bluuebunny/crossref_metadata_2025_split huggingface dataset:
Deposition of Hyperphosphorylated Tau in Cerebellum of PS1 E280A Alzheimer's Disease
Authors: Sepulveda‐Falla Diego , Matschke Jakob , Bernreuther Christian , Hagel Christian , Puig Berta , Villegas Andres , Garcia Gloria , Zea Julian , Gomez‐Mancilla Baltazar , Ferrer Isidre , Lopera Francisco , Glatzel Markus 
Published: December 2010

AbstractEarly‐onset familial Alzheimer's disease (AD) caused by presenilin‐1 mutation E280A (PS1‐E280A) presents wide clinical and neuropathological variabilities. We characterized clinically and neuropathologically PS1‐E280A focusing in cerebellar involvement and compared it with early‐onset sporadic Alzheimer's disease (EOSAD). Twelve E280A brains and 12 matched EOSAD brains were analyzed for beta‐amyloid and hyperphosphorylated tau (pTau) morphology, beta‐amyloid subspecies 1–40, 1–42 levels, pTau levels, and expression of stress kinases in frontal cortex and cerebellum. The data were correlated to clinical and genetic findings. We observed higher beta‐amyloid load, beta‐amyloid 1–42 and pTau concentrations in frontal cortex of PS1‐E280A compared with EOSAD. High beta‐amyloid load was found in the cerebellum of PS1‐E280A and EOSAD patients. In PS1‐E280A, beta‐amyloid localized to the molecular and Purkinje cell layers, whereas EOSAD showed them in Purkinje and granular cell layers. Surprisingly, 11 out of 12 PS1‐E280A patients showed deposition of pTau in the cerebellum. Also, seven out of 12 PS1‐E280A patients presented cerebellar ataxia. We conclude that deposition of beta‐amyloid in the cerebellum is prominent in early‐onset AD irrespective of genetic or sporadic origin. The presence of pTau in cerebellum in PS1‐E280A underscores the relevance of cerebellar involvement in AD and might be correlated to clinical phenotype.
LARGE-DATA SOLUTION OF A MODEL SYSTEM FOR SINGULAR SHOCKS
Authors: SEVER MICHAEL 
Published: December 2010

A suitably modified front-tracking algorithm is used to solve a class of Cauchy problems for a pair of conservation laws known as the model system for singular shocks or as the Keyfitz–Kranzer system. Initial data of large oscillation and including a finite number of positive Dirac masses in one of the dependent variables is permitted.For such initial data, a distribution solution is constructed up to an arbitrary given finite time T. At any given time up to T, the constructed solution is uniformly bounded in space except possibly at a finite number of points. With respect to time, our solutions are weakly Lipshitz in the space of measures on ℝ. However, our solutions are not traditional weak solutions, because of the unavoidable appearance of singular shocks carrying finite Dirac mass. Furthermore, the bounded parts of our solutions are of lower than customary regularity, being of bounded 2-variation in space, pointwise but not uniformly with respect to time.
Expression of Snail in Epidermal Keratinocytes Promotes Cutaneous Inflammation and Hyperplasia Conducive to Tumor Formation
Authors: Du Fei , Nakamura Yoshikazu , Tan Tuan-Lin , Lee Pedro , Lee Robert , Yu Benjamin , Jamora Colin 
Published: December 2010

Abstract
Although metastasis is the most lethal consequence of tumor progression, comparatively little is known regarding the molecular machinery governing this process. In many carcinomas, there is a robust correlation between the expression of the transcription factor Snail and a poor prognosis, but the contribution of this protein to the metastatic process remains unresolved. Interestingly, the prolonged expression of Snail in epidermal keratinocytes is sufficient to recapitulate early features of metastasis. However, it does so without inducing a complete epithelial-mesenchymal transition (EMT), a developmental phenomenon mediated by Snail that is extensively invoked as the mechanism fueling tumorigenesis. Instead, we found that the local invasiveness of keratinocytes is the consequence of the recruitment and activity of macrophages. Moreover, keratinocyte proliferation is the product of an IL-17/IL-6/Stat3 signaling module initiated by activated resident γδT cells in the transgenic skin. Together, these phenotypes prime the transgenic skin for the formation and metastasis of tumors in response to chemically induced carcinogenesis. Thus, the contribution of Snail to the progression of carcinomas is largely through the creation of a hyperproliferative and inflammatory niche that facilitates tumor development and dissemination. Cancer Res; 70(24); 10080–9. ©2010 AACR.
Active Immunotherapy Induces Antibody Responses That Target Tumor Angiogenesis
Authors: Schoenfeld Jonathan , Jinushi Masahisa , Nakazaki Yukoh , Wiener Daniel , Park Joosang , Soiffer Robert , Neuberg Donna , Mihm Martin , Hodi F. Stephen , Dranoff Glenn 
Published: December 2010

Abstract
The inhibition of VEGF signaling with antibodies or small molecules achieves clinical benefits in diverse solid malignancies. Nonetheless, therapeutic effects are usually not sustained, and most patients eventually succumb to progressive disease, indicating that antiangiogenic strategies require additional optimization. Vaccination with lethally irradiated, autologous tumor cells engineered to secrete granulocyte-macrophage colony stimulating factor (GM-CSF) and antibody blockade of cytotoxic T lymphocyte–associated antigen-4 (CTLA-4) trigger a tumor vasculopathy in some long-term responding subjects. These reactions are characterized by disrupted tumor blood vessels in association with lymphocyte and granulocyte infiltrates and zonal areas of ischemic tumor necrosis. However, the mechanisms underlying this immune-mediated destruction of the tumor vasculature remain to be clarified. Here, we show that GM-CSF–secreting tumor cell vaccines and CTLA-4 blockade elicit a functionally important humoral reaction against multiple angiogenic cytokines. Antibodies to angiopoietin-1 and angiopoietin-2 block Tie-2 binding, downstream signaling, endothelial cell tube formation, and macrophage chemotaxis. Antibodies to macrophage inhibitory factor (MIF) attenuate macrophage Tie-2 expression and matrix metalloproteinase-9 (MMP-9) production. Together, these results delineate an immunotherapy-induced host response that broadly targets the angiogenic network in the tumor microenvironment. Cancer Res; 70(24); 10150–60. ©2010 AACR.
Pemetrexed Indirectly Activates the Metabolic Kinase AMPK in Human Carcinomas
Authors: Rothbart Scott B. , Racanelli Alexandra C. , Moran Richard G. 
Published: December 2010

Abstract
The chemotherapeutic drug pemetrexed, an inhibitor of thymidylate synthase, has an important secondary target in human leukemic cells, aminoimidazolecarboxamide ribonucleotide formyltransferase (AICART), the second folate-dependent enzyme of purine biosynthesis. The purine intermediate aminoimidazolecarboxamide ribonucleotide (ZMP), which accumulates behind this block, transmits an inhibitory signal to the mTORC1 complex via activation of the cellular energy sensor AMP-activated kinase (AMPK). Given that the PI3K-AKT-mTOR pathway is frequently deregulated during carcinogenesis, we asked whether the indirect activation of AMPK by pemetrexed offers an effective therapeutic strategy for carcinomas with defects in this pathway. Activation of AMPK by ZMP in pemetrexed-treated colon and lung carcinoma cells and the downstream consequences of this activation were strikingly more robust than previously seen in leukemic cells. Genetic experiments demonstrated the intermediacy of AICART inhibition and the centrality of AMPK activation in these effects. Whereas AMPK activation resulted in marked inhibition of mTORC1, other targets of AMPK were phosphorylated that were not mTORC1-dependent. Whereas AMPK activation is thought to require AMPKα T172 phosphorylation, pemetrexed also activated AMPK in carcinoma cells null for LKB1, the predominant AMPKα T172 kinase whose deficiency is common in lung adenocarcinomas. Like rapamycin analogs, pemetrexed relieved feedback suppression of PI3K and AKT, but the prolonged accumulation of unphosphorylated 4E-BP1, a tight-binding inhibitor of cap-dependent translation, was seen following AMPK activation. Our findings indicate that AMPK activation by pemetrexed inhibits mTORC1-dependent and -independent processes that control translation and lipid metabolism, identifying pemetrexed as a targeted therapeutic agent for this pathway that differs significantly from rapamycin analogs. Cancer Res; 70(24); 10299–309. ©2010 AACR.
CXCL12 Mediates Immunosuppression in the Lymphoma Microenvironment after Allogeneic Transplantation of Hematopoietic Cells
Authors: Dürr Christoph , Pfeifer Dietmar , Claus Rainer , Schmitt-Graeff Annette , Gerlach Ulrike V. , Graeser Ralph , Krüger Sophie , Gerbitz Armin , Negrin Robert S. , Finke Jürgen , Zeiser Robert 
Published: December 2010

Abstract
Clinical studies indicate a role of allogeneic hematopoietic cell transplantation (alloHCT) for patients with refractory or recurrent B-cell lymphoma (BCL) indicative of a graft-versus-tumor effect. However, the relevance of local immunosuppression in the BCL microenvironment by donor-derived regulatory T cells (Treg) after alloHCT is unclear. Therefore, we studied Treg recruitment after alloHCT in different murine BCL models and the impact of lymphoma-derived chemoattractive signals. Luciferase transgenic Tregs accumulated in murine BCL microenvironment and microarray-based analysis of BCL tissues revealed increased expression of CXCL9, CXCL10, and CXCL12. In vivo blocking identified the CXCR4/CXCL12 axis as being critical for Treg attraction toward BCL. In contrast to Tregs, effector T cells displayed low levels of CXCR4 and were not affected by the pharmacologic blockade. Most important, blocking CXCR4 not only reduced Treg migration toward tumor tissue but also enhanced antitumor responses after alloHCT. CXCL12 production was dependent on antigen-presenting cells (APC) located in the lymphoma microenvironment, and their diphtheria-toxin receptor (DTR)-based depletion in CD11c.DTR-Tg mice significantly reduced Treg accumulation within BCL tissue. CXCL12 was also detected in human diffuse, large BCL tissues indicative of its potential clinical relevance. In conclusion, we demonstrate that Tregs are recruited toward BCL after alloHCT by infiltrating host APCs in a CXCL12-dependent fashion. Blocking CXCR4 enhanced antitumor effects and prolonged survival of tumor-bearing mice by reducing local Treg accumulation, indicating that CXCR4 is a potential target to interfere with tumor escape after alloHCT. Cancer Res; 70(24); 10170–81. ©2010 AACR.
NEDD8-Targeting Drug MLN4924 Elicits DNA Rereplication by Stabilizing Cdt1 in S Phase, Triggering Checkpoint Activation, Apoptosis, and Senescence in Cancer Cells
Authors: Lin Jie Jessie , Milhollen Michael A. , Smith Peter G. , Narayanan Usha , Dutta Anindya 
Published: December 2010

Abstract
MLN4924 is a first-in-class experimental cancer drug that inhibits the NEDD8-activating enzyme, thereby inhibiting cullin-RING E3 ubiquitin ligases and stabilizing many cullin substrates. The mechanism by which MLN4924 inhibits cancer cell proliferation has not been defined, although it is accompanied by DNA rereplication and attendant DNA damage. Here we show that stabilization of the DNA replication factor Cdt1, a substrate of cullins 1 and 4, is critical for MLN4924 to trigger DNA rereplication and inhibit cell proliferation. Even only 1 hour of exposure to MLN4924, which was sufficient to elevate Cdt1 for 4–5 hours, was found to be sufficient to induce DNA rereplication and to activate apoptosis and senescence pathways. Cells in S phase were most susceptible, suggesting that MLN4924 will be most toxic on highly proliferating cancers. Although MLN4924-induced cell senescence seems to be dependent on induction of p53 and its downstream effector p21Waf1, we found that p53−/− and p21−/− cells were even more susceptible than wild-type cells to MLN4924. Our results suggested that apoptosis, not senescence, might be more important for the antiproliferative effect of MLN4924. Furthermore, our findings show that transient exposure to this new investigational drug should be useful for controlling p53-negative cancer cells, which often pose significant clinical challenge. Cancer Res; 70(24); 10310–20. ©2010 AACR.
Coexpression Network Analysis Identifies Transcriptional Modules Related to Proastrocytic Differentiation and Sprouty Signaling in Glioma
Authors: Ivliev Alexander E. , 't Hoen Peter A.C. , Sergeeva Marina G. 
Published: December 2010

Abstract
Gliomas are primary brain tumors with high mortality and heterogeneous biology that is insufficiently understood. In this study, we performed a systematic analysis of the intrinsic organization of complex glioma transcriptome to gain deeper knowledge of the tumor biology. Gene coexpression relationships were explored in 790 glioma samples from 5 published patient cohorts treated at different institutions. We identified 20 coexpression modules that were common to all the data sets and associated with proliferation, angiogenesis, hypoxia, immune response, genomic alterations, cell differentiation phenotypes, and other features inherent to glial tumors. A collection of high-quality signatures for the respective processes was obtained using cross-data set summarization of the modules' gene composition. Individual modules were found to be organized into higher order coexpression groups, the two largest of them associated with glioblastoma and oligodendroglioma, respectively. We identified a novel prognostic gene expression signature (185 genes) linked to a proastrocytic pattern of tumor cell differentiation. This “proastrocytic” signature was associated with long survival and defined a subgroup of the previously established “proneural” class of gliomas. A strong negative correlation between proastrocytic and proneural markers across differentiated tumors underscored the distinction between these subtypes of glioma. Interestingly, one further novel signature in glioma was identified that was associated with EGFR (epidermal growth factor receptor) gene amplification and suggested that EGF signaling in glioma may be a subject to regulation by Sprouty family proteins. In summary, this integrated analysis of the glioma transcriptome provided several novel insights into molecular heterogeneity and pathogenesis of glial tumors. Cancer Res; 70(24); 10060–70. ©2010 AACR.
Coexpression of Oct4 and Nanog Enhances Malignancy in Lung Adenocarcinoma by Inducing Cancer Stem Cell–Like Properties and Epithelial–Mesenchymal Transdifferentiation
Authors: Chiou Shih-Hwa , Wang Mong-Lien , Chou Yu-Ting , Chen Chi-Jen , Hong Chun-Fu , Hsieh Wang-Ju , Chang Hsin-Tzu , Chen Ying-Shan , Lin Tzu-Wei , Hsu Han-Sui , Wu Cheng-Wen 
Published: December 2010

Abstract
Epithelial–mesenchymal transition (EMT), a critical process of cancer invasion and metastasis, is associated with stemness property of cancer cells. Though Oct4 and Nanog are homebox transcription factors essential to the self-renewal of stem cells and are expressed in several cancers, the role of Oct4/Nanog signaling in tumorigenesis is still elusive. Here microarray and quantitative real-time PCR analysis showed a parallel, elevated expression of Oct4 and Nanog in lung adenocarcinoma (LAC). Ectopic expressions of Oct4 and Nanog in LACs increased the percentage of CD133-expressing subpopulation and sphere formation, enhanced drug resistance, and promoted EMT. Ectopic expressions of Oct4 and Nanog activated Slug and enhanced the tumor-initiating capability of LAC. Furthermore, double knockdown of Oct4 and Nanog suppressed the expression of Slug, reversed the EMT process, blocked the tumorigenic and metastatic ability, and greatly improved the mean survival time of transplanted immunocompromised mice. The immunohistochemical analysis demonstrated that expressions of Oct4, Nanog, and Slug were present in high-grade LAC, and triple positivity of Oct4/Nanog/Slug indicated a worse prognostic value of LAC patients. Our results support the notion that the Oct4/Nanog signaling controls epithelial–mesenchymal transdifferentiation, regulates tumor-initiating ability, and promotes metastasis of LAC. Cancer Res; 70(24); 10433–44. ©2010 AACR.
Identification of PP2A Complexes and Pathways Involved in Cell Transformation
Authors: Sablina Anna A. , Hector Melissa , Colpaert Nathalie , Hahn William C. 
Published: December 2010

Abstract
The simian virus 40 small t (SV40ST) oncoprotein interacts with protein phosphatase 2A (PP2A), an abundantly expressed family of serine–threonine phosphatases. This interaction is essential for the transformation of human cells by SV40, and several PP2A subunits have been implicated as tumor suppressor genes. However, the pathways controlled by specific PP2A complexes involved in cell transformation remain incompletely understood. Using a comprehensive loss-of-function approach, we identified 4 PP2A regulatory subunits [B56α, B56γ, PR72/PR130, and PTPA (protein phosphatase 2A activator)], which when suppressed replaced the expression of SV40ST in human cell transformation. We found that manipulation of complexes containing PP2A B56α, B56γ, and PR72/PR130 activates the pathways regulated by c-Myc, Wnt, and PI3K (phosphoinositide 3-kinase)/Akt in a manner that depends on their specific phosphatase activity. In contrast, suppression of PTPA disrupts the assembly of PP2A heterotrimeric complexes, which leads to the activation of these same oncogenic pathways. These observations delineate the PP2A family members and pathways perturbed by SV40ST during human cell transformation. Cancer Res; 70(24); 10474–84. ©2010 AACR.
Twenty-Second Annual Pezcoller Symposium: RNA Biology and Cancer
Authors: Bernards René , Filipowicz Witold , Livingston David M. , Mihich Enrico 
Published: December 2010

Abstract
The 22nd annual Pezcoller Symposium titled “RNA Biology and Cancer” was held in Trento, Italy, on June 10–12, 2010. The program of the symposium was developed by Drs. Rene Bernards, Witold Filipowicz, and David Livingston; they cochaired the meeting in cooperation with Dr. Enrico Mihich. The topics discussed included the opportunities offered by small RNA as tools for cancer drug development, the role of noncoding RNAs, the biochemistry of small RNAs, the function of micro RNA in cancer, and RNAs as diagnostics and therapeutics in cancer. Cancer Res; 70(24); 10034–7. ©2010 AACR.
Histone H3 Lysine 79 Methyltransferase Dot1 Is Required for Immortalization by MLL Oncogenes
Authors: Chang Ming-Jin , Wu Hongyu , Achille Nicholas J. , Reisenauer Mary Rose , Chou Chau-Wen , Zeleznik-Le Nancy J. , Hemenway Charles S. , Zhang Wenzheng 
Published: December 2010

Abstract
Chimeric oncoproteins resulting from fusion of MLL to a wide variety of partnering proteins cause biologically distinctive and clinically aggressive acute leukemias. However, the mechanism of MLL-mediated leukemic transformation is not fully understood. Dot1, the only known histone H3 lysine 79 (H3K79) methyltransferase, has been shown to interact with multiple MLL fusion partners including AF9, ENL, AF10, and AF17. In this study, we utilize a conditional Dot1l deletion model to investigate the role of Dot1 in hematopoietic progenitor cell immortalization by MLL fusion proteins. Western blot and mass spectrometry show that Dot1-deficient cells are depleted of the global H3K79 methylation mark. We find that loss of Dot1 activity attenuates cell viability and colony formation potential of cells immortalized by MLL oncoproteins but not by the leukemic oncoprotein E2a-Pbx1. Although this effect is most pronounced for MLL-AF9, we find that Dot1 contributes to the viability of cells immortalized by other MLL oncoproteins that are not known to directly recruit Dot1. Cells immortalized by MLL fusions also show increased apoptosis, suggesting the involvement of Dot1 in survival pathways. In summary, our data point to a pivotal requirement for Dot1 in MLL fusion protein–mediated leukemogenesis and implicate Dot1 as a potential therapeutic target. Cancer Res; 70(24); 10234–42. ©2010 AACR.
Peroxisome Proliferator-Activated Receptor-γ Activation Inhibits Tumor Metastasis by Antagonizing Smad3-Mediated Epithelial-Mesenchymal Transition
Authors: Reka Ajaya Kumar , Kurapati Himabindu , Narala Venkata R. , Bommer Guido , Chen Jun , Standiford Theodore J. , Keshamouni Venkateshwar G. 
Published: December 2010

Abstract
Epithelial-mesenchymal transition (EMT) was shown to confer tumor cells with abilities essential for metastasis, including migratory phenotype, invasiveness, resistance to apoptosis, evading immune surveillance, and tumor stem cell traits. Therefore, inhibition of EMT can be an important therapeutic strategy to inhibit tumor metastasis. Here, we show that activation of peroxisome proliferator-activated receptor γ (PPAR-γ) inhibits transforming growth factor β (TGF-β)-induced EMT in lung cancer cells and prevents metastasis by antagonizing Smad3 function. Activation of PPAR-γ by synthetic ligands (troglitazone and rosiglitazone) or by a constitutively active form of PPAR-γ prevents TGF-β–induced loss of E-cadherin expression and inhibits the induction of mesenchymal markers (vimentin, N-cadherin, fibronectin) and matrix metalloproteases. Consistently, activation of PPAR-γ also inhibited EMT-induced migration and invasion of lung cancer cells. Furthermore, effects of PPAR-γ ligands were attenuated by siRNA-mediated knockdown of PPAR-γ, indicating that the ligand-induced responses are PPAR-γ dependent. Selective knockdown of Smad2 and Smad3 by siRNA showed that TGF-β–induced EMT is Smad3 dependent in lung cancer cells. Activation of PPAR-γ inhibits TGF-β–induced Smad transcriptional activity but had no effect on the phosphorylation or nuclear translocation of Smads. Consistently, PPAR-γ activation prevented TGF-β–induced transcriptional repression of E-cadherin promoter and inhibited transcriptional activation of N-cadherin promoter. Finally, treatment of mice with troglitazone or knockdown of Smad3 in tumor cells significantly inhibited TGF-β–induced experimental metastasis in SCID-Beige mice. Together, with the low toxicity profile of PPAR-γ ligands, our data show that these ligands may serve as potential therapeutic agents to inhibit metastasis. Mol Cancer Ther; 9(12); 3221–32. ©2010 AACR.
The Transmembrane Adaptor Cbp/PAG1 Controls the Malignant Potential of Human Non–Small Cell Lung Cancers That Have c-Src Upregulation
Authors: Kanou Takashi , Oneyama Chitose , Kawahara Kunimitsu , Okimura Akira , Ohta Mitsunori , Ikeda Naoki , Shintani Yasushi , Okumura Meinoshin , Okada Masato 
Published: December 2010

Abstract
The tyrosine kinase c-Src is upregulated in various human cancers, although the precise regulatory mechanism underlying this upregulation is unclear. We previously reported that a transmembrane adaptor Csk-binding protein (Cbp; PAG1) plays an important role in controlling the cell transformation that is induced by the activation of c-Src. To elucidate the in vivo role of Cbp, we examined the function of Cbp in lung cancer cell lines and tissues. In this study, we found that Cbp was markedly downregulated in human non–small cell lung cancer (NSCLC) cells. The ectopic expression of Cbp suppressed the anchorage-independent growth of the NSCLC cell lines (A549 and Lu99) that had upregulated c-Src, whereas the Cbp expression had little effect on other NSCLC cell lines (PC9 and Lu65) that express normal levels of c-Src. The expression of Cbp suppressed the kinase activity of c-Src in A549 cells by recruiting c-Src and its negative regulator, C-terminal Src kinase (Csk), to lipid rafts. The treatment with Src inhibitors, such as PP2, dasatinib, and saracatinib, also suppressed the growth of A549 cells. Furthermore, Cbp expression attenuated the ability of A549 cells to form tumors in nude mice, invade in vitro, and metastasize in vivo. In addition, we found a significant inverse correlation between the level of Cbp expression and the extent of lymph node metastasis in human lung cancers. These results indicate that Cbp is required for the Csk-mediated inactivation of c-Src and may control the promotion of malignancy in NSCLC tumors that are characterized by c-Src upregulation. Mol Cancer Res; 9(1); 103–14 ©2010 AACR.