Prognostic and predictive value of centrally reviewed Ki-67 labeling index in postmenopausal women with endocrine-responsive breast cancer: results from Breast International Group Trial 1-98 comparing adjuvant tamoxifen with letrozole.

PURPOSE: To evaluate the prognostic and predictive value of Ki-67 labeling index (LI) in a trial comparing letrozole (Let) with tamoxifen (Tam) as adjuvant therapy in postmenopausal women with early breast cancer. PATIENTS AND METHODS: Breast International Group (BIG) trial 1-98 randomly assigned 8,010 patients to four treatment arms comparing Let and Tam with sequences of each agent. Of 4,922 patients randomly assigned to receive 5 years of monotherapy with either agent, 2,685 had primary tumor material available for central pathology assessment of Ki-67 LI by immunohistochemistry and had tumors confirmed to express estrogen receptors after central review. The prognostic and predictive value of centrally measured Ki-67 LI on disease-free survival (DFS) were assessed among these patients using proportional hazards modeling, with Ki-67 LI values dichotomized at the median value of 11%. RESULTS: Higher values of Ki-67 LI were associated with adverse prognostic factors and with worse DFS (hazard ratio [HR; high:low] = 1.8; 95% CI, 1.4 to 2.3). The magnitude of the treatment benefit for Let versus Tam was greater among patients with high tumor Ki-67 LI (HR [Let:Tam] = 0.53; 95% CI, 0.39 to 0.72) than among patients with low tumor Ki-67 LI (HR [Let:Tam] = 0.81; 95% CI, 0.57 to 1.15; interaction P = .09). CONCLUSION: Ki-67 LI is confirmed as a prognostic factor in this study. High Ki-67 LI levels may identify a patient group that particularly benefits from initial Let adjuvant therapy.

Library-instructional materials center skills, 1968

The School Library-Instructional Materials Center should be designed to serve the total curriculum of a school. Much of a teacher's learning comes when he works with a librarian to provide his students wit the necessary and appropriate skills for a unit of s study.

Electron microscopic visualization of protein-DNA interactions at the estrogen responsive element and in the first intron of the Xenopus laevis vitellogenin gene.

Stable protein-DNA complexes can be assembled in vitro at the 5' end of Xenopus laevis vitellogenin genes using extracts of nuclei from estrogen-induced frog liver and visualized by electron microscopy. Complexes at the three following sites can be identified on the gene B2: the transcription initiation site, the estrogen responsive element (ERE) and in the first intron. The complex at the transcription initiation site is stabilized by dinucleotides and thus represents a ternary transcription complex. The formation of the complexes at the two other sites is enhanced by estrogen and is reduced by tamoxifen, an antagonist of estrogen, while this latter effect is reversed by adding an excess of hormone. No sequence homology is apparent between the site containing the ERE and the binding site in intron I and functional tests in MCF-7 cells suggest that these two sites are not equivalent. Finally, we made use of previously characterized deletion mutants of the 5' flanking region of the gene B1, a close relative of the gene B2, to demonstrate that the 13-bp palindromic core element of the ERE is involved in the formation of the complexes observed upstream of the transcription initiation site.

Controlling anomalous stresses in soft field-responsive systems

We report a phenomenon occurring in field-responsive suspensions: shear-induced anomalous stresses. Competition between a rotating field and a shear flow originates a multiplicity of anomalous stress behaviors in suspensions of bound dimers constituted by induced dipoles. The great variety of stress regimes includes nonmonotonic behaviors, multiresonances, negative viscosity effect, and blockades. The reversibility of the transitions between the different regimes and the self-similarity of the stresses make this phenomenon controllable and therefore applicable to modify macroscopic properties of soft condensed matter phases.

SAP Control del balanç de materials

L'empresa fícticia EcsCables S.A., que està destinada a la fabricació de cables d'energia de mitja i alta tensió, té uns desviaments en el balanç de materials. L'objectiu d'aquest projecte és la de resoldre les anomalies derivades per mitjà del programari SAP, que serà l'eina imprescindible per poder saber amb certesa que està passant. Amb les dades extretes i amb l'ajuda d'un segon ERP intern anomenat Planifer s'intentarà esbrinar les causes del desviament.

Hypertension. Angio-oedème sous inhibition de l'enzyme de conversion de l'angiotensine et de la dipeptidyl-peptidase-4 [Angioedema during ACE and DPP-4 inhibition]

Angioedema is a rare side effect of angiotensin converting enzyme (ACE) inhibitors. Its cause is probably related to the accumulation of bradykinin and substance P, i.e. two proinflammatory peptides normally inactivated by ACE. Angioedema occurs most of the time at the early phase of treatment, but may also develop during long-term treatment. It might involve the gastro-intestinal tract, leading to abdominal pain, vomiting and/or diarrhea, as well as pancreatitis. Dipeptidyl-ptidase-4 (DPP-4) is another enzyme allowing the degradation of bradykinin and substance P. Co-administering an ACE inhibitor and a DPP-4 inhibitor (as an antidiabetic agent) increases significantly the risk of angioedema.

Materials de suport a l'ensenyament/aprenentatge per competències

Aquest article presenta el projecte de Millora de Qualitat Docent que ofereix un disseny d’intervenció i materials de suport per a l’ensenyament i aprenentatge de competències en l’espai de seminari. Els eixos en els que es fonamenta la nostra proposta són: la identificació de les competències a assolir, l’autoavaluació com a eina formativa i la tutoria com a espai de suport en aquest procés d’aprenentatge. La intervenció s’adreça als estudiants de Grau i als professors tutors. Els materials de suport elaborats fan referència a: qüestionari online d’autopercepció del nivell de competències genèriques, qüestionari tutorial de detecció de necessitats i disseny del procés tutorial. En base a la reflexió derivada de l’elaboració d’aquest treball i en relació a l’experiència docent universitària com a professors tutors, podem constatar que l’adquisició de les competències és un procés perceptible que requereix d’un temps variable segons cada estudiant, que implica la conscienciació i participació activa del mateix i, que aquest procés requereix de l’espai de tutoria per a poder-lo dur a terme.

Regulation of the transforming growth factor beta-responsive transcription factor CTF-1 by calcineurin and calcium/calmodulin-dependent protein kinase IV.

Transforming growth factor beta (TGF-beta) is a pluripotent peptide hormone that regulates various cellular activities, including growth, differentiation, and extracellular matrix protein gene expression. We previously showed that TGF-beta induces the transcriptional activation domain (TAD) of CTF-1, the prototypic member of the CTF/NF-I family of transcription factors. This induction correlates with the proposed role of CTF/NF-I binding sites in collagen gene induction by TGF-beta. However, the mechanisms of TGF-beta signal transduction remain poorly understood. Here, we analyzed the role of free calcium signaling in the induction of CTF-1 transcriptional activity by TGF-beta. We found that TGF-beta stimulates calcium influx and mediates an increase of the cytoplasmic calcium concentration in NIH3T3 cells. TGF-beta induction of CTF-1 is inhibited in cells pretreated with thapsigargin, which depletes the endoplasmic reticulum calcium stores, thus further arguing for the potential relevance of calcium mobilization in TGF-beta action. Consistent with this possibility, expression of a constitutively active form of the calcium/calmodulin-dependent phosphatase calcineurin or of the calcium/calmodulin-dependent kinase IV (DeltaCaMKIV) specifically induces the CTF-1 TAD and the endogenous mouse CTF/NF-I proteins. Both calcineurin- and DeltaCaMKIV-mediated induction require the previously identified TGF-beta-responsive domain of CTF-1. The immunosuppressants cyclosporin A and FK506 abolish calcineurin-mediated induction of CTF-1 activity. However, TGF-beta still induces the CTF-1 TAD in cells treated with these compounds or in cells overexpressing both calcineurin and DeltaCaMKIV, suggesting that other calcium-sensitive enzymes might mediate TGF-beta action. These results identify CTF/NF-I as a novel calcium signaling pathway-responsive transcription factor and further suggest multiple molecular mechanisms for the induction of CTF/NF-I transcriptional activity by growth factors.

Results and harmonization guidelines from two large-scale international Elispot proficiency panels conducted by the Cancer Vaccine Consortium (CVC/SVI).

The Cancer Vaccine Consortium of the Sabin Vaccine Institute (CVC/SVI) is conducting an ongoing large-scale immune monitoring harmonization program through its members and affiliated associations. This effort was brought to life as an external validation program by conducting an international Elispot proficiency panel with 36 laboratories in 2005, and was followed by a second panel with 29 participating laboratories in 2006 allowing for application of learnings from the first panel. Critical protocol choices, as well as standardization and validation practices among laboratories were assessed through detailed surveys. Although panel participants had to follow general guidelines in order to allow comparison of results, each laboratory was able to use its own protocols, materials and reagents. The second panel recorded an overall significantly improved performance, as measured by the ability to detect all predefined responses correctly. Protocol choices and laboratory practices, which can have a dramatic effect on the overall assay outcome, were identified and lead to the following recommendations: (A) Establish a laboratory SOP for Elispot testing procedures including (A1) a counting method for apoptotic cells for determining adequate cell dilution for plating, and (A2) overnight rest of cells prior to plating and incubation, (B) Use only pre-tested serum optimized for low background: high signal ratio, (C) Establish a laboratory SOP for plate reading including (C1) human auditing during the reading process and (C2) adequate adjustments for technical artifacts, and (D) Only allow trained personnel, which is certified per laboratory SOPs to conduct assays. Recommendations described under (A) were found to make a statistically significant difference in assay performance, while the remaining recommendations are based on practical experiences confirmed by the panel results, which could not be statistically tested. These results provide initial harmonization guidelines to optimize Elispot assay performance to the immunotherapy community. Further optimization is in process with ongoing panels.

Mutations in B3GALT6, which encodes a glycosaminoglycan linker region enzyme, cause a spectrum of skeletal and connective tissue disorders.

Proteoglycans (PGs) are a major component of the extracellular matrix in many tissues and function as structural and regulatory molecules. PGs are composed of core proteins and glycosaminoglycan (GAG) side chains. The biosynthesis of GAGs starts with the linker region that consists of four sugar residues and is followed by repeating disaccharide units. By exome sequencing, we found that B3GALT6 encoding an enzyme involved in the biosynthesis of the GAG linker region is responsible for a severe skeletal dysplasia, spondyloepimetaphyseal dysplasia with joint laxity type 1 (SEMD-JL1). B3GALT6 loss-of-function mutations were found in individuals with SEMD-JL1 from seven families. In a subsequent candidate gene study based on the phenotypic similarity, we found that B3GALT6 is also responsible for a connective tissue disease, Ehlers-Danlos syndrome (progeroid form). Recessive loss-of-function mutations in B3GALT6 result in a spectrum of disorders affecting a broad range of skeletal and connective tissues characterized by lax skin, muscle hypotonia, joint dislocation, and spinal deformity. The pleiotropic phenotypes of the disorders indicate that B3GALT6 plays a critical role in a wide range of biological processes in various tissues, including skin, bone, cartilage, tendon, and ligament.

Cement Stabilization of Embankment Materials, 2015

Embankment subgrade soils in Iowa are generally rated as fair to poor as construction materials. These soils can exhibit low bearing strength, high volumetric instability, and freeze/thaw or wet/dry durability problems. Cement stabilization offers opportunities to improve these soils conditions. The objective of this study was to develop relationships between soil index properties, unconfined compressive strength and cement content. To achieve this objective, a laboratory study was conducted on 28 granular and non-granular materials obtained from 9 active construction sites in Iowa. The materials consisted of glacial till, loess, and alluvium sand. Type I/II portland cement was used for stabilization. Stabilized and unstabilized specimens were prepared using Iowa State University 2 in. by 2 in. compaction apparatus. Specimens were prepared, cured, and tested for unconfined compressive strength (UCS) with and without vacuum saturation. Percent fines content (F200), AASHTO group index (GI), and Atterberg limits were tested before and after stabilization. The results were analyzed using multi-variate statistical analysis to assess influence of the various soil index properties on post-stabilization material properties. Results indicated that F200, liquid limit, plasticity index, and GI of the materials generally decreased with increasing cement content. The UCS of the stabilized specimens increased with increasing cement content, as expected. The average saturated UCS of the unstabilized materials varied between 0 and 57 psi. The average saturated UCS of stabilized materials varied between 44 and 287 psi at 4% cement content, 108 and 528 psi at t 8% cement content, and 162 and 709 psi at 12% cement content. The UCS of the vacuum saturated specimens was on average 1.5 times lower than that of the unsaturated specimens. Multi-variate statistical regression models are provided in this report to predict F200, plasticity index, GI, and UCS after treatment, as a function of cement content and soil index properties.

Lack of angiotensin I accumulation after converting enzyme blockade by enalapril or lisinopril in man.

In nine normal volunteers, a series of five venous blood samples was obtained before and up to 24 h after converting enzyme inhibition by a single oral dose of enalapril or lisinopril. Plasma renin activity and blood angiotensin I were measured. A close linear relationship was found between the increase in plasma renin activity and the increase in blood angiotensin I. The linear correlation between plasma renin activity and blood angiotensin I remained after converting enzyme inhibition. Thus, the rise in angiotensin I after inhibition of the conversion of angiotensin I to angiotensin II is due to an enhanced release of renin rather than to accumulation of angiotensin I.

Demonstration and Field Evaluation of Alternative Portland Cement Concrete Pavement Reinforcement Materials, Construction Report, HR-1069, 1998

The function of dowel bars is the transfer of a load across the transverse joint from one pavement slab to the adjoining slab. In the past, these transfer mechanisms have been made of steel. However, pavement damage such as loss of bonding, deterioration, hollowing, cracking and spalling start to occur when the dowels begin to corrode. A significant amount of research has been done to evaluate alternative types of materials for use in the reinforcement of concrete pavements. Initial findings have indicated that stainless steel and fiber composite materials possess properties, such as flexural strength and corrosion resistance, that are equivalent to the Department of Transportation specifications for standard steel, 1 1/2 inch diameter dowel bars. Several factors affect the load transfer of dowels; these include diameter, alignment, grouting, bonding, spacing, corrosion resistance, joint spacing, slab thickness and dowel embedment length. This research is directed at the analysis of load transfer based on material type and dowel spacing. Specifically, this research is directed at analyzing the load transfer characteristics of: (a) 8-inch verses 12-inch spacing, and (b) alternative dowel material compared to epoxy coated steel dowels, will also be analyzed. This report documents the installation of the test sections, placed in 1997. Dowel material type and location are identified. Construction observations and limitations with each dowel material are shown.

Image Analysis for the Characterization of Materials for Highway Construction : Phase I, Progress Report, HR-346, 1992

The major objective of this project is to evaluate image analysis for characterizing air voids in Portland cement contract (PCC) and asphalt concrete (AC) and aggregate gradation in asphalt concrete. Phase 1 of this project has concentrated on evaluation and refinement of sample preparation techniques, evaluation of methods and instruments for conducting image analysis, and finally, analysis and comparison of a select portion of samples. Preliminary results suggest a strong correlation between the results obtained from the linear traverse method and image analysis methods for determining percent air voids in concrete. Preliminary work with asphalt samples has shown that damage caused by a high vacuum of the conventional scanning electron microscope (SEM) may too disruptive. Alternative solutions have been explored, including confocal microscopy and low vacuum electron microscopy. Additionally, a conventional high vacuum SEM operating at a marginal operating vacuum may suffice.