bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prognostic value and functional consequences of cell cycle inhibitor p27Kip1 loss in medulloblastoma
Authors: Hatton Beryl A , Ellison David W , Gajjar Amar , Kool Marcel , Fero Matthew , Olson James M 
Published: March 2013

Abstract

Background
The cyclin-dependent kinase inhibitor p27Kip1 functions during normal cerebellar development and has demonstrated tumor suppressor functions in mouse models of medulloblastoma. Because P27 loss is associated with increased proliferation, we assessed whether P27 absence in surgical medulloblastoma specimens correlated with response to therapy in pediatric patients enrolled in two large studies. Additionally, we examined the functional consequence of p27

Kip1
loss in the SmoA1 medulloblastoma model to distinguish whether p27Kip1 reduces tumor initiation or slows tumor progression.

Findings
Analysis of 87 well-characterized patient samples identified a threshold of P27 staining at which significant P27 loss correlated with poor patient outcome. The same criteria, applied to a second test set of tissues from 141 patients showed no difference in survival between patients with minimal P27 staining and others, suggesting that P27 levels alone are not a sufficient prognostic indicator for identifying standard-risk patients that may fail standard therapy. These findings were in contrast to prior experiments completed using a mouse medulloblastoma model. Analysis of cerebellar tumor incidence in compound mutant mice carrying the activated Smoothened (SmoA1) allele that were heterozygous or nullizygous for p27

Kip1
revealed that p27Kip1 loss did not alter the frequency of tumor initiation. Tumors haploinsufficient or nullizygous for p27

Kip1
were, however, more invasive and displayed a higher proliferative index, suggesting p27Kip1 loss may contribute to SmoA1 medulloblastoma progression.

Conclusions
These studies revealed P27 loss affects medulloblastoma progression rather than initiation and that this putative biomarker should not be used for stratifying children with medulloblastoma to risk-based therapeutic regimens.
In vitro characterization of a chitosan skin regenerating template as a scaffold for cells cultivation
Authors: Mohd Hilmi Abu Bakar , Halim Ahmad Sukari , Hassan Asma , Lim Chin Keong , Noorsal Kartini , Zainol Ismail 
Published: March 2013

Abstract
Chitosan is a marine-derived product that has been widely used in clinical applications, especially in skin reconstruction. The mammalian scaffolds derived from bovine and porcine material have many limitations, for example, prion transmission and religious concerns. Therefore, we created a chitosan skin regenerating template (SRT) and investigated the behavior of fibroblast cell-scaffold constructs. Primary human dermal fibroblasts (HDF) were isolated and then characterized using vimentin and versican. HDF were seeded into chitosan SRT at a density of 3×106 cells/cm2 for fourteen days. Histological analysis and live cells imaging revealed that the cell-chitosan constructs within interconnected porous chitosan showed significant interaction between the cells as well as between the cells and the chitosan. Scanning electron microscopy (SEM) analysis revealed cells spreading and covering the pores. As the pore sizes of the chitosan SRT range between 40–140 μm, an average porosity is about 93 ± 12.57% and water uptake ratio of chitosan SRT is 536.02 ± 14.29%, it is a supportive template for fibroblast attachment and has potential in applications as a dermal substitute.
Phase III Randomized, Placebo-Controlled Trial of Docetaxel With or Without Gefitinib in Recurrent or Metastatic Head and Neck Cancer: An Eastern Cooperative Oncology Group Trial
Authors: Argiris Athanassios , Ghebremichael Musie , Gilbert Jill , Lee Ju-Whei , Sachidanandam Kamakshi , Kolesar Jill M. , Burtness Barbara , Forastiere Arlene A. 
Published: March 2013

PurposeWe hypothesized that the addition of gefitinib, an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, to docetaxel would enhance therapeutic efficacy in squamous cell carcinoma of the head and neck (SCCHN).Patients and MethodsPatients with recurrent or metastatic SCCHN with Eastern Cooperative Oncology Group (ECOG) performance status of 2, or patients with ECOG performance status of 0 to 2 but were previously treated with chemotherapy, were randomly assigned to receive weekly docetaxel plus either placebo (arm A) or gefitinib 250 mg/d, orally (arm B) until disease progression. At the time of progression, patients in the placebo arm could receive single-agent gefitinib. EGFR, c-MET, and KRAS mutations and polymorphisms in drug metabolizing enzymes and transporters were evaluated by pyrosequencing.ResultsTwo hundred seventy patients were enrolled before the study was closed early at interim analysis (arm A, n = 136; arm B, n = 134). Median overall survival was 6.0 months in arm A versus 7.3 months in arm B (hazard ratio, 0.93; 95% CI, 0.72 to 1.21; P = .60). An unplanned subset analysis showed that gefitinib improved survival in patients younger than 65 years (median 7.6 v 5.2 months; P = .04). Also, there was a trend for improved survival in patients with c-MET wild-type (5.7 v 3.6 months; P = .09) regardless of treatment. Grade 3/4 toxicities were comparable between the two arms except that grade 3/4 diarrhea was more common with docetaxel/gefitinib. Of 18 eligible patients who received gefitinib after disease progression in arm A, one patient had a partial response.ConclusionThe addition of gefitinib to docetaxel was well tolerated but did not improve outcomes in poor prognosis but otherwise unselected patients with SCCHN.
A Positive Regulatory Domain in CCAAT/Enhancer Binding Protein β (C/EBPβ) Is Required for the Glucocorticoid-Mediated Displacement of Histone Deacetylase 1 (HDAC1) from the C/ebpα Promoter and Maximum Adipogenesis
Authors: Abdou Houssein-Salem , Atlas Ella , Haché Robert J. G. 
Published: March 2013

AbstractGlucocorticoids promote adipogenesis and contribute to the metabolic syndrome through a number of mechanisms. One of the effectors of glucocorticoid action is the CCAAT/enhancer binding protein β (C/EBPβ). C/EBPβ is a basic leucine-zipper transcription factor involved in diverse processes including differentiation, cellular proliferation, and inflammation. C/EBPβ transcriptional activity is regulated, in part, by its acetylation profile resulting from its dynamic interaction with either acetylases general control nonrepressed protein 5/p300/CBP associated factor (GCN5/PCAF) or deacetylase complexes (mSin3A/histone deacetylase 1 [HDAC1]). Glucocorticoid treatment of preadipocytes promotes C/EBPβ acetylation, leading to mSin3A/HDAC1 dissociation from C/EBPβ and resulting in C/ebpα promoter activation at the onset of adipogenesis, thus increasing the differentiation rate. We recently showed that the regulatory domain 1 (RD1) of C/EBPβ contains four residues (153–156) required for its interaction with HDAC1, therefore supporting RD1 proposed inhibitory role. In an attempt to further elucidate the intrinsic regulatory property of RD1, we sought to characterize the regulatory potential of the N terminus region of RD1 (residues 141–149). In this study, we show that C/EBPβΔ141–149 transcriptional activity was compromised on the C/ebpα, but not on the Pparγ, promoter. Additionally, the ability of C/EBPβΔ141–149 to induce adipogenesis in NIH 3T3 cells was compromised when compared with C/EBPβwt owing to a delayed expression of C/ebpα at the onset of differentiation. Furthermore, the data suggest that the reduced expression of C/ebpα in cells expressing C/EBPβΔ141–149 was due to a persistent recruitment of HDAC1 to the C/ebpα promoter after glucocorticoid treatment. Together, these results suggest that amino acids 141–149 of C/EBPβ act as a positive regulatory domain required for maximum transcriptional activity.
Facile Synthesis of Well-dispersed Hollow Mesoporous Silica Nanoparticles Using Iron Oxide Nanoparticles as Template
Authors: Ikuno Takaaki , Nomura Atsuro , Iyoki Kenta , Sugawara-Narutaki Ayae , Okubo Tatsuya , Shimojima Atsushi 
Published: March 2013

Abstract
A facile approach is demonstrated for the preparation of hollow mesoporous silica nanoparticles with large pore volume and high dispersibility. Core–shell nanoparticles consisting of iron oxide (α-Fe2O3) core and mesostructured silica–surfactant composite shell are treated with hexamethyldisiloxane under acidic conditions to achieve capping of silanol groups and removal of both surfactants and the Fe2O3 cores in a single step.
Retained surgical sponges, needles and instruments
Authors: Hariharan D , Lobo DN 
Published: March 2013

Introduction Retained sponges and instruments (RSI) due to surgery are a recognised medical ‘never event’ and have catastrophic implications for patients, healthcare professionals and medical care providers. The aim of this review was to elucidate the extent of the problem of RSI and to identify preventative strategies. Methods A comprehensive literature search was performed on MEDLINE®, Embase™, the Science Citation Index and Google™ Scholar for articles published in English between January 2000 and June 2012. Studies outlining the incidence, risk, management and attempts to prevent RSI following surgical intervention were retrieved. Results The overall incidence of RSI is low although its incidence is substantially higher in operations performed on open cavities. Sponges are the most commonly retained item when compared with needles and instruments. Clinical presentation is varied, leading to avoidable morbidity, and the error is indefensible medicolegally. Risk factors include emergency operations, operations involving unexpected change in procedure, raised body mass index, and a failure to perform accurate sponge and instrument counts. The existing strategy for prevention is manual counting of sponges and instruments undertaken by surgical personnel. This, however, is fallible. Computer assisted counting of sponges using barcodes and gauze sponges tagged with a radiofrequency identification device aiding manual counting have been trialled recently, with success. Conclusions Vigilance among operating theatre personnel is paramount if RSI is to be prevented. Prospective multicentre trials to assess efficacy of new technologies aiding manual counting should be undertaken if this medical error is to be eliminated completely.
The Clinical Significance of Urinary Neopterin in the Follow-up of Patients after Exeresis of a Malignant Melanoma
Authors: Mura P. , Barriere M. , Papet Y. , Reiss D. , Camenen I. , Vaillant L. , Lorette G. 
Published: March 2013

Summary Serial urinary neopterin determinations were performed in 151 patients after exeresis of a malignant melanoma. Values for patients clinically free of disease at the end of the observation were similar to those of healthy subjects. No significant varia tions were observed in patients with cutaneous meta stases. The most important variations were found in patients who developed ganglionic and above all visceral metastases. These data suggest that neopterin determination could be very useful in the follow-up of patients with a malignant melanoma and especially for detecting visceral metastases occurences.
Insights into Enzymic Catalysis from Studies on Dihydrofolate Reductases
Authors: Benkovic Stephen J. , Adams Joseph A. , Fierke Carol A. , Naylor Adel M. 
Published: March 2013

Summary The role of DHFR in the maintenance of cellular DNA has sparked wide interest in the structure and dynamics of this enzyme. Kinetic studies of specific amino acid replacements on the enzyme isolated from E. coli has proved useful in the detailing of hydrophobic and ionic interactions both proximal and distal to the site of chemical transformation (e. g. Phe-31, Leu-54 and Arg-44). Despite the low sequence homology shared by the E. coli and L. easei enzymes, the free energy profiles are surprisingly comparable. This probably is the result of the high degree of structural similarity of the active site surfaces, but the deleterious effects of subtle replacements (e. g. Leu-54-Ile) at strictly conserved amino acids underscore the latters unique role in attaining the required catalytic efficiency for the enzyme.
Pteridines, LXXXVIII. Oxidations and Reactions of 2- and 4-Thiolumazine Derivatives. Synthesis and Properties of Pteridine-Sulfinates and -sulfonates
Authors: Bartke Michael , Pfleiderer Wolfgang 
Published: March 2013

Summary Selective oxidations of 2-thiolumazines (10-12) by H20 2 and KMn04 respectively in basic medium led to the corresponding stable pteridin-4-one-2-sulfinates (13-15) and -sulfonates (16-18), which can be isolated in the form of their potassium salts. On oxidation of 6,7-diphenyl-2-thiolumazine (12) with 1 equivalent of H20 2 resulted the 6,7-diphenyl-pteridin-4-one-2-sulfenate (22), which is regarded as an intermediate in the formation of the sulfinates. Characterization was done by elemental analysis, pKa determination, and UV-, IR- and IH-NMR-spectra.Acid and base hydrolyse the sulfinate and sulfonate groups to the 2-hydroxy derivative. Treatment of the pteridin-4-one-2-sulfinate with strong anhydrous acids such as formic acid or sulfuric acid affects S02 elimination to the corresponding 2-H-pteridin-4-one (19-21).The oxidative desulfurization of 2-thiolumazines can be achieved directly with H20 2 and m-chloroperbenzoic acid in formic acid. Analogously nucleophilic displacement reactions of the 2-thione group proceeded under mild conditions by H20 2 oxidation in the presence of various amines to give the corresponding pterin derivatives (25.-;-32, 36-39). 6,7-Diphenyl-4-thiolumazine (44) shows similar reactions on oxidation in the presence of amines (43, 54), but the corresponding 4-sulfinate and sulfonate are too unstable in this series to be isolated. S02 elimination does not take place since hydrolysis is the preferred reaction mode.
Pteridines, IXC. Synthesis, Oxidations and Reactions of 6- and 7-Hydroxy-2-thiolumazines Selective Cytotoxicity of Carboxypeptidase-activated Methotrexate ex-Peptides
Authors: Bartke Michael , Pfleiderer Wolfgang 
Published: March 2013

Summary Various 6-(10, 11) and 7-hydroxy-2-thiolumazines (8,9) have been synthesized and oxidations of the thioamide function studied . H20 2 Oxidation of 7-hydroxy-2-thiolumazine (8) in basic medium leads to pteridine-4,7- dione-2-sulfinate (12), which eliminates S02 in anhydrous acids. Oxidative desulfurization of 8 and its 8- methyl derivative 9 proceeds directly in formic acid with H20 2 and m-chloroperbenzoic acid to give 16 and 17 respectively. KMn04 oxidation forms the pteridine-4,7,dione-2-sulfonates (14, 15), which react under hydrolytic conditions to give the corresponding 2-hydroxy derivtives (18, 19) and on displacement with ammonium acetate/ammonia at elevated temperature form the pterin derivatives 20 and 21.2-Thio-pteridine-4,6-dione (10) oxidizes also to the corresponding 2-sulfonate (22), which could only be isolated after addition of potassium bisulfite in the form of the dipotassium 7,8-dihydropteridine-4,6-dione- 2,7-disulfonate (23) adduct.The newly synthesized compounds have been characterized by elemental analyses, pKa determinations, UVand IH-NMR-spectra.
Selective Cytotoxicity of Carboxypeptidase-activated Methotrexate ex-Peptides
Authors: Vitols Karin S. , Montejano Yolanda D. , Kuefner Ulrike , Huennekens F. M. 
Published: March 2013

Summary Methotrexate ex-pep tides (derivatives in which an amino acid is linked covalently to the ex-carboxyl of the glutamate residue on the parent drug) can be hydrolyzed by specific carboxypeptidases to yield free Methotrexate (MTX) and the corresponding amino acid. Studies with L12l0 cells in suspension culture have shown that the MTX pep tides can serve as "pro-drugs": Because of their inability to be taken up by cells, they are relatively non-toxic. When co-administered with appropriate carboxypeptidases, however, they become equitoxic with MTX. In the present investigation, the potential of the MTX-ala/carboxypeptidase A combination for providing regional cytotoxicity was demonstrated in a model system involving L12l0 cells propagated in semi-solid agarose. When cells and one of the components (MTX peptide or carboxypeptidase) were distributed uniformly throughout the agarose, and the other component was immobilized at the center, a discrete zone of cell kill radiated from the fixed component. These results suggest the possibility of developing a new mode of cancer chemotherapy involving circulating MTX peptides in conjunction with carboxypeptidases linked covalently to tumor-targeted monoclonal antibodies.
Pterin Metabolism In Haemodialysis Patients
Authors: Altmann Paul , Sawyer Nick , Cunningham John , Marsh Frank , Hamon Chris , Blair John A. 
Published: March 2013

Summary Patients undertaking maintenance haemodialysis may develop a variety of neurological disorders, the most serious of which is aluminium induced encephalopathy. Abnormally raised serum concentrations of pterins are found in dialysis patients, and neonates with tetrahydrobiopterin deficiency develop mental dysfunction. Dihydropteridine reductase, essential for maintenance of normal levels of tetrahydrobiopterin, is inhibited when aluminium is added to brain homogenate at similar concentrations to those found in aluminium encephalopathy. We have previously shown that erythrocyte dihydropteridine reductase activity was reduced in non-encephalopathic dialysis patients and inversely related to serum aluminium concentration. Concentrations of serum biopterin derivatives were raised but not related to either aluminium or dihydropteridine reductase. In this study of 17 haemodialysis patients, serum biopterin (13.6 ± 1.3 μg/l) and neopterin (66.2 ± 7.4 μg/l) concentrations were raised compared with normal subjects' biopterin (2.4 ± 0.4 g/l) and neopterin (2.8 ± 0.4 μg/l) values (p = 0.0001). When neopterin and biopterin concentrations were corrected for predialysis serum creatinine a weak relationship appeared between them (r = 0.49, P = 0.04). Erythrocyte dihydropteridine reductase was not related to the creatinine corrected neopterin (r = -0.5, p = 0.2), but there was a significant relationship between DHPR and corrected biopterin (r = 0.986, p = 0.0001) and between corrected biopterin and bone aluminium content (r = 0.68, P = 0.03). Our results support the possibility that aluminium causes changes in pterin metabolism which are analogous to those found in Type II hyperphenylalaninaemia. Serum biopterin concentration, corrected for pre-dialysis serum creatinine, can be used satisfactorily to study tetrahydrobiopterin metabolism in haemodialysis patients. However neopterin/biopterin ratios are unpredictably disturbed and cannot be so used. Serum neopterin concentrations are raised more than anticipated from the biopterin concentrations, and this may be due to neopterin release from macrophages activated by dialysis membranes and/or reduced conversion of dihydroneopterin triphosphate to tetrahydrobiopterin.
Pteridines, XC Syntheses, Oxidations, Properties, and Reactions of 2-Thiopteridine-4,6, 7- trione Derivatives
Authors: Bartke Michael , Pfleiderer Wolfgang 
Published: March 2013

Summary A new efficient synthesis for 2-thiopteridine-4,6,7-triones (6-10, 15) has been found in the condendation of the appropriate 5,6-diaminopyrimidine (1-5, 14) with oxalic acid in DMF. Analogous condensations with dimethyl oxalate led to S-alkylation probably via an intermediate O-methylation of the DMF. 8-Methyl-2- thiopteridine-4,6,7-trione (10) shows a ring contraction to 9-methyl-2-thioxanthine (13) on base treatment. Oxidations by H20 2 and KMn04 respectively lead to the corresponding 2-sulfinate 22 and the 2-sulfonates 17 -19. Oxidative desulfurization takes place in formic acid with H 20 2 forming first the sulfinate 22, which then eliminates S02 to give pteridine-4,6,7-trione (23). Nucleophilic displacements of the 2-sulfonate group by ammonia and amines form the corresponding leucopterin derivatives 20, 21 and 24. The newly synthesized compounds have been characterized by elemental analyses, UV-spectra and pKa-determinations. The ionization sequences of the acidic hydrogens have been assigned based on these physical data .
Synthesis of the Folylpolyglutamate Synthetase Inhibitor Nα-Pteroyl-Lornithine and its Nδ-Benzoyl and Nδ-Hemiphthaloyl Derivatives, and an Improved Synthesis of Nα-( 4-Amino-4-deoxypteroy1)-Nδ-hemiphthaloyl-Lornithine
Authors: Rosowsky Andre , Bader Henry , Forsch Ronald A. 
Published: March 2013

Summary N10-Formylpteroic acid may be prepared from folic acid by sequentially heating with formic acid and cleaving the glutamate side chain with carboxypeptidase G1. Condensation of the product with the Nα,O bis( trimethylsilyl) derivative of Nδ-(tert-butyloxycarbonyl)-L-ornithine via a modification of the carboxyliccarbonic anhydride peptide synthesis, followed by stepwise removal of the N10-formyl group with NaOH and of the Nδ-tert-butyloxycarbonyl group with trifluoroacetic acid affords Nα-pteroyl-L-ornithine. A similar sequence, starting from methyl Nδ-benzoyl-L-ornithinate and methyl Nδ-phthaloyl-L-ornithinate and using gentle treatment with sodium hydroxide in DMSO to selectively remove the methyl ester and N10-formyl groups while hydrolyzing only one of the phthaloyl amide bonds, gives the hitherto undescribed compounds Nδ-benzoyl- and Nδ-hemiphthaloyl-Nα-pteroyl-L-ornithine, respectively. An improved synthesis of Nδ-hemiphthaloyl- Nα-(4-amino-4-deoxypteroyl)-L-ornithine, based on the same chemistry but using 4-amino-4-deoxyN10- formylpteroic acid and methyl Nδ-phthaloyl-L-ornithinate, is also described.
Purification and Characterization of a Carbonyl Reductase from Human Liver, which is Competent in the Reduction of 6-Pyruvoyl-Tetrahydropterin
Authors: Steinerstauch Petra , Sawada Yoshitomo , Leimbacher Walter , Ghisla Sandro , Curtius Hans-Christoph 
Published: March 2013

Summary
An enzyme which reduces 6-pyruvoyl-tetrahydropterin has been purified to apparent homogeneity from human liver. It consists of a single polypeptide chain with a molecular weight of 35 kDa, has an isoelectric point of 5.9 ± 0.1 and contains no glycosyl residues. The pure enzyme has a specific activity of 450 mU/mg protein at pH 7.0 in 10 mM potassium phosphate buffer. It converts 6-pyruvoyl-tetrahydropterin to 6-lactoyltetrahydropterin by transfer of the pro 4R-hydrogen of NADPH to form the side chain -OH at position C(2') of the substrate. Km values are 1.8 J..lM for 6-pyruvoyl-tetrahydropterin and 5.5 J..lM for NADPH. Polyclonal antibodies raised against the purified enzyme recognize 6-pyruvoyl-tetrahydropterin reductase in Western blot and ELISA but do not cross-react with human sepiapterin reductase. The enzyme appears to be identical with aldose reductase.
Four Different Markers for Activated Cell Mediated Immunity Compared with the Clinical Stages of HIV Infection
Authors: Caruso Arnaldo , Francesco Maria de , Gonzales Rosanna , Pollara Patrizia , Zanoni Lorenzo , Foresti Ida , Turano Adolfo 
Published: March 2013

Summary Activated cell-mediated immunity, as defined by four markers, has been studied in HIV-infected patients, and compared with the clinical stages of HIV infection. All the values obtained with such markers (interferon-y expressed on lymphocytes, soluble CD8, soluble IL-2 receptor, and serum neopterin) were observed to increase with the progressive stages of HIV infection, with the highest figures occurring in stage IV-C patients. Since the replication of HIV depend strictly on the stimulation of infected cells, T-cell activation in vitro might contribute to a further spread of HIV-1 in infected subjects. Thus permanent or multiple stimulation of the cellular immune system could be an important cofactor in the progression of this syndrome.