bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Ubiquitous Conserved Glycopeptidase Gcp Prevents Accumulation of Toxic Glycated Proteins
Authors: Katz Chen , Cohen-Or Ifat , Gophna Uri , Ron Eliora Z. 
Published: August 2010

ABSTRACT

Amadori-modified proteins (AMPs) are the products of nonenzymatic glycation formed by reaction of reducing sugars with primary amine-containing amino acids and can develop into advanced glycated end products (AGEs), highly stable toxic compounds. AGEs are known to participate in many age-related human diseases, including cardiovascular, neurological, and liver diseases. The metabolism of these glycated proteins is not yet understood, and the mechanisms that reduce their accumulation are not known so far. Here, we show for
Escherichia coli
that a conserved glycopeptidase (Gcp, also called Kae1), which is encoded by nearly every sequenced genome in the three domains of life, prevents the accumulation of Amadori products and AGEs. Using mutants, we show that Gcp depletion results in accumulation of AMPs and eventually leads to the accumulation of AGEs. We demonstrate that Gcp binds to glycated proteins, including pyruvate dehydrogenase, previously shown to be a glycation-prone enzyme. Our experiments also show that the severe phenotype of Gcp depletion can be relieved under conditions of low intracellular glycation. As glycated proteins are ubiquitous, the involvement of Gcp in the metabolism of AMPs and AGEs is likely to have been conserved in evolution, suggesting a universal involvement of Gcp in cellular aging and explaining the essentiality of Gcp in many organisms.

IMPORTANCE
Glycated proteins (Amadori-modified proteins [AMPs] and advanced glycated end products [AGEs]) are known to participate in many age-related diseases. Their existence in fast-growing organisms was considered unlikely, as their formation was assumed to be slow. Yet, recent evidence demonstrated their existence in bacteria, and our data suggest a bacterial mechanism that reduced their accumulation. We identify in
Escherichia coli
a protein, Gcp, which carries out this function. Gcp is conserved in all domains of life and is essential in many organisms. Although it was annotated as a chaperon protease, there were no experimental data to support this function. Our findings are compatible with the annotation and will open up studies of the bacterial metabolism of glycated proteins. Furthermore, the data from the bacterial systems may also be instrumental in understanding the metabolism of glycated proteins, including their toxicity in human health and disease.
Giant short-faced bear (Arctodus simus) from late Wisconsinan deposits at Cowichan Head, Vancouver Island, British Columbia
Authors: Steffen Martina L. , Harington C. R. 
Published: August 2010

A giant short-faced bear ( Arctodus simus ) ulna fragment was found at the base of exposed Quaternary sediments at Cowichan Head, southern Vancouver Island, British Columbia. In this paper, the ulna fragment and its geological context are described and a reasonable taphonomic trajectory is presented. The radiocarbon age of 22 750 ± 140 BP on the bone indicates that these bears were on Vancouver Island during the late Wisconsinan. A likely source for the Cowichan Head A. simus was from the mainland to the southeast.
Catastrophic tidal expansion in the Bay of Fundy, CanadaEarth Sciences Sector (ESS) Contribution 20090423.
Authors: Shaw John , Amos Carl L. , Greenberg David A. , O’Reilly Charles T. , Parrott D. Russell , Patton Eric 
Published: August 2010

Tidal models for the Bay of Fundy, Canada — site of the highest recorded modern tide — show that tidal amplification began in the early Holocene and by ca. 5000 BP the range was almost 80% of the present range. Empirical data consisting of 146 sea-level index points and other observations appear to contradict model results. Aggregated relative sea-level data for Chignecto Bay and Minas Basin show that rapid tidal expansion began ca. 3400 BP. However, if we separate these two geographically separate data sets, evidence for this rapid late-Holocene tidal expansion is confined to Minas Basin. We explain this singularity by positing a barrier at the mouth of Minas Basin, at the Minas Passage, that delayed tidal expansion. With the rapid breakdown of this barrier and near-instantaneous tidal expansion, water temperature dropped, tidal currents and turbidity increased, and the form of the inner estuary was changed from lagoonal–mesotidal to macrotidal. We argue that the catastrophic breakdown of the barrier is related in the aboriginal legend of Glooscap, showing that aboriginal peoples observed the rapid environmental changes and preserved an oral record for 3400 years.
LOW COST FABRICATION OF SUB-WAVELENGTH STRUCTURES ON LARGE-AREA POLYMER SHEET BY UV CURING AND NANO-IMPRINTING PROCESSES
Authors: TSAI HUNG-YIN , TING CHIA-JEN 
Published: August 2010

Anti-reflection layers made from sub-wavelength structures or nanostructure arrays have been extensively studied due to the high demand of the solar cell markets and the use of consuming electronics such as plane displays, glasses, prisms, videos, and the monitors of the camera. Conventionally, this anti-reflection layer was fabricated by multilayer films deposition through sputtering, wet-coating or sol-gel. However, these methods have several disadvantages such as process instability, high cost and high temperature procedure. In the current study, fabrication methods of UV curing and nano-imprinting processes are proposed to produce large-area polymer sheets with sub-wavelength structures (SWS). Porous anodic alumina (PAA) mold of nano-holes was used to fabricate SWS on a PET sheet with UV photoresists of refractive index of 1.53 by roll-to-roll processing. The reflectance of SWS on PET decreases from 9.39 to 4.25% at the wavelength of 550 nm. The contact angle changes from 78.1° to 103.2°. The porous anodic alumina mold was also used to imprint a PMMA film and SWS were obtained by hot embossing at different temperatures. The reflectance changes from 4.25 to 2.16% at the wavelength of 550 nm after nano-imprinting. A successful low cost approach to produce large-area polymer sheets with SWS is obtained by both UV curing and nano-imprinting processes.
Human Papillomavirus Seropositivity Synergizes withMDM2Variants to Increase the Risk of Oral Squamous Cell Carcinoma
Authors: Chen Xingming , Sturgis Erich M. , Lei Dapeng , Dahlstrom Kristina , Wei Qingyi , Li Guojun 
Published: August 2010

AbstractThe increasing incidence of oral squamous cell carcinoma (OSCC) in young adults has been associated with sexually transmitted infections of human papillomavirus (HPV), particularly HPV16. Given the roles of p53 in tumor suppression and of HPV E6 and MDM2 oncoproteins in p53 degradation, we evaluated HPV16 L1 seropositivity and MDM2 promoter variants to examine their possible associations with OSCC risk in a case-control study of 325 patients and 335 cancer-free matched controls. Compared with individuals having MDM2-rs2279744 GT or GG genotypes and HPV16 L1 seronegativity, the TT genotype and HPV16 L1 seronegativity were found to be associated with an odds ratio (OR) of 1.25 [95% confidence interval (CI), 1.06–2.19] for OSCC risk, and GT/GG and HPV16 L1 seropositivity were associated with an OR of 2.81 (95% CI, 1.67–4.74). For those with both the TT genotype and HPV16 L1 seropositivity, the associated OR was 5.57 (95% CI, 2.93–10.6). Similar results were observed for the MDM2-rs937283 polymorphism. Moreover, there was a borderline significant or significant interaction between the individual or combined MDM2 genotypes of the two polymorphisms and HPV16 L1 seropositivity (Pint = 0.060 for MDM2-rs2279744, Pint = 0.009 for MDM2-rs937283, and Pint = 0.005 for the combined MDM2 genotypes) on risk of OSCC. Notably, that effect modification was particularly pronounced in never smokers and never drinkers, and for oropharyngeal as opposed to oral cavity cancer. Taken together, our results indicate that the risk of OSCC associated with HPV16 L1 seropositivity is modified by MDM2 promoter polymorphisms. Cancer Res; 70(18); 7199–208. ©2010 AACR.
Chemotrap-1: An Engineered Soluble Receptor That Blocks Chemokine-Induced Migration of Metastatic Cancer CellsIn vivo
Authors: Lanati Silvia , Dunn Darryl B. , Roussigné Myriam , Emmett Maxine S. , Carriere Virginie , Jullien Denis , Budge Jessica , Fryer Justin , Erard Monique , Cailler Françoise , Girard Jean-Phillippe , Bates David O. 
Published: August 2010

AbstractCancer and dendritic cells recognize and migrate toward chemokines secreted from lymphatics and use this mechanism to invade the lymphatic system, and cancer cells metastasize through it. The lymphatic-secreted chemokine ligand CCL21 has been identified as a key regulatory molecule in the switch to a metastatic phenotype in melanoma and breast cancer cells. However, it is not known whether CCL21 inhibition is a potential therapeutic strategy for inhibition of metastasis. Here, we describe an engineered CCL21-soluble inhibitor, Chemotrap-1, which inhibits migration of metastatic melanoma cells in vivo. Two-hybrid, pull-down, and coimmunoprecipitation assays allowed us to identify a naturally occurring human zinc finger protein with CCL21 chemokine-binding properties. Further analyses revealed a short peptide (∼70 amino acids), with a predicted coiled-coil structure, which is sufficient for association with CCL21. This CCL21 chemokine-binding peptide was then fused to the Fc region of human IgG1 to generate Chemotrap-1, a human chemokine-binding Fc fusion protein. Surface plasmon resonance and chemotaxis assays showed that Chemotrap-1 binds CCL21 and inhibits CCL21-induced migration of melanoma cells in vitro with subnanomolar affinity. In addition, Chemotrap-1 blocked migration of melanoma cells toward lymphatic endothelial cells in vitro and in vivo. Finally, Chemotrap-1 strongly reduced lymphatic invasion, tracking, and metastasis of CCR7-expressing melanoma cells in vivo. Together, these results show that CCL21 chemokine inhibition by Chemotrap-1 is a potential therapeutic strategy for metastasis and provide further support for the hypothesis that lymphatic-mediated metastasis is a chemokine-dependent process. Cancer Res; 70(20); 8138–48. ©2010 AACR.
Cyclin D2–Cyclin-Dependent Kinase 4/6 Is Required for Efficient Proliferation and Tumorigenesis following Apc Loss
Authors: Cole Alicia M. , Myant Kevin , Reed Karen R. , Ridgway Rachel A. , Athineos Dimitris , Van den Brink Gijs R. , Muncan Vanesa , Clevers Hans , Clarke Alan R. , Sicinski Peter , Sansom Owen J. 
Published: August 2010

AbstractInactivation of the Apc gene is recognized as the key early event in the development of sporadic colorectal cancer (CRC), where its loss leads to constitutive activation of β-catenin/T-cell factor 4 signaling and hence transcription of Wnt target genes such as c-Myc. Our and other previous studies have shown that although cyclin D1 is required for adenoma formation, it is not immediately upregulated following Apc loss within the intestine, suggesting that proliferation following acute Apc loss may be dependent on another D-type cyclin. In this study, we investigated the expression and functional relevance of cyclin D2 following Apc loss in the intestinal epithelium. Cyclin D2 is upregulated immediately following Apc loss, which corresponded with a significant increase in cyclin-dependent kinase 4 (CDK4) and hyperphosphorylated Rb levels. Deficiency of cyclin D2 resulted in a reduction in enterocyte proliferation and crypt size within Apc-deficient intestinal epithelium. Moreover, cyclin D2 dramatically reduced tumor growth and development in ApcMin/+ mice. Importantly, cyclin D2 knockout did not affect proliferation of normal enterocytes, and furthermore, CDK4/6 inhibition also suppressed the proliferation of adenomatous cells and not normal cells from ApcMin/+ mice. Taken together, these results indicate that cyclin D–CDK4/6 complexes are required for the efficient proliferation of cells with deregulated Wnt signaling, and inhibiting this complex may be an effective chemopreventative strategy in CRC. Cancer Res; 70(20); 8149–58. ©2010 AACR.
Deficiency of Splicing Factor 1 Suppresses the Occurrence of Testicular Germ Cell Tumors
Authors: Zhu Rui , Heaney Jason , Nadeau Joseph H. , Ali Sara , Matin Angabin 
Published: August 2010

Abstract
Testicular germ cell tumors (TGCT) originate from germ cells. The 129-Ter and M19 (129.MOLF-Chr19 consomic) mouse strains have extremely high incidences of TGCTs. We found that the expression levels of Sf1-encoded splicing factor 1 (SF1) can modulate the incidence of TGCTs. We generated mice with inactivated Sf1. Sf1 null mice (Sf1−/−) died before birth. Mice with one intact allele of Sf1 (Sf1+/−) were viable but expressed reduced levels of Sf1. When Sf1-deficient mice (Sf1+/−) were crossed to the 129-Ter and M19 strains, we observed decreased incidence of TGCTs in Sf1+/−;Ter and Sf1+/−;M19/+ mice compared with that in control cohorts. Therefore, Sf1 deficiency protects against TGCT development in both strains. Sf1 is expressed in the testes. We found that Sf1 levels vary significantly in the testes of inbred strains such as 129 and MOLF, and as such Sf1 is an oncogenic tumor-susceptibility factor from 129. Our results also highlight the complications involved in evaluating Sf1 levels and TGCT incidences. When a large number of tumor-promoting factors are present in a strain, the protective effect of lower Sf1 levels is masked. However, when the dosage of tumor-promoting factors is reduced, the protective effect of lower Sf1 levels becomes apparent. SF1 is involved in splicing of specific pre-mRNAs in cells. Alternate splicing generates the complex proteosome in eukaryotic cells. Our data indicate that Sf1 levels in mouse strains correlate with their incidences of TGCTs and implicate the importance of splicing mechanisms in germ cell tumorigenesis. Cancer Res; 70(18); 7264–72. ©2010 AACR.
Loss of PTEN Binding Adapter Protein NHERF1 from Plasma Membrane in Glioblastoma Contributes to PTEN Inactivation
Authors: Molina Jennifer R. , Morales Fabiana C. , Hayashi Yuho , Aldape Kenneth D. , Georgescu Maria-Magdalena 
Published: August 2010

Abstract
Glioblastoma multiforme (GBM) is a severe brain malignancy with limited treatment and dismal prognosis. The tumor suppressor PTEN, a major inhibitor of the phosphatidylinositol-3-OH kinase (PI3K)/Akt pathway, is frequently deleted in GBM tumors. PTEN antagonizes PI3K by dephosphorylating PI3K phosphoinositide substrates at the plasma membrane. The PTEN binding adapter protein NHERF1/EBP50 is overexpressed in GBM but its effects on tumorigenesis have yet to be determined. Here, we show that NHERF1 is localized to the plasma membrane in normal astrocytes and to the cytoplasm of GBM tumor cells. This cytoplasmic shift paralleled an altered membrane distribution of wild-type PTEN with consecutive Akt activation. Membrane re-targeting of NHERF1 in GBM cells recruited PTEN to the membrane and suppressed Akt activation and cell proliferation. Conversely, NHERF1 depletion in GBM cells with membrane-localized NHERF1 increased cell proliferation and Akt activation. Our findings define a tumor suppressor role for NHERF1 at the plasma membrane, and reveal a novel mechanism for PI3K/Akt activation through PTEN inactivation caused by a loss of membrane-localized NHERF1. Cancer Res; 70(17); 6697–703. ©2010 AACR.
Functional Roles of Multiple Feedback Loops in Extracellular Signal-Regulated Kinase and Wnt Signaling Pathways That Regulate Epithelial-Mesenchymal Transition
Authors: Shin Sung-Young , Rath Oliver , Zebisch Armin , Choo Sang-Mok , Kolch Walter , Cho Kwang-Hyun 
Published: August 2010

Abstract
Epithelial-mesenchymal transition (EMT) is a key event in the generation of invasive tumor cells. A hallmark of EMT is the repression of E-cadherin expression, which is regulated by various signal transduction pathways including extracellular signal-regulated kinase (ERK) and Wnt. These pathways are highly interconnected via multiple coupled feedback loops (CFL). As the function of such coupled feedback regulations is difficult to analyze experimentally, we used a systems biology approach where computational models were designed to predict biological effects that result from the complex interplay of CFLs. Using epidermal growth factor (EGF) and Wnt as input and E-cadherin transcriptional regulation as output, we established an ordinary differential equation model of the ERK and Wnt signaling network containing six feedback links and used extensive computer simulations to analyze the effects of these feedback links in isolation and different combinations. The results show that the feedbacks can generate a rich dynamic behavior leading to various dose-response patterns and have a decisive role in determining network responses to EGF and Wnt. In particular, we made two important findings: first, that coupled positive feedback loops composed of phosphorylation of Raf kinase inhibitor RKIP by ERK and transcriptional repression of RKIP by Snail have an essential role in causing a switch-like behavior of E-cadherin expression; and second, that RKIP expression inhibits EMT progression by preventing E-cadherin suppression. Taken together, our findings provide us with a system-level understanding of how RKIP can regulate EMT progression and may explain why RKIP is downregulated in so many metastatic cancer cells. Cancer Res; 70(17); 6715–24. ©2010 AACR.
γ-Secretase Inhibitors Enhance Temozolomide Treatment of Human Gliomas by Inhibiting Neurosphere Repopulation and Xenograft Recurrence
Authors: Gilbert Candace A. , Daou Marie-Claire , Moser Richard P. , Ross Alonzo H. 
Published: August 2010

Abstract
Malignant gliomas are treated with a combination of surgery, radiation, and temozolomide (TMZ), but these therapies ultimately fail due to tumor recurrence. In glioma cultures, TMZ treatment significantly decreases neurosphere formation; however, a small percentage of cells survive and repopulate the culture. A promising target for glioma therapy is the Notch signaling pathway. Notch activity is upregulated in many gliomas and can be suppressed using γ-secretase inhibitors (GSI). Using a neurosphere recovery assay and xenograft experiments, we analyzed if the addition of GSIs with TMZ treatment could inhibit repopulation and tumor recurrence. We show that TMZ + GSI treatment decreased neurosphere formation and inhibited neurosphere recovery. This enhancement of TMZ treatment occurred through inhibition of the Notch pathway and depended on the sequence of drug administration. In addition, ex vivo TMZ + GSI treatment of glioma xenografts in immunocompromised mice extended tumor latency and survival, and in vivo TMZ + GSI treatment blocked tumor progression in 50% of mice with preexisting tumors. These data show the importance of the Notch pathway in chemoprotection and repopulation of TMZ-treated gliomas. The addition of GSIs to current treatments is a promising approach to decrease brain tumor recurrence. Cancer Res; 70(17); 6870–9. ©2010 AACR.
Spontaneous Tumorigenesis in Mice Overexpressing the p53-Negative Regulator Mdm4
Authors: Xiong Shunbin , Pant Vinod , Suh Young-Ah , Van Pelt Carolyn S. , Wang Yongxing , Valentin-Vega Yasmine A. , Post Sean M. , Lozano Guillermina 
Published: August 2010

Abstract
High levels of the critical p53 inhibitor Mdm4 is common in tumors that retain a wild-type p53 allele, suggesting that Mdm4 overexpression is an important mechanism for p53 inactivation during tumorigenesis. To test this hypothesis in vivo, we generated transgenic mice with widespread expression of Mdm4. Two independent lines of transgenic mice, Mdm4Tg1 and Mdm4Tg15, developed spontaneous tumors, the most prevalent of which were sarcomas. To determine whether overexpression of Mdm4 also cooperated with p53 heterozygosity to induce tumorigenesis, we generated Mdm4Tg1 p53+/− mice. These mice had significantly accelerated tumorigenesis and a distinct tumor spectrum with more carcinomas and significantly fewer lymphomas than p53+/− or Mdm4Tg1 mice. Importantly, the remaining wild-type p53 allele was retained in most Mdm4Tg1 p53+/− tumors. Mdm4 is thus a bona fide oncogene in vivo and cooperates with p53 heterozygosity to drive tumorigenesis. These Mdm4 mice will be invaluable for in vivo drug studies of Mdm4 inhibitors. Cancer Res; 70(18); 7148–54. ©2010 AACR.
Ratio of miR-196s to HOXC8 Messenger RNA Correlates with Breast Cancer Cell Migration and Metastasis
Authors: Li Yong , Zhang Maoxiang , Chen Huijun , Dong Zheng , Ganapathy Vadivel , Thangaraju Muthusamy , Huang Shuang 
Published: August 2010

Abstract
Expression profiling has identified metastasis-associated microRNAs (miRNA) but technical limitations hinder the discovery of metastasis-suppressing miRNAs. In this study, we sought metastasis-suppressing miRNAs by functional screening. Individual miRNAs were lentivirally introduced into metastatic MDA-MB-231 breast cancer cells and analyzed for effects on cell migration, a critical step in cancer metastasis. Among 486 miRNAs screened, 14 were identified that included all of the members of the miRNA-196 family (miR-196a1, miR-196a2, and miR-196b). Enforced expression of miR-196a1/2 or miR-196b abrogated in vitro invasion and in vivo spontaneous metastasis of breast cancer cells, indicating that members of the miR-196 family are potent metastasis suppressors. We found that miR-196 inhibited the expression of transcription factor HOXC8. Functional linkage was implied by small interfering RNA–mediated knockdown of HOXC8, which suppressed cell migration and metastasis, and by ectopic expression of HOXC8, which prevented the effects of miR-196 on cell migration and metastasis. Unlike other metastasis-associated miRNAs that have been described, the expressions of miR-196 were not correlated with breast cancer cell migration or the metastatic status of clinical breast tumor specimens. Instead, we detected an excellent correlation between the ratio of miR-196 to HOXC8 messages and the migratory behavior of breast cancer cell lines as well as the metastatic status of clinical samples. Our findings identify miRNA-196s as potent metastasis suppressors and reveal that the ratio of miR-196s to HOXC8 mRNA might be an indicator of the metastatic capability of breast tumors. Cancer Res; 70(20); 7894–904. ©2010 AACR.