bluuebunny/crossref_metadata_2025_split huggingface dataset:
New transition state–based inhibitor for human ornithine decarboxylase inhibits growth of tumor cells
Authors: Wu Fang , Grossenbacher Doris , Gehring Heinz 
Published: June 2007

AbstractPyridoxal 5′-phosphate (PLP)–dependent ornithine decarboxylase (ODC) is the key enzyme in polyamine synthesis. ODC is overexpressed in many tumor cells and thus a potential drug target. Here we show the design and synthesis of a coenzyme-substrate analogue as a novel precursor inhibitor of ODC. Structural analysis of the crystal structure of human ODC disclosed an additional hydrophobic pocket surrounding the ε-amino group of its substrate ornithine. Molecular modeling methods showed favorable interactions of the BOC-protected pyridoxyl-ornithine conjugate, termed POB, in the active site of human ODC. The synthesized and purified POB completely inhibited the activity of newly induced ODC activity at 100 μmol/L in glioma LN229 and COS7 cells. In correlation with the inhibition of ODC activity, a time-dependent inhibition of cell growth was observed in myeloma, glioma LN18 and LN229, Jurkat, COS7, and SW2 small-cell lung cancer cells if DNA synthesis and cell number were measured, but not in the nontumorigenic human aortic smooth muscle cells. POB strongly inhibited cell proliferation not only of low-grade glioma LN229 cells in a dose-dependent manner (IC50 ∼50 μmol/L) but also of high-grade glioblastoma multiforme cells. POB is much more efficient in inhibiting proliferation of several types of tumor cells than α-dl-difluoromethylornithine, the best known irreversible inhibitor of ODC. [Mol Cancer Ther 2007;6(6):1831–9]
Orphan G protein–coupled receptor GPR56 plays a role in cell transformation and tumorigenesis involving the cell adhesion pathway
Authors: Ke Ning , Sundaram Roshni , Liu Guohong , Chionis John , Fan Wufang , Rogers Cheryl , Awad Tarif , Grifman Mirta , Yu Dehua , Wong-Staal Flossie , Li Qi-Xiang 
Published: June 2007

Abstract
GPR56 is an orphan G protein–coupled receptor, mutations of which have recently been associated with bilateral frontoparietal polymicrogyria, a rare neurologic disease that has implications in brain development. However, no phenotype beyond central nervous system has yet been described for the GPR56-null mutations despite abundant GPR56 expression in many non–central nervous system adult tissues. In the present study, we show that higher GPR56 expression is correlated with the cellular transformation phenotypes of several cancer tissues compared with their normal counterparts, implying a potential oncogenic function. RNA interference–mediated GPR56 silencing results in apoptosis induction and reduced anchorage-independent growth of cancer cells via increased anoikis, whereas cDNA overexpression resulted in increased foci formation in mouse fibroblast NIH3T3 cell line. When GPR56 silencing was induced in vivo in several xenograft tumor models, significant tumor responses (including regression) were observed, suggesting the potential of targeting GPR56 in the development of tumor therapies. The expression profiling of GPR56-silenced A2058 melanoma cell line revealed several genes whose expression was affected by GPR56 silencing, particularly those in the integrin-mediated signaling and cell adhesion pathways. The potential role of GPR56 in cancer cell adhesion was further confirmed by the observation that GPR56 silencing also reduced cell adhesion to the extracellular matrix, which is consistent with the observed increase in anoikis and reduction in anchorage-independent growth phenotypes. The oncogenic potential and apparent absence of physiologic defects in adult human tissues lacking GPR56, as well as the targetable nature of G protein–coupled receptor by small molecule or antibody, make GPR56 an attractive drug target for the development of cancer therapies. [Mol Cancer Ther 2007;6(6):1840–50]
Mismatched nucleotides as the lesions responsible for radiosensitization with gemcitabine: a new paradigm for antimetabolite radiosensitizers
Authors: Flanagan Sheryl A. , Robinson Blaine W. , Krokosky Christina M. , Shewach Donna S. 
Published: June 2007

Abstract
Radiation sensitization by 2′,2′-difluoro-2′-deoxycytidine (dFdCyd) has correlated with dATP depletion [dFdCDP-mediated inhibition of ribonucleotide reductase (RR)] and S-phase accumulation. We hypothesized that radiosensitization by dFdCyd is due to nucleotide misincorporations in the presence of deoxynucleotide triphosphate pool imbalances, which, if not repaired, augments cell death following irradiation. The ability of dFdCyd to produce misincorporations was measured as pSP189 plasmid mutations in hMLH1-deficient [mismatch repair (MMR) deficient] and hMLH1-expressing (MMR proficient) HCT116 cells. Only MMR-deficient cells showed a significant increase in nucleotide misincorporations (2- to 3-fold increase; P ≤ 0.01) after radiosensitizing concentrations of dFdCyd ± 5 Gy radiation, which persisted for at least 96 h. dFdCyd (10 nmol/L) did not radiosensitize MMR-proficient HCT116 or A549 cells, but following small interfering RNA–mediated suppression of hMLH1, this concentration produced excellent radiosensitization (radiation enhancement ratios = 1.6 ± 0.1 and 1.5 ± 0.1, respectively; P &lt; 0.05) and a 2.5-fold increase in mutation frequency in A549 cells. Cytosine arabinoside (1-β-d-arabinofuranosylcytosine), which can be incorporated into DNA but does not inhibit RR, failed to radiosensitize MMR-deficient cells or increase mutation frequency in the MMR-deficient and MMR-proficient cells. However, the RR inhibitor hydroxyurea radiosensitized MMR-deficient cells and increased nucleotide misincorporations (≥5-fold increase; P &lt; 0.05), thus further implicating the inhibition of RR as the mechanism underlying radiosensitization by dFdCyd. These data showed that the presence and persistence of mismatched nucleotides is integral to radiosensitization by dFdCyd and suggest a role for hMLH1 deficiency in eliciting the radiosensitizing effect. [Mol Cancer Ther 2007;6(6):1858–68]
Primary versus Single-Stage Revision Anterior Cruciate Ligament Reconstruction Using Autologous Hamstring Tendon Grafts
Authors: Weiler Andreas , Schmeling Arno , Stöhr Ivonne , Kääb Max J. , Wagner Michael 
Published: June 2007

Background There is a low level of evidence about clinical results after anterior cruciate ligament (ACL) revision reconstruction using autologous hamstring tendon grafts. Hypothesis Anterior cruciate ligament revision reconstruction improves knee stability but shows inferior results for functional and subjective outcome and knee stability compared with primary reconstruction. Study Design Cohort study; Level of evidence, 2. Methods Between October 1997 and July 2005, 166 single-stage or 2-stage revision ACL reconstructions were done using different graft types. One hundred twenty-four cases underwent a single-stage revision reconstruction with autologous hamstring tendon grafts. At the time of data analysis, 67 cases fulfilled the criteria of minimum 2-year follow-up. Five patients were lost to follow-up (follow-up rate, 91%). Four patients (6%) who experienced graft rupture were counted as failures but not subjected to further detailed analysis. Because of loss to follow-up and exclusion criteria (n = 12), 50 patients were included in the study. For a comparative matched-group analysis, patients with a primary hamstring tendon graft ACL reconstruction were selected out of a database with minimum 2 years’ follow-up (N = 284). Patients were followed using the International Knee Documentation Committee (IKDC) and Lysholm scores, KT-1000 arthrometer testing, and additional functional tests. Results Four of 62 available patients (6.5%) in the revision group experienced graft failure, which was comparable to 16 of 284 (5.6%) in the primary reconstruction group. When the 2 matched groups of 50 patients were further compared, postoperative IKDC results showed no significant differences between groups. The manual maximum KT-1000 arthrometer side-to-side difference was 2.1 ± 1.6 mm for the revision group and 2.2 ± 1.1 mm for the primary reconstruction group. The Lysholm score was significantly better in the primary reconstruction group (P = .014). The incidence of postoperative positive pivot-shift test results was not significantly different. The primary reconstruction group showed significantly less extension deficits. Functional testing revealed significantly better results for the primary reconstruction group for stair climbing, squatting, knee bending, and duck walk. Conclusions In our patient series, primary ACL reconstruction showed significantly better results in Lysholm score, although the IKDC score and objective knee stability showed no significant difference between the groups. Thus, parameters other than measurable knee stability must be responsible for the inferior results of the revision reconstruction group.
ISHAPE: new rapid and accurate software for haplotyping
Authors: Delaneau Olivier , Coulonges Cédric , Boelle Pierre-Yves , Nelson George , Spadoni Jean-Louis , Zagury Jean-François 
Published: June 2007

Abstract

Background
We have developed a new haplotyping program based on the combination of an iterative multiallelic EM algorithm (IEM), bootstrap resampling and a pseudo Gibbs sampler. The use of the IEM-bootstrap procedure considerably reduces the space of possible haplotype configurations to be explored, greatly reducing computation time, while the adaptation of the Gibbs sampler with a recombination model on this restricted space maintains high accuracy. On large SNP datasets (>30 SNPs), we used a segmented approach based on a specific partition-ligation strategy. We compared this software, Ishape (Iterative Segmented HAPlotyping by Em), with reference programs such as Phase, Fastphase, and PL-EM. Analogously with Phase, there are 2 versions of Ishape: Ishape1 which uses a simple coalescence model for the pseudo Gibbs sampler step, and Ishape2 which uses a recombination model instead.

Results
We tested the program on 2 types of real SNP datasets derived from Hapmap: adjacent SNPs (high LD) and SNPs spaced by 5 Kb (lower level of LD). In both cases, we tested 100 replicates for each size: 10, 20, 30, 40, 50, 60, and 80 SNPs. For adjacent SNPs Ishape2 is superior to the other software both in terms of speed and accuracy. For SNPs spaced by 5 Kb, Ishape2 yields similar results to Phase2.1 in terms of accuracy, and both outperform the other software.
In terms of speed, Ishape2 runs about 4 times faster than Phase2.1 with 10 SNPs, and about 10 times faster with 80 SNPs. For the case of 5kb-spaced SNPs, Fastphase may run faster with more than 100 SNPs.

Conclusion
These results show that the Ishape heuristic approach for haplotyping is very competitive in terms of accuracy and speed and deserves to be evaluated extensively for possible future widespread use.
Prognostic factors associated with the survival of oral and pharyngeal carcinoma in Taiwan
Authors: Chen Ping-Ho , Shieh Tien-Yu , Ho Pei-Shan , Tsai Chi-Cheng , Yang Yi-Hsin , Lin Ying-Chu , Ko Min-Shan , Tsai Pei-Chien , Chiang Shang-Lun , Tu Hung-Pin , Ko Ying-Chin 
Published: June 2007

Abstract

Background
In Taiwan, a distinct ethnic group variation in incidence and mortality rates has been suggested for most carcinomas. Our aim is to identify the role of prognostic factors associated with the survival of oral and pharyngeal carcinoma in Taiwan.

Methods
Taiwan Cancer Registry records of 9039 subjects diagnosed with oral and pharyngeal carcinoma were analyzed. The population was divided into three ethnic groups by residence, which were Taiwanese aborigines, Hakka and Hokkien communities. Five-year survival rates were estimated by Kaplan-Meier methods. Ethnic curves differed significantly by log-rank test; therefore separate models for Taiwanese aborigines, Hakka and Hokkien were carried out. The Cox multivariate proportional hazards model was used to examine the role of prognostic factors on ethnic survival.

Results
The five-year survival rates of oral and pharyngeal carcinoma were significantly poorer for Hokkien community (53.9%) and Taiwanese aborigines community (58.1%) compared with Hakka community (60.5%). The adjusted hazard ratio of Taiwanese aborigines versus Hakka was 1.07 (95%CI, 0.86–1.33) for oral and pharyngeal carcinoma mortality, and 1.16 (95%CI, 1.01–1.33) for Hokkien versus Hakka. Males had significantly poor prognosis than females. Subjects with tongue and/or mouth carcinoma presented the worst prognosis, whereas lip carcinoma had the best prognosis. Subjects with verrucous carcinoma had better survival than squamous cell carcinoma. Prognosis was the worst in elderly subjects, and subjects who underwent surgery had the highest survival rate.

Conclusion
Our study presented that predictive variables in oral and pharyngeal carcinoma survival have been: ethnic groups, period of diagnosis, gender, diagnostic age, anatomic site, morphologic type, and therapy.
Deficient supplies of drugs for life threatening diseases in an African community
Authors: Lufesi Norman N , Andrew Marit , Aursnes Ivar 
Published: June 2007

Abstract

Background
In Malawi essential drugs are provided free of charge to patients at all public health facilities in order to ensure equitable access to health care. The country thereby spends about 30% of the national health budget on drugs. In order to investigate the level of drug shortages and eventually find the reasons for the drugs shortages in Malawi, we studied the management of the drug supplies for common and life threatening diseases such as pneumonia and malaria in a random selection of health centres.

Methods
In July and August 2005 we visited eight out of a total of 37 health centres chosen at random in the Lilongwe District, Malawi. We recorded the logistics of eight essential and widely used drugs which according to the treatment guidelines should be available at all health centres. Five drugs are used regularly to treat pneumonia and three others to treat acute malaria. Out-of-stock situations in the course of one year were recorded retrospectively. We compared the quantity of each drug recorded on the Stock Cards with the actual stock of the drug on the shelves at the time of audit. We reviewed 8,968 Patient Records containing information on type and amount of drugs prescribed during one month.

Results
On average, drugs for treating pneumonia were out of stock for six months during one year of observation (median value 167 days); anti-malarial drugs were lacking for periods ranging from 42 to138 days. The cross-sectional audit was even more negative, but here too the situation was more positive for anti-malarial drugs. The main reason for the shortage of drugs was insufficient deliveries from the Regional Medical Store. Benzyl penicillin was in shortest supply (4% received). The median value for non-availability was 240 days in the course of a year. The supply was better for anti-malarial drugs, except for quinine injections (9 %). Only 66 % of Stock Card records of quantities received were reflected in Patient Records showing quantities dispensed.

Conclusion
We conclude that for the eight index drugs the levels of supply are unacceptable. The main reason for the observed shortage of drugs at the health centres was insufficient deliveries from the Regional Medical Store. A difference between the information recorded on the Stock Cards at the health centres and that recorded in the Patient Records may have contributed to the overall poor drug supply situation. In order to ensure equitable access to life saving drugs, logistics in general should be put in order before specific disease management programmes are initiated.
LongSAGE analysis of skeletal muscle at three prenatal stages in Tongcheng and Landrace pigs
Authors: Tang Zhonglin , Li Yong , Wan Ping , Li Xiaoping , Zhao Shuhong , Liu Bang , Fan Bin , Zhu Mengjin , Yu Mei , Li Kui 
Published: June 2007

Abstract
Background
Obese and lean pig breeds show obvious differences in muscle growth; however, the molecular mechanism underlying phenotype variation remains unknown. Prenatal muscle development programs postnatal performance. Here, we describe a genome-wide analysis of differences in prenatal skeletal muscle between Tongcheng (a typical indigenous Chinese breed) and Landrace (a leaner Western breed) pigs.

Results
We generated transcriptome profiles of skeletal muscle from Tongcheng and Landrace pigs at 33, 65 and 90 days post coitus (dpc), using long serial analysis of gene expression (LongSAGE). We sequenced 317,115 LongSAGE tags and identified 1,400 and 1,201 differentially expressed transcripts during myogenesis in Tongcheng and Landrace pigs, respectively. From these, the Gene Ontology processes and expression patterns of these differentially expressed genes were constructed. Most of the genes showed different expression patterns in the two breeds. We also identified 532, 653 and 459 transcripts at 33, 65 and 90 dpc, respectively, that were differentially expressed between the two breeds. Growth factors, anti-apoptotic factors and genes involved in the regulation of protein synthesis were up-regulated in Landrace pigs. Finally, 12 differentially expressed genes were validated by quantitative PCR.

Conclusion
Our data show that gene expression phenotypes differ significantly between the two breeds. In particular, a slower muscle growth rate and more complicated molecular changes were found in Tongcheng pigs, while genes responsible for increased cellular growth and myoblast survival were up-regulated in Landrace pigs. Our analyses will assist in the identification of candidate genes for meat production traits and elucidation of the development of prenatal skeletal muscle in mammals.
The extra domain A of fibronectin stimulates murine mast cells via Toll-like receptor 4
Authors: Gondokaryono Srie Prihianti , Ushio Hiroko , Niyonsaba François , Hara Mutsuko , Takenaka Hiroshi , Jayawardana Sumanasiri T M , Ikeda Shigaku , Okumura Ko , Ogawa Hideoki 
Published: June 2007

AbstractThe activation of mast cells by extra domain A of fibronectin (FN-EDA), an endogenous ligand of TLR4, and its contribution to the pathogenesis of rheumatoid arthritis (RA) in vivo were examined. FN-EDA, but no other domain of the fibronectin fragment, III11 (FN-III11) and III12 (FN-III12), stimulated bone marrow-derived murine mast cells (BMMCs) dose-dependently to secret cytokines (TNF-α, IL-6, and IL-1β), similar to the pattern produced by LPS. FN-EDA-induced cytokine production was mediated by TLR4, as cytokine production by FN-EDA was absent in TLR4-deficient (TLR4−/−) BMMCs. We examined the roles of TLR4-mediated mast cell activation by this form of fibronectin fragment in the pathogenesis of RA in vivo. The injection of FN-EDA, but not FN-III11and FN-III12, to joints resulted in joint swelling of mice in vivo. Genetically mast cell-deficient WBB6F1-W/Wv mice exhibited significantly less swelling and cytokine production compared with mast cell-sufficient +/+ mice, suggesting that swelling and inflammatory cytokine production were partially dependent on tissue mast cells. Reduced swelling and cytokine production were recovered by the reconstitution of tissue mast cells by the injection of BMMCs from wild-type mice but not from TLR4−/− mice. Altogether, these results suggest that the TLR4-mediated activation of mast cells by endogenous ligand FN-EDA might contribute to the pathogenesis of RA through proinflammatory cytokine production.
Techniques for predicting the lifetimes of wave-swept macroalgae: a primer on fracture mechanics and crack growth
Authors: Mach Katharine J. , Nelson Drew V. , Denny Mark W. 
Published: June 2007

SUMMARYBiomechanical analyses of intertidal and shallow subtidal seaweeds have elucidated ways in which these organisms avoid breakage in the presence of exceptional hydrodynamic forces imposed by pounding surf. However, comparison of algal material properties to maximum hydrodynamic forces predicts lower rates of breakage and dislodgment than are actually observed. Why the disparity between prediction and reality? Most previous research has measured algal material properties during a single application of force, equivalent to a single wave rushing past an alga. In contrast, intertidal macroalgae may experience more than 8000 waves a day. This repeated loading can cause cracks– introduced, for example, by herbivory or abrasion – to grow and eventually cause breakage, yet fatigue crack growth has not previously been taken into account. Here, we present methods from the engineering field of fracture mechanics that can be used to assess consequences of repeated force imposition for seaweeds. These techniques allow quantification of crack growth in wave-swept macroalgae, a first step towards considering macroalgal breakage in the realistic context of repeated force imposition. These analyses can also be applied to many other soft materials.
Death by small forces: a fracture and fatigue analysis of wave-swept macroalgae
Authors: Mach Katharine J. , Hale Benjamin B. , Denny Mark W. , Nelson Drew V. 
Published: June 2007

SUMMARY
Wave-swept macroalgae are subjected to large hydrodynamic forces as each wave breaks on shore, loads that are repeated thousands of times per day. Previous studies have shown that macroalgae can easily withstand isolated impositions of maximal field forces. Nonetheless, macroalgae break frequently. Here we investigate the possibility that repeated loading by sub-lethal forces can eventually cause fracture by fatigue. We determine fracture toughness, in the form of critical strain energy release rate, for several flat-bladed macroalgae, thereby assessing their resistance to complete fracture in the presence of cracks. Critical energy release rates are evaluated through single-edge-notch, pull-to-break tests and single-edge-notch, repeated-loading tests. Crack growth at sub-critical energy release rates is measured in repeated-loading tests, providing a first assessment of algal breakage under conditions of repeated loading. We then estimate the number of imposed waves required for un-notched algal blades to reach the point of complete fracture. We find that, if not checked by repair, fatigue crack growth from repeated sub-lethal stresses may completely fracture individuals within days. Our results suggest that fatigue may play an important role in macroalgal breakage.
Physiological regulation of glucose transporter (GLUT4) protein content in brown trout (Salmo trutta) skeletal muscle
Authors: Díaz Mònica , Capilla Encarnación , Planas Josep V. 
Published: June 2007

SUMMARYIn brown trout, red and white skeletal muscle express the insulin-regulatable glucose transporter 4 (btGLUT4). We have previously shown that the mRNA expression of btGLUT4 in red muscle, but not white muscle, is altered under experimental conditions designed to cause changes in the plasma levels of insulin, such as fasting, insulin and arginine administration. In order to determine whether changes of btGLUT4 expression at the mRNA level are correlated with changes at the protein level, we performed in vivoexperiments to alter blood insulin concentrations and determined the abundance of btGLUT4 protein in trout red and white skeletal muscle by immunoblotting using an antibody to salmon GLUT4. In the present study we show that btGLUT4 protein content in red muscle decreases after fasting and increases after insulin administration. By contrast, btGLUT4 protein content in white muscle decreases after fasting but is not affected by insulin treatment. Our results show a good correlation between the changes observed in btGLUT4 protein and the previously reported changes in mRNA levels in response to alterations in circulating insulin, indicating that the regulation of btGLUT4 in brown trout takes place predominantly in the red skeletal muscle.