CiteULike: Author Gerald

Gene expression-based survival prediction in lung adenocarcinoma: a multi-site, blinded validation study.

2008-07-22T19:55:30-00:00

Nature medicine (20 July 2008)

Although prognostic gene expression signatures for survival in early-stage lung cancer have been proposed, for clinical application, it is critical to establish their performance across different subject populations and in different laboratories. Here we report a large, training-testing, multi-site, blinded validation study to characterize the performance of several prognostic models based on gene expression for 442 lung adenocarcinomas. The hypotheses proposed examined whether microarray measurements of gene expression either alone or combined with basic clinical covariates (stage, age, sex) could be used to predict overall survival in lung cancer subjects. Several models examined produced risk scores that substantially correlated with actual subject outcome. Most methods performed better with clinical data, supporting the combined use of clinical and molecular information when building prognostic models for early-stage lung cancer. This study also provides the largest available set of microarray data with extensive pathological and clinical annotation for lung adenocarcinomas.

Native nonmuscle myosin II stability and light chain binding in Drosophila melanogaster.

JD Franke — 2008-07-15T17:04:00-00:00

Cell motility and the cytoskeleton, Vol. 63, No. 10. (October 2006), pp. 604-622.

Native nonmuscle myosin IIs play essential roles in cellular and developmental processes throughout phylogeny. Individual motor molecules consist of a heterohexameric complex of three polypeptides which, when properly assembled, are capable of force generation. Here, we more completely characterize the properties, relationships and associations that each subunit has with one another in Drosophila melanogaster. All three native nonmuscle myosin II polypeptide subunits are expressed in close to constant stoichiometry to each other throughout development. We find that the stability of two subunits, the heavy chain and the regulatory light chain, depend on one another whereas the stability of the third subunit, the essential light chain, does not depend on either the heavy chain or regulatory light chain. We demonstrate that heavy chain aggregates, which form when regulatory light chain is lacking, associate with the essential light chain in vivo-thus showing that regulatory light chain association is required for heavy chain solubility. By immunodepletion we find that the majority of both light chains are associated with the nonmuscle myosin II heavy chain but pools of free light chain and/or light chain bound to other proteins are present. We identify four myosins (myosin II, myosin V, myosin VI and myosin VIIA) and a microtubule-associated protein (asp/Abnormal spindle) as binding partners for the essential light chain (but not the regulatory light chain) through mass spectrometry and co-precipitation. Using an in silico approach we identify six previously uncharacterized genes that contain IQ-motifs and may be essential light chain binding partners.

Endogenous human microRNAs that suppress breast cancer metastasis

Sohail Tavazoie — 2008-01-10T06:08:57-00:00

Nature, Vol. 451, No. 7175., pp. 147-152.

The role of SPINK1 in ETS rearrangement-negative prostate cancers.

SA Tomlins — 2008-06-11T10:25:22-00:00

Cancer cell, Vol. 13, No. 6. (June 2008), pp. 519-528.

ETS gene fusions have been characterized in a majority of prostate cancers; however, the key molecular alterations in ETS-negative cancers are unclear. Here we used an outlier meta-analysis (meta-COPA) to identify SPINK1 outlier expression exclusively in a subset of ETS rearrangement-negative cancers ( approximately 10% of total cases). We validated the mutual exclusivity of SPINK1 expression and ETS fusion status, demonstrated that SPINK1 outlier expression can be detected noninvasively in urine, and observed that SPINK1 outlier expression is an independent predictor of biochemical recurrence after resection. We identified the aggressive 22RV1 cell line as a SPINK1 outlier expression model and demonstrate that SPINK1 knockdown in 22RV1 attenuates invasion, suggesting a functional role in ETS rearrangement-negative prostate cancers.

A Life History Trade-Off Between Flight Ability and Reproductive Behavior in Male Field Crickets (Gryllus texensis)

Guerra — 2007-09-04T10:00:00-00:00

Journal of Insect Behavior, Vol. 20, No. 4. (July 2007), pp. 377-387.

Interlaboratory comparability study of cancer gene expression analysis using oligonucleotide microarrays.

KK Dobbin — 2008-04-15T13:14:59-00:00

Clinical cancer research : an official journal of the American Association for Cancer Research, Vol. 11, No. 2 Pt 1. (15 January 2005), pp. 565-572.

A key step in bringing gene expression data into clinical practice is the conduct of large studies to confirm preliminary models. The performance of such confirmatory studies and the transition to clinical practice requires that microarray data from different laboratories are comparable and reproducible. We designed a study to assess the comparability of data from four laboratories that will conduct a larger microarray profiling confirmation project in lung adenocarcinomas. To test the feasibility of combining data across laboratories, frozen tumor tissues, cell line pellets, and purified RNA samples were analyzed at each of the four laboratories. Samples of each type and several subsamples from each tumor and each cell line were blinded before being distributed. The laboratories followed a common protocol for all steps of tissue processing, RNA extraction, and microarray analysis using Affymetrix Human Genome U133A arrays. High within-laboratory and between-laboratory correlations were observed on the purified RNA samples, the cell lines, and the frozen tumor tissues. Intraclass correlation within laboratories was only slightly stronger than between laboratories, and the intraclass correlation tended to be weakest for genes expressed at low levels and showing small variation. Finally, hierarchical cluster analysis revealed that the repeated samples clustered together regardless of the laboratory in which the experiments were done. The findings indicate that under properly controlled conditions it is feasible to perform complete tumor microarray analysis, from tissue processing to hybridization and scanning, at multiple independent laboratories for a single study.

Classroom Questioning with Immediate Electronic Response: Do Clickers Improve Learning

Yourstone — 2008-02-15T13:13:51-00:00

Decision Sciences The Journal of Innovative Education, Vol. 6, No. 1. (January 2008), pp. 75-88.

A physical map of the highly heterozygous Populus genome: integration with the genome sequence and genetic map and analysis of haplotype variation

Kelleher — 2007-06-10T15:06:54-00:00

The Plant Journal, Vol. 50, No. 6. (June 2007), pp. 1063-1078.

A genome-wide screen for promoter methylation in lung cancer identifies novel methylation markers for multiple malignancies.

DS Shames — 2007-05-10T15:56:20-00:00

PLoS Med, Vol. 3, No. 12. (December 2006)

BACKGROUND: Promoter hypermethylation coupled with loss of heterozygosity at the same locus results in loss of gene function in many tumor cells. The "rules" governing which genes are methylated during the pathogenesis of individual cancers, how specific methylation profiles are initially established, or what determines tumor type-specific methylation are unknown. However, DNA methylation markers that are highly specific and sensitive for common tumors would be useful for the early detection of cancer, and those required for the malignant phenotype would identify pathways important as therapeutic targets. METHODS AND FINDINGS: In an effort to identify new cancer-specific methylation markers, we employed a high-throughput global expression profiling approach in lung cancer cells. We identified 132 genes that have 5' CpG islands, are induced from undetectable levels by 5-aza-2'-deoxycytidine in multiple non-small cell lung cancer cell lines, and are expressed in immortalized human bronchial epithelial cells. As expected, these genes were also expressed in normal lung, but often not in companion primary lung cancers. Methylation analysis of a subset (45/132) of these promoter regions in primary lung cancer (n = 20) and adjacent nonmalignant tissue (n = 20) showed that 31 genes had acquired methylation in the tumors, but did not show methylation in normal lung or peripheral blood cells. We studied the eight most frequently and specifically methylated genes from our lung cancer dataset in breast cancer (n = 37), colon cancer (n = 24), and prostate cancer (n = 24) along with counterpart nonmalignant tissues. We found that seven loci were frequently methylated in both breast and lung cancers, with four showing extensive methylation in all four epithelial tumors. CONCLUSIONS: By using a systematic biological screen we identified multiple genes that are methylated with high penetrance in primary lung, breast, colon, and prostate cancers. The cross-tumor methylation pattern we observed for these novel markers suggests that we have identified a partial promoter hypermethylation signature for these common malignancies. These data suggest that while tumors in different tissues vary substantially with respect to gene expression, there may be commonalities in their promoter methylation profiles that represent targets for early detection screening or therapeutic intervention.

Relationship of Gene Expression and Chromosomal Abnormalities in Colorectal Cancer

Dafna Tsafrir — 2007-04-20T14:19:51-00:00

Cancer Res, Vol. 66, No. 4. (15 February 2006), pp. 2129-2137.

Several studies have verified the existence of multiple chromosomal abnormalities in colon cancer. However, the relationships between DNA copy number and gene expression have not been adequately explored nor globally monitored during the progression of the disease. In this work, three types of array-generated data (expression, single nucleotide polymorphism, and comparative genomic hybridization) were collected from a large set of colon cancer patients at various stages of the disease. Probes were annotated to specific chromosomal locations and coordinated alterations in DNA copy number and transcription levels were revealed at specific positions. We show that across many large regions of the genome, changes in expression level are correlated with alterations in DNA content. Often, large chromosomal segments, containing multiple genes, are transcriptionally affected in a coordinated way, and we show that the underlying mechanism is a corresponding change in DNA content. This implies that whereas specific chromosomal abnormalities may arise stochastically, the associated changes in expression of some or all of the affected genes are responsible for selecting cells bearing these abnormalities for clonal expansion. Indeed, particular chromosomal regions are frequently gained and overexpressed (e.g., 7p, 8q, 13q, and 20q) or lost and underexpressed (e.g., 1p, 4, 5q, 8p, 14q, 15q, and 18) in primary colon tumors, making it likely that these changes favor tumorigenicity. Furthermore, we show that these aberrations are absent in normal colon mucosa, appear in benign adenomas (albeit only in a small fraction of the samples), become more frequent as disease advances, and are found in the majority of metastatic samples. (Cancer Res 2006; 66(4): 2129-37) 10.1158/0008-5472.CAN-05-2569

The grateful dead: calcium and cell death in plant innate immunity

Wei Ma — 2007-10-20T18:43:14-00:00

Cellular Microbiology, Vol. 9, No. 11. (November 2007), pp. 2571-2585.

v6 Integrin Regulates Renal Fibrosis and Inflammation in Alport Mouse

Hahm — 2007-01-27T11:11:33-00:00

American Journal of Pathology, Vol. 170, No. 1. (1 January 2007), pp. 110-125.

An estrogen receptor-negative breast cancer subset characterized by a hormonally regulated transcriptional program and response to androgen

AS Doane — 2006-02-21T15:45:17-00:00

Oncogene, Vol. aop, No. current.

Genes that mediate breast cancer metastasis to lung

Andy Minn — 2005-07-27T22:46:24-00:00

Nature, Vol. 436, No. 7050., pp. 518-524.

JunD reduces tumor angiogenesis by protecting cells from oxidative stress.

D Gerald — 2007-09-21T08:31:55-00:00

Cell, Vol. 118, No. 6. (17 September 2004), pp. 781-794.

Reactive oxygen species (ROS) are implicated in the pathophysiology of various diseases, including cancer. In this study, we show that JunD, a member of the AP-1 family of transcription factors, reduces tumor angiogenesis by limiting Ras-mediated production of ROS. Using junD-deficient cells, we demonstrate that JunD regulates genes involved in antioxidant defense, H2O2 production, and angiogenesis. The accumulation of H2O2 in junD-/- cells decreases the availability of FeII and reduces the activity of HIF prolyl hydroxylases (PHDs) that target hypoxia-inducible factors-alpha (HIFalpha) for degradation. Subsequently, HIF-alpha proteins accumulate and enhance the transcription of VEGF-A, a potent proangiogenic factor. Our study uncovers the mechanism by which JunD protects cells from oxidative stress and exerts an antiangiogenic effect. Furthermore, we provide new insights into the regulation of PHD activity, allowing immediate reactive adaptation to changes in O2 or iron levels in the cell.

the search for the holy grant: (mis)allocating money in european political science

Schneider — 2007-05-31T11:24:50-00:00

European Political Science, Vol. 6, No. 2. (June 2007), pp. 160-168.

why is european political science so unproductive and what should be done about it: a symposium

Schneider — 2007-05-31T11:24:50-00:00

European Political Science, Vol. 6, No. 2. (June 2007), pp. 156-159.

Spatial representativeness of single tower measurements and the imbalance problem with eddy-covariance fluxes: results of a large-eddy simulation study

Steinfeld — 2007-04-22T00:58:18-00:00

Boundary-Layer Meteorology, Vol. 123, No. 1. (April 2007), pp. 77-98.

Cyclin D1, a novel molecular marker of minimal residual disease, in metastatic neuroblastoma.

IY Cheung — 2007-06-12T16:30:35-00:00

J Mol Diagn, Vol. 9, No. 2. (April 2007), pp. 237-241.

Accurate monitoring of minimal residual disease (MRD) is critical for the management of metastatic neuroblastoma (NB). We evaluated cyclin D1 (CCND1), a cell-cycle control gene, as a novel MRD marker of NB. Using quantitative reverse transcriptase-polymerase chain reaction, we studied CCND1 expression in 133 solid tumors of different histological types, including 39 NB tumors, and examined its potential clinical utility as an early response marker in the bone marrows before and after treatment of 118 stage 4 patients enrolled after induction chemotherapy in an immunotherapy protocol. Based on 40 normal marrow and peripheral blood samples, a CCND1 transcript value greater than the mean + 2 SD was defined as positive. Sensitivity of this assay was one NB cell in 10(6) normal mononuclear cells. CCND1 transcript levels were high in NB, breast cancer, and Ewing family tumors. Among the NB patients evaluated, early (2.5 months from protocol entry) marrow response was strongly associated with both progression-free (P=0.0001) and overall survival (P=0.0006). CCND1 response remained predictive of survival among a subset of 66 patients who had no histological evidence of marrow disease before immunotherapy. We conclude that CCND1 has potential clinical utility as a novel molecular marker of MRD in the bone marrow of patients with metastatic NB.

Chromosomal stasis in diploids contrasts with genome restructuring in auto- and allopolyploid taxa of Hepatica (Ranunculaceae)

Weiss-Schneeweiss — 2007-04-19T00:26:31-00:00

New Phytologist, Vol. 174, No. 3. (May 2007), pp. 669-682.

Multiclass cancer diagnosis using tumor gene expression signatures.

S Ramaswamy — 2005-04-18T17:06:23-00:00

Proc Natl Acad Sci U S A, Vol. 98, No. 26. (18 December 2001), pp. 15149-15154.

The optimal treatment of patients with cancer depends on establishing accurate diagnoses by using a complex combination of clinical and histopathological data. In some instances, this task is difficult or impossible because of atypical clinical presentation or histopathology. To determine whether the diagnosis of multiple common adult malignancies could be achieved purely by molecular classification, we subjected 218 tumor samples, spanning 14 common tumor types, and 90 normal tissue samples to oligonucleotide microarray gene expression analysis. The expression levels of 16,063 genes and expressed sequence tags were used to evaluate the accuracy of a multiclass classifier based on a support vector machine algorithm. Overall classification accuracy was 78%, far exceeding the accuracy of random classification (9%). Poorly differentiated cancers resulted in low-confidence predictions and could not be accurately classified according to their tissue of origin, indicating that they are molecularly distinct entities with dramatically different gene expression patterns compared with their well differentiated counterparts. Taken together, these results demonstrate the feasibility of accurate, multiclass molecular cancer classification and suggest a strategy for future clinical implementation of molecular cancer diagnostics.

MAD2 haplo-insufficiency causes premature anaphase and chromosome instability in mammalian cells.

LS Michel — 2007-03-30T17:33:16-00:00

Nature, Vol. 409, No. 6818. (18 January 2001), pp. 355-359.

The mitotic checkpoint protein hsMad2 is required to arrest cells in mitosis when chromosomes are unattached to the mitotic spindle. The presence of a single, lagging chromosome is sufficient to activate the checkpoint, producing a delay at the metaphase-anaphase transition until the last spindle attachment is made. Complete loss of the mitotic checkpoint results in embryonic lethality owing to chromosome mis-segregation in various organisms. Whether partial loss of checkpoint control leads to more subtle rates of chromosome instability compatible with cell viability remains unknown. Here we report that deletion of one MAD2 allele results in a defective mitotic checkpoint in both human cancer cells and murine primary embryonic fibroblasts. Checkpoint-defective cells show premature sister-chromatid separation in the presence of spindle inhibitors and an elevated rate of chromosome mis-segregation events in the absence of these agents. Furthermore, Mad2+/- mice develop lung tumours at high rates after long latencies, implicating defects in the mitotic checkpoint in tumorigenesis.

A gene expression signature predicts survival of patients with stage I non-small cell lung cancer.

Y Lu — 2007-03-15T14:28:12-00:00

PLoS Med, Vol. 3, No. 12. (December 2006)

BACKGROUND: Lung cancer is the leading cause of cancer-related death in the United States. Nearly 50% of patients with stages I and II non-small cell lung cancer (NSCLC) will die from recurrent disease despite surgical resection. No reliable clinical or molecular predictors are currently available for identifying those at high risk for developing recurrent disease. As a consequence, it is not possible to select those high-risk patients for more aggressive therapies and assign less aggressive treatments to patients at low risk for recurrence. METHODS AND FINDINGS: In this study, we applied a meta-analysis of datasets from seven different microarray studies on NSCLC for differentially expressed genes related to survival time (under 2 y and over 5 y). A consensus set of 4,905 genes from these studies was selected, and systematic bias adjustment in the datasets was performed by distance-weighted discrimination (DWD). We identified a gene expression signature consisting of 64 genes that is highly predictive of which stage I lung cancer patients may benefit from more aggressive therapy. Kaplan-Meier analysis of the overall survival of stage I NSCLC patients with the 64-gene expression signature demonstrated that the high- and low-risk groups are significantly different in their overall survival. Of the 64 genes, 11 are related to cancer metastasis (APC, CDH8, IL8RB, LY6D, PCDHGA12, DSP, NID, ENPP2, CCR2, CASP8, and CASP10) and eight are involved in apoptosis (CASP8, CASP10, PIK3R1, BCL2, SON, INHA, PSEN1, and BIK). CONCLUSIONS: Our results indicate that gene expression signatures from several datasets can be reconciled. The resulting signature is useful in predicting survival of stage I NSCLC and might be useful in informing treatment decisions.

The Role of Parents in Early Intervention: Implications for Social Work

Mahoney — 2007-01-21T04:09:53-00:00

Children and Schools, Vol. 29, No. 1. (January 2007), pp. 7-15.

Distinct organ-specific metastatic potential of individual breast cancer cells and primary tumors.

AJ Minn — 2007-01-29T16:06:55-00:00

J Clin Invest, Vol. 115, No. 1. (January 2005), pp. 44-55.

We used bioluminescence imaging to reveal patterns of metastasis formation by human breast cancer cells in immunodeficient mice. Individual cells from a population established in culture from the pleural effusion of a breast cancer patient showed distinct patterns of organ-specific metastasis. Single-cell progenies derived from this population exhibited markedly different abilities to metastasize to the bone, lung, or adrenal medulla, which suggests that metastases to different organs have different requirements. Transcriptomic profiling revealed that these different single-cell progenies similarly express a previously described "poor-prognosis" gene expression signature. Unsupervised classification using the transcriptomic data set supported the hypothesis that organ-specific metastasis by breast cancer cells is controlled by metastasis-specific genes that are separate from a general poor-prognosis gene expression signature. Furthermore, by using a gene expression signature associated with the ability of these cells to metastasize to bone, we were able to distinguish primary breast carcinomas that preferentially metastasized to bone from those that preferentially metastasized elsewhere. These results suggest that the bone-specific metastatic phenotypes and gene expression signature identified in a mouse model may be clinically relevant.

Mapping Land-Cover and Mangrove Structures with Remote Sensing Techniques: A Contribution to a Synoptic GIS in Support of Coastal Management in North Brazil

Gesche Krause — 2006-05-18T16:06:19-00:00

Environmental Management, Vol. 34, No. 3. (September 2004), pp. 429-440.

This article deals with the development and application of a cartographic database for a synoptic Geographic Information System (GIS). Its purpose is the storage and evaluation of the heterogeneous datasets of the interdisciplinary scientific research program MADAM (Mangrove Dynamics and Management), which aims to develop recommendations for a tailored integrated coastal management scheme for the mangrove ecosystem at Bragança (North Brazil). The article describes the integration of remote sensing data, aerial photographs, as well as point data provided by fieldwork from different scientific fields. Using various innovative processing techniques and different scale-resolution levels, an assessment of temporal–spatial changes of the mangrove peninsula and the adjacent rural socioeconomic impact area, the type of mangrove structure, as well as a land-use cover analyses was undertaken. The definition of the spatial level of detail was found to be a major issue in the development of the GIS, as well as during the processing and analysis procedures. A division between strong and weak patterns in the mangrove ecosystem could be made, which implies different management measures and sets of specific interdisciplinary studies and monitoring at hierarchical scales.

Remote Control: A Practitioner's Guide to Managing Virtual Teams

Gerald Falkowski — 2005-11-03T00:20:56-00:00

(31 May 2005)

Remote Control: A Practitioner's Guide to Virtual Teams by Gerald Falkowski and Stephen Troutman takes the best from their IHRIM Journal columns and provides step-by-step guidance in achieving and sustaining opertaional excellence from any company's virtual team(s) based on the authors' 60+ years of combined experience working with virtual teams from IBM and IBM clients. While this book is appropriate for people in global businesses, it is equally applicable to individuals that need to work together virtually with others for any reason -- even if only across town.

Integration of gene expression profiling and clinical variables to predict prostate carcinoma recurrence after radical prostatectomy.

AJ Stephenson — 2006-10-31T10:59:29-00:00

Cancer, Vol. 104, No. 2. (15 July 2005), pp. 290-298.

BACKGROUND: Gene expression profiling of prostate carcinoma offers an alternative means to distinguish aggressive tumor biology and may improve the accuracy of outcome prediction for patients with prostate carcinoma treated by radical prostatectomy. METHODS: Gene expression differences between 37 recurrent and 42 nonrecurrent primary prostate tumor specimens were analyzed by oligonucleotide microarrays. Two logistic regression modeling approaches were used to predict prostate carcinoma recurrence after radical prostatectomy. One approach was based exclusively on gene expression differences between the two classes. The second approach integrated prognostic gene variables with a validated postoperative predictive model based on standard variables (nomogram). The predictive accuracy of these modeling approaches was evaluated by leave-one-out cross-validation (LOOCV) and compared with the nomogram. RESULTS: The modeling approach using gene variables alone accurately classified 59 (75%) tissue samples in LOOCV, a classification rate substantially higher than expected by chance. However, this predictive accuracy was inferior to the nomogram (concordance index, 0.75 vs. 0.84, P = 0.01). Models combining clinical and gene variables accurately classified 70 (89%) tissue samples and the predictive accuracy using this approach (concordance index, 0.89) was superior to the nomogram (P = 0.009) and models based on gene variables alone (P < 0.001). Importantly, the combined approach provided a marked improvement for patients whose nomogram-predicted likelihood of disease recurrence was in the indeterminate range (7-year disease progression-free probability, 30-70%; concordance index, 0.83 vs. 0.59, P = 0.01). CONCLUSIONS: Integration of gene expression signatures and clinical variables produced predictive models for prostate carcinoma recurrence that perform significantly better than those based on either clinical variables or gene expression information alone.

Racial Distancing in a Southern City: Latino Immigrants Views of Black Americans

Paula Mcclain — 2006-07-05T12:10:40-00:00

The Journal of Politics, Vol. 68, No. 3. (August 2006), pp. 571-584.

Policy and Practice: Knowledge and Beliefs of Education Professionals Related to the Inclusion of Students with Disabilities in a State Assessment

Crawford — 2006-07-27T19:27:57-00:00

Remedial and Special Education, Vol. 27, No. 4. (August 2006), pp. 208-217.

Lack of long-term adverse adrenal effects from inhaled triamcinolone: Lung Health Study II.

MS Eichenhorn — 2006-04-24T05:10:45-00:00

Chest, Vol. 124, No. 1. (July 2003), pp. 57-62.

STUDY OBJECTIVE: Inhaled corticosteroids (ICS) are widely used in the treatment of COPD. One of the potential adverse effects of their use is the development of adrenal suppression. Our study aimed to determine the effects of ICS on adrenal function over 3 years of use in patients with COPD. METHODS: Two hundred twenty-one subjects were recruited from the 1,116 patients already enrolled in Lung Health Study II and were randomized to receive either triamcinolone, 1,200 microg, or placebo daily. Basal cortisol levels and cortisol levels at 30 min and 60 min following cosyntropin injection were measured at study entry and after 1 year and 3 years of participation. RESULTS: Basal cortisol levels in the placebo group were higher than in those receiving active drug at all time points and rose through the study period. There was no suppression of cortisol levels after cosyntropin stimulation at any study point in any subgroup. CONCLUSION: Use of inhaled triamcinolone, 1,200 microg/d, over 3 years does not suppress baseline adrenal function or diminish adrenal responsiveness to cosyntropin stimulation.