bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mutations in the U5 Region Adjacent to the Primer Binding Site Affect tRNA Cleavage by Human Immunodeficiency Virus Type 1 Reverse Transcriptase In Vivo
Authors: Oh Jangsuk , McWilliams Mary Jane , Julias John G. , Hughes Stephen H. 
Published: November 2007

ABSTRACTIn retroviruses, the first nucleotide added to the tRNA primer defines the end of the U5 region in the right long terminal repeat, and the subsequent removal of this tRNA primer by RNase H exactly defines the U5 end of the linear double-stranded DNA. In most retroviruses, the entire tRNA is removed by RNase H cleavage at the RNA/DNA junction. However, the RNase H domain of human immunodeficiency virus type 1 (HIV-1) reverse transcriptase cleaves the tRNA 1 nucleotide from the RNA/DNA junction at the U5/primer binding site (PBS) junction, which leaves an rA residue at the U5 terminus. We made sequence changes at the end of the U5 region adjacent to the PBS in HIV-1 to determine whether such changes affect the specificity of tRNA primer cleavage by RNase H. In some of the mutants, RNase H usually removed the entire tRNA, showing that the cleavage specificity was shifted by 1 nucleotide. This result suggests that the tRNA cleavage specificity of the HIV-1 RNase domain H depends on sequences in U5.
Reduced fertility among shoe manufacturing workers
Authors: Sallmén M , Neto M , Mayan O N 
Published: November 2007

Objectives:To investigate whether fertility is reduced among female shoe manufacturing workers exposed to organic solvents.Methods:A retrospective study was conducted on time to pregnancy (TTP) among 250 Portuguese shoe manufacturing workers exposed to solvents and 250 unexposed women working in stores of food units and storehouses. Data on TTP and related factors were collected by face-to-face interviews. The participation rate was 92%, and 81% of the workers (197 exposed women and 209 unexposed women) provided data for the analyses. Exposure assessment was based on hygienic measurements in the workplaces. TTP data were analysed with discrete proportional hazards regression.Results:Female exposure to solvents was associated with reduced fertility (adjusted fecundability density ratio (FDR) 0.55, CI 0.40 to 0.74 for low exposure, and FDR 0.70, CI 0.52 to 0.94 for high exposure). The findings were robust in different sensitivity analyses. A slightly stronger association was found among women with regular menstrual cycles. Exposure for less than 6 years was more strongly associated with reduced fertility (FDR 0.50, CI 0.30 to 0.83 and FDR 0.50, CI 0.28 to 0.90 for low and high exposure, respectively) than at least 6 years of exposure (FDR 0.60, CI 0.39 to 0.92 and FDR 0.86, CI 0.57 to 1.29 for low and high exposure, respectively). There was an interaction between solvent exposure and female smoking or use of coffee, the exposed women who smoke or use coffee being highly fecund.Conclusions:The findings provide further evidence that exposure to organic solvents is hazardous for female reproduction. The observed association may be related to any of the following solvents commonly used in shoe manufacturing:n-hexane and hexane isomers, toluene, methyl ethyl ketone, acetone, ethyl acetate and dichloromethane.
Size distribution and total number concentration of ultrafine and accumulation mode particles and hospital admissions in children and the elderly in Copenhagen, Denmark
Authors: Andersen Z J , Wahlin P , Raaschou-Nielsen O , Ketzel M , Scheike T , Loft S 
Published: November 2007

Objectives:To study the association between short-term exposure to ultrafine particles and morbidity in Copenhagen, Denmark.Methods:We studied the association between urban background levels of the total number concentration of particles (NCtot, 6–700 nm in diameter) measured at a single site (15 May 2001 to 31 December 2004) and hospital admissions due to cardiovascular (CVD) and respiratory disease (RD) in the elderly (age ⩾65 years), and due to asthma in children (age 5–18 years). We examined these associations in the presence of PM10, PM2.5(particulate matter <10 and 2.5 µm in diameter, respectively) and ambient gasses. We utilised data on size distribution to calculate NCtotfor four modes with median diameters 12, 23, 57 and 212 nm, and NC100(number concentration of particles <100 nm in diameter) and examined their associations with health outcomes. We used a time series Poisson generalised additive model adjusted for overdispersion, season, day of the week, public holidays, school holidays, influenza, pollen and meteorology, with up to 5 days’ lagged exposure.Results and conclusions:The adverse health effects of particulate matter on CVD and RD hospital admissions in the elderly were mainly mediated by PM10and accumulation mode particles with lack of effects for NC100. For paediatric asthma, accumulation mode particles, NC100and nitrogen oxides (mainly from traffic related sources) were relevant, whereas PM10appeared to have little effect. Our results suggest that particle volume/mass from long-range transported air pollution is relevant for CVD and RD admissions in the elderly, and possibly particle numbers from traffic sources for paediatric asthma.
Strong Convergence of Cesàro Mean Iterations for Nonexpansive Nonself-Mappings in Banach Spaces
Authors: Wangkeeree Rabian 
Published: November 2007

AbstractLet "Equation missing" be a real uniformly convex Banach space which admits a weakly sequentially continuous duality mapping from "Equation missing" to "Equation missing", "Equation missing" a nonempty closed convex subset of "Equation missing" which is also a sunny nonexpansive retract of "Equation missing", and "Equation missing" a non-expansive nonself-mapping with "Equation missing". In this paper, we study the strong convergence of two sequences generated by "Equation missing" and "Equation missing" for all "Equation missing", where "Equation missing", "Equation missing" is a real sequence in an interval "Equation missing", and "Equation missing" is a sunny non-expansive retraction of "Equation missing" onto "Equation missing". We prove that "Equation missing" and "Equation missing" converge strongly to "Equation missing" and "Equation missing", respectively, as "Equation missing", where "Equation missing" is a sunny non-expansive retraction of "Equation missing" onto "Equation missing". The results presented in this paper generalize, extend, and improve the corresponding results of Matsushita and Kuroiwa and many others.
An Algorithm Based on Resolvant Operators for Solving Positively Semidefinite Variational Inequalities
Authors: Sun Juhe , Zhang Shaowu , Zhang Liwei 
Published: November 2007

AbstractA new monotonicity, "Equation missing"-monotonicity, is introduced, and the resolvant operator of an "Equation missing"-monotone operator is proved to be single-valued and Lipschitz continuous. With the help of the resolvant operator, the positively semidefinite general variational inequality (VI) problem VI "Equation missing" is transformed into a fixed point problem of a nonexpansive mapping. And a proximal point algorithm is constructed to solve the fixed point problem, which is proved to have a global convergence under the condition that "Equation missing" in the VI problem is strongly monotone and Lipschitz continuous. Furthermore, a convergent path Newton method is given for calculating "Equation missing"-solutions to the sequence of fixed point problems, enabling the proximal point algorithm to be implementable.
Progressive loss of epidermal growth factor receptor in a subpopulation of breast cancers: implications in target-directed therapeutics
Authors: Choong Lee-Yee , Lim Simin , Loh Marie Chiew-Shia , Man Xiaohui , Chen Yunhao , Toy Weiyi , Pan Mengfei , Chen Chien-Shing , Poonepalli Anuradha , Hande M. Prakash , Tan Puay-Hoon , Salto-Tellez Manuel , Wong Chow-Yin , Shah Nilesh , Druker Brian J. , Lim Yoon-Pin 
Published: November 2007

AbstractUnderstanding the molecular etiology and heterogeneity of disease has a direct effect on cancer therapeutics. To identify novel molecular changes associated with breast cancer progression, we conducted phosphoproteomics of the MCF10AT model comprising isogenic, ErbB2- and ErbB3-positive, xenograft-derived cell lines that mimic different stages of breast cancer. Using in vitro animal model and clinical breast samples, our study revealed a marked reduction of epidermal growth factor receptor (EGFR) expression with breast cancer progression. Such diminution of EGFR expression was associated with increased resistance to Gefitinib/Iressa in vitro. Fluorescence in situ hybridization showed that loss of EGFR gene copy number was one of the key mechanisms behind the low/null expression of EGFR in clinical breast tumors. Statistical analysis on the immunohistochemistry data of EGFR expression from 93 matched normal and breast tumor samples showed that (a) diminished EGFR expression could be detected as early as in the preneoplastic lesion (ductal carcinoma in situ) and this culminated in invasive carcinomas; (b) EGFR expression levels could distinguish between normal tissue versus carcinoma in situ and invasive carcinoma with high statistical significance (P &lt; 0.001, n = 81). However, no significant correlation of EGFR expression with disease-free survival and overall survival was observed. This is the first time EGFR expression has been tracked meaningfully and developmentally from the normal condition through disease progression using in vitro, xenograft, and matched normal and tumor samples. Thus, our study provides a new insight into the role of EGFR in breast cancer development. Although no value of EGFR expression in prognosis was found, our findings are likely to have implications in the design of clinical trials targeting the EGFR family of proteins in breast cancer. [Mol Cancer Ther 2007;6(11):2828–42]
Discovery of lactoquinomycin and related pyranonaphthoquinones as potent and allosteric inhibitors of AKT/PKB: mechanistic involvement of AKT catalytic activation loop cysteines
Authors: Toral-Barza Lourdes , Zhang Wei-Guo , Huang Xinyi , McDonald Leonard A. , Salaski Edward J. , Barbieri Laurel R. , Ding Wei-Dong , Krishnamurthy Girija , Hu Yong Bo , Lucas Judy , Bernan Valerie S. , Cai Ping , Levin Jeremy I. , Mansour Tarek S. , Gibbons James J. , Abraham Robert T. , Yu Ker 
Published: November 2007

Abstract
The serine/threonine kinase AKT/PKB plays a critical role in cancer and represents a rational target for therapy. Although efforts in targeting AKT pathway have accelerated in recent years, relatively few small molecule inhibitors of AKT have been reported. The development of selective AKT inhibitors is further challenged by the extensive conservation of the ATP-binding sites of the AGC kinase family. In this report, we have conducted a high-throughput screen for inhibitors of activated AKT1. We have identified lactoquinomycin as a potent inhibitor of AKT kinases (AKT1 IC50, 0.149 ± 0.045 μmol/L). Biochemical studies implicated a novel irreversible interaction of the inhibitor and AKT involving a critical cysteine residue(s). To examine the role of conserved cysteines in the activation loop (T-loop), we studied mutant AKT1 harboring C296A, C310A, and C296A/C310A. Whereas the ATP-pocket inhibitor, staurosporine, indiscriminately targeted the wild-type and all three mutant-enzymes, the inhibition by lactoquinomycin was drastically diminished in the single mutants C296A and C310A, and completely abolished in the double mutant C296A/C310A. These data strongly implicate the binding of lactoquinomycin to the T-loop cysteines as critical for abrogation of catalysis, and define an unprecedented mechanism of AKT inhibition by a small molecule. Lactoquinomycin inhibited cellular AKT substrate phosphorylation induced by growth factor, loss of PTEN, and myristoylated AKT. The inhibition was substantially attenuated by coexpression of C296A/C310A. Moreover, lactoquinomycin reduced cellular mammalian target of rapamycin signaling and cap-dependent mRNA translation initiation. Our results highlight T-loop targeting as a new strategy for the generation of selective AKT inhibitors. [Mol Cancer Ther 2007;6(11):OF1–11]
Exemestane's 17-hydroxylated metabolite exerts biological effects as an androgen
Authors: Ariazi Eric A. , Leitão Andrei , Oprea Tudor I. , Chen Bin , Louis Teresa , Bertucci Anne Marie , Sharma Catherine G.N. , Gill Shaun D. , Kim Helen R. , Shupp Heather A. , Pyle Jennifer R. , Madrack Alexis , Donato Anne L. , Cheng Dong , Paige James R. , Jordan V. Craig 
Published: November 2007

Abstract
Aromatase inhibitors (AI) are being evaluated as long-term adjuvant therapies and chemopreventives in breast cancer. However, there are concerns about bone mineral density loss in an estrogen-free environment. Unlike nonsteroidal AIs, the steroidal AI exemestane may exert beneficial effects on bone through its primary metabolite 17-hydroexemestane. We investigated 17-hydroexemestane and observed it bound estrogen receptor α (ERα) very weakly and androgen receptor (AR) strongly. Next, we evaluated 17-hydroexemestane in MCF-7 and T47D breast cancer cells and attributed dependency of its effects on ER or AR using the antiestrogen fulvestrant or the antiandrogen bicalutamide. 17-Hydroexemestane induced proliferation, stimulated cell cycle progression and regulated transcription at high sub-micromolar and micromolar concentrations through ER in both cell lines, but through AR at low nanomolar concentrations selectively in T47D cells. Responses of each cell type to high and low concentrations of the non-aromatizable synthetic androgen R1881 paralleled those of 17-hydroexemestane. 17-Hydroexemestane down-regulated ERα protein levels at high concentrations in a cell type–specific manner similarly as 17β-estradiol, and increased AR protein accumulation at low concentrations in both cell types similarly as R1881. Computer docking indicated that the 17β-OH group of 17-hydroexemestane relative to the 17-keto group of exemestane contributed significantly more intermolecular interaction energy toward binding AR than ERα. Molecular modeling also indicated that 17-hydroexemestane interacted with ERα and AR through selective recognition motifs employed by 17β-estradiol and R1881, respectively. We conclude that 17-hydroexemestane exerts biological effects as an androgen. These results may have important implications for long-term maintenance of patients with AIs. [Mol Cancer Ther 2007;6(11):2817–27]
Imaging of hypoxia-driven gene expression in an orthotopic liver tumor model
Authors: Brader Peter , Riedl Christopher Cesare , Woo Yanghee , Ponomarev Vladimir , Zanzonico Pat , Wen Bixiu , Cai Shangde , Hricak Hedvig , Fong Yuman , Blasberg Ronald , Serganova Inna 
Published: November 2007

Abstract
The purpose of this study was to monitor hypoxia in an orthotopic liver tumor model using a hypoxia-sensitive reporter imaging system and to image enhanced gene expression after clamping the hepatic artery. C6 and RH7777 Morris hepatoma cells were transduced with a triple reporter gene (HSV1-tk/green fluorescent protein/firefly luciferase—triple fusion), placed under the control of a HIF-1–inducible hypoxia responsive element (HRE). The cells showed inducible luciferase activity and green fluorescent protein expression in vitro. Isolated reporter-transduced Morris hepatoma cells were used to produce tumors in livers of nude rats, and the effect of hepatic artery clamping was evaluated. Tumor hypoxia was shown by immunofluorescence microscopy with the hypoxia marker EF5 [2-(2-nitro-1H-imidazol-1-yl)-N-(2,2,3,3,3-pentafluoropropyl acetamide)] and the fluorescent perfusion marker Hoechst 33342, and by pO2 electrode measurements. For tumor hypoxia imaging with the HRE-responsive reporter, both luciferase bioluminescence and [18F]2′-fluoro-2′-deoxyarabinofuranosyl-5-ethyluracil positron emission tomography was done, and the presence of hypoxia in Morris hepatoma tumors were successfully imaged by both techniques. Transient clamping of the hepatic artery caused cessation of tumor perfusion and severe hypoxia in liver tumors, but not in adjacent liver tissue. These results show that the orthotopic reporter-transduced RH7777 Morris hepatomas are natively hypoxic and poorly perfused in this animal model, and that the magnitude of hypoxia can be monitored using a HRE-responsive reporter system for both bioluminescence and positron emission tomography imaging. However, the severity of tumor ischemia after permanent ligation of the hepatic artery limits our ability to image severe hypoxia in this animal model. [Mol Cancer Ther 2007;6(11):2900–8]
Stress testing at the cellular and molecular level to unravel cellular dysfunction and growth factor signal transduction defects: What Molecular Cell Biology can learn from Cardiology
Authors: Waltenberger Johannes 
Published: November 2007

SummaryClinical medicine has been revolutionized by the impact of cellular and molecular biology in the past 30 years. This article focuses on a novel approach, whereby the clinically proven and important concept of patient or organ stress testing is being applied to cellular models, thereby developing and validating novel quantitative molecular and cellular stress tests. One example is monocyte chemotaxis analysis, whereby circulating monocytes freshly isolated from peripheral blood are being tested for their migratory responsiveness towards relevant biological stimuli such as growth factors or chemokines. These stimuli are relevant for recruiting monocytes to sites of local inflammation such as during wound healing or arteriogenesis, i.e. growth of collateral arteries. Initial clinical studies to validate “ligand-induced monocyte chemotaxis” indicate that this parameter is impaired in the presence of various cardiovascular risk factors including diabetes mellitus, hypercholesterolemia or smoking. In addition, there is proof of concept that impaired monocyte chemotaxis is reversible as shown for anti-oxidants in smokers. Moreover, the parameter “ligand-induced monocyte chemotaxis” is of great relevance for basic science (including Molecular Cell Biology) as unravelling the underlying molecular mechanisms of cellular dysfunction will certainly stimulate our understanding of the molecular basis of cellular function. This article highlights the concept of stress testing in modern medicine. Cellular stress testing is introduced as a novel and intriguing approach, which was developed as bedside-to-bench. Future prospective clinical trials will have to validate the predictive value of cellular stress testing.
Development of a National Cruciate Ligament Surgery Registry
Authors: Granan Lars-Petter , Bahr Roald , Steindal Kjersti , Furnes Ove , Engebretsen Lars 
Published: November 2007

Background No prospective surveillance system exists for monitoring the outcome of cruciate ligament surgery. Purpose This article is intended to describe the development and procedures of the Norwegian National Knee Ligament Registry (NKLR), including baseline results from the first 2 years of operation. Study Design Cohort study (prevalence); Level of evidence, 1. Methods The NKLR was established on June 7, 2004 to collect information prospectively on all cases of cruciate ligament reconstruction surgery in Norway. Information on the details of surgery is gathered through a registration form completed by the surgeon postoperatively, and a validated knee outcome score form is completed by the patients preoperatively and at follow-ups on all patients at 2, 5, and 10 years postoperatively. Hospital compliance was examined in 2005 and 2006. Results A total of 2793 primary cruciate ligament reconstruction surgeries were registered by 57 hospitals. This corresponds to an annual population incidence of primary anterior cruciate ligament reconstruction surgeries of 34 per 100 000 citizens (85 per 100 000 citizens in the main at-risk age group of 16–39 years). After 21 months of operation, the NKLR had an overall compliance of 97% when compared with the hospital records. Conclusions A national population-based cruciate ligament registry has been developed, implemented, and maintained in Norway. The registry will each year enroll approximately 1500 primary cruciate ligament reconstruction cases. It is expected that inadequate procedures and devices can be identified, as well as prognostic factors associated with good and poor outcomes, at least for the most frequent categories.
Regional Foot Pressure during Running, Cutting, Jumping, and Landing
Authors: Orendurff Michael S. , Rohr Eric S. , Segal Ava D. , Medley Jonathan W. , Green John R. , Kadel Nancy J. 
Published: November 2007

Background Evaluating shoes during sport-related movements may provide a better assessment of plantar loads associated with repetitive injury and provide more specific data for comparing shoe cushioning characteristics. Hypothesis Accelerating, cutting, and jumping pressures will be higher than in straight running, differentiating regional shoe cushioning performance in sport-specific movements. Study Design Controlled laboratory study. Materials and Methods Peak pressures on seven anatomic regions of the foot were assessed in 10 male college athletes during running straight ahead, accelerating, cutting left, cutting right, jump take-off, and jump landing wearing Speed TD and Air Pro Turf Low shoes (Nike, Beaverton, Ore). Pedar insoles (Novel, Munich, Germany) were sampled at 99 Hz during the 6 movements. Results Cutting and jumping movements demonstrated more than double the pressure at the heel compared with running straight, regardless of shoe type. The Air Pro Turf showed overall lower pressure for all movement types ( P < .0377). Cutting to the left, the Air Pro Turf shoe had lower heel pressures (36.6 ± 12.5 N/cm2) than the Speed TD (50.3 ± 11.2 N/cm2) ( P < .0001), and the Air Pro Turf had lower great toe pressures than the Speed TD (44.8 ± 8.1 N/cm2 vs 54.4 ± 8.4 N/cm2; P = .0002). The Air Pro Turf also had significantly lower pressures than the Speed TD at the central forefoot during acceleration (38.2 ± 8.3 N/cm2 vs 50.8 ± 7.4 N/cm2; P <.0001). Conclusion Sport-related movements load the plantar surface of the foot more than running straight. Shoe cushioning characteristics were more robustly assessed during sport-related movements (4 significant results detected) compared with running straight (1 significant result detected). Clinical Relevance There is an interaction between shoe cushioning characteristics and sport-related movements that may influence plantar pressure and repetitive stress injuries.