bluuebunny/crossref_metadata_2025_split huggingface dataset:
Regorafenib (BAY 73‐4506): A new oral multikinase inhibitor of angiogenic, stromal and oncogenic receptor tyrosine kinases with potent preclinical antitumor activity
Authors: Wilhelm Scott M. , Dumas Jacques , Adnane Lila , Lynch Mark , Carter Christopher A. , Schütz Gunnar , Thierauch Karl‐Heinz , Zopf Dieter 
Published: December 2010

AbstractAngiogenesis, a critical driver of tumor development, is controlled by interconnected signaling pathways. Vascular endothelial growth factor receptor (VEGFR) 2 and tyrosine kinase with immunoglobulin and epidermal growth factor homology domain 2 play crucial roles in the biology of normal and tumor vasculature. Regorafenib (BAY 73‐4506), a novel oral multikinase inhibitor, potently inhibits these endothelial cell kinases in biochemical and cellular kinase phosphorylation assays. Furthermore, regorafenib inhibits additional angiogenic kinases (VEGFR1/3, platelet‐derived growth factor receptor‐β and fibroblast growth factor receptor 1) and the mutant oncogenic kinases KIT, RET and B‐RAF. The antiangiogenic effect of regorafenib was demonstrated in vivo by dynamic contrast‐enhanced magnetic resonance imaging. Regorafenib administered once orally at 10 mg/kg significantly decreased the extravasation of Gadomer in the vasculature of rat GS9L glioblastoma tumor xenografts. In a daily (qd)×4 dosing study, the pharmacodynamic effects persisted for 48 hr after the last dosing and correlated with tumor growth inhibition (TGI). A significant reduction in tumor microvessel area was observed in a human colorectal xenograft after qd×5 dosing at 10 and 30 mg/kg. Regorafenib exhibited potent dose‐dependent TGI in various preclinical human xenograft models in mice, with tumor shrinkages observed in breast MDA‐MB‐231 and renal 786‐O carcinoma models. Pharmacodynamic analyses of the breast model revealed strong reduction in staining of proliferation marker Ki‐67 and phosphorylated extracellular regulated kinases 1/2. These data demonstrate that regorafenib is a well‐tolerated, orally active multikinase inhibitor with a distinct target profile that may have therapeutic benefit in human malignancies.
Lack of ex vivo peripheral and intrahepatic α‐fetoprotein‐specific CD4+ responses in hepatocellular carcinoma
Authors: Witkowski Mario , Spangenberg Hans Christian , Neumann‐Haefelin Christoph , Büttner Nico , Breous Ekaterina , Kersting Nadine , Drognitz Oliver , Hopt Ulrich T. , Blum Hubert E. , Semmo Nasser , Thimme Robert 
Published: December 2010

AbstractHepatocellular carcinoma (HCC) is one of the most common malignancies with a poor prognosis and limited therapeutic options that is often characterized by the expression of the tumor‐associated antigen α‐fetoprotein (AFP). CD4+ helper T cells are important in generating potent anticancer immunity as they prime and expand CD8+ T‐cell memory and may also have direct antitumor activity. However, very little information is currently available about the relative frequency, immunodominance and peripheral versus intratumoral distribution of AFP‐specific CD4+ T‐cell responses in patients with HCC. We, therefore, analyzed AFP‐specific CD4+ responses in blood and tumor tissue of patients with HCC by using overlapping peptides spanning the entire AFP protein and novel sensitive approaches such as antigen‐specific upregulation of CD154. We found that AFP‐specific CD4+ T‐cell responses were not detectable in the peripheral blood ex vivo. However, after in vitro stimulation, AFP‐specific CD4+ T‐cell responses were detectable in a large fraction of patients targeting different previously unreported epitopes with no clear immunodominance. These results indicate that AFP‐specific CD4+ T‐cell responses are not completely deleted but only present at very low frequencies. Importantly, AFP‐specific CD4+ T‐cell responses were also rarely detectable in tumor tissue, suggesting that the relative absence of these cells in the circulation ex vivo is not due to a rapid accumulation to the tumor side. Taken together, these results suggest that the lack of sufficient CD4+ T‐cell help, especially within the tumor tissue, may be one central mechanism responsible for the failure of AFP‐specific immune responses to control HCC progression.
Bcl‐2 promotes malignant progression in a PDGF‐B‐dependent murine model of oligodendroglioma
Authors: Doucette Tiffany , Yang Yuhui , Zhang Wei , Fuller Gregory N. , Suki Dima , Fults Daniel W. , Rao Ganesh 
Published: December 2010

AbstractA significant subset of gliomas arises after activation of the proproliferative platelet‐derived growth factor (PDGF) pathway. The progression of low‐grade gliomas to more malignant tumors may be due to oncogenic cellular programs combining with those suppressing apoptosis. Antiapoptotic genes are overexpressed in a variety of cancers, and the antiapoptotic gene, BCL2, is associated with treatment resistance and tumor recurrence in gliomas. However, the impact of antiapoptotic gene expression to tumor formation and progression is unclear. We overexpressed Bcl‐2 in a PDGFB‐dependent mouse model of oligodendroglioma, a common glioma subtype, to assess its effect in vivo. We hypothesized that the antiapoptotic effect would complement the proproliferative effect of PDGFB to promote tumor formation and progression to anaplastic oligodendroglioma (AO). Here, we show that coexpression of PDGFB and Bcl‐2 results in a higher overall tumor formation rate compared to PDGFB alone. Coexpression of PDGFB and Bcl‐2 promotes progression to AO with prominent foci of necrosis, a feature of high‐grade gliomas. Median tumor latency was shorter in mice injected with PDGFB and Bcl‐2 compared to those injected with PDGFB alone. Although independent expression of Bcl‐2 was insufficient to induce tumors, suppression of apoptosis (detected by cleaved caspase‐3 expression) was more pronounced in AOs induced by PDGFB and Bcl‐2 compared to those induced by PDGFB alone. Tumor cell proliferation (detected by phosphohistone H3 activity) was also more robust in high‐grade tumors induced by PDGFB and Bcl‐2. Our results indicate that suppressed apoptosis enhances oligodendroglioma formation and engenders a more malignant phenotype.
Cancer risks for monoallelic MUTYH mutation carriers with a family history of colorectal cancer
Authors: Win Aung Ko , Cleary Sean P. , Dowty James G. , Baron John A. , Young Joanne P. , Buchanan Daniel D. , Southey Melissa C. , Burnett Terrilea , Parfrey Patrick S. , Green Roger C. , Marchand Loïc Le , Newcomb Polly A. , Haile Robert W. , Lindor Noralane M. , Hopper John L. , Gallinger Steven , Jenkins Mark A. 
Published: December 2010

AbstractCancer risks for a person who has inherited a MUTYH mutation from only one parent (monoallelic mutation carrier) are uncertain. Using the Colon Cancer Family Registry and Newfoundland Familial Colon Cancer Registry, we identified 2,179 first‐ and second‐degree relatives of 144 incident colorectal cancer (CRC) cases who were monoallelic or biallelic mutation carriers ascertained by sampling population complete cancer registries in the United States, Canada and Australia. Using Cox regression weighted to adjust for sampling on family history, we estimated that the country‐, age‐ and sex‐specific standardized incidence ratios (SIRs) for monoallelic mutation carriers, compared to the general population, were: 2.04 (95% confidence interval, CI 1.56–2.70; p < 0.001) for CRC, 3.24 (95%CI 2.18–4.98; p < 0.001) for gastric cancer, 3.09 (95%CI 1.07–12.25; p = 0.07) for liver cancer and 2.33 (95%CI 1.18–5.08; p = 0.02) for endometrial cancer. Age‐specific cumulative risks to age 70 years, estimated using the SIRs and US population incidences, were: for CRC, 6% (95%CI 5–8%) for men and 4% (95%CI 3–6%) for women; for gastric cancer, 2% (95%CI 1–3%) for men and 0.7% (95%CI 0.5–1%) for women; for liver cancer, 1% (95%CI 0.3–3%) for men and 0.3% (95%CI 0.1–1%) for women and for endometrial cancer, 4% (95%CI 2–8%). There was no evidence of increased risks for cancers of the brain, pancreas, kidney, lung, breast or prostate. Monoallelic MUTYH mutation carriers with a family history of CRC, such as those identified from screening multiple‐case CRC families, are at increased risk of colorectal, gastric, endometrial and possibly liver cancers.
Human ZNF312b oncogene is regulated by Sp1 binding to its promoter region through DNA demethylation and histone acetylation in gastric cancer
Authors: Song In‐Sung , Ha Ga‐Hee , Kim Jeong‐Min , Jeong So‐Young , Lee Han‐Chul , Kim Yong Sung , Kim Yung‐Jin , Kwon Taeg Kyu , Kim Nam‐Soon 
Published: December 2010

AbstractIn a previous study, human ZNF312b was identified as a cell proliferation‐associated oncogene via the K‐ras/extracellular signal‐regulated kinase cascade in gastric cancer. However, the mechanism concerning its transcriptional activation remains unknown. Here, we show that DNA methylation and histone acetylation of the ZNF312b promoter function as a switch for ZNF312b transcriptional activation in gastric cancer. The transcription level of ZNF312b was increased by treatment with a demethylating agent, 5‐aza‐2′‐deoxycytidine and the histone deacetylase inhibitor sodium butyrate, in several human cancer cell lines including gastric cancer. Consistent with these results, epigenetic analysis, such as pyrosequencing, bisulfate sequencing and methyl‐specific polymerase chain reaction (MSP), showed that the expression level of ZNF312b is highly dependent on the degree of DNA methylation in gastric cancer cell lines. In addition, by ChIP assay using anti‐acetyl/methyl H3K9 antibodies, histone acetylation was shown to mediate the expression of the ZNF312b gene. Interestingly, ChIP assay using the Sp1 antibody revealed that the binding of transcription factor Sp1 to the ZNF312b promoter for its transcriptional activation requires DNA demethylation and histone acetylation. Moreover, a knockdown of Sp1 resulted in a decrease in ERK‐mediated proliferation via downregulation of the ZNF312b gene in gastric cancer cells. Taken together, these results suggest that the aberrant expression of ZNF312b promotes gastric tumorigenesis through epigenetic modification of its promoter region and provides a molecular mechanism for ZNF312b expression to contribute to the progression of gastric cancer.
Bortezomib induces apoptosis in T lymphoma cells and natural killer lymphoma cells independent of Epstein‐Barr virus infection
Authors: Iwata Seiko , Yano Shoko , Ito Yoshinori , Ushijima Yoko , Gotoh Kensei , Kawada Jun‐ichi , Fujiwara Shigeyoshi , Sugimoto Koichi , Isobe Yasushi , Nishiyama Yukihiro , Kimura Hiroshi 
Published: December 2010

AbstractEpstein‐Barr virus (EBV), which infects not only B cells, but also T cells and natural killer (NK) cells, is associated with multiple lymphoid malignancies. Recently, the proteasome inhibitor bortezomib was reported to induce apoptosis of EBV‐transformed B cells. We evaluated the killing effect of this proteasome inhibitor on EBV‐associated T lymphoma cells and NK lymphoma cells. First, we found that bortezomib treatment decreased the viability of multiple T and NK cell lines. No significant difference was observed between EBV‐positive and EBV‐negative cell lines. The decreased viability in response to bortezomib treatment was abrogated by a pan‐caspase inhibitor. The induction of apoptosis was confirmed by flow cytometric assessment of annexin V staining. Additionally, cleavage of caspases and polyadenosine diphosphate‐ribose polymerase, increased expression of phosphorylated IκB, and decreased expression of inhibitor of apoptotic proteins were detected by immunoblotting in bortezomib‐treated cell lines. We found that bortezomib induced lytic infection in EBV‐positive T cell lines, although the existence of EBV did not modulate the killing effect of bortezomib. Finally, we administered bortezomib to peripheral blood mononuclear cells from five patients with EBV‐associated lymphoproliferative diseases. Bortezomib had a greater killing effect on EBV‐infected cells. These results indicate that bortezomib killed T or NK lymphoma cells by inducing apoptosis, regardless of the presence or absence of EBV.
Influence of circumferential notch and fatigue crack on the mechanical integrity of biodegradable magnesium‐based alloy in simulated body fluid
Authors: Bobby Kannan M. , Singh Raman R.K. , Witte F. , Blawert C. , Dietzel W. 
Published: December 2010

AbstractApplications of magnesium alloys as biodegradable orthopaedic implants are critically dependent on the mechanical integrity of the implant during service. In this study, the mechanical integrity of an AZ91 magnesium alloy was studied using a constant extension rate tensile (CERT) method. The samples in two different geometries that is, circumferentially notched (CN), and circumferentially notched and fatigue cracked (CNFC), were tested in air and in simulated body fluid (SBF). The test results show that the mechanical integrity of the AZ91 magnesium alloy decreased substantially (∼50%) in both the CN and CNFC samples exposed to SBF. Fracture surface analysis revealed secondary cracks suggesting stress corrosion cracking susceptibility of the alloy in SBF. © 2010 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2011.
Effect of cold‐setting calcium‐ and magnesium phosphate matrices on protein expression in osteoblastic cells
Authors: Ewald Andrea , Helmschrott Kerstin , Knebl Georg , Mehrban Nazia , Grover Liam M. , Gbureck Uwe 
Published: December 2010

AbstractBone loss due to accidents or tissue diseases requires replacement of the structure by either autografts, allografts, or artificial materials. Reactive cements, which are based on calcium phosphate chemistry, are commonly used in nonload bearing areas such as the craniofacial region. Some of these materials are resorbed by the host under physiological conditions and replaced by bone. The aim of this study was to test different calcium and magnesium cement composites in vitro for their use as bone substitution material. Phase composition of calcium deficient hydroxyapatite (Ca9(PO4)5HPO4OH), brushite (CaHPO4·2H2O), and struvite (MgNH4PO4·6H2O) specimens has been determined by means of X‐ray diffraction, and compressive strength was measured. Cell growth and activity of osteoblastic cells (MG 63) on the different surfaces was determined, and the expression of bone marker proteins was analyzed by western blotting. Cell activity normalized to cell number revealed higher activity of the osteoblasts on brushite and struvite when compared to hydroxyapatite and also the expression of osteoblastic marker proteins was highest on brushite scaffolds. While brushite sets under acidic conditions, formation of struvite occurs under physiological pH, similar to hydroxyapatite cements, providing the possibility of additional modifications with proteins or other active components. © 2010 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 2011.
Acyclic edge coloring of 2‐degenerate graphs
Authors: Basavaraju Manu , Chandran L. Sunil 
Published: December 2010

AbstractAn acyclic edge coloring of a graph is a proper edge coloring such that there are no bichromatic cycles. The acyclic chromatic index of a graph is the minimum number k such that there is an acyclic edge coloring using k colors and is denoted by a′(G). A graph is called 2‐degenerate if any of its induced subgraph has a vertex of degree at most 2. The class of 2‐degenerate graphs properly contains series–parallel graphs, outerplanar graphs, non − regular subcubic graphs, planar graphs of girth at least 6 and circle graphs of girth at least 5 as subclasses. It was conjectured by Alon, Sudakov and Zaks (and much earlier by Fiamcik) that a′(G)⩽Δ + 2, where Δ = Δ(G) denotes the maximum degree of the graph. We prove the conjecture for 2‐degenerate graphs. In fact we prove a stronger bound: we prove that if G is a 2‐degenerate graph with maximum degree Δ, then a′(G)⩽Δ + 1. © 2010 Wiley Periodicals, Inc. J Graph Theory 69: 1–27, 2012
Four nephrology myths debunked
Authors: Rachoin Jean‐Sebastien , Cerceo Elizabeth A 
Published: December 2010

AbstractThere are many controversial topics relating to renal disease in hospitalized patients. The aim of this review is to shed light on some important and often debated issues. Hypothyroidism, unlike myxedema, is not a cause of hyponatremia (although it can be sometimes seen in conjunction with the latter) and additional investigations should be done to determine its etiology. Sodium bicarbonate is effective for treatment of hyperkalemia primarily by enhancing renal potassium elimination rather than by translocating potassium into cells. Acetaminophen can be a cause of metabolic acidosis by causing 5‐oxoprolinuria. Furosemide (and sulfa containing diuretics) can safely be used in patients with an allergy to sulfa‐containing antibiotics (SCA). Journal of Hospital Medicine 2010;. © 2010 Society of Hospital Medicine.
Intra‐hospital transfers to a higher level of care: Contribution to total hospital and intensive care unit (ICU) mortality and length of stay (LOS)
Authors: Escobar Gabriel J. , Greene John D. , Gardner Marla N. , Marelich Gregory P. , Quick Bryon , Kipnis Patricia 
Published: December 2010

AbstractBACKGROUND:Patients who experience intra‐hospital transfers to a higher level of care (eg, ward to intensive care unit [ICU]) are known to have high mortality. However, these findings have been based on single‐center studies or studies that employ ICU admissions as the denominator.OBJECTIVE:To employ automated bed history data to examine outcomes of intra‐hospital transfers using all hospital admissions as the denominator.DESIGN:Retrospective cohort study.SETTING:A total of 19 acute care hospitals.PATIENTS:A total of 150,495 patients, who experienced 210,470 hospitalizations, admitted to these hospitals between November 1st, 2006 and January 31st, 2008.MEASUREMENTS:Predictors were age, sex, admission type, admission diagnosis, physiologic derangement on admission, and pre‐existing illness burden; outcomes were: 1) occurrence of intra‐hospital transfer, 2) death following admission to the hospital, 3) death following transfer, and 4) total hospital length of stay (LOS).RESULTS:A total of 7,868 hospitalizations that began with admission to either a general medical surgical ward or to a transitional care unit (TCU) had at least one transfer to a higher level of care. These hospitalizations constituted only 3.7% of all admissions, but accounted for 24.2% of all ICU admissions, 21.7% of all hospital deaths, and 13.2% of all hospital days. Models based on age, sex, preadmission laboratory test results, and comorbidities did not predict the occurrence of these transfers.CONCLUSIONS:Patients transferred to higher level of care following admission to the hospital have excess mortality and LOS. Journal of Hospital Medicine 2010;. © 2010 Society of Hospital Medicine.
Rhodium‐ and ruthenium‐catalysed hydrogen isotope exchange
Authors: Lockley W. J. S. , Hesk D. 
Published: December 2010

AbstractMetal‐catalysed hydrogen isotope exchange has been widely used in the preparation of deuterium‐ and tritium‐labelled compounds. This review details the development and utility of homogeneous and heterogeneous rhodium and ruthenium catalysts for the preparation of deuterium‐ and tritium‐labelled compounds by hydrogen isotope exchange methodology. Copyright © 2010 John Wiley & Sons, Ltd.
Nickel‐catalyzed hydrogen isotope exchange
Authors: Heys J. Richard 
Published: December 2010

AbstractNickel metal in various forms is useful for the catalytic exchange labeling of a wide range of compounds from isotopic water or isotopic hydrogen gas sources. Substantial investigative work has been done on the metal's activities in simple test compounds, providing information useful for selecting or developing conditions for labeling of more complex substances. In addition, Raney nickel has been shown to be particularly useful for labeling of carbohydrates, for which the assembled empirical data are sufficient for limited predictive purposes in new glycosides. Copyright © 2010 John Wiley & Sons, Ltd.
The efficiency of solvent‐free catalyst systems in the synthesis of tritium‐labelled biologically active compounds
Authors: Shevchenko Valerii P. , Nagaev Igor Yu. , Myasoedov Nikolay F. 
Published: December 2010

AbstractModern theories about the processes that take place inside solvent‐free catalyst systems are considered and the various factors that have an effect on the successful introduction of tritium into organic compounds are summarized. Obtaining labelled compounds using solvent‐free catalyst systems, liquid‐phase methods, and isotopic exchange with tritiated water are all regarded as various manifestations of the same set of occurrences in the presence of tritium, a substrate and a catalyst. The use of various isotopic exchange methods has made possible the introduction of tritium into practically any type of biologically active compound. This will enable scientists to carry out more detailed studies of the processes inside living organisms. Copyright © 2010 John Wiley & Sons, Ltd.
Metal‐catalysed hydrogen isotope exchange labelling: a brief overview
Authors: Lockley William J. S. , Heys J. Richard 
Published: December 2010

AbstractAn overview is given of this Special Issue of the Journal of Labelled Compounds and Radiopharmaceuticals dealing with the subject of metal‐catalysed hydrogen isotope exchange labelling. In addition to summarizing the areas covered by the contributed papers, the overview also adds some historical information and gives short reviews of those areas and metals, not specifically covered by the contributed papers. Copyright © 2010 John Wiley & Sons, Ltd.
A rheological interface model and its space–time finite element formulation for fluid–structure interaction
Authors: Legay Antoine , Zilian Andreas , Janssen Christian 
Published: December 2010

AbstractThis contribution discusses extended physical interface models for fluid–structure interaction problems and investigates their phenomenological effects on the behavior of coupled systems by numerical simulation. Besides the various types of friction at the fluid–structure interface the most interesting phenomena are related to effects due to additional interface stiffness and damping. The paper introduces extended models at the fluid–structure interface on the basis of rheological devices (Hooke, Newton, Kelvin, Maxwell, Zener). The interface is decomposed into a Lagrangian layer for the solid‐like part and an Eulerian layer for the fluid‐like part. The mechanical model for fluid–structure interaction is based on the equations of rigid body dynamics for the structural part and the incompressible Navier–Stokes equations for viscous flow. The resulting weighted residual form uses the interface velocity and interface tractions in both layers in addition to the field variables for fluid and structure. The weak formulation of the whole coupled system is discretized using space–time finite elements with a discontinuous Galerkin method for time‐integration leading to a monolithic algebraic system. The deforming fluid domain is taken into account by deformable space–time finite elements and a pseudo‐structure approach for mesh motion. The sensitivity of coupled systems to modification of the interface model and its parameters is investigated by numerical simulation of flow induced vibrations of a spring supported fluid‐immersed cylinder. It is shown that the presented rheological interface model allows to influence flow‐induced vibrations. Copyright © 2010 John Wiley & Sons, Ltd.