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Author Sharma, P.; Allison, J.P. url  openurl
  Title Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential Type Journal Article
  Year 2015 Publication Abbreviated Journal Cell  
  Volume (down) 161 Issue 2 Pages 205-214  
  Keywords  
  Abstract Research in two fronts has enabled the development of therapies that provide significant benefit to cancer patients. One area stems from a detailed knowledge of mutations that activate or inactivate signaling pathways that drive cancer development. This work triggered the development of targeted therapies that lead to clinical responses in the majority of patients bearing the targeted mutation, although responses are often of limited duration. In the second front are the advances in molecular immunology that unveiled the complexity of the mechanisms regulating cellular immune responses. These developments led to the successful targeting of immune checkpoints to unleash anti-tumor T cell responses, resulting in durable long-lasting responses but only in a fraction of patients. In this Review, we discuss the evolution of research in these two areas and propose that intercrossing them and increasing funding to guide research of combination of agents represent a path forward for the development of curative therapies for the majority of cancer patients.  
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  Notes Approved no  
  Call Number UofT @ ankit.sinha @ Serial 45097  
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Author Ramachandra, T.V.; Bharath, A.H.; Sowmyashree, M.V. url  openurl
  Title Monitoring urbanization and its implications in a mega city from space: Spatiotemporal patterns and its indicators Type Journal Article
  Year 2015 Publication Abbreviated Journal Journal of Environmental Management  
  Volume (down) 148 Issue Pages 67-81  
  Keywords Delhi; Remote sensing; Spatial metrics; Urbanization; Urban sprawl  
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  Series Volume Series Issue Edition  
  ISSN 0301-4797 ISBN Medium  
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  Notes Approved no  
  Call Number CES @ dilipnaidu.gt @ Serial 43048  
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Author Yogurtcu, O.N.; Johnson, M.E. url  openurl
  Title Theory of bi-molecular association dynamics in 2D for accurate model and experimental parameterization of binding rates Type Journal Article
  Year 2015 Publication Abbreviated Journal J Chem Phys  
  Volume (down) 143 Issue 8 Pages 084117  
  Keywords Jhu, Fpr, Cme  
  Abstract The dynamics of association between diffusing and reacting molecular species are routinely quantified using simple rate-equation kinetics that assume both well-mixed concentrations of species and a single rate constant for parameterizing the binding rate. In two-dimensions (2D), however, even when systems are well-mixed, the assumption of a single characteristic rate constant for describing association is not generally accurate, due to the properties of diffusional searching in dimensions d ≤ 2. Establishing rigorous bounds for discriminating between 2D reactive systems that will be accurately described by rate equations with a single rate constant, and those that will not, is critical for both modeling and experimentally parameterizing binding reactions restricted to surfaces such as cellular membranes. We show here that in regimes of intrinsic reaction rate (ka) and diffusion (D) parameters ka/D > 0.05, a single rate constant cannot be fit to the dynamics of concentrations of associating species independently of the initial conditions. Instead, a more sophisticated multi-parametric description than rate-equations is necessary to robustly characterize bimolecular reactions from experiment. Our quantitative bounds derive from our new analysis of 2D rate-behavior predicted from Smoluchowski theory. Using a recently developed single particle reaction-diffusion algorithm we extend here to 2D, we are able to test and validate the predictions of Smoluchowski theory and several other theories of reversible reaction dynamics in 2D for the first time. Finally, our results also mean that simulations of reactive systems in 2D using rate equations must be undertaken with caution when reactions have ka/D > 0.05, regardless of the simulation volume. We introduce here a simple formula for an adaptive concentration dependent rate constant for these chemical kinetics simulations which improves on existing formulas to better capture non-equilibrium reaction dynamics from dilute to dense systems.  
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  ISSN 0021-9606 ISBN Medium  
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  Notes Approved no  
  Call Number AG @ matthewjvarga @ Serial 46618  
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Author Cajigas, I.; Leib, D.E.; Cochrane, J.; Luo, H.; Swyter, K.R.; Chen, S.; Clark, B.S.; Thompson, J.; Yates, J.R.; Kingston, R.E.; Kohtz, J.D. openurl 
  Title Evf2 lncRNA/BRG1/DLX1 interactions reveal RNA-dependent inhibition of chromatin remodeling Type Journal Article
  Year 2015 Publication Abbreviated Journal Development (Cambridge, England)  
  Volume (down) 142 Issue 15 Pages 2641--2652  
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  Abstract Transcription-regulating long non-coding RNAs (lncRNAs) have the potential to control the site-specific expression of thousands of target genes. Previously, we showed that Evf2, the first described ultraconserved lncRNA, increases the association of transcriptional activators (DLX homeodomain proteins) with key DNA enhancers but represses gene expression. In this report, mass spectrometry shows that the Evf2-DLX1 ribonucleoprotein (RNP) contains the SWI/SNF-related chromatin remodelers Brahma-related gene 1 (BRG1, SMARCA4) and Brahma-associated factor (BAF170, SMARCC2) in the developing mouse forebrain. Evf2 RNA colocalizes with BRG1 in nuclear clouds and increases BRG1 association with key DNA regulatory enhancers in the developing forebrain. While BRG1 directly interacts with DLX1 and Evf2 through distinct binding sites, Evf2 directly inhibits BRG1 ATPase and chromatin remodeling activities. In vitro studies show that both RNA-BRG1 binding and RNA inhibition of BRG1 ATPase/remodeling activity are promiscuous, suggesting that context is a crucial factor in RNA-dependent chromatin remodeling inhibition. Together, these experiments support a model in which RNAs convert an active enhancer to a repressed enhancer by directly inhibiting chromatin remodeling activity, and address the apparent paradox of RNA-mediated stabilization of transcriptional activators at enhancers with a repressive outcome. The importance of BRG1/RNA and BRG1/homeodomain interactions in neurodevelopmental disorders is underscored by the finding that mutations in Coffin-Siris syndrome, a human intellectual disability disorder, localize to the BRG1 RNA-binding and DLX1-binding domains.  
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  ISSN 1477-9129 ISBN Medium  
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  Notes Approved no  
  Call Number AG @ matthewjvarga @ Serial 47024  
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Author Ferlay, J.; Soerjomataram, I.; Dikshit, R.; Eser, S.; Mathers, C.; Rebelo, M.; Parkin, D.M.; Forman, D.; Bray, F. url  openurl
  Title Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012 Type Journal Article
  Year 2015 Publication Abbreviated Journal Int J Cancer  
  Volume (down) 136 Issue 5 Pages E359-86  
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  Abstract Estimates of the worldwide incidence and mortality from 27 major cancers and for all cancers combined for 2012 are now available in the GLOBOCAN series of the International Agency for Research on Cancer. We review the sources and methods used in compiling the national cancer incidence and mortality estimates, and briefly describe the key results by cancer site and in 20 large “areas” of the world. Overall, there were 14.1 million new cases and 8.2 million deaths in 2012. The most commonly diagnosed cancers were lung (1.82 million), breast (1.67 million), and colorectal (1.36 million); the most common causes of cancer death were lung cancer (1.6 million deaths), liver cancer (745,000 deaths), and stomach cancer (723,000 deaths).  
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  Notes Approved no  
  Call Number UofT @ ankit.sinha @ Serial 45319  
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Author Tursich, M.; Ros, T.; Frewen, P.A.; Kluetsch, R.C.; Calhoun, V.D.; Lanius, R.A. url  doi
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  Title Distinct intrinsic network connectivity patterns of post-traumatic stress disorder symptom clusters Type Journal Article
  Year 2015 Publication Acta Psychiatrica Scandinavica Abbreviated Journal Acta Psychiatr Scand  
  Volume (down) 132 Issue 1 Pages 29-38  
  Keywords adult survivors of child abuse; functional neuroimaging; multivariate analysis; post-traumatic stress disorders  
  Abstract OBJECTIVE: Post-traumatic stress disorder (PTSD) is considered a multidimensional disorder, with distinct symptom clusters including re-experiencing, avoidance/numbing, hyperarousal, and most recently depersonalization/derealization. However, the extent of differing intrinsic network connectivity underlying these symptoms has not been fully investigated. We therefore investigated the degree of association between resting connectivity of the salience (SN), default mode (DMN), and central executive (CEN) networks and PTSD symptom severity. METHOD: Using resting-state functional MRI data from PTSD participants (n = 21), we conducted multivariate analyses to test whether connectivity of extracted independent components varied as a function of re-experiencing, avoidance/numbing, hyperarousal, and depersonalization/derealization. RESULTS: Hyperarousal symptoms were associated with reduced connectivity of posterior insula/superior temporal gyrus within SN [peak Montreal Neurological Institute (MNI): -44, -8, 0, t = -4.2512, k = 40]. Depersonalization/derealization severity was associated with decreased connectivity of perigenual anterior cingulate/ventromedial prefrontal cortex within ventral anterior DMN (peak MNI: 8, 40, -4; t = -3.8501; k = 15) and altered synchrony between two DMN components and between DMN and CEN. CONCLUSION: Our results are consistent with prior research showing intrinsic network disruptions in PTSD and imply heterogeneous connectivity patterns underlying PTSD symptom dimensions. These findings suggest possible biomarkers for PTSD and its dissociative subtype.  
  Address Department of Neuroscience, The University of Western Ontario, London, ON, Canada  
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  ISSN 0001-690X ISBN Medium  
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  Notes PMID:25572430 Approved no  
  Call Number UU @ jana.mullerova @ Serial 42195  
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Author Park, B.-C.; Yim, Y.-I.; Zhao, X.; Olszewski, M.B.; Eisenberg, E.; Greene, L.E. doi  openurl
  Title The clathrin-binding and J-domains of GAK support the uncoating and chaperoning of clathrin by Hsc70 in the brain Type Journal Article
  Year 2015 Publication Abbreviated Journal Journal of Cell Science  
  Volume (down) 128 Issue 20 Pages 3811-3821  
  Keywords JHU, CME, hsc70  
  Abstract Cyclin-G-associated kinase (GAK), the ubiquitously expressed J-domain protein, is essential for the chaperoning and uncoating of clathrin that is mediated by Hsc70 (also known as HSPA8). Adjacent to the C-terminal J-domain that binds to Hsc70, GAK has a clathrin-binding domain that is linked to an N-terminal kinase domain through a PTEN-like domain. Knocking out GAK in fibroblasts caused inhibition of clathrin-dependent trafficking, which was rescued by expressing a 62-kDa fragment of GAK, comprising just the clathrin-binding and J-domains. Expressing this fragment as a transgene in mice rescued the lethality and the histological defects caused by knocking out GAK in the liver or in the brain. Furthermore, when both GAK and auxilin (also known as DNAJC6), the neuronal-specific homolog of GAK, were knocked out in the brain, mice expressing the 62-kDa GAK fragment were viable, lived a normal life-span and had no major behavior abnormalities. However, these mice were about half the size of wild-type mice. Therefore, the PTEN-like domains of GAK and auxilin are not essential for Hsc70-dependent chaperoning and uncoating of clathrin, but depending on the tissue, these domains appear to increase the efficiency of these co-chaperones.  
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  ISSN 1477-9137 0021-9533 ISBN Medium  
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  Notes Times cited: 15 Approved no  
  Call Number AG @ matthewjvarga @ Serial 46698  
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Author Al-Awqati, Q. url  openurl
  Title Kidney growth and hypertrophy: the role of mTOR and vesicle trafficking Type Journal Article
  Year 2015 Publication Abbreviated Journal J Clin Invest  
  Volume (down) 125 Issue 6 Pages 2267-2270  
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  Abstract The kidney, like other organs, grows in constant proportion to the rest of the body. When one kidney is removed, the remaining one hypertrophies. In a comprehensive series of studies, Chen et al. show that growth during maturation is mediated by the mTORC1 signaling pathway, which is induced by EGF-like peptides, and requires PI3K, PDK, AKT, mTORC2, and activation of mTORC1 through the combined effects of TSC and RHEB as part of a multiprotein complex localized on lysosomes. However, compensatory growth is mediated by amino acids, which act on mTORC1 independently of the previous pathway, and requires a class III PI3K (VPS34) that is known to be involved in vesicle trafficking to the lysosomes.  
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  Series Volume Series Issue Edition  
  ISSN 0021-9738 ISBN Medium  
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  Notes Approved no  
  Call Number UofT @ mathieu.lemaire @ Serial 45804  
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Author Al-Nouri, Z.L.; Reese, J.A.; Terrell, D.R.; Vesely, S.K.; George, J.N. url  openurl
  Title Drug-induced thrombotic microangiopathy: a systematic review of published reports Type Journal Article
  Year 2015 Publication Abbreviated Journal Blood  
  Volume (down) 125 Issue 4 Pages 616-618  
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  Abstract Many patients with syndromes of thrombotic microangiopathy (TMA), including thrombotic thrombocytopenic purpura and hemolytic-uremic syndrome, have been reported to have a drug-induced etiology, and many different drugs have been suspected as a cause of TMA. We established criteria to assess the strength of evidence for a causal association of a drug with TMA and systematically searched for all published reports of drug-induced TMA. We identified 1569 articles: 604 were retrieved for review, 344 reported evaluable data for 586 individual patients, 43 reported evaluable data on 46 patient groups. Seventy-eight drugs were described; 22 had evidence supporting a definite causal association with TMA. Three drugs accounted for 61 of the 104 patient reports with definite evidence (quinine, 34; cyclosporine, 15; tacrolimus, 12). Twenty additional drugs had evidence supporting a probable association with TMA. These criteria and data can provide support for clinicians evaluating patients with suspected TMA.  
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  ISSN 0006-4971 ISBN Medium  
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  Notes Approved no  
  Call Number UofT @ mathieu.lemaire @ Serial 45847  
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Author Albers, J.; Danzer, C.; Rechsteiner, M.; Lehmann, H.; Brandt, L.P.; Hejhal, T.; Catalano, A.; Busenhart, P.; Gonçalves, A.F.; Brandt, S.; Bode, P.K.; Bode-Lesniewska, B.; Wild, P.J.; Frew, I.J. url  openurl
  Title A versatile modular vector system for rapid combinatorial mammalian genetics Type Journal Article
  Year 2015 Publication Abbreviated Journal J Clin Invest  
  Volume (down) 125 Issue 4 Pages 1603-1619  
  Keywords Animals; Apoptosis; Caspase 9; Cells, Cultured; Cloning, Molecular; Clustered Regularly Interspaced Short Palindromic Repeats; Doxycycline; Drug Resistance; Gene Deletion; Gene Knockdown Techniques; Genetic Vectors; Humans; Hypoxia-Inducible Factor 1, alpha Subunit; Lentivirus; Mice; Mice, SCID; PTEN Phosphohydrolase; Recombination, Genetic; research support, non-u.s. gov’t; Retinoblastoma Protein; RNA, Small Interfering; Sarcoma, Experimental; Transduction, Genetic; Tumor Suppressor Protein p53; Xenograft Model Antitumor Assays; Cas9/CRIPSR; Journal club  
  Abstract Here, we describe the multiple lentiviral expression (MuLE) system that allows multiple genetic alterations to be introduced simultaneously into mammalian cells. We created a toolbox of MuLE vectors that constitute a flexible, modular system for the rapid engineering of complex polycistronic lentiviruses, allowing combinatorial gene overexpression, gene knockdown, Cre-mediated gene deletion, or CRISPR/Cas9-mediated (where CRISPR indicates clustered regularly interspaced short palindromic repeats) gene mutation, together with expression of fluorescent or enzymatic reporters for cellular assays and animal imaging. Examples of tumor engineering were used to illustrate the speed and versatility of performing combinatorial genetics using the MuLE system. By transducing cultured primary mouse cells with single MuLE lentiviruses, we engineered tumors containing up to 5 different genetic alterations, identified genetic dependencies of molecularly defined tumors, conducted genetic interaction screens, and induced the simultaneous CRISPR/Cas9-mediated knockout of 3 tumor-suppressor genes. Intramuscular injection of MuLE viruses expressing oncogenic H-RasG12V together with combinations of knockdowns of the tumor suppressors cyclin-dependent kinase inhibitor 2A (Cdkn2a), transformation-related protein 53 (Trp53), and phosphatase and tensin homolog (Pten) allowed the generation of 3 murine sarcoma models, demonstrating that genetically defined autochthonous tumors can be rapidly generated and quantitatively monitored via direct injection of polycistronic MuLE lentiviruses into mouse tissues. Together, our results demonstrate that the MuLE system provides genetic power for the systematic investigation of the molecular mechanisms that underlie human diseases.  
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  Series Volume Series Issue Edition  
  ISSN 0021-9738 ISBN Medium  
  Area Expedition Conference  
  Notes Approved no  
  Call Number UofT @ mathieu.lemaire @ Serial 45848  
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