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James T. Rutka

Bio: James T. Rutka is an academic researcher from University of Toronto. The author has contributed to research in topics: Epilepsy surgery & Epilepsy. The author has an hindex of 84, co-authored 618 publications receiving 30391 citations. Previous affiliations of James T. Rutka include Princeton University & Toronto Western Hospital.


Papers
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Journal ArticleDOI
TL;DR: It is shown that gold and silver nanoparticles coated with antibodies can regulate the process of membrane receptor internalization and show that nanoparticles should no longer be viewed as simple carriers for biomedical applications, but can also play an active role in mediating biological effects.
Abstract: Nanostructures of different sizes, shapes and material properties have many applications in biomedical imaging, clinical diagnostics and therapeutics1,2,3,4,5,6. In spite of what has been achieved so far, a complete understanding of how cells interact with nanostructures of well-defined sizes, at the molecular level, remains poorly understood. Here we show that gold and silver nanoparticles coated with antibodies can regulate the process of membrane receptor internalization. The binding and activation of membrane receptors and subsequent protein expression strongly depend on nanoparticle size. Although all nanoparticles within the 2–100 nm size range were found to alter signalling processes essential for basic cell functions (including cell death)7, 40- and 50-nm nanoparticles demonstrated the greatest effect. These results show that nanoparticles should no longer be viewed as simple carriers for biomedical applications, but can also play an active role in mediating biological effects. The findings presented here may assist in the design of nanoscale delivery and therapeutic systems and provide insights into nanotoxicity.

2,511 citations

Journal ArticleDOI
TL;DR: The authors' integrative genomics approach to a large cohort of medulloblastomas has identified four disparate subgroups with distinct demographics, clinical presentation, transcriptional profiles, genetic abnormalities, and clinical outcome.
Abstract: Purpose Recent genomic approaches have suggested the existence of multiple distinct subtypes of medulloblastoma. We studied a large cohort of medulloblastomas to determine how many subgroups of the disease exist, how they differ, and the extent of overlap between subgroups. Methods We determined gene expression profiles and DNA copy number aberrations for 103 primary medulloblastomas. Bioinformatic tools were used for class discovery of medulloblastoma subgroups based on the most informative genes in the data set. Immunohistochemistry for subgroup-specific signature genes was used to determine subgroup affiliation for 294 nonoverlapping medulloblastomas on two independent tissue microarrays. Results Multiple unsupervised analyses of transcriptional profiles identified the following four distinct, nonoverlapping molecular variants: WNT, SHH, group C, and group D. Supervised analysis of these four subgroups revealed significant subgroup-specific demographics, histology, metastatic status, and DNA copy number aberrations. Immunohistochemistry for DKK1 (WNT), SFRP1 (SHH), NPR3 (group C), and KCNA1 (group D) could reliably and uniquely classify formalin-fixed medulloblastomas in approximately 98% of patients. Group C patients (NPR3-positive tumors) exhibited a significantly diminished progression-free and overall survival irrespective of their metastatic status. Conclusion Our integrative genomics approach to a large cohort of medulloblastomas has identified four disparate subgroups with distinct demographics, clinical presentation, transcriptional profiles, genetic abnormalities, and clinical outcome. Medulloblastomas can be reliably assigned to subgroups through immunohistochemistry, thereby making medulloblastoma subclassification widely available. Future research on medulloblastoma and the development of clinical trials should take into consideration these four distinct types of medulloblastoma.

1,084 citations

Journal ArticleDOI
TL;DR: From the Institute of Biomaterials and Biomedical Engineering (B.Y.S.K., J.T.R., W.W.C.C.), Terrence Donnelly Centre for Cellular and Biomolecular Research, and the Department of Chemical Engineering.
Abstract: From the Institute of Biomaterials and Biomedical Engineering (B.Y.S.K., W.C.W.C.), Terrence Donnelly Centre for Cellular and Biomolecular Research (B.Y.S.K., W.C.W.C.), the Department of Materials Science and Engineering (W.C.W.C.), and the Department of Chemical Engineering (W.C.W.C.), University of Toronto (B.Y.S.K., J.T.R., W.C.W.C.); and the Division of Neurosurgery (B.Y.S.K., J.T.R.) and the Arthur and Sonia Labatt Brain Tumour Research Centre ( J.T.R.), Hospital for Sick Children (B.Y.S.K., J.T.R.) — both in Toronto. Address reprint requests to Dr. Chan at the Institute of Biomaterials and Biomedical Engineering, Donnelly Centre for Cellular and Biomolecular Research, 164 College St., 407, University of Toronto, Toronto, ON M5S 3G9, Canada, or at warren.chan@ utoronto.ca.

878 citations

Journal ArticleDOI
TL;DR: It is reported that a subset of children with medulloblastoma carry germline and somatic mutations in SUFU (encoding the human suppressor of fused) of the SHH pathway, accompanied by loss of heterozygosity of the wildtype allele.
Abstract: The sonic hedgehog (SHH) signaling pathway directs the embryonic development of diverse organisms and is disrupted in a variety of malignancies. Pathway activation is triggered by binding of hedgehog proteins to the multipass Patched-1 (PTCH) receptor, which in the absence of hedgehog suppresses the activity of the seven-pass membrane protein Smoothened (SMOH). De-repression of SMOH culminates in the activation of one or more of the GLI transcription factors that regulate the transcription of downstream targets. Individuals with germline mutations of the SHH receptor gene PTCH are at high risk of developmental anomalies and of basal-cell carcinomas, medulloblastomas and other cancers (a pattern consistent with nevoid basal-cell carcinoma syndrome, NBCCS). In keeping with the role of PTCH as a tumor-suppressor gene, somatic mutations of this gene occur in sporadic basal-cell carcinomas and medulloblastomas. We report here that a subset of children with medulloblastoma carry germline and somatic mutations in SUFU (encoding the human suppressor of fused) of the SHH pathway, accompanied by loss of heterozygosity of the wildtype allele. Several of these mutations encode truncated proteins that are unable to export the GLI transcription factor from nucleus to cytoplasm, resulting in the activation of SHH signaling. SUFU is a newly identified tumor-suppressor gene that predisposes individuals to medulloblastoma by modulating the SHH signaling pathway through a newly identified mechanism.

799 citations

Journal ArticleDOI
Paul A. Northcott1, Paul A. Northcott2, David Shih1, John Peacock1, Livia Garzia1, A. Sorana Morrissy1, Thomas Zichner, Adrian M. Stütz, Andrey Korshunov2, Jüri Reimand1, Steven E. Schumacher3, Rameen Beroukhim4, Rameen Beroukhim3, David W. Ellison, Christian R. Marshall1, Anath C. Lionel1, Stephen C. Mack1, Adrian M. Dubuc1, Yuan Yao1, Vijay Ramaswamy1, Betty Luu1, Adi Rolider1, Florence M.G. Cavalli1, Xin Wang1, Marc Remke1, Xiaochong Wu1, Readman Chiu5, Andy Chu5, Eric Chuah5, Richard Corbett5, Gemma Hoad5, Shaun D. Jackman5, Yisu Li5, Allan Lo5, Karen Mungall5, Ka Ming Nip5, Jenny Q. Qian5, Anthony Raymond5, Nina Thiessen5, Richard Varhol5, Inanc Birol5, Richard A. Moore5, Andrew J. Mungall5, Robert A. Holt5, Daisuke Kawauchi, Martine F. Roussel, Marcel Kool2, David T.W. Jones2, Hendrick Witt6, Africa Fernandez-L7, Anna Kenney8, Robert J. Wechsler-Reya9, Peter B. Dirks1, Tzvi Aviv1, Wiesława Grajkowska, Marta Perek-Polnik, Christine Haberler10, Olivier Delattre11, Stéphanie Reynaud11, François Doz11, Sarah S. Pernet-Fattet12, Byung Kyu Cho13, Seung-Ki Kim13, Kyu-Chang Wang13, Wolfram Scheurlen, Charles G. Eberhart14, Michelle Fèvre-Montange15, Anne Jouvet15, Ian F. Pollack16, Xing Fan17, Karin M. Muraszko17, G. Yancey Gillespie18, Concezio Di Rocco19, Luca Massimi19, Erna M.C. Michiels20, Nanne K. Kloosterhof20, Pim J. French20, Johan M. Kros20, James M. Olson21, Richard G. Ellenbogen22, Karel Zitterbart23, Leos Kren23, Reid C. Thompson8, Michael K. Cooper8, Boleslaw Lach24, Boleslaw Lach25, Roger E. McLendon26, Darell D. Bigner26, Adam M. Fontebasso27, Steffen Albrecht28, Steffen Albrecht27, Nada Jabado27, Janet C. Lindsey29, Simon Bailey29, Nalin Gupta30, William A. Weiss30, László Bognár31, Almos Klekner31, Timothy E. Van Meter, Toshihiro Kumabe32, Teiji Tominaga32, Samer K. Elbabaa33, Jeffrey R. Leonard34, Joshua B. Rubin34, Linda M. Liau35, Erwin G. Van Meir36, Maryam Fouladi37, Hideo Nakamura38, Giuseppe Cinalli, Miklós Garami39, Peter Hauser39, Ali G. Saad40, Achille Iolascon41, Shin Jung42, Carlos Gilberto Carlotti43, Rajeev Vibhakar44, Young Shin Ra45, Shenandoah Robinson, Massimo Zollo41, Claudia C. Faria1, Jennifer A. Chan46, Michael J. Levy21, Poul H. Sorensen5, Matthew Meyerson3, Scott L. Pomeroy3, Yoon Jae Cho47, Gary D. Bader1, Uri Tabori1, Cynthia Hawkins1, Eric Bouffet1, Stephen W. Scherer1, James T. Rutka1, David Malkin1, Steven C. Clifford29, Steven J.M. Jones5, Jan O. Korbel, Stefan M. Pfister6, Stefan M. Pfister2, Marco A. Marra5, Michael D. Taylor1 
02 Aug 2012-Nature
TL;DR: Somatic copy number aberrations (SCNAs) in 1,087 unique medulloblastomas are reported, including recurrent events targeting TGF-β signalling in Group 3, and NF-κB signalling in Groups 4, which suggest future avenues for rational, targeted therapy.
Abstract: Medulloblastoma, the most common malignant paediatric brain tumour, is currently treated with nonspecific cytotoxic therapies including surgery, whole-brain radiation, and aggressive chemotherapy. As medulloblastoma exhibits marked intertumoural heterogeneity, with at least four distinct molecular variants, previous attempts to identify targets for therapy have been underpowered because of small samples sizes. Here we report somatic copy number aberrations (SCNAs) in 1,087 unique medulloblastomas. SCNAs are common in medulloblastoma, and are predominantly subgroup-enriched. The most common region of focal copy number gain is a tandem duplication of SNCAIP, a gene associated with Parkinson's disease, which is exquisitely restricted to Group 4α. Recurrent translocations of PVT1, including PVT1-MYC and PVT1-NDRG1, that arise through chromothripsis are restricted to Group 3. Numerous targetable SCNAs, including recurrent events targeting TGF-β signalling in Group 3, and NF-κB signalling in Group 4, suggest future avenues for rational, targeted therapy.

749 citations


Cited by
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[...]

08 Dec 2001-BMJ
TL;DR: There is, I think, something ethereal about i —the square root of minus one, which seems an odd beast at that time—an intruder hovering on the edge of reality.
Abstract: There is, I think, something ethereal about i —the square root of minus one. I remember first hearing about it at school. It seemed an odd beast at that time—an intruder hovering on the edge of reality. Usually familiarity dulls this sense of the bizarre, but in the case of i it was the reverse: over the years the sense of its surreal nature intensified. It seemed that it was impossible to write mathematics that described the real world in …

33,785 citations

Journal ArticleDOI
18 Nov 2004-Nature
TL;DR: The development of a xenograft assay that identified human brain tumour initiating cells that initiate tumours in vivo gives strong support for the CSC hypothesis as the basis for many solid tumours, and establishes a previously unidentified cellular target for more effective cancer therapies.
Abstract: The cancer stem cell (CSC) hypothesis suggests that neoplastic clones are maintained exclusively by a rare fraction of cells with stem cell properties. Although the existence of CSCs in human leukaemia is established, little evidence exists for CSCs in solid tumours, except for breast cancer. Recently, we prospectively isolated a CD133+ cell subpopulation from human brain tumours that exhibited stem cell properties in vitro. However, the true measures of CSCs are their capacity for self renewal and exact recapitulation of the original tumour. Here we report the development of a xenograft assay that identified human brain tumour initiating cells that initiate tumours in vivo. Only the CD133+ brain tumour fraction contains cells that are capable of tumour initiation in NOD-SCID (non-obese diabetic, severe combined immunodeficient) mouse brains. Injection of as few as 100 CD133+ cells produced a tumour that could be serially transplanted and was a phenocopy of the patient's original tumour, whereas injection of 10(5) CD133- cells engrafted but did not cause a tumour. Thus, the identification of brain tumour initiating cells provides insights into human brain tumour pathogenesis, giving strong support for the CSC hypothesis as the basis for many solid tumours, and establishes a previously unidentified cellular target for more effective cancer therapies.

7,120 citations

Journal Article
TL;DR: The identification and purification of a cancer stem cell from human brain tumors of different phenotypes that possesses a marked capacity for proliferation, self-renewal, and differentiation is reported.
Abstract: Most current research on human brain tumors is focused on the molecular and cellular analysis of the bulk tumor mass. However, there is overwhelming evidence in some malignancies that the tumor clone is heterogeneous with respect to proliferation and differentiation. In human leukemia, the tumor clone is organized as a hierarchy that originates from rare leukemic stem cells that possess extensive proliferative and self-renewal potential, and are responsible for maintaining the tumor clone. We report here the identification and purification of a cancer stem cell from human brain tumors of different phenotypes that possesses a marked capacity for proliferation, self-renewal, and differentiation. The increased self-renewal capacity of the brain tumor stem cell (BTSC) was highest from the most aggressive clinical samples of medulloblastoma compared with low-grade gliomas. The BTSC was exclusively isolated with the cell fraction expressing the neural stem cell surface marker CD133. These CD133+ cells could differentiate in culture into tumor cells that phenotypically resembled the tumor from the patient. The identification of a BTSC provides a powerful tool to investigate the tumorigenic process in the central nervous system and to develop therapies targeted to the BTSC.

4,899 citations

01 Feb 2015
TL;DR: In this article, the authors describe the integrative analysis of 111 reference human epigenomes generated as part of the NIH Roadmap Epigenomics Consortium, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression.
Abstract: The reference human genome sequence set the stage for studies of genetic variation and its association with human disease, but epigenomic studies lack a similar reference. To address this need, the NIH Roadmap Epigenomics Consortium generated the largest collection so far of human epigenomes for primary cells and tissues. Here we describe the integrative analysis of 111 reference human epigenomes generated as part of the programme, profiled for histone modification patterns, DNA accessibility, DNA methylation and RNA expression. We establish global maps of regulatory elements, define regulatory modules of coordinated activity, and their likely activators and repressors. We show that disease- and trait-associated genetic variants are enriched in tissue-specific epigenomic marks, revealing biologically relevant cell types for diverse human traits, and providing a resource for interpreting the molecular basis of human disease. Our results demonstrate the central role of epigenomic information for understanding gene regulation, cellular differentiation and human disease.

4,409 citations

Journal ArticleDOI
TL;DR: The authors found that approximately 5% of patients with malignant gliomas have a family history of glioma and most of these familial cases are associated with rare genetic syndromes, such as neurofibromatosis types 1 and 2, the Li−Fraumeni syndrome (germ-line p53 mutations associated with an increased risk of several cancers), and Turcot's syndrome (intestinal polyposis and brain tumors).
Abstract: Approximately 5% of patients with malignant gliomas have a family history of gliomas. Some of these familial cases are associated with rare genetic syndromes, such as neurofibromatosis types 1 and 2, the Li−Fraumeni syndrome (germ-line p53 mutations associated with an increased risk of several cancers), and Turcot’s syndrome (intestinal polyposis and brain tumors). 10 However, most familial cases have

3,823 citations