Cases journal, 2009
Authors
Chung, Caroline, Al Ali, Jaber, Owen, David A, Weiss, Alan A, Yoshida, Eric M, Tai, Isabella T
Publication Abstract
Hepatocellular carcinoma (HCC) is the most common primary tumor of the liver worldwide. The incidence of HCC is increasing in North America secondary to rises in chronic liver disease from alcohol abuse and viral hepatitis. HCC most commonly metastasizes hematogenously or through lymphatics to the lungs and regional lymph nodes. Involvement of small bowel is rare and typically results from direct invasion and extension. We examined the molecular features related to this extremely rare case of isolated duodenal metastasis of HCC and noted p53 and Ki-67 positive staining. Here, we review the possible molecular and immunohistochemical studies that may aid definitive diagnosis and the evidence for the management of metastatic hepatocellular carcinoma.

Genome research, 2009
Authors
Freeman, J Douglas, Warren, René L, Webb, John R, Nelson, Brad H, Holt, Robert A
Publication Abstract
T-cell receptor (TCR) genomic loci undergo somatic V(D)J recombination, plus the addition/subtraction of nontemplated bases at recombination junctions, in order to generate the repertoire of structurally diverse T cells necessary for antigen recognition. TCR beta subunits can be unambiguously identified by their hypervariable CDR3 (Complement Determining Region 3) sequence. This is the site of V(D)J recombination encoding the principal site of antigen contact. The complexity and dynamics of the T-cell repertoire remain unknown because the potential repertoire size has made conventional sequence analysis intractable. Here, we use 5'-RACE, Illumina sequencing, and a novel short read assembly strategy to sample CDR3(beta) diversity in human T lymphocytes from peripheral blood. Assembly of 40.5 million short reads identified 33,664 distinct TCR(beta) clonotypes and provides precise measurements of CDR3(beta) length diversity, usage of nontemplated bases, sequence convergence, and preferences for TRBV (T-cell receptor beta variable gene) and TRBJ (T-cell receptor beta joining gene) gene usage and pairing. CDR3 length between conserved residues of TRBV and TRBJ ranged from 21 to 81 nucleotides (nt). TRBV gene usage ranged from 0.01% for TRBV17 to 24.6% for TRBV20-1. TRBJ gene usage ranged from 1.6% for TRBJ2-6 to 17.2% for TRBJ2-1. We identified 1573 examples of convergence where the same amino acid translation was specified by distinct CDR3(beta) nucleotide sequences. Direct sequence-based immunoprofiling will likely prove to be a useful tool for understanding repertoire dynamics in response to immune challenge, without a priori knowledge of antigen.

Genome research, 2009
Authors
Krzywinski, Martin, Schein, Jacqueline, Birol, Inanç, Connors, Joseph, Gascoyne, Randy, Horsman, Doug, Jones, Steven J, Marra, Marco A
Publication Abstract
We created a visualization tool called Circos to facilitate the identification and analysis of similarities and differences arising from comparisons of genomes. Our tool is effective in displaying variation in genome structure and, generally, any other kind of positional relationships between genomic intervals. Such data are routinely produced by sequence alignments, hybridization arrays, genome mapping, and genotyping studies. Circos uses a circular ideogram layout to facilitate the display of relationships between pairs of positions by the use of ribbons, which encode the position, size, and orientation of related genomic elements. Circos is capable of displaying data as scatter, line, and histogram plots, heat maps, tiles, connectors, and text. Bitmap or vector images can be created from GFF-style data inputs and hierarchical configuration files, which can be easily generated by automated tools, making Circos suitable for rapid deployment in data analysis and reporting pipelines.

Cancer research, 2008
Authors
Wang, Gang, Wang, Jun, Sadar, Marianne D
Publication Abstract
The androgen-signaling pathway plays an important role in the development and hormonal progression of prostate cancer to the castrate-resistant stage (also called androgen-independent or hormone refractory). The Wnt pathway and beta-catenin contribute to prostate biology and pathology. Here application of Affymetrix GeneChip analysis revealed the genomic similarity of the LNCaP hollow fiber model to clinical samples and identified genes with differential expression during hormonal progression. The fiber model samples clustered according to the expression profile of androgen-regulated genes to provide genomic evidence for the reactivation of the AR signaling pathway in castrate-resistant prostate cancer. Pathway-based characterization of gene expression identified activation of the Wnt pathway. Together with the increased expression of AR and beta-catenin, there was increased nuclear colocalization and interaction of endogenous AR and beta-catenin in castrate-resistant prostate cancer from castrated mice. Surprisingly, no interaction or colocalization of AR and beta-catenin could be detected in xenografts from noncastrated mice. These studies provide the first in vivo evidence to support aberrant activation of the AR through the Wnt/beta-catenin signaling pathway during progression of prostate cancer to the terminal castrate-resistant stage.

The Journal of experimental medicine, 2007
Authors
Leong, Kevin G, Niessen, Kyle, Kulic, Iva, Raouf, Afshin, Eaves, Connie, Pollet, Ingrid, Karsan, Aly
Publication Abstract
Aberrant expression of Jagged1 and Notch1 are associated with poor outcome in breast cancer. However, the reason that Jagged1 and/or Notch overexpression portends a poor prognosis is unknown. We identify Slug, a transcriptional repressor, as a novel Notch target and show that elevated levels of Slug correlate with increased expression of Jagged1 in various human cancers. Slug was essential for Notch-mediated repression of E-cadherin, which resulted in beta-catenin activation and resistance to anoikis. Inhibition of ligand-induced Notch signaling in xenografted Slug-positive/E-cadherin-negative breast tumors promoted apoptosis and inhibited tumor growth and metastasis. This response was associated with down-regulated Slug expression, reexpression of E-cadherin, and suppression of active beta-catenin. Our findings suggest that ligand-induced Notch activation, through the induction of Slug, promotes tumor growth and metastasis characterized by epithelial-to-mesenchymal transition and inhibition of anoikis.

Molecular systems biology, 2007
Authors
Ewing, Rob M, Chu, Peter, Elisma, Fred, Li, Hongyan, Taylor, Paul, Climie, Shane, McBroom-Cerajewski, Linda, Robinson, Mark D, O'Connor, Liam, Li, Michael, Taylor, Rod, Dharsee, Moyez, Ho, Yuen, Heilbut, Adrian, Moore, Lynda, Zhang, Shudong, Ornatsky, Olga, Bukhman, Yury V, Ethier, Martin, Sheng, Yinglun, Vasilescu, Julian, Abu-Farha, Mohamed, Lambert, Jean-Philippe, Duewel, Henry S, Stewart, Ian I, Kuehl, Bonnie, Hogue, Kelly, Colwill, Karen, Gladwish, Katharine, Muskat, Brenda, Kinach, Robert, Adams, Sally-Lin, Moran, Michael F, Morin, Gregg B, Topaloglou, Thodoros, Figeys, Daniel
Publication Abstract
Mapping protein-protein interactions is an invaluable tool for understanding protein function. Here, we report the first large-scale study of protein-protein interactions in human cells using a mass spectrometry-based approach. The study maps protein interactions for 338 bait proteins that were selected based on known or suspected disease and functional associations. Large-scale immunoprecipitation of Flag-tagged versions of these proteins followed by LC-ESI-MS/MS analysis resulted in the identification of 24,540 potential protein interactions. False positives and redundant hits were filtered out using empirical criteria and a calculated interaction confidence score, producing a data set of 6463 interactions between 2235 distinct proteins. This data set was further cross-validated using previously published and predicted human protein interactions. In-depth mining of the data set shows that it represents a valuable source of novel protein-protein interactions with relevance to human diseases. In addition, via our preliminary analysis, we report many novel protein interactions and pathway associations.

Blood, 2006
Authors
Leong, Kevin G, Karsan, Aly
Publication Abstract
Members of the Notch family of transmembrane receptors play an important role in cell fate determination. Over the past decade, a role for Notch in the pathogenesis of hematologic and solid malignancies has become apparent. Numerous cellular functions and microenvironmental cues associated with tumorigenesis are modulated by Notch signaling, including proliferation, apoptosis, adhesion, epithelial-to-mesenchymal transition, and angiogenesis. It is becoming increasingly evident that Notch signaling can be both oncogenic and tumor suppressive. This review highlights recent findings regarding the molecular and functional aspects of Notch-mediated neoplastic transformation. In addition, cellular mechanisms that potentially explain the complex role of Notch in tumorigenesis are discussed.

Current treatment options in oncology, 2005
Authors
Caron, Nadine R, Clark, Orlo H
Publication Abstract
Papillary thyroid cancer (PTC), the most common thyroid malignancy, is associated with cervical lymph node metastases in 30% to 90% of patients. While surgery is the primary treatment modality for PTC, radioactive iodine and thyroid hormone suppression often complement the treatment plan. Although thyroid hormone suppression may decrease the incidence of recurrent disease and radioactive iodine may diagnose and treat metastases, lymph node dissection (LND) is the mainstay treatment for clinically evident cervical lymph node metastases. The surgical treatment options published in the literature include the traditional radical LND, the modified radical LND, the selective LND (compartment-based resection based on documented lymph node metastases), and a 'berry picking' resection (in which only the grossly abnormal lymph nodes are excised). At the University of California, San Francisco, we prefer the modified radical LND with preservation of the cervical sensory nerves for the first lymph node dissection with the 'berry picking' procedure limited to surgical treatment of recurrent nodal metastases in previously resected lymph node basins. Some centers are evaluating the potential role of sentinel lymph node biopsies for PTC. While the extent of lymphadenectomy is debated, most physicians treating patients with PTC agree that clinical evidence of lymphatic metastases should be surgically exercised and there is no role for prophylactic LND.

CMAJ : Canadian Medical Association journal = journal de l'Association medicale canadienne, 2005
Authors
Caron, Nadine R

Science (New York, N.Y.), 2003
Authors
Marra, Marco A, Jones, Steven J M, Astell, Caroline R, Holt, Robert A, Brooks-Wilson, Angela, Butterfield, Yaron S N, Khattra, Jaswinder, Asano, Jennifer K, Barber, Sarah A, Chan, Susanna Y, Cloutier, Alison, Coughlin, Shaun M, Freeman, Doug, Girn, Noreen, Griffith, Obi L, Leach, Stephen R, Mayo, Michael, McDonald, Helen, Montgomery, Stephen B, Pandoh, Pawan K, Petrescu, Anca S, Robertson, A Gordon, Schein, Jacqueline E, Siddiqui, Asim, Smailus, Duane E, Stott, Jeff M, Yang, George S, Plummer, Francis, Andonov, Anton, Artsob, Harvey, Bastien, Nathalie, Bernard, Kathy, Booth, Timothy F, Bowness, Donnie, Czub, Martin, Drebot, Michael, Fernando, Lisa, Flick, Ramon, Garbutt, Michael, Gray, Michael, Grolla, Allen, Jones, Steven, Feldmann, Heinz, Meyers, Adrienne, Kabani, Amin, Li, Yan, Normand, Susan, Stroher, Ute, Tipples, Graham A, Tyler, Shaun, Vogrig, Robert, Ward, Diane, Watson, Brynn, Brunham, Robert C, Krajden, Mel, Petric, Martin, Skowronski, Danuta M, Upton, Chris, Roper, Rachel L
Publication Abstract
We sequenced the 29,751-base genome of the severe acute respiratory syndrome (SARS)-associated coronavirus known as the Tor2 isolate. The genome sequence reveals that this coronavirus is only moderately related to other known coronaviruses, including two human coronaviruses, HCoV-OC43 and HCoV-229E. Phylogenetic analysis of the predicted viral proteins indicates that the virus does not closely resemble any of the three previously known groups of coronaviruses. The genome sequence will aid in the diagnosis of SARS virus infection in humans and potential animal hosts (using polymerase chain reaction and immunological tests), in the development of antivirals (including neutralizing antibodies), and in the identification of putative epitopes for vaccine development.
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