bluuebunny/crossref_metadata_2025 huggingface dataset:
Annexin A1 released from apoptotic cells acts through formyl peptide receptors to dampen inflammatory monocyte activation via JAK/STAT/SOCS signalling
Authors: Pupjalis Danute , Goetsch Julia , Kottas Diane J. , Gerke Volker , Rescher Ursula
Published: December 2010

The immunosuppressive effects of apoptotic cells involve inhibition of pro‐inflammatory cytokine release and establishment of an anti‐inflammatory cytokine profile, thus limiting the degree of inflammation and promoting resolution. We report here that this is in part mediated by the release of the anti‐inflammatory mediator annexin A1 from apoptotic cells and the functional activation of annexin A1 receptors of the formyl peptide receptor (FPR) family on target cells. Supernatants from apoptotic neutrophils or the annexin A1 peptidomimetic Ac2‐26 significantly reduced IL‐6 signalling and the release of TNF‐α from endotoxin‐challenged monocytes. Ac2‐26 activated STAT3 in a JAK‐dependent manner, resulting in upregulated SOCS3 levels, and depletion of SOCS3 reversed the Ac2‐26‐mediated inhibition of IL‐6 signalling. This identifies annexin A1 as part of the anti‐inflammatory pattern of apoptotic cells and links the activation of FPRs to established signalling pathways triggering anti‐inflammatory responses.
Insurance Status and Treatment Candidacy of Hepatitis C Patients: Analysis of Population-Based Data From the United States Δσ
Authors: Stepanova Maria , Kanwal Fasiha , El-Serag Hashem B. , Younossi Zobair M.
Published: December 2010

Successful treatment with antiviral therapy could potentially reduce morbidity and mortality in patients with hepatitis C virus (HCV) infection. However, at the population level, these benefits may be offset by a limited number of patients who have access to antiviral treatment. Using data from the National Health and Nutrition Examination Survey conducted in 2005-2008, we analyzed the health insurance status and treatment candidacy of HCV-positive (HCV+) individuals. A total of 10,582 subjects were examined; of those, 1.16% had detectable HCV RNA and were defined as HCV+. The HCV+ patients were less likely to be insured than HCV-negative individuals (61.2% versus 81.2%;

P

= 0.004). Among those with health insurance, HCV+ patients were less likely to have private insurance, whereas the coverage by Medicare/Medicaid and other government-sponsored plans was similar to the rest of the population. In multivariate analysis, HCV infection was an independent predictor of being uninsured even after adjustment for demographic disparity of the HCV+ cohort (odds ratio, 0.43; 95% confidence interval, 0.24-0.78). Of all HCV+ patients, 66.7% were eligible for anti-HCV treatment. However, only 54.3% of HCV+ treatment candidates had any type of insurance coverage. Finally, only 36.3% of HCV+ patients were potentially eligible for treatment and had health insurance.

Conclusion:

A high proportion of HCV+ patients are currently uninsured, and many have publicly funded health insurance. Among those who could be candidates for treatment, the rate of insurance coverage is even lower. These findings can have important implications for health insurance coverage of these patients under the new health care reform legislation in the United States. (Hepatology 2011)
Childhood hodgkin's lymphoma, non‐hodgkin's lymphoma and factors related to the immune system: The escale study (SFCE)
Authors: Rudant Jérémie , Orsi Laurent , Monnereau Alain , Patte Catherine , Pacquement Hélène , Landman‐Parker Judith , Bergeron Christophe , Robert Alain , Michel Gérard , Lambilliotte Anne , Aladjidi Nathalie , Gandemer Virginie , Lutz Patrick , Margueritte Geneviève , Plantaz Dominique , Méchinaud Françoise , Hémon Denis , Clavel Jacqueline
Published: December 2010

The study investigated the role of factors considered related to the early stimulation of the immune system in the aetiology of childhood lymphoma. The national registry‐based case–control study, Escale, was carried out in France over the period 2003–2004. Population controls were frequency matched with the cases on age and gender. Data were obtained from structured telephone questionnaires administered to mothers. Odds ratios (ORs) were estimated using unconditional regression models adjusted for potential confounders. Data from 128 cases of Hodgkin's lymphoma (HL) aged 5–14 years, 164 cases of non‐Hodgkin's lymphoma (NHL) aged 2–14 years and 1,312 controls were analyzed. Negative associations were observed between HL and day care attendance [OR = 0.5 (0.2–1.2)] and between HL and repeated early common infections among non‐breastfed children [OR = 0.3 (.2–0.7), p = 0.003] [OR for breastfed children: 1.0 (.5–2.1)], but not for the other factors investigated. Negative associations were observed between NHL and birth order 3 or more [OR = 0.7 (0.4–1.1)], prolonged breastfeeding [OR = 0.5 (0.3–1.0)], regular contact with farm animals [OR = 0.5 (0.3–1.0)], frequent farm visits in early life [OR = 0.6 (0.4–1.1)] and history of asthma [OR = 0.6 (0.3–1.1)]. In conclusion, the results partly support the hypothesis that an abnormal maturation of the immune system may play a role in childhood HL or NHL, and call for further investigations.
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

Angiogenesis, 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

Hepatocellular 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

A 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

Cancer 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

In 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

Epstein‐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.
Required, practical, or unnecessary? An examination and demonstration of propensity score matching using longitudinal secondary data
Authors: Padgett Ryan D. , Salisbury Mark H. , An Brian P. , Pascarella Ernest T.
Published: December 2010

Using longitudinal data, this chapter demonstrates propensity score matching and ordinary least squares regression across several models to examine the necessity of implementing propensity score matching techniques.
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

Applications 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

Bone 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

An 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

There 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

BACKGROUND:

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

Metal‐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

Nickel 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

Modern 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

An 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

This 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.
RANKL expression is related to treatment outcome of patients with localized, high‐grade osteosarcoma
Authors: Lee Jun Ah , Jung Jun Soo , Kim Dong Ho , Lim Jung Sub , Kim Min Suk , Kong Chang‐Bae , Song Won Seok , Cho Wan Hyeong , Jeon Dae‐Geun , Lee Soo‐Yong , Koh Jae‐Soo
Published: December 2010

Background

The receptor activator of nuclear factor κB ligand (RANKL/TNFSF11) is expressed in metastatic bone cancer cells and has been suggested to play a key role in cell migration and metastatic behavior. We determined whether RANKL expression is correlated to clinical behavior of localized, high‐grade osteosarcoma.

Patients and methods

This retrospective, immunohistochemical study was performed using materials obtained from 40 patients treated at Korea Cancer Center Hospital between 1995 and 2007. Prechemotherapy biopsy samples were stained for RANKL and correlations between RANKL expression and clinical characteristics and outcomes were evaluated. Staining was interpreted in a semiquantitative manner using an intensity based scoring system.

Results

Thirty cases (75.0%) stained positively for RANKL; 15 (50.0%) had a high RANKL score (≥ 4) and the other 15 a low RANKL score (≤3). RANKL expression and RANKL scores were not related to age, sex, tumor location, tumor volume, or pathologic subtype. However, RANKL expression was related to a poor response to preoperative chemotherapy (P = 0.03) and a high RANKL score was associated with inferior survival. The 5‐year event‐free survival of patients with RANKL score ≥4 was 17.8 ± 10.5%, which was far worse than those with RANKL scores 1–3 or 0 (50.0 ± 15.8%, 56.0 ± 13.7%, respectively, P = 0.02).

Conclusions

The RANKL–RANK–OPG axis might be a promising target for the treatment of osteosarcoma, but further studies are needed to verify our data in a larger cohort. Pediatr Blood Cancer 2011;56:738–743. © 2010 Wiley‐Liss, Inc.
A photo‐degradable helix: Synthesis, structure, and photolysis of optically active poly[2,7‐bis(4‐t‐butylphenyl)‐9‐methylfluoren‐9‐yl acrylate]
Authors: Sakamoto Takeshi , Watanabe Kento , Shichibu Yukatsu , Konishi Katsuaki , Sato Shin‐Ichiro , Nakano Tamaki
Published: December 2010

2,7‐Bis(4‐t‐butylphenyl)‐9‐methylfluoren‐9‐yl acrylate (BBPMFA) was synthesized and polymerized using α,α′‐azobisisobutyronitrile or n‐Bu3B‐air as a radical initiator and using the complex of 9‐fluorenyllithium with (S)‐(+)‐1‐(2‐pyrrolidinylmethyl)pyrrolidine as an optically active anionic initiator. Although the radical polymerization led to rather low‐molecular‐weight products at low yields, the anionic polymerization afforded polymers with higher molecular weights in higher yields. The poly(BBPMFA) obtained by the anionic polymerization was slightly rich in isotacticity (meso diad 57%) and showed an intense circular dichroism (CD) spectrum and large dextrorotation. The intensity of the CD spectrum and magnitude of optical activity increased with an increase in Mn, suggesting that the polymer possesses a preferred‐handed helical conformation. The CD spectrum disappeared within 1 s on irradiation to the polymer in a CHCl3 solution using a 500‐W Hg‐Xe lamp. This was ascribed to fast photolysis of the ester linkage leading to a loss of helical conformation of the entire chain. Photolysis products of poly(BBPMFA) were poly(acrylic acid) and 2,7‐bis(4‐t‐butylphenyl)‐9‐methylenefluorene (2,7‐bis(4‐t‐butylphenyl)dibenzofulvene). The photolysis reaction seemed to proceed through the “unzipping” mechanism. The rate constant of photolysis of poly(BBPMFA) under irradiation at monochromated 325 nm was around 0.01 s−1 independent of molecular weight. Photolysis at 325 nm was approximately 2400 times faster than that for chemical ester solvolysis under a neutral condition in the dark. © 2010 Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem, 2011
Exploring sparsely populated states of macromolecules by diamagnetic and paramagnetic NMR relaxation
Authors: Clore G. Marius
Published: December 2010

Sparsely populated states of macromolecules, characterized by short lifetimes and high free‐energies relative to the predominant ground state, often play a key role in many biological, chemical, and biophysical processes. In this review, we briefly summarize various new developments in NMR spectroscopy that permit these heretofore invisible, sparsely populated states to be detected, characterized, and in some instances visualized. Relaxation dispersion spectroscopy yields detailed kinetic information on processes involving species characterized by distinct chemical shifts with lifetimes in the ∼50 μs−10 ms range and populations as low as 0.5%. In the fast exchange regime (time scale less than ∼250−500 μs), the footprint of sparsely populated states can be observed on paramagnetic relaxation enhancement profiles measured on the resonances of the major species, thereby yielding structural information that is directly related to paramagnetic center‐nuclei distances from which it is possible, under suitable circumstances, to compute a structure or ensemble of structures for the minor species. Finally, differential transverse relaxation measurements can be used to detect lifetime broadening effects that directly reflect the unidirectional rates for the conversion of NMR‐visible into high‐molecular weight NMR‐invisible species. Examples of these various approaches are presented.
Strain mapping in layers and devices by electron holography
Authors: Hytch Martin , Cherkashin Nikolay , Reboh Shay , Houdellier Florent , Claverie Alain
Published: December 2010

Strain can be measured at the micron scale by Raman spectroscopy and X‐ray diffraction, but at the nanoscale, the only viable tool is transmission electron microscopy (TEM). TEM techniques can be divided into two categories: diffraction based techniques such as convergent‐beam‐electron‐diffraction or nanobeam electron diffraction, and imaged based techniques such as high‐resolution electron microscopy or the new technique of dark‐field electron holography (HoloDark). The latter has recently been invented to measure strain to high precision (2 × 10−4), nanometer spatial resolution, and for micron fields of view. In this article, we present two latest and typical results from the HoloDark technique (which is applicable to all standard focused‐ion beam prepared crystalline samples): mapping of strain in contact etch stop layers induced strain structures, and in implanted layers, In such materials and structures, the Holodark technique, although still perfectible, has no competitor.
An exact method for analysis following a two‐stage phase II cancer clinical trial
Authors: Jovic Gordana , Whitehead John
Published: December 2010

This paper presents an exact method for the analysis of a phase II cancer clinical trial conducted using a two‐stage design in which early stopping may be allowed for either futility or efficacy. The method provides a point and interval estimate of the response probability associated with the treatment under investigation and a p‐value for testing whether this exceeds some standard null value. Two‐stage designs are often used in phase II trials in oncology for reasons of ethics and efficiency, but this design feature is seldom taken into account when the results are analyzed. After any two‐stage design or multi‐stage design, the method for analysis should take into account the previous interim analyses performed, otherwise the results will be biased. In this paper, an approximate approach based on a log‐odds ratio parameterisation will be compared with an exact method through the calculation of the precise coverage probabilities of each approach. Copyright © 2010 John Wiley & Sons, Ltd.
Confounder‐adjusted estimates of the risk difference using propensity score‐based weighting
Authors: Ukoumunne Obioha C. , Williamson Elizabeth , Forbes Andrew B. , Gulliford Martin C. , Carlin John B.
Published: December 2010

Confounder‐adjusted estimates of the risk difference are often difficult to obtain by direct regression adjustment. Estimates can be obtained from a propensity score‐based method using inverse probability‐of‐exposure weights to balance groups defined by exposure status with respect to confounders. Simulation was used to evaluate the performance of this method. The simulation model incorporated a binary confounder and a normally distributed confounder into logistic models of exposure status, and disease status conditional on exposure status. Data were generated for combinations of values of several design parameters, including the odds ratio relating each of the confounders to exposure status, the odds ratio relating each of the confounders to disease status and the total sample size. For most design parameter combinations (474 of 486), the absolute bias in the estimated risk difference was less than 1 percentage point, and it was never greater than 3 percentage points. The confidence interval generally had close to nominal 95 per cent coverage, but was prone to poor coverage levels (as low as 78.5 per cent) when both the confounder‐to‐exposure and confounder‐to‐outcome odds ratios were 5, consistent with strong confounding. The simulation results showed that the conditions that are favourable for good performance of the weighting method are: reasonable overlap in the propensity score distributions of the exposed and non‐exposed groups and a large sample size. Copyright © 2010 John Wiley & Sons, Ltd.
Inference on the rate ratio of recurrent events for the matched pairs design
Authors: Sumi Mariko , Tango Toshiro
Published: December 2010

As statistical methods for testing the null hypothesis of no difference between two groups for the matched pairs design, the paired‐ttest, Wilcoxon signed rank sum test and McNemar test are well known. However, there is no simple test for the comparison of incidence rate of recurrent events. This paper proposes a simple statistical method and a sample size formula for the comparison of counts of recurrent events over a specified period of observation under the matched pairs design, where the subject‐specific incidence of recurrent events is assumed to follow a time‐homogeneous Poisson process. As a special case, the proposed method is found to be virtually equivalent in form to Mantel–Haenszel method for a common rate ratio among the set of stratified tables based on person‐time data. The proposed methods are illustrated with the within‐arm comparison of data from a clinical trial of 59 epileptics with baseline count data. Copyright © 2010 John Wiley & Sons, Ltd.
Planning and analysis of cross‐over trials in infertility
Authors: Makubate Boikanyo , Senn Stephen
Published: December 2010

The use of cross‐over trials in investigating treatments for infertility is discussed. A simple possible approach to analyzing such trials using the Mantel–Haenszel procedure is explained. A more flexible approach based on the normal–binomial mixture model of Ezzet and Whitehead is examined. It is shown how this may be implemented in various statistical packages by applying it to two real examples of trials in infertility. An approach that may be used to compare designs via simulation is explained briefly. It is concluded that provided that cross‐over trials in infertility are regarded as parallel group trials with extra information rather than as cross‐over trials with missing information, their use may be more promising than that has previously been concluded. Copyright © 2010 John Wiley & Sons, Ltd.
An application of Harrell's C‐index to PH frailty models
Authors: Van Oirbeek R. , Lesaffre E.
Published: December 2010

Frailty models are encountered in many medical applications, yet little research has been devoted to develop measures that quantify the predictive ability of these models. In this paper, we elaborate on the concept of the concordance probability to clustered data, resulting in an ‘Overall Conditional C‐index’ or bfCO, C and an ‘Overall Marginal C‐index’ or CO, M. Both Overall C‐indices can be split up into a ‘Between Conditional’ or CB, C and a ‘Between Marginal C‐index’ or CB, M and into a ‘Within Conditional’ or CW, C and a ‘Within Marginal C‐index’ or CW, M. For PH frailty models of the power variance family, CW, C and CW, M are equivalent resulting in one ‘Within C‐index’ CW. We propose an application of Harrell's C‐index to estimate the proposed indices within a likelihood and a Bayesian context and the performances of their point estimates and confidence/credible intervals are compared in an extensive simulation study. This simulation study shows that the point estimates of CW and CB, M perform good within both a likelihood and Bayesian context but that the point estimates of CB, C show less bias for the Bayesian approach than for the likelihood approach. The 95 per cent confidence/credible intervals also possess good coverage properties, given that the point estimates perform good. The performance of the C‐indices is evaluated on a real data set. Copyright © 2010 John Wiley & Sons, Ltd.
Arrays of Silicon Micro/Nanostructures Formed in Suspended Configurations for Deterministic Assembly Using Flat and Roller‐Type Stamps
Authors: Yang Yumi , Hwang Youngkyu , Cho Hyun A , Song Jung‐Hoon , Park Seong‐Ju , Rogers John A. , Ko Heung Cho
Published: December 2010

The ability to create and manipulate large arrays of inorganic semiconductor micro/nanostructures for integration on unconventional substrates provides new possibilities in device engineering. Here, simple methods are described for the preparation of structures of single crystalline silicon in suspended and tethered configurations that facilitate their deterministic assembly using transfer‐printing techniques. Diverse shapes (e.g., straight or curved edges), thicknesses (between 55 nm and 3 μm), and sizes (areas of 4000 μm2 to 117 mm2) of structures in varied layouts (regular or irregular arrays, with dense or sparse coverages) can be achieved, using either flat or cylindrical roller‐type stamps. To demonstrate the technique, printing with 100% yield onto curved, rigid supports of glass and ceramics and onto thin sheets of plastic is shown. The fabrication of a printed array of silicon p+–i–n+ junction photodiodes on plastic is representative of device‐printing capabilities.
Isolation and partial characterization of Mexican taro (Colocasia esculenta L.) starch
Authors: Agama‐Acevedo Edith , Garcia‐Suarez Francisco J. , Gutierrez‐Meraz Felipe , Sanchez‐Rivera Mirna M. , San Martin Eduardo , Bello‐Pérez Luis A.
Published: December 2010

Taro starch was isolated from Mexican variety and its morphological, physicochemical, and molecular characteristics were evaluated. Yield starch (in dry basis) was 81%, and this starch had low AM content (2.5%). Taro starch granules showed a mixture of shapes with sizes between 1 and 5 µm. Taro starch presented an A‐type XRD pattern with a crystallinity level of 38.26%. Solubility and water retention capacity did not change in the temperature range of 50–70°C and thereafter they increased as temperature increased too. Taro starch showed high peak viscosity due to its high AP content. The peak temperature of gelatinization of taro starch was 80.6°C with an enthalpy value of 10.6 J/g, with low retrogradation rate due to its low AM content. Weight‐average molar mass (Mw) and gyration radius (Rz) of taro starch were 1.21 ± 0.8 × 109 g/mol and 424 ± 70 nm, respectively. Taro tuber could be an alternative for starch isolation with functional and physicochemical characteristics for food and non‐food applications.
Systematic analysis of the effect of temperature profiles on reactions in tubular reactors
Authors: Wu J. , Platzer B.
Published: December 2010

A more or less pronounced temperature distribution existing in reactors has a strong influence on the conversion at the reactor outlet. Generally, isothermal or other strongly simplified models seem to fail. However, with their low expense of calculation they are good approaches for a rough reactor design and play an important role in books of chemical reaction engineering. Ideal isothermal models dominate the chapters of reactor design in these books. Thus, a systematic study of the influence of the temperature profile is done here. The influence of plug and laminar flow, heat transfer, reaction heat, operation states, and the temperature dependence of physical parameters is discussed. Some non‐isothermal tubular reactor models are developed for irreversible, homogeneous reactions. The models have an increasing complexity. This article focuses at first on the study of some special cases having analytical solutions. Here some new solutions are presented. Half‐analytical and numerical methods are used for the analysis, too. Beside the Arrhenius' law, a linear temperature profile is also used to calculate the reaction rate constant for small temperature differences. The analytical solutions of the concentration profiles in the reactor and the mean concentration at the outlet position are obtained for zeroth, first, and second order reactions by solving the species conservation equation. For non‐analytical integration terms (e.g. for variable viscosity problems) the relations between the mean concentration of the reactant bar cA/ cAoand the dimensionless parameter z/(LDaw) are obtained with a numerical method. In order to find a connection between these models, an effective reaction coefficient is introduced. The results are discussed in detail.
Heparin cofactor II‐thrombin complex and dermatan sulphate:chondroitin sulphate ratio are biomarkers of short‐ and long‐term treatment effects in mucopolysaccharide diseases
Authors: Langford‐Smith Kia Jane , Mercer Jean , Petty June , Tylee Karen , Church Heather , Roberts Jane , Moss Gill , Jones Simon , Wynn Rob , Wraith J. Ed , Bigger Brian W.
Published: December 2010

Early detection of mucopolysaccharidosis (MPS) is an important factor in treatment success; therefore, good disease biomarkers are vital. We evaluate heparin cofactor II‐thrombin complex (HCII‐T) as a biomarker in serum and dried blood spots (DBS) of MPS patients. Serum HCII‐T and urine dermatan sulphate:chondroitin sulphate (DS:CS) ratio are also compared longitudinally against clinical outcomes in MPSI, II and VI patients following treatment. Samples were collected from MPS patients at the Royal Manchester Children's Hospital. DS:CS ratio was obtained by measuring the area density of spots from 2D electrophoresis of urinary glycosaminoglycans. Serum and DBS HCII‐T was measured by sandwich ELISA. Serum HCII‐T is elevated approximately 25‐fold in MPS diseases that store DS, clearly distinguishing untreated MPSI, II and VI patients from unaffected age‐matched controls. Serum HCII‐T is also elevated in MPSIII, which leads to storage of heparan sulphate, with an increase of approximately 4‐fold over unaffected age‐matched controls. Urine DS:CS ratio and serum HCII‐T decrease in response to treatment of MPSI, II and VI patients. HCII‐T appears to respond rapidly to perturbations in treatment, whilst DS:CS ratio responds more slowly. HCII‐T is a suitable biomarker for MPSI, II and VI, and it may also be informative for MPS diseases storing HS alone, such as MPSIII, although the elevation observed is smaller. In treated MPS patients, HCII‐T and DS:CS ratio appear to measure short‐term and long‐term treatment outcomes, respectively. The potential value of HCII‐T measurement in DBS for newborn screening of MPS diseases warrants further investigation.