad promoters tend to have a concentrated activity of H3K9ac and RNA polymerase II binding in the centered and downstream regions. A subset of promoters with high gene expression level, compared to subsets with low and medium gene expression, shows dramatic increase in H3K9ac activity in the upstream cluster only; this may indicate that promoters in the centered and downstream clusters are predominantly regulated at post-initiation steps. Furthermore, the upstream cluster is depleted in CpG islands and more likely to regulate un-annotated genes.

Conclusions

Clustering core promoters according to their surrounding acetylation signal is a promising approach for the study of histone modifications. When examining promoters clustered into groups according to their surrounding H3K9 acetylation signal, we find that the relative localization and intensity of H3K9ac is very specific depending on characteristic sequence features of the promoter. Experimental data from DeepCAGE and ChIP-chip experiments using undifferentiated (monocyte) and differentiated (macrophage) THP-1 cells leads us to the same conclusions.
NGX6 gene mediated by promoter methylation as a potential molecular marker in colorectal cancer
Authors: Liu Minji , Peng Ya , Wang Xiaoyan , Guo Qin , Shen Shourong , Li Guiyuan
Published: May 2010

Background

Nasopharyngeal carcinoma associated gene 6 (NGX6) is down-regulated in most colon cancer cell lines and tumor tissues when compared with their normal tissue samples. As a novel suppress tumor gene, it could inhibit colon cancer cell growth and cell cycle progression. However, little is known about the transcriptional mechanisms controlling NGX6 gene expression. Recent findings suggest that epigenetic inactivation of multiple tumor suppressor genes plays an important role in the tumorigenesis of colorectal carcinoma (CRC). In this study, we explored the role of DNA methylation in regulation of NGX6 transcription.

Methods

In the present study, we cloned the NGX6 promoter with characteristics of a CpG island by luciferase reporter assay. Then, the CpG methylation status around the NGX6 promoter region in colon cancer cell lines and colorectal tumor tissues was examined by methylation-specific PCR and bisulfite DNA sequencing. Finally, 5-Aza-2'-deoxycytidine (5-Aza-dC) treatment was used to confirm the correlation between NGX6 promoter methylation and its gene inactivation.

Results

The sequence spanning positions -157 to +276 was identified as the NGX6 promoter, in which no canonical TATA boxes were found, while two CAAT boxes and GC boxes were discovered. Methylation status was observed more frequently in 40 colorectal cancer samples than in 40 adjacent normal mucosa samples (18/40 versus 7/40; P < 0.05). An analysis correlating gene methylation status with clinicopathological cancer features revealed that dense methylation of the NGX6 promoter was associated with colorectal cancer patients age (P < 0.05). Moreover, a trend was shown toward metastasis status and primary site in colorectal carcinomas with NGX6 promoter methylation (p = 0.056 and P = 0.067, respectively). In addition, 5-Aza-dC could induce NGX6 mRNA expression and NGX6 promoter demethylation in HT-29 cells.

Conclusions

Down-regulation of NGX6 gene is related to the promoter methylation. DNA methylation of NGX6 promoter might be a potential molecular marker for diagnosis or prognosis, or serve as a therapeutic target.
Antitumor and antiangiogenic effect of the dual EGFR and HER-2 tyrosine kinase inhibitor lapatinib in a lung cancer model
Authors: Diaz Roque , Nguewa Paul A , Parrondo Ricardo , Perez-Stable Carlos , Manrique Irene , Redrado Miriam , Catena Raul , Collantes Maria , Peñuelas Ivan , Díaz-González Juan Antonio , Calvo Alfonso
Published: May 2010

Background

There is strong evidence demonstrating that activation of epidermal growth factor receptors (EGFRs) leads to tumor growth, progression, invasion and metastasis. Erlotinib and gefitinib, two EGFR-targeted agents, have been shown to be relevant drugs for lung cancer treatment. Recent studies demonstrate that lapatinib, a dual tyrosine kinase inhibitor of EGFR and HER-2 receptors, is clinically effective against HER-2-overexpressing metastatic breast cancer. In this report, we investigated the activity of lapatinib against non-small cell lung cancer (NSCLC).

Methods

We selected the lung cancer cell line A549, which harbors genomic amplification of EGFR and HER-2. Proliferation, cell cycle analysis, clonogenic assays, and signaling cascade analyses (by western blot) were performed in vitro. In vivo experiments with A549 cells xenotransplanted into nude mice treated with lapatinib (with or without radiotherapy) were also carried out.

Results

Lapatinib dramatically reduced cell proliferation (P < 0.0001), DNA synthesis (P < 0.006), and colony formation capacity (P < 0.0001) in A549 cells in vitro. Furthermore, lapatinib induced G1 cell cycle arrest (P < 0.0001) and apoptotic cell death (P < 0.0006) and reduced cyclin A and B1 levels, which are regulators of S and G2/M cell cycle stages, respectively. Stimulation of apoptosis in lapatinib-treated A549 cells was correlated with increased cleaved PARP, active caspase-3, and proapoptotic Bak-1 levels, and reduction in the antiapoptic IAP-2 and Bcl-xL protein levels. We also demonstrate that lapatinib altered EGFR/HER-2 signaling pathways reducing p-EGFR, p-HER-2, p-ERK1/2, p-AKT, c-Myc and PCNA levels. In vivo experiments revealed that A549 tumor-bearing mice treated with lapatinib had significantly less active tumors (as assessed by PET analysis) (P < 0.04) and smaller in size than controls. In addition, tumors from lapatinib-treated mice showed a dramatic reduction in angiogenesis (P < 0.0001).

Conclusion

Overall, these data suggest that lapatinib may be a clinically useful agent for the treatment of lung cancer.
Interference with Activator Protein-2 transcription factors leads to induction of apoptosis and an increase in chemo- and radiation-sensitivity in breast cancer cells
Authors: Thewes Verena , Orso Francesca , Jäger Richard , Eckert Dawid , Schäfer Sabine , Kirfel Gregor , Garbe Stephan , Taverna Daniela , Schorle Hubert
Published: May 2010

Background

Activator Protein-2 (AP-2) transcription factors are critically involved in a variety of fundamental cellular processes such as proliferation, differentiation and apoptosis and have also been implicated in carcinogenesis. Expression of the family members AP-2α and AP-2γ is particularly well documented in malignancies of the female breast. Despite increasing evaluation of single AP-2 isoforms in mammary tumors the functional role of concerted expression of multiple AP-2 isoforms in breast cancer remains to be elucidated. AP-2 proteins can form homo- or heterodimers, and there is growing evidence that the net effect whether a cell will proliferate, undergo apoptosis or differentiate is partly dependent on the balance between different AP-2 isoforms.

Methods

We simultaneously interfered with all AP-2 isoforms expressed in ErbB-2-positive murine N202.1A breast cancer cells by conditionally over-expressing a dominant-negative AP-2 mutant.

Results

We show that interference with AP-2 protein function lead to reduced cell number, induced apoptosis and increased chemo- and radiation-sensitivity. Analysis of global gene expression changes upon interference with AP-2 proteins identified 139 modulated genes (90 up-regulated, 49 down-regulated) compared with control cells. Gene Ontology (GO) investigations for these genes revealed Cell Death and Cell Adhesion and Migration as the main functional categories including 25 and 12 genes, respectively. By using information obtained from Ingenuity Pathway Analysis Systems we were able to present proven or potential connections between AP-2 regulated genes involved in cell death and response to chemo- and radiation therapy, (i.e. Ctgf, Nrp1, Tnfaip3, Gsta3) and AP-2 and other main apoptosis players and to create a unique network.

Conclusions

Expression of AP-2 transcription factors in breast cancer cells supports proliferation and contributes to chemo- and radiation-resistance of tumor cells by impairing the ability to induce apoptosis. Therefore, interference with AP-2 function could increase the sensitivity of tumor cells towards therapeutic intervention.
Gene expression profile and genomic alterations in colonic tumours induced by 1,2-dimethylhydrazine (DMH) in rats
Authors: Femia Angelo Pietro , Luceri Cristina , Toti Simona , Giannini Augusto , Dolara Piero , Caderni Giovanna
Published: May 2010

Background

Azoxymethane (AOM) or 1,2-dimethylhydrazine (DMH)-induced colon carcinogenesis in rats shares many phenotypical similarities with human sporadic colon cancer and is a reliable model for identifying chemopreventive agents. Genetic mutations relevant to human colon cancer have been described in this model, but comprehensive gene expression and genomic analysis have not been reported so far. Therefore, we applied genome-wide technologies to study variations in gene expression and genomic alterations in DMH-induced colon cancer in F344 rats.

Methods

For gene expression analysis, 9 tumours (TUM) and their paired normal mucosa (NM) were hybridized on 4 × 44K Whole rat arrays (Agilent) and selected genes were validated by semi-quantitative RT-PCR. Functional analysis on microarray data was performed by GenMAPP/MappFinder analysis. Array-comparative genomic hybridization (a-CGH) was performed on 10 paired TUM-NM samples hybridized on Rat genome arrays 2 × 105K (Agilent) and the results were analyzed by CGH Analytics (Agilent).

Results

Microarray gene expression analysis showed thatDefcr4,Igfbp5,Mmp7, Nos2, S100A8andS100A9were among the most up-regulated genes in tumours (Fold Change (FC) compared with NM: 183, 48, 39, 38, 36 and 32, respectively), whileSlc26a3,Mptx,RetlnaandMuc2were strongly down-regulated (FC: -500; -376, -167, -79, respectively). Functional analysis showed that pathways controlling cell cycle, protein synthesis, matrix metalloproteinases, TNFα/NFkB, and inflammatory responses were up-regulated in tumours, while Krebs cycle, the electron transport chain, and fatty acid beta oxidation were down-regulated. a-CGH analysis showed that four TUM out of ten had one or two chromosomal aberrations. Importantly, one sample showed a deletion on chromosome 18 includingApc.

Conclusion

The results showed complex gene expression alterations in adenocarcinomas encompassing many altered pathways. While a-CGH analysis showed a low degree of genomic imbalance, it is interesting to note that one of the alterations concernedApc, a key gene in colorectal carcinogenesis. The fact that many of the molecular alterations described in this study are documented in human colon tumours confirms the relevance of DMH-induced cancers as a powerful tool for the study of colon carcinogenesis and chemoprevention.
The association between green space and cause-specific mortality in urban New Zealand: an ecological analysis of green space utility
Authors: Richardson Elizabeth , Pearce Jamie , Mitchell Richard , Day Peter , Kingham Simon
Published: May 2010

Background

There is mounting international evidence that exposure to green environments is associated with health benefits, including lower mortality rates. Consequently, it has been suggested that the uneven distribution of such environments may contribute to health inequalities. Possible causative mechanisms behind the green space and health relationship include the provision of physical activity opportunities, facilitation of social contact and the restorative effects of nature. In the New Zealand context we investigated whether there was a socioeconomic gradient in green space exposure and whether green space exposure was associated with cause-specific mortality (cardiovascular disease and lung cancer). We subsequently asked what is the mechanism(s) by which green space availability may influence mortality outcomes, by contrasting health associations for different types of green space.

Methods

This was an observational study on a population of 1,546,405 living in 1009 small urban areas in New Zealand. A neighbourhood-level classification was developed to distinguish between usable (i.e., visitable) and non-usable green space (i.e., visible but not visitable) in the urban areas. Negative binomial regression models were fitted to examine the association between quartiles of area-level green space availability and risk of mortality from cardiovascular disease (n = 9,484; 1996 - 2005) and from lung cancer (n = 2,603; 1996 - 2005), after control for age, sex, socio-economic deprivation, smoking, air pollution and population density.

Results

Deprived neighbourhoods were relatively disadvantaged in total green space availability (11% less total green space for a one standard deviation increase in NZDep2001 deprivation score, p < 0.001), but had marginally more usable green space (2% more for a one standard deviation increase in deprivation score, p = 0.002). No significant associations between usable or total green space and mortality were observed after adjustment for confounders.

Conclusion

Contrary to expectations we found no evidence that green space influenced cardiovascular disease mortality in New Zealand, suggesting that green space and health relationships may vary according to national, societal or environmental context. Hence we were unable to infer the mechanism in the relationship. Our inability to adjust for individual-level factors with a significant influence on cardiovascular disease and lung cancer mortality risk (e.g., diet and alcohol consumption) will have limited the ability of the analyses to detect green space effects, if present. Additionally, green space variation may have lesser relevance for health in New Zealand because green space is generally more abundant and there is less social and spatial variation in its availability than found in other contexts.
The role of weight status, gender and self-esteem in following a diet among middle-school children in Sicily (Italy)
Authors: Ferrante Margherita , Fiore Maria , Sciacca Gina E , Leon Luca , Sciacca Salvatore , Castaing Marine , Modonutti Gianbattista
Published: May 2010

Background

Weight-related issues such as obesity, dieting and eating disorders in adolescents are major public health problems. Moreover, undertaking a diet tends to be common among school children and the reasons for doing so are not always related to weight status. The objectives of the study were to evaluate the role of body mass index (BMI), gender and self-esteem in the adoption of a diet in middle-school Sicilian children.

Methods

The survey included middle-school children in some Sicilian provinces. Weight status was determined by sex-specific body mass index for age according to the international BMI cut-off proposed by Cole. Classic chi-square test and linear trend chi-square were used to compare percentages. Univariate and multivariate logistic regressions were computed to study the risk of dieting according to weight status (with the underweight group as the reference group), gender, self-esteem adjusted for province. Adjusted odds ratios (ORs) and 95% confidence intervals (CI) along with associated p-values were furnished.

Results

The survey showed that 45.2% of the children were of average-weight, 6.6% were underweight, 12.6% were overweight and 2.9% were clinically obese. The missing data were up to 32.8%. Regarding dieting, 26.3% of the children stated that they had been on a diet during the last three months, 56.4% claimed they had not, and 17.2% did not answer. Age was not associated with dieting (p = 0.76). More girls than boys had undertaken a diet (31.4% versus 21.4%, p < 0.0001). Self-esteem had an influence on the choice of following a diet; in fact, 40.8%, 28.5% and 20.9% of the children with negative, normal and positive self-esteem were following a diet (trend p < 0.0001). The multivariate analysis showed that self-esteem seemed to influence more girls than boys (p = 0.06), and stratified analysis by gender indicated that it seemed more influent in girls (p = 0.0008) than in boys (p = 0.01).

Conclusions

In addition to the relation between dieting and BMI, our results highlight the link between dieting, gender and self-esteem. We underline the importance of interventions within the context of health education in order to improve global self-esteem and to encourage proper eating habits to prevent weight-related health problems.
Cyclin K and cyclin D1b are oncogenic in myeloma cells
Authors: Marsaud Véronique , Tchakarska Guergana , Andrieux Geoffroy , Liu Jian-Miao , Dembele Doulaye , Jost Bernard , Wdzieczak-Bakala Joanna , Renoir Jack-Michel , Sola Brigitte
Published: May 2010

Background

Aberrant expression of cyclin D1 is a common feature in multiple myeloma (MM) and always associated with mantle cell lymphoma (MCL).CCND1gene is alternatively spliced to produce two cyclin D1 mRNA isoforms which are translated in two proteins: cyclin D1a and cyclin D1b. Both isoforms are present in MM cell lines and primary cells but their relative role in the tumorigenic process is still elusive.

Results

To test the tumorigenic potential of cyclin D1bin vivo, we generated cell clones derived from the non-CCND1expressing MM LP-1 cell line, synthesizing either cyclin D1b or cyclin K, a structural homolog and viral oncogenic form of cyclin D1a. Immunocompromised mice injecteds.c. with LP-1K or LP-1D1b cells develop tumors at the site of injection. Genome-wide analysis of LP-1-derived cells indicated that several cellular processes were altered by cyclin D1b and/or cyclin K expression such as cell metabolism, signal transduction, regulation of transcription and translation. Importantly, cyclin K and cyclin D1b have no major action on cell cycle or apoptosis regulatory genes. Moreover, they impact differently cell functions. Cyclin K-expressing cells have lost their migration properties and display enhanced clonogenic capacities. Cyclin D1b promotes tumorigenesis through the stimulation of angiogenesis.

Conclusions

Our study indicates that cyclin D1b participates into MM pathogenesisviapreviously unrevealed actions.
A comparative genome analysis of gene expression reveals different regulatory mechanisms between mouse and human embryo pre-implantation development
Authors: He Kan , Zhao Hongbo , Wang Qishan , Pan Yuchun
Published: May 2010

Background

Pre-implantation development is a crucial step in successful implantation and pregnancy in mammals. It has been studied in depth, but mostly in laboratory animal models. Less is known about the regulatory mechanism involved in the pre-implantation development in humans and about the comparative aspects.

Methods

Here, we employed the microarray datasets from the public database library of GEO and applied comparative analysis of genome wide temporal gene expression data based on statistical analysis and functional annotation for both mouse and human, demonstrating the discordance between the regulatory mechanisms of both mouse and human pre-implantation development.

Results

There were differences between mouse and human pre-implantation development both in the global gene expression pattern and in the expression changes of individual genes at each stage, including different major transient waves of transcription profiles and some stage-specific genes and significantly related pathways. There also appeared to be different functional changes from one stage to another between mouse and human.

Conclusions

The analysis presented here lead to interesting and complementary conclusions that the regulatory mechanism of human pre-implantation development is not completely the same as the mouse. Not as the fact that 1-cell to 2-cell stage is important for mouse pre-implantation development, the 4-cell stage and 8-cell stage are both essential for human. Unlike in mouse, of which most of pathways found were related to energy, RNA and protein metabolism, the identified pathways in human were mostly disease-related and associated with human pre-implantation embryonic development. All of these suggest that a further comparative analysis should be required for applying the result of mouse expression data to human research or therapy, particularly in pre-implantation developments. Our study provides several potential targets of genes and pathways for studying the regulatory mechanism of human pre-implantation development using mouse model.
Solid-surface vitrification is an appropriate and convenient method for cryopreservation of isolated rat follicles
Authors: Xing Weijie , Zhou Canquan , Bian Jiang , Montag Markus , Xu Yanwen , Li Yubin , Li Tao
Published: May 2010

Background

Cryopreservation of isolated follicles may be a potential option to restore fertility in young women with cancer, because it can prevent the risks of cancer transmission. Several freezing protocols are available, including slow-rate freezing, open-pulled straws vitrification (OPS) and solid-surface vitrification (SSV, a new freezing technique). The purpose of our study was to investigate the effects of these freezing procedures on viability, ultrastructure and developmental capacity of isolated rat follicles.

Methods

Isolated follicles from female Sprague-Dawley rats were randomly assigned to SSV, OPS and slow-rate freezing groups for cryopreservation. Follicle viability assessment and ultrastructural examination were performed after thawing. In order to study the developmental capacity of thawed follicles, we performed in vitro culture with a three-dimensional (3D) system by alginate hydrogels.

Results

Our results showed that the totally viable rate of follicles vitrified by SSV (64.76%) was slightly higher than that of the OPS group (62.38%) and significantly higher than that of the slow-rate freezing group (52.65%; P < 0.05). The ultrastructural examination revealed that morphological alterations were relatively low in the SSV group compared to the OPS and slow-rate freezing groups. After in vitro culture within a 3D system using alginate hydrogels, we found the highest increase (28.90 ± 2.21 μm) in follicle diameter in follicles from the SSV group. The estradiol level in the SSV group was significantly higher than those in the OPS and slow-rate freezing groups at the end of a 72-hr culture period (P < 0.05).

Conclusions

Our results suggest that the SSV method is an appropriate and convenient method for cryopreservation of isolated rat follicles compared with the conventional slow-rate freezing method and the OPS method.
Ultra-high throughput sequencing-based small RNA discovery and discrete statistical biomarker analysis in a collection of cervical tumours and matched controls
Authors: Witten Daniela , Tibshirani Robert , Gu Sam Guoping , Fire Andrew , Lui Weng-Onn
Published: May 2010

Background

Ultra-high throughput sequencing technologies provide opportunities both for discovery of novel molecular species and for detailed comparisons of gene expression patterns. Small RNA populations are particularly well suited to this analysis, as many different small RNAs can be completely sequenced in a single instrument run.

Results

We prepared small RNA libraries from 29 tumour/normal pairs of human cervical tissue samples. Analysis of the resulting sequences (42 million in total) defined 64 new human microRNA (miRNA) genes. Both arms of the hairpin precursor were observed in twenty-three of the newly identified miRNA candidates. We tested several computational approaches for the analysis of class differences between high throughput sequencing datasets and describe a novel application of a log linear model that has provided the most effective analysis for this data. This method resulted in the identification of 67 miRNAs that were differentially-expressed between the tumour and normal samples at a false discovery rate less than 0.001.

Conclusions

This approach can potentially be applied to any kind of RNA sequencing data for analysing differential sequence representation between biological sample sets.
Fertility Preservation in Adolescents and Young Adults With Cancer
Authors: Levine Jennifer , Canada Andrea , Stern Catharyn J.
Published: May 2010

Preservation of fertility is important to adolescent and young adult (AYA) survivors of cancer. Many survivors will maintain their reproductive potential after the successful completion of treatment for cancer. However total-body irradiation, radiation to the gonads, and chemotherapy regimens containing high-dose alkylators can place women at risk for acute ovarian failure or premature menopause and men at risk for temporary or permanent azoospermia. The most effective and established means of preserving fertility in this population is embryo cryopreservation in women and sperm cryopreservation in men before the initiation of cancer-directed therapy. Cryopreservation of mature oocytes is also becoming more commonplace as methods of thawing become more sophisticated. The use of in vitro fertilization and intracytoplasmic sperm injection has added to the viability of sperm and oocyte cryopreservation. Cryopreservation and transplantation of gonadal tissue in both males and females remains experimental but continues to be evaluated. Hormonal suppression has not been shown to be effective in males but may have promise in females, although larger scale trials are needed to evaluate this. Providing information about risk of infertility and possible interventions to maintain reproductive potential are critical for the AYA population at the time of diagnosis. Given the competing demands of providing complicated and detailed information about cancer treatment, the evolving information related to fertility preservation, and the ethical issues involved, it may be preferable, where possible, to have a specialized team, rather than the primary oncologist, address these issues with AYA patients.
Classical Cyclophosphamide, Methotrexate, and Fluorouracil Chemotherapy Is More Effective in Triple-Negative, Node-Negative Breast Cancer: Results From Two Randomized Trials of Adjuvant Chemoendocrine Therapy for Node-Negative Breast Cancer
Authors: Colleoni Marco , Cole Bernard F. , Viale Giuseppe , Regan Meredith M. , Price Karen N. , Maiorano Eugenio , Mastropasqua Mauro G. , Crivellari Diana , Gelber Richard D. , Goldhirsch Aron , Coates Alan S. , Gusterson Barry A.
Published: May 2010

Purpose

Retrospective studies suggest that primary breast cancers lacking estrogen receptor (ER) and progesterone receptor (PR) and not overexpressing human epidermal growth factor receptor 2 (HER2; triple-negative tumors) are particularly sensitive to DNA-damaging chemotherapy with alkylating agents.

Patients and Methods

Patients enrolled in International Breast Cancer Study Group Trials VIII and IX with node-negative, operable breast cancer and centrally assessed ER, PR, and HER2 were included (n = 2,257). The trials compared three or six courses of adjuvant classical cyclophosphamide, methotrexate, and fluorouracil (CMF) with or without endocrine therapy versus endocrine therapy alone. We explored patterns of recurrence by treatment according to three immunohistochemically defined tumor subtypes: triple negative, HER2 positive and endocrine receptor absent, and endocrine receptor present.

Results

Patients with triple-negative tumors (303 patients; 13%) were significantly more likely to have tumors > 2 cm and grade 3 compared with those in the HER2-positive, endocrine receptor–absent, and endocrine receptor–present subtypes. No clear chemotherapy benefit was observed in endocrine receptor–present disease (hazard ratio [HR], 0.90; 95% CI, 0.74 to 1.11). A statistically significantly greater benefit for chemotherapy versus no chemotherapy was observed in triple-negative breast cancer (HR, 0.46; 95% CI, 0.29 to 0.73; interaction P = .009 v endocrine receptor–present disease). The magnitude of the chemotherapy effect was lower in HER2-positive endocrine receptor–absent disease (HR, 0.58; 95% CI, 0.29 to 1.17; interaction P = .24 v endocrine receptor–present disease).

Conclusion

The magnitude of benefit of CMF chemotherapy is largest in patients with triple-negative, node-negative breast cancer.
Advanced Hepatocellular Carcinoma: Which Staging Systems Best Predict Prognosis?
Authors: Huitzil-Melendez Fidel-David , Capanu Marinela , O'Reilly Eileen M. , Duffy Austin , Gansukh Bolorsukh , Saltz Leonard L. , Abou-Alfa Ghassan K.
Published: May 2010

Purpose

The purpose of cancer staging systems is to accurately predict patient prognosis. The outcome of advanced hepatocellular carcinoma (HCC) depends on both the cancer stage and the extent of liver dysfunction. Many staging systems that include both aspects have been developed. It remains unknown, however, which of these systems is optimal for predicting patient survival.

Patients and Methods

Patients with advanced HCC treated over a 5-year period at Memorial Sloan-Kettering Cancer Center were identified from an electronic medical record database. Patients with sufficient data for utilization in all staging systems were included. TNM sixth edition, Okuda, Barcelona Clinic Liver Cancer (BCLC), Cancer of the Liver Italian Program (CLIP), Chinese University Prognostic Index (CUPI), Japan Integrated Staging (JIS), and Groupe d'Etude et de Traitement du Carcinome Hepatocellulaire (GETCH) systems were ranked on the basis of their accuracy at predicting survival by using concordance index (c-index). Other independent prognostic variables were also identified.

Results

Overall, 187 eligible patients were identified and were staged by using the seven staging systems. CLIP, CUPI, and GETCH were the three top-ranking staging systems. BCLC and TNM sixth edition lacked any meaningful prognostic discrimination. Performance status, AST, abdominal pain, and esophageal varices improved the discriminatory ability of CLIP.

Conclusion

In our selected patient population, CLIP, CUPI, and GETCH were the most informative staging systems in predicting survival in patients with advanced HCC. Prospective validation is required to determine if they can be accurately used to stratify patients in clinical trials and to direct the appropriate need for systemic therapy versus best supportive care. BCLC and TNM sixth edition were not helpful in predicting survival outcome, and their use is not supported by our data.
Phase II Study of Cediranib, an Oral Pan–Vascular Endothelial Growth Factor Receptor Tyrosine Kinase Inhibitor, in Patients With Recurrent Glioblastoma
Authors: Batchelor Tracy T. , Duda Dan G. , di Tomaso Emmanuelle , Ancukiewicz Marek , Plotkin Scott R. , Gerstner Elizabeth , Eichler April F. , Drappatz Jan , Hochberg Fred H. , Benner Thomas , Louis David N. , Cohen Kenneth S. , Chea Houng , Exarhopoulos Alexis , Loeffler Jay S. , Moses Marsha A. , Ivy Percy , Sorensen A. Gregory , Wen Patrick Y. , Jain Rakesh K.
Published: May 2010

Purpose

Glioblastoma is an incurable solid tumor characterized by increased expression of vascular endothelial growth factor (VEGF). We performed a phase II study of cediranib in patients with recurrent glioblastoma.

Methods

Cediranib, an oral pan-VEGF receptor tyrosine kinase inhibitor, was administered (45 mg/d) until progression or unacceptable toxicity to patients with recurrent glioblastoma. The primary end point was the proportion of patients alive and progression free at 6 months (APF6). We performed magnetic resonance imaging (MRI) and plasma and urinary biomarker evaluations at multiple time points.

Results

Thirty-one patients with recurrent glioblastoma were accrued. APF6 after cediranib was 25.8%. Radiographic partial responses were observed by MRI in 17 (56.7%) of 30 evaluable patients using three-dimensional measurements and in eight (27%) of 30 evaluable patients using two-dimensional measurements. For the 15 patients who entered the study taking corticosteroids, the dose was reduced (n = 10) or discontinued (n = 5). Toxicities were manageable. Grade 3/4 toxicities included hypertension (four of 31; 12.9%); diarrhea (two of 31; 6.4%); and fatigue (six of 31; 19.4%). Fifteen (48.4%) of 31 patients required at least one dose reduction and 15 patients required temporary drug interruptions due to toxicity. Drug interruptions were not associated with outcome. Changes in plasma placental growth factor, basic fibroblast growth factor, matrix metalloproteinase (MMP) -2, soluble VEGF receptor 1, stromal cell–derived factor-1α, and soluble Tek/Tie2 receptor and in urinary MMP-9/neutrophil gelatinase-associated lipocalin activity after cediranib were associated with radiographic response or survival.

Conclusion

Cediranib monotherapy for recurrent glioblastoma is associated with encouraging proportions of radiographic response, 6-month progression-free survival, and a steroid-sparing effect with manageable toxicity. We identified early changes in circulating molecules as potential biomarkers of response to cediranib. The efficacy of cediranib and the predictive value of these candidate biomarkers will be explored in prospective trials.
Phase II Study of Sorafenib in Combination With Docetaxel and Cisplatin in the Treatment of Metastatic or Advanced Gastric and Gastroesophageal Junction Adenocarcinoma: ECOG 5203
Authors: Sun Weijing , Powell Mark , O'Dwyer Peter J. , Catalano Paul , Ansari Rafat H. , Benson Al B.
Published: May 2010

Purpose

The combination of sorafenib with chemotherapy is well-tolerated and is associated with encouraging response rates in several malignances. Both docetaxel and cisplatin are active in gastric cancer. A phase II study was conducted to determine the efficacy and toxicity of combined sorafenib, docetaxel, and cisplatin in patients with metastatic or advanced adenocarcinoma of stomach or gastroesophageal junction (GEJ).

Patients and Methods

Forty-four chemotherapy-naïve patients with Eastern Cooperative Oncology Group performance status 0 or 1, of whom 80% had metastatic disease and two thirds had poorly differentiated gastric or GEJ adenocarcinoma, were enrolled. The treatment regimen was sorafenib 400 mg orally twice a day for 21 days, docetaxel 75 mg/m2 intravenously on day 1, and cisplatin 75 mg/m2 intravenously on day 1, repeated every 21 days. The primary end point was response rate to the combination. Toxicity, overall survival, and progression-free survival were assessed as secondary end points.

Results

Eighteen of the 44 eligible and treated patients showed partial responses (41%; 90% CI, 28% to 54%). The median progression-free survival was 5.8 months (90% CI, 5.4 to 7.4 months). The median overall survival was 13.6 months (90% CI, 8.6 to 16.1 month). The major toxicity of this regimen was neutropenia, which reached grade 3 to 4 in 64% of patients. One patient experienced hemorrhage at the tumor site.

Conclusion

The combination of sorafenib, docetaxel, and cisplatin has an encouraging efficacy profile with tolerable toxicity. Additional studies of sorafenib with chemotherapy are warranted in gastric cancer.
Brain Tumors: From Childhood Through Adolescence Into Adulthood
Authors: Kieran Mark W. , Walker David , Frappaz Didier , Prados Michael
Published: May 2010

The transition from childhood to adulthood through adolescence has been clearly identified as a time of great physical, psychological, emotional, social, and sexual change. Clinical care is currently divided into adult or pediatric care; adolescent patients require specific expertise that most clinical practices do not have. When illness coincides with the adolescent transition, the health system is severely challenged. Health systems historically have varied widely in the age they choose for allocating an individual to the adult model of health care. Tumors of the CNS complicate the difficult adjustments required in adolescents and young adults by virtue of their morbidity, complex treatment, and prognosis. Some brain tumors are unique to children, some occur predominantly in adults, and others peak in adolescence. Delays in the diagnosis of brain tumors can occur at any age but are particularly common in adolescence because of difficulties of accessing health systems, the difficulties of discriminating pathologic from typical adolescent behavioral characteristics, and changing endocrine function. Coming to terms with the cancer diagnosis; coping personally, socially, and financially with cancer treatments; accepting the risk of a shortened life span; confronting acquired disability; and coping with complex rehabilitation and adjusted plans for life are challenges for which there are no established specialist health models. This article will discuss the changing brain tumor profile of children, adolescents, and adults, with a focus on our limited understanding of the adolescent/young adult transition period.
Emersonian Terrorism: John Brown, Islam, and Postsecular Violence
Authors: Ziser Michael
Published: May 2010

Under the influence of Calvinist and radical abolitionist John Brown, Ralph Waldo Emerson reconsidered the value of political activism rooted in absolutist and sectarian religious beliefs. Retreating from the earlier declarations of secular and democratic individualism for which he is best known, Emerson came to embrace even the most extreme forms of militancy—up to and including terroristic violence—as legitimate means to engage in the modern secular political process. Representing Brown's abolitionism as an approved form of zealotry, Emerson began to praise historical religious warriors, most notably the Muslim martyrs ready to die for their faith. Viewing such militancy as not just appropriate but necessary within a constitutional arrangement whose founding violence is suppressed, he anticipated a key strain of contemporary postsecular scholarship (led by Talal Asad) that sees American fascination with the figure of the Muslim terrorist as a symptom of the modern West's own contradictory and incomplete process of secularization. At the same time, also under the influence of John Brown and his volunteer army, Emerson articulated a model for practical action that depended neither on the lone individual nor on the sanctioning power of the state but rather on the temporary and partial congruence of multiple individuals. What emerges from this conjunction of political theology and rescaling is an Emersonian political model of violent action carried out by a small, loosely confederated, religiously motivated group of individuals—an Emerson of the terror cell.
The Formation of Forgiveness in Piers Plowman
Authors: Deagman Rachael
Published: May 2010

This essay shows that the C-text of William Langland's Piers Plowman articulates difficulties with the process of learning to forgive, a process that for medieval Christians requires mutuality and participation in the sacrament of penance. Tracing the terms forgeue and forgeueness through the poem, the essay draws out examples of medieval agents participating in the craft of forgiveness with varying degrees of inadequacy when compared with Jesus Christ, the embodiment of forgiveness. It focuses on two versions of community in the poem: the political model of forgiveness in the Mede sequence and the community of sacramental practice that emerges later. Learning to distinguish among the renderings of forgiveness, from advocating it to seeking it to embodying it, is central to the process of this experiential poem, because it demands the recognition and naming of the debilitating effects of sin.
Laureation and Identity: Rewriting Literary History in John Skelton's Garland of Laurel
Authors: Breen Dan
Published: May 2010

This essay attempts to contribute to the wide-ranging discussion of periodization in medieval and early modern studies through a new reading of Skelton's Garland of Laurel. The essay argues that Skelton recreates the laurel as a symbol of continuing poetic and historical service rather than of preeminent status gained as a reward for past literary work. Further, the poem's version of literary and artistic tradition requires that poetry must take its place alongside other forms of artistic representation to form a full and complex account of history. Skelton here reconceptualizes artistic tradition as continuous, inclusive, and constituted by a collaborative ethic of poetic, historical, and moral obligation. As such, the Garland may assist medievalists and especially early modernists in developing new approaches to historical periodization by providing a literary model of cultural continuity, and encouraging discussions of literary treatments of duty, labor, and moral responsibility.
Shakespeare's Speech
Authors: Schalkwyk David
Published: May 2010

Posing the unusual question of what Shakespeare's speech might be in relation to the texts that go under the name “William Shakespeare,” this essay puts to the question a number of assumptions in literary theory about character, subjectivity, genre, the place of the author in a literary text, and language as a system and its relation to performative speech acts. Considering the prevalence of oaths in Shakespeare's texts, the first part argues that the perfomative requirements of this speech act demand a minimal conception of literary character as an entity that can perform a speech act and sustain its ethical consequences. For oaths (and related speech acts) to be intelligible in a literary text, the subjectivity performing them has to maintain a constant identity, and cannot be in flux or divided against itself. Concluding that none of the oaths performed by Shakespeare's characters is an instance of Shakespeare's speech, the second part of the essay addresses the speech (especially oaths) of Shakespeare's sonnets. Here matters are more complex, for the conclusions reached earlier, about the nature of the performative and its relation to a stable identity and the speech of the author, are undermined in surprising ways.
Cdk5rap2 regulates centrosome function and chromosome segregation in neuronal progenitors
Authors: Lizarraga Sofia B. , Margossian Steven P. , Harris Marian H. , Campagna Dean R. , Han An-Ping , Blevins Sherika , Mudbhary Raksha , Barker Jane E. , Walsh Christopher A. , Fleming Mark D.
Published: May 2010

Microcephaly affects ∼1% of the population and is associated with mental retardation, motor defects and, in some cases, seizures. We analyzed the mechanisms underlying brain size determination in a mouse model of human microcephaly. The Hertwig's anemia (an) mutant shows peripheral blood cytopenias, spontaneous aneuploidy and a predisposition to hematopoietic tumors. We found that the an mutation is a genomic inversion of exon 4 of Cdk5rap2, resulting in an in-frame deletion of exon 4 from the mRNA. The finding that CDK5RAP2 human mutations cause microcephaly prompted further analysis of Cdk5rap2an/an mice and we demonstrated that these mice exhibit microcephaly comparable to that of the human disease, resulting from striking neurogenic defects that include proliferative and survival defects in neuronal progenitors. Cdk5rap2an/an neuronal precursors exit the cell cycle prematurely and many undergo apoptosis. These defects are associated with impaired mitotic progression coupled with abnormal mitotic spindle pole number and mitotic orientation. Our findings suggest that the reduction in brain size observed in humans with mutations in CDK5RAP2 is associated with impaired centrosomal function and with changes in mitotic spindle orientation during progenitor proliferation.