bluuebunny/crossref_metadata_2025_split huggingface dataset:
Long-term patterns in the decay, collapse, and abundance of trees with hollows in the mountain ash (Eucalyptus regnans) forests of Victoria, southeastern Australia
Authors: Lindenmayer David B. , Wood Jeff T. 
Published: January 2010

Large trees with hollows are an important component of stand structural complexity worldwide. Understanding their population dynamics is needed to manage cavity-dependent biota. We quantified long-term rates of collapse of 302 measured trees with hollows in 1939-aged regrowth mountain ash ( Eucalyptus regnans F. Muell.) forest in southeastern Australia. We identified time-dependent dynamics in which the collapse rates of trees slowed from ∼4% annually between 1983 and 1993 to ∼2.2% between 1993 and 2007. Transitions of trees between different decay states (forms) also slowed over time. Nevertheless, during the 24-year period of our study, over half of our marked and measured trees had fallen, but there was no recruitment of new trees with hollows. Under current projections, few trees with hollows will occur on our field sites by ∼2050, although more had been forecast in earlier investigations. Such a paucity of trees with hollows in extensive areas of regrowth mountain ash forests will lead to a shortage of nesting and sheltering sites for cavity-dependent biota. We suggest a short–medium (10- to 100-year) focus on the conservation of old growth and multi-aged stands will be needed to maintain populations of those species strongly associated with trees with hollows in mountain ash forests.
Approximate Fixed Points for Nonexpansive and Quasi-Nonexpansive Mappings in Hyperspaces
Authors: Liu Zeqing , Ume Jeong Sheok , Kang Shin Min 
Published: January 2010

AbstractThis paper provides a few convergence results of the Ishikawa iteration sequence with errors for nonexpansive and quasi-nonexpansive mappings in hyperspaces. The results presented in this paper improve and generalize some results in the literature.
Silencing of RON Receptor Signaling Promotes Apoptosis and Gemcitabine Sensitivity in Pancreatic Cancers
Authors: Logan-Collins Jocelyn , Thomas Ryan M. , Yu Peter , Jaquish Dawn , Mose Evangeline , French Randall , Stuart William , McClaine Rebecca , Aronow Bruce , Hoffman Robert M. , Waltz Susan E. , Lowy Andrew M. 
Published: January 2010

AbstractThe RON receptor tyrosine kinase is overexpressed in premalignant pancreatic intraepithelial neoplasia (PanIN) and in the majority of pancreatic cancers. In pancreatic cells, RON is an important K-Ras effector and RON ligand can enhance migration/invasion and apoptotic resistance. However, the pathobiological significance of RON overexpression in pancreatic cancers has yet to be fully established. In this study, we demonstrate that RON signaling mediates a unique transcriptional program that is conserved between cultured cells derived from murine PanIN or human pancreatic cancer cells grown as subcutaneous tumor xenografts. In both systems, RON signaling regulates expression of genes implicated in cancer-cell survival, including Bcl-2 and the transcription factors signal transducer and activator of transcription 3 (STAT 3) and c-Jun. shRNA-mediated silencing of RON in pancreatic cancer xenografts inhibited their growth, primarily by increasing susceptibility to apoptosis and by sensitizing them to gemcitabine treatment. Escape from RON silencing was associated with re-expression of RON and/or expression of phosphorylated forms of the related c-Met or epidermal growth factor receptors. These findings indicate that RON signaling mediates cell survival and in vivo resistance to gemcitabine in pancreatic cancer, and they reveal mechanisms through which pancreatic cancer cells may circumvent RON-directed therapies. Cancer Res; 70(3); 1130–40
ZNF238 Is Expressed in Postmitotic Brain Cells and Inhibits Brain Tumor Growth
Authors: Tatard Valérie M. , Xiang Chaomei , Biegel Jaclyn A. , Dahmane Nadia 
Published: January 2010

Abstract
Brain tumors such as medulloblastoma (MB) and glioblastoma multiforme (GBM) can derive from neural precursors. For instance, many MBs are thought to arise from the uncontrolled proliferation of cerebellar granule neuron precursors (GNP). GNPs normally proliferate in early postnatal stages in mice but then they become postmitotic and differentiate into granule neurons. The proliferation of neural precursors, GNPs, as well as at least subsets of GBM and MB depends on Hedgehog signaling. However, the gene functions that are lost or suppressed in brain tumors and that normally promote the proliferation arrest and differentiation of precursors remain unclear. Here we have identified a member of the BTB-POZ and zinc finger family, ZNF238, as a factor highly expressed in postmitotic GNPs and differentiated neurons. In contrast, proliferating GNPs as well as MB and GBM express low or no ZNF238. Functionally, inhibition of ZNF238 expression in mouse GNPs decreases the expression of the neuronal differentiation markers MAP2 and NeuN and downregulates the expression of the cell cycle arrest protein p27, a regulator of GNP differentiation. Conversely, reinstating ZNF238 expression in MB and GBM cells drastically decreases their proliferation and promotes cell death. It also downregulates cyclin D1 while increasing MAP2 and p27 protein levels. Importantly, ZNF238 antagonizes MB and GBM tumor growth in vivo in xenografts. We propose that the antiproliferative functions of ZNF238 in normal GNPs and possibly other neural precursors counteract brain tumor formation. ZNF238 is thus a novel brain tumor suppressor and its reactivation in tumors could open a novel anticancer strategy. Cancer Res; 70(3); 1236–46
Efficacious Immune Therapy in Chronic Myelogenous Leukemia (CML) Recognizes Antigens That Are Expressed on CML Progenitor Cells
Authors: Biernacki Melinda A. , Marina Ovidiu , Zhang Wandi , Liu Fenglong , Bruns Ingmar , Cai Ann , Neuberg Donna , Canning Christine M. , Alyea Edwin P. , Soiffer Robert J. , Brusic Vladimir , Ritz Jerome , Wu Catherine J. 
Published: January 2010

AbstractCurative effects of graft-versus-leukemia–based therapies such as donor lymphocyte infusion (DLI) for chronic myelogenous leukemia (CML) may result from immunologic ablation of self-renewing CML progenitor cells. Patients who achieved durable remissions after DLI developed a significant B-cell lymphocytosis after treatment, which did not occur in patients who were unresponsive to DLI. In this study, we identified antigen targets of this B-cell response by probing two immunoproteomic platforms with plasma immunoglobulins from seven CML patients with clinically apparent graft-versus-leukemia responses after DLI. In total, 62 antigens elicited greater reactivity from post-DLI versus pre-DLI plasma. Microarray analysis revealed that &gt;70% of the antigens were expressed in CML CD34+ cells, suggesting that expression in malignant progenitor cells is a feature common to antibody targets of DLI. We confirmed elevated expression of three target antigens (RAB38, TBCE, and DUSP12) in CML that together consistently elicited antibody responses in 18 of 21 of an additional cohort of CML patients with therapeutic responses, but not in normal donors and rarely in non-CML patients. In summary, immunologic targets of curative DLI responses include multiple antigens on CML progenitor cells, identifying them as potential immunogens for vaccination and/or monitoring of immunotherapeutics designed to eliminate myeloid leukemia stem cells. Cancer Res; 70(3); 906–15
Phase I Trial of Intraperitoneal Administration of an Oncolytic Measles Virus Strain Engineered to Express Carcinoembryonic Antigen for Recurrent Ovarian Cancer
Authors: Galanis Evanthia , Hartmann Lynn C. , Cliby William A. , Long Harry J. , Peethambaram Prema P. , Barrette Brigitte A. , Kaur Judith S. , Haluska Paul J. , Aderca Ileana , Zollman Paula J. , Sloan Jeff A. , Keeney Gary , Atherton Pamela J. , Podratz Karl C. , Dowdy Sean C. , Stanhope C. Robert , Wilson Timothy O. , Federspiel Mark J. , Peng Kah-Whye , Russell Stephen J. 
Published: January 2010

AbstractEdmonston vaccine strains of measles virus (MV) have shown significant antitumor activity in preclinical models of ovarian cancer. We engineered MV to express the marker peptide carcinoembryonic antigen (MV-CEA virus) to also permit real-time monitoring of viral gene expression in tumors in the clinical setting. Patients with Taxol and platinum-refractory recurrent ovarian cancer and normal CEA levels were eligible for this phase I trial. Twenty-one patients were treated with MV-CEA i.p. every 4 weeks for up to 6 cycles at seven different dose levels (103–109 TCID50). We observed no dose-limiting toxicity, treatment-induced immunosuppression, development of anti-CEA antibodies, increase in anti-MV antibody titers, or virus shedding in urine or saliva. Dose-dependent CEA elevation in peritoneal fluid and serum was observed. Immunohistochemical analysis of patient tumor specimens revealed overexpression of measles receptor CD46 in 13 of 15 patients. Best objective response was dose-dependent disease stabilization in 14 of 21 patients with a median duration of 92.5 days (range, 54–277 days). Five patients had significant decreases in CA-125 levels. Median survival of patients on study was 12.15 months (range, 1.3–38.4 months), comparing favorably to an expected median survival of 6 months in this patient population. Our findings indicate that i.p. administration of MV-CEA is well tolerated and results in dose-dependent biological activity in a cohort of heavily pretreated recurrent ovarian cancer patients. Cancer Res; 70(3); 875–82
BRCA1 Represses Amphiregulin Gene Expression
Authors: Lamber Ekaterina P. , Horwitz Andrew A. , Parvin Jeffrey D. 
Published: January 2010

Abstract
BRCA1, the breast cancer- and ovarian cancer-specific tumor suppressor, can be a transcriptional repressor or a transcriptional activator, depending on the promoter context. To identify the genes activated or repressed by BRCA1, we have analyzed microarray results from cells depleted of BRCA1 and revealed a number of genes regulated by BRCA1 on the level of transcription. Among the genes repressed by BRCA1, we have identified amphiregulin (AREG) and early growth response-1 (EGR1). Results indicate that BRCA1 regulates AREG transcription directly through binding to the AREG promoter, however, we could not detect BRCA1 on the EGR1 promoter, suggesting that EGR1 is indirectly regulated by BRCA1. In an attempt to identify the mechanism of the AREG transcriptional repression by BRCA1, we have mapped two independent BRCA1 response elements on the AREG located at positions −202/−182 and +19/+122. BRCA1 depletion leads to induction of the AREG protein. Taken together, our data build the connection between BRCA1 loss of function and AREG upregulation—a change in gene expression often observed in breast cancer. Cancer Res; 70(3); 996–1005
Chemogenomic Profiling Provides Insights into the Limited Activity of Irreversible EGFR Inhibitors in Tumor Cells Expressing the T790M EGFR Resistance Mutation
Authors: Sos Martin L. , Rode Haridas B. , Heynck Stefanie , Peifer Martin , Fischer Florian , Klüter Sabine , Pawar Vijaykumar G. , Reuter Cecile , Heuckmann Johannes M. , Weiss Jonathan , Ruddigkeit Lars , Rabiller Matthias , Koker Mirjam , Simard Jeffrey R. , Getlik Matthäus , Yuza Yuki , Chen Tzu-Hsiu , Greulich Heidi , Thomas Roman K. , Rauh Daniel 
Published: January 2010

Abstract
Reversible epidermal growth factor receptor (EGFR) inhibitors are the first class of small molecules to improve progression-free survival of patients with EGFR-mutated lung cancers. Second-generation EGFR inhibitors introduced to overcome acquired resistance by the T790M resistance mutation of EGFR have thus far shown limited clinical activity in patients with T790M-mutant tumors. In this study, we systematically analyzed the determinants of the activity and selectivity of the second-generation EGFR inhibitors. A focused library of irreversible as well as structurally corresponding reversible EGFR-inhibitors was synthesized for chemogenomic profiling involving over 79 genetically defined NSCLC and 19 EGFR-dependent cell lines. Overall, our results show that the growth-inhibitory potency of all irreversible inhibitors against the EGFRT790M resistance mutation was limited by reduced target inhibition, linked to decreased binding velocity to the mutant kinase. Combined treatment of T790M-mutant tumor cells with BIBW-2992 and the phosphoinositide-3-kinase/mammalian target of rapamycin inhibitor PI-103 led to synergistic induction of apoptosis. Our findings offer a mechanistic explanation for the limited efficacy of irreversible EGFR inhibitors in EGFRT790M gatekeeper-mutant tumors, and they prompt combination treatment strategies involving inhibitors that target signaling downstream of the EGFR. Cancer Res; 70(3); 868–74
Resveratrol Promotes Autophagic Cell Death in Chronic Myelogenous Leukemia Cells via JNK-Mediated p62/SQSTM1 Expression and AMPK Activation
Authors: Puissant Alexandre , Robert Guillaume , Fenouille Nina , Luciano Frederic , Cassuto Jill-Patrice , Raynaud Sophie , Auberger Patrick 
Published: January 2010

Abstract
Autophagy that is induced by starvation or cellular stress can enable cancer cell survival by sustaining energy homeostasis and eliminating damaged organelles and proteins. In response to stress, cancer cells have been reported to accumulate the protein p62/SQSTM1 (p62), but its role in the regulation of autophagy is controversial. Here, we report that the plant phytoalexin resveratrol (RSV) triggers autophagy in imatinib-sensitive and imatinib-resistant chronic myelogenous leukemia (CML) cells via JNK-dependent accumulation of p62. JNK inhibition or p62 knockdown prevented RSV-mediated autophagy and antileukemic effects. RSV also stimulated AMPK, thereby inhibiting the mTOR pathway. AMPK knockdown or mTOR overexpression impaired RSV-induced autophagy but not JNK activation. Lastly, p62 expression and autophagy in CD34+ progenitors from patients with CML was induced by RSV, and disrupting autophagy protected CD34+ CML cells from RSV-mediated cell death. We concluded that RSV triggered autophagic cell death in CML cells via both JNK-mediated p62 overexpression and AMPK activation. Our findings show that the JNK and AMPK pathways can cooperate to eliminate CML cells via autophagy. Cancer Res; 70(3); 1042–52
PSF1, a DNA Replication Factor Expressed Widely in Stem and Progenitor Cells, Drives Tumorigenic and Metastatic Properties
Authors: Nagahama Yumi , Ueno Masaya , Miyamoto Satoru , Morii Eiichi , Minami Takashi , Mochizuki Naoki , Saya Hideyuki , Takakura Nobuyuki 
Published: January 2010

AbstractPSF1 (partner of sld five 1) is an evolutionarily conserved DNA replication factor implicated in DNA replication in lower species that is strongly expressed in a wide range of normal stem cell populations and progenitor cell populations. Because stem and progenitor cells possess high proliferative capacity, we hypothesized that PSF1 may play an important role in tumor growth. To begin to investigate PSF1 function in cancer cells, we cloned the mouse PSF1 promoter and generated lung and colon carcinoma cells that stably express a PSF1 promoter-reporter gene. Reporter expression in cells correlated with endogenous PSF1 mRNA expression. In a tumor cell xenograft model, high levels of reporter expression correlated with high proliferative activity, serial transplantation potential, and metastatic capability. Notably, cancer cells expressing reporter levels localized to perivascular regions in tumors and displayed expression signatures related to embryonic stem cells. RNAi-mediated silencing of endogenous PSF1 inhibited cancer cell growth by disrupting DNA synthesis and chromosomal segregation. These findings implicate PSF1 in tumorigenesis and offer initial evidence of its potential as a theranostic target. Cancer Res; 70(3); 1215–24
PERK–Dependent Regulation of Ceramide Synthase 6 and Thioredoxin Play a Key Role inmda-7/IL-24–Induced Killing of Primary Human Glioblastoma Multiforme Cells
Authors: Yacoub Adly , Hamed Hossein A. , Allegood Jeremy , Mitchell Clint , Spiegel Sarah , Lesniak Maciej S. , Ogretmen Besim , Dash Rupesh , Sarkar Devanand , Broaddus William C. , Grant Steven , Curiel David T. , Fisher Paul B. , Dent Paul 
Published: January 2010

AbstractMelanoma differentiation associated gene-7(mda-7) encodes IL-24, a cytokine that can selectively trigger apoptosis in transformed cells. Recombinant mda-7 adenovirus (Ad.mda-7) effectively kills glioma cells, offering a novel gene therapy strategy to address deadly brain tumors. In this study, we defined the proximal mechanisms by which Ad-mda-7 kills glioma cells. Key factors implicated included activation of the endoplasmic reticulum stress kinase protein kinase R–like endoplasmic reticulum kinase (PERK), Ca++ elevation, ceramide generation and reactive oxygen species (ROS) production. PERK inhibition blocked ceramide or dihydroceramide generation, which were critical for Ca++ induction and subsequent ROS formation. Activation of autophagy and cell death relied upon ROS formation, the inhibition of which ablated Ad.mda-7–killing activity. In contrast, inhibiting TRX induced by Ad.MDA-7 enhanced tumor cytotoxicity and improved animal survival in an orthotopic tumor model. Our findings indicate that mda-7/IL-24 induces an endoplasmic reticulum stress response that triggers production of ceramide, Ca2+, and ROS, which in turn promote glioma cell autophagy and cell death. Cancer Res; 70(3); 1120–9
Radiosensitization of Epidermal Growth Factor Receptor/HER2–Positive Pancreatic Cancer Is Mediated by Inhibition of Akt Independent of Ras Mutational Status
Authors: Kimple Randall J. , Vaseva Angelina V. , Cox Adrienne D. , Baerman Kathryn M. , Calvo Benjamin F. , Tepper Joel E. , Shields Janiel M. , Sartor Carolyn I. 
Published: January 2010

Abstract
Purpose: Epidermal growth factor receptor (EGFR) family members (e.g., EGFR, HER2, HER3, and HER4) are commonly overexpressed in pancreatic cancer. We investigated the effects of inhibition of EGFR/HER2 signaling on pancreatic cancer to elucidate the role(s) of EGFR/HER2 in radiosensitization and to provide evidence in support of further clinical investigations.
Experimental Design: Expression of EGFR family members in pancreatic cancer lines was assessed by quantitative reverse transcription-PCR. Cell growth inhibition was determined by MTS assay. The effects of inhibition of EGFR family receptors and downstream signaling pathways on in vitro radiosensitivity were evaluated using clonogenic assays. Growth delay was used to evaluate the effects of nelfinavir on in vivo tumor radiosensitivity.
Results: Lapatinib inhibited cell growth in four pancreatic cancer cell lines, but radiosensitized only wild-type K-ras–expressing T3M4 cells. Akt activation was blocked in a wild-type K-ras cell line, whereas constitutive phosphorylation of Akt and extracellular signal-regulated kinase (ERK) was seen in lines expressing mutant K-ras. Overexpression of constitutively active K-ras (G12V) abrogated lapatinib-mediated inhibition of both Akt phosphorylation and radiosensitization. Inhibition of MAP/ERK kinase/ERK signaling with U0126 had no effect on radiosensitization, whereas inhibition of activated Akt with LY294002 (enhancement ratio, 1.2-1.8) or nelfinavir (enhancement ratio, 1.2-1.4) radiosensitized cells regardless of K-ras mutation status. Oral nelfinavir administration to mice bearing mutant K-ras–containing Capan-2 xenografts resulted in a greater than additive increase in radiation-mediated tumor growth delay (synergy assessment ratio of 1.5).
Conclusions: Inhibition of EGFR/HER2 enhances radiosensitivity in wild-type K-ras pancreatic cancer. Nelfinavir, and other phosphoinositide 3-kinase/Akt inhibitors, are effective pancreatic radiosensitizers regardless of K-ras mutation status. Clin Cancer Res; 16(3); 912–23
Suppression of Liver Tumor Growth and Metastasis by Adiponectin in Nude Mice through Inhibition of Tumor Angiogenesis and Downregulation of Rho Kinase/IFN-Inducible Protein 10/Matrix Metalloproteinase 9 Signaling
Authors: Man Kwan , Ng Kevin T.P. , Xu Aimin , Cheng Qiao , Lo Chung Mau , Xiao Jiang Wei , Sun Bai Shun , Lim Zophia X.H. , Cheung Jerry S. , Wu Ed X. , Sun Chris K.W. , Poon Ronnie T.P. , Fan Sheung Tat 
Published: January 2010

Abstract
Purpose: We aimed to investigate the effects of adiponectin on liver cancer growth and metastasis and explore the underlying mechanisms.
Experimental Design: An orthotopic liver tumor nude mice model with distant metastatic potential was applied. Either Ad-adiponectin (1 × 108; treatment group) or Ad-luciferase (control group) was injected via portal vein after tumor implantation. Tumor growth and metastasis were monitored by Xenogen In vivo Imaging System. Hepatic stellate cell activation by α-smooth muscle actin staining, microvessel density by CD34 staining, macrophage infiltration in tumor tissue, and cell signaling leading to invasion, migration [Rho kinase (ROCK), IFN-inducible protein 10 (IP10), and matrix metalloproteinase 9], and angiogenesis [vascular endothelial growth factor (VEGF) and angiopoietin 1] were also compared. Tumor-nontumor margin was examined under electron microscopy. Direct effects of adiponectin on liver cancer cells and endothelial cells were further investigated by a series of functional studies.
Results: Tumor growth was significantly inhibited by adiponectin treatment, accompanied by a lower incidence of lung metastasis. Hepatic stellate cell activation and macrophage infiltration in the liver tumors were suppressed by adiponectin treatment, along with decreased microvessel density. The treatment group had less Ki-67–positive tumor cells and downregulated protein expression of ROCK1, proline-rich tyrosine kinase 2, and VEGF. Tumor vascular endothelial cell damage was found in the treatment group under electron microscopy. In vitro functional study showed that adiponectin not only downregulated the ROCK/IP10/VEGF signaling pathway but also inhibited the formation of lamellipodia, which contribute to cell migration.
Conclusion: Adiponectin treatment significantly inhibited liver tumor growth and metastasis by suppression of tumor angiogenesis and downregulation of the ROCK/IP10/matrix metalloproteinase 9 pathway. Clin Cancer Res; 16(3); 967–77