Meta-analysis and dose-response metaregression: circulating insulin-like growth factor I (IGF-I) and mortality

Context: IGF-I plays a central role in metabolism and growth regulation. High IGF-I levels are associated with increased cancer risk and low IGF-I levels with increased risk for cardiovascular disease. Objective: Our objective was to determine the relationship between circulating IGF-I levels and mortality in the general population using random-effects meta-analysis and dose-response metaregression. Data Sources: We searched PubMed, EMBASE, Web of Science, and Cochrane Library from 1985 to September 2010 to identify relevant studies. Study Selection: Population-based cohort studies and (nested) case-control studies reporting on the relation between circulating IGF-I and mortality were assessed for eligibility. Data Extraction: Data extraction was performed by two investigators independently, using a standardized data extraction sheet. Data Synthesis: Twelve studies, with 14,906 participants, were included. Overall, risk of bias was limited. Mortality in subjects with low or high IGF-I levels was compared with mid-centile reference categories. All-cause mortality was increased in subjects with low as well as high IGF-I, with a hazard ratio (HR) of 1.27 (95% CI = 1.08–1.49) and HR of 1.18 (95% CI = 1.04–1.34), respectively. Dose-response metaregression showed a U-shaped relation of IGF-I and all-cause mortality (P = 0.003). The predicted HR for the increase in mortality comparing the 10th IGF-I with the 50th percentile was 1.56 (95% CI = 1.31–1.86); the predicted HR comparing the 90th with the 50th percentile was 1.29 (95% CI = 1.06–1.58). A U-shaped relationship was present for both cancer mortality and cardiovascular mortality. Conclusions: Both low and high IGF-I concentrations are associated with increased mortality in the general population.

Multimodal treatment for high-risk prostate cancer with high-dose intensity-modulated radiation therapy preceded or not by radical prostatectomy, concurrent intensified-dose docetaxel and long-term androgen deprivation therapy: results of a prospective phase II trial.

BACKGROUND The optimal management of high-risk prostate cancer remains uncertain. In this study we assessed the safety and efficacy of a novel multimodal treatment paradigm for high-risk prostate cancer. METHODS This was a prospective phase II trial including 35 patients with newly diagnosed high-risk localized or locally advanced prostate cancer treated with high-dose intensity-modulated radiation therapy preceded or not by radical prostatectomy, concurrent intensified-dose docetaxel-based chemotherapy and long-term androgen deprivation therapy. Primary endpoint was acute and late toxicity evaluated with the Common Terminology Criteria for Adverse Events version 3.0. Secondary endpoint was biochemical and clinical recurrence-free survival explored with the Kaplan-Meier method. RESULTS Acute gastro-intestinal and genito-urinary toxicity was grade 2 in 23% and 20% of patients, and grade 3 in 9% and 3% of patients, respectively. Acute blood/bone marrow toxicity was grade 2 in 20% of patients. No acute grade ≥ 4 toxicity was observed. Late gastro-intestinal and genito-urinary toxicity was grade 2 in 9% of patients each. No late grade ≥ 3 toxicity was observed. Median follow-up was 63 months (interquartile range 31-79). Actuarial 5-year biochemical and clinical recurrence-free survival rate was 55% (95% confidence interval, 35-75%) and 70% (95% confidence interval, 52-88%), respectively. CONCLUSIONS In our phase II trial testing a novel multimodal treatment paradigm for high-risk prostate cancer, toxicity was acceptably low and mid-term oncological outcome was good. This treatment paradigm, thus, may warrant further evaluation in phase III randomized trials.

STUDIES OF THE MOLECULAR MECHANISMS OF CHROMOSOME ABERRATION FORMATION (DNA REPAIR, CROSSLINKS, MITOMYCIN C)

The objective of this research has been to study the molecular basis for chromosome aberration formation. Predicated on a variety of data, Mitomycin C (MMC)-induced DNA damage has been postulated to cause the formation of chromatid breaks (and gaps) by preventing the replication of regions of the genome prior to mitosis. The basic protocol for these experiments involved treating synchronized Hela cells in G(,1)-phase with a 1 (mu)g/ml dose of MMC for one hour. After removing the drug, cells were then allowed to progress to mitosis and were harvested for analysis by selective detachment. Utilizing the alkaline elution assay for DNA damage, evidence was obtained to support the conclusion that Hela cells can progress through S-phase into mitosis with intact DNA-DNA interstrand crosslinks. A higher level of crosslinking was observed in those cells remaining in interphase compared to those able to reach mitosis at the time of analysis. Dual radioisotope labeling experiments revealed that, at this dose, these crosslinks were associated to the same extent with both parental and newly replicated DNA. This finding was shown not to be the result of a two-step crosslink formation mechanism in which crosslink levels increase with time after drug treatment. It was also shown not to be an artefact of the double-labeling protocol. Using neutral CsCl density gradient ultracentrifugation of mitotic cells containing BrdU-labeled newly replicated DNA, control cells exhibited one major peak at a heavy/light density. However, MMC-treated cells had this same major peak at the heavy/light density, in addition to another minor peak at a density characteristic for light/light DNA. This was interpreted as indicating either: (1) that some parental DNA had not been replicated in the MMC treated sample or; (2) that a recombination repair mechanism was operational. To distinguish between these two possibilities, flow cytometric DNA fluorescence (i.e., DNA content) measurements of MMC-treated and control cells were made. These studies revealed that the mitotic cells that had been treated with MMC while in G(,1)-phase displayed a 10-20% lower DNA content than untreated control cells when measured under conditions that neutralize chromosome condensation effects (i.e., hypotonic treatment). These measurements were made under conditions in which the binding of the drug, MMC, was shown not to interfere with the stoichiometry of the ethidium bromide-mithramycin stain. At the chromosome level, differential staining techniques were used in an attempt to visualize unreplicated regions of the genome, but staining indicative of large unreplicated regions was not observed. These results are best explained by a recombinogenic mechanism. A model consistent with these results has been proposed.^

Comparison of Tumor Shrinkage and Cumulative Dose Distribution for Lung Cancers

Background: The physical characteristic of protons is that they deliver most of their radiation dose to the target volume and deliver no dose to the normal tissue distal to the tumor. Previously, numerous studies have shown unique advantages of proton therapy over intensity-modulated radiation therapy (IMRT) in conforming dose to the tumor and sparing dose to the surrounding normal tissues and the critical structures in many clinical sites. However, proton therapy is known to be more sensitive to treatment uncertainties such as inter- and intra-fractional variations in patient anatomy. To date, no study has clearly demonstrated the effectiveness of proton therapy compared with the conventional IMRT under the consideration of both respiratory motion and tumor shrinkage in non-small cell lung cancer (NSCLC) patients. Purpose: This thesis investigated two questions for establishing a clinically relevant comparison of the two different modalities (IMRT and proton therapy). The first question was whether or not there are any differences in tumor shrinkage between patients randomized to IMRT versus passively scattered proton therapy (PSPT). Tumor shrinkage is considered a standard measure of radiation therapy response that has been widely used to gauge a short-term progression of radiation therapy. The second question was whether or not there are any differences between the planned dose and 5D dose under the influence of inter- and intra-fractional variations in the patient anatomy for both modalities. Methods: A total of 45 patients (25 IMRT patients and 20 PSPT patients) were used to quantify the tumor shrinkage in terms of the change of the primary gross tumor volume (GTVp). All patients were randomized to receive either IMRT or PSPT for NSCLC. Treatment planning goals were identical for both groups. All patients received 5 to 8 weekly repeated 4-dimensional computed tomography (4DCT) scans during the course of radiation treatments. The original GTVp contours were propagated to T50 of weekly 4DCT images using deformable image registration and their absolute volumes were measured. Statistical analysis was performed to compare the distribution of tumor shrinkage between the two population groups. In order to investigate the difference between the planned dose and the 5D dose with consideration of both breathing motion and anatomical change, we re-calculated new dose distributions at every phase of the breathing cycle for all available weekly 4DCT data sets which resulted 50 to 80 individual dose calculations for each of the 7 patients presented in this thesis. The newly calculated dose distributions were then deformed and accumulated to T50 of the planning 4DCT for comparison with the planned dose distribution. Results: At the end of the treatment, both IMRT and PSPT groups showed mean tumor volume reductions of 23.6% ( 19.2%) and 20.9% ( 17.0 %) respectively. Moreover, the mean difference in tumor shrinkage between two groups is 3% along with the corresponding 95% confidence interval, [-8%, 14%]. The rate of tumor shrinkage was highly correlated with the initial tumor volume size. For the planning dose and 5D dose comparison study, all 7 patients showed a mean difference of 1 % in terms of target coverage for both IMRT and PSPT treatment plans. Conclusions: The results of the tumor shrinkage investigation showed no statistically significant difference in tumor shrinkage between the IMRT and PSPT patients, and the tumor shrinkage between the two modalities is similar based on the 95% confidence interval. From the pilot study of comparing the planned dose with the 5D dose, we found the difference to be only 1%. Overall impression of the two modalities in terms of treatment response as measured by the tumor shrinkage and 5D dose under the influence of anatomical change that were designed under the same protocol (i.e. randomized trial) showed similar result.

Capilla del M.I.T. de Eero Saarinen, 1950-55 : sincretismo en la armonía de los opuestos

La historia de la arquitectura se ha medido - en parte - por la evolución de las modas, épocas y estilos de la arquitectura religiosa. En la aparición de las nuevas capillas interreligiosas universitarias de los años '50 de Norteamérica, la capilla del M.I.T., bautizada tras su inauguración como “Kresge Chapel” en honor al apellido de su benefactor, fue el máximo exponente como prototipo en esta época marcada por la aparición nuevas conciencias de posguerra. (II Guerra Mundial). La tesis centra su investigación en esta capilla, cómo nació en respuesta a la necesidad de compatibilizar la enseñanza reglada científico tecnológica con una formación religiosa y humanista, para el programa impuesto como ampliación del campus universitario del MIT en el barrio universitario de Cambridge, Boston, Massachussets, en torno a dos edificios principales a proyectar: capilla y auditorio. Desde el trabajo de investigación se aporta la información documental necesaria para saber cómo evolucionó desde sus primeros bocetos hasta su construcción. Su nacimiento como necesidad en la sociedad universitaria no fue nada espontáneo, quedando a medias entre la influencia escandinavo - alemana y la tradición americano-luterana de anteriores iglesias neoclásicas herederas del “Plan Akron”. La formación académica y profesional dirigida por su padre, Eliel Saarinen, suman junto a los viajes del arquitecto, una herencia “genética” para con este prototipo ajeno al emergente “estilo internacional” y ayudan a comprender la dimensión compleja de lo que es capaz de representar la capilla. La capilla es refugio emocional de la luz y es un punto de inflexión notable en la recuperación del tipo centrado renovado y evolucionado, que junto con el doble recurso lumínico - efectista, de la vertical para el altar y horizontal inferior, distribuido desde el perímetro ondulado en el interior, el ejemplo es muestra la promoción de una cierta sensibilidad para con las nuevas formas de la "religión" emergentes en la Norteamérica de los años 50. Desde el sincretismo como mecanismo y principal “modus operandi” proyectual, FE versus RAZÓN, aparecen como dualismo permanente en todas las fases del proyecto, desde un proceso de búsqueda de la armonía de ambos y para cada uno de ellos. Con el estudio del modelo prototípico del MIT, buscamos el "patrón" empleado por el arquitecto en su proyección de "nueva iglesia" adaptado a la diversidad cultural y religiosa y de las nuevas y diferentes sensibilidades humanistas para el proyecto. ----------------------------------------------------- SUMMARY--------------------------------------------------- The history of architecture is measured - in part - by the evolution of fashion, periods and styles of religious architecture. In the emergence of the new interfaith university chapel of the 1950s in North America, the chapel of MIT, named after its inauguration as "Kresge Chapel" in honor of its benefactor, was the best example of a prototype, in this time so marked by the emergence of new postwar consciousnesses. The thesis focuses its research on this chapel; how it came about in response to the need to reconcile formal scientific and technological education with religious and humanist training for the program imposed as an extension of the campus of MIT in the university district of Cambridge, Boston Massachusetts, around two main projected buildings : Chapel and auditorium. From research work has been obtained the documentary information necessary to know how it evolved from the first sketches to its construction. Its creation as a necessity of the university society was not at all spontaneous, being halfway between the Scandinavian influence - German and the American Lutheran tradition of neoclassical churches, the heirs to the "Akron Plan". The academic and professional training directed by his father, Eliel Saarinen, together with the travels of the architect, a "genetic" heritage with this external prototype for the emerging "international style", and help to understand the complex dimension of what the chapel is capable of representing. The chapel is an emotional refuge of light and is a remarkable turning point in the recovery of such focused renewed and evolved, along with the double lumen resource - gimmicky, vertical to the altar and lower horizontal, distributed from the undulating perimeter inside, the example is shown to promote a certain sensitivity to the new forms of "religion" but vague religious profile emerging in the America of the 50s. From the syncretism as a mechanism and main "modus operandi" of the project, FAITH versus REASON appears as permanent dualism in all phases of the project from a process of finding the harmony of both and for each of them. With the study of the prototypical model of MIT, we seek the "pattern" used by the architect in his projection of "new church" adapted to the cultural and religious diversity and new and different humanist sensitivities for the project. El desarrollo vierte la luz suficiente para entender los patrones de lo arquitectónico en la capilla, que hacen de ella, la comunión armónica y perfecta de los nombrados opuestos en el campus universitario del MIT. En el camino, además, la investigación arroja luz y orden sobre las fases del proyecto a través de la contribución, recogida, clasificación y orden de los datos, fechas y documentos gráficos, a día de hoy dispersos y confusamente publicados, debido a la no existencia de un estudio profundo y completo como el que pretende ser este trabajo, por ser una obra fundamental en la historia de la arquitectura moderna. El patrón final demostrará el artificio sincrético de cada una de las partes - cada uno en sí misma y cosidas todas - formando el "Ima Summis" de la capilla; resultado de la acción proyectual deducida de su serie genética descifrada. De esta forma, lo sincrético, aparece como el principal atributo del hecho construido, pasando de lo místico a lo científico, de lo intuitivo a lo razonado y siempre con el vehículo de su arquitectura para la interpretación de lo inefable al interior. En cuanto a la estructura de la tesis, se inicia el desarrollo a partir de una introducción en la que se declaran las intenciones y se describe el contexto de lo investigado en torno a la hipótesis principal anunciada en el subtítulo de la tesis. Frente a consideraciones previas de la capilla y de la propia investigación, se expone y explica la hipótesis principal, junto a otros objetivos secundarios. Para finalizar la introducción, se describe el método seguido como estrategia y se justifica la estructura de redacción del documento para la compresión de este trabajo hacia sus conclusiones. Es en el primer capítulo, el C1, donde se inicia el cuerpo central mediante la exposición historiográfica de la situación y contexto previo a la capilla como antecedentes. En un segundo capítulo, el C2, se aborda el estudio del desarrollo del proyecto y de la obra y construcción de la capilla, base documental necesaria. Para ello se inicia con la descripción del lugar, del encargo y del programa, para pasar a mostrar con detalle las distintas propuestas de cada una de las fases del proyecto. En definitiva, qué se proyecto, cómo evolucionó el proyecto y en qué fases transcurrió, para entre otras cuestiones, entender el cambio de estilo desde una fase influenciada por la capilla de Mies construida en el ITT de Chicago, (denominadas en este trabajo por esta influencia como modelos “miesianos”) y la fase reencuentro con el modus de hacer iniciado por su padre Eliel, a través de un modelo a medias de una herencia escandinavo - alemana y la tradición luterano - americana, (denominada en este trabajo como herencia o modelos “saariniana/os”). The development sheds enough light to understand the architectural patterns of the chapel, making it the perfect and harmonic communion named opposites on the campus of MIT. Along the way, furthermore, the research sheds light and order on the phases of the project through the contribution, collection, sorting and order of data, dates and graphic documents, today scattered and confusingly published, due to inexistence of a deep and comprehensive study like this work is meant to be, in the context of such a seminal work in the history of modern architecture. The final pattern will demonstrate the syncretic artifice of each of the parts - each in itself and all together - forming the "Ima Summis" of the chapel; the result of the project action deducted from its deciphered genetic series. Being the SYNCRETIC, the main attribute of the built matter, passing from the mystical to the scientific, from the intuitive to the reasoned and always with the vehicle of architecture as the representation of the ineffable. As for the structure of the thesis, the development starts from an introduction in which the intentions are declared and the context of that which is investigated is described, in terms of the main hypothesis announced in the subtitle of the thesis. Faced with previous considerations of the chapel and the research itself, the principal hypothesis is expressed and explained, along with other secondary objectives. To conclude the introduction, the method followed is described as a strategy and the structuring of the document is justified for the compression of this work towards its conclusions. It is in the first chapter of the thesis, the C1, where the main body of the work is initiated through the historiographical account of the situation and context prior to the chapel as antecedents. A second chapter, C2, addresses the study of the development of the project and of the work and construction of the chapel, based on the necessary documentary evidence. To this end, the analysis begins with the description of the place, the commission and the program, moving on to analyze in detail the various proposals of each phase. What is projected, how it evolved and through what phases passed the project to, among other questions, understand the change in style between the phase of influence of Mies through the projected chapel in the ITT of Chicago chapel (called in this work as "miesian" influences or models) and the reunion with the modus of making initiated by his father Eliel, through a model equally at once of Scandinavian-German heritage and of the American-Lutheran tradition, (referred to in this work as "saarinian" inheritance or models). Para el tercer capítulo, el C3, se llevan a estudio y análisis, los elementos más destacables en los que se prueban las particularidades llamadas “genéticas” en cada uno de las partes principales detectadas en la capilla. Desde ellas se rastrean las influencias - a veces sinergias - que ayudan a justificar y conformar una clasificación genética en torno a cuatro patrones principales, de los que poder discernir al final del capítulo, el “patrón matriz” de la propia capilla en base a la concurrencia de los órdenes arquitectónicos que los conforman. Una vez obtenida la información y orden necesario, se puede afrontar el punto álgido de esta tesis con el cuarto capítulo, el C4, en el que se justifica la capacidad sincrética de la capilla como respuesta a la hipótesis principal señalada en el subtítulo. Para ello se inicia el capítulo con el enfoque y contexto del término “sincretismo” y “sincrético”, aportando la justificación de sus usos para con esta investigación, antes de explicar que la capilla es sincrética por la suma de dos claves fundamentales. La clave primera, correspondiente a la capacidad interconfesional y aconfesional de la capilla, y su capacidad de trascender al interior desde ambas situaciones además de ser reconocible por el religioso y a la vez por el científico. Y la clave segunda, que corresponde a la suma de las distintas partes sincréticas, cada una en si mismas, capaz de sumar todas juntas, este edificio sincrético de los nombrados opuestos. Una vez discernido las claves de lo sincrético en la capilla y a pesar de su doble carácter SACRO Y PROFANO, una comparativa posiciona a la capilla como único entre los ejemplos interconfesionales construidos en los ´50, sin haberse repetido de igual manera y mismo resultado en el tiempo, ni en ninguna otra universidad o centro tecnológico. Así la exposición de este trabajo finaliza con el último capítulo, el C5, en el que desde esa comparativa, una serie de cuestiones unen y distancian a la del MIT y dan acierto a la apuesta inicial, concluyendo que la hipótesis y el patrón de la misma, es el patrón de lo sincrético que modela el ”modus operandi ” del arquitecto. Tras el desarrollo, la investigación cierra filas en torno a cuatro conclusiones para los cuatro capítulos principales; C2, C3, C4, C5. La capilla del MIT como modelo prototípico no se repite en el tiempo, ni en ninguna otra universidad y se posiciona como el mejor prototipo – hito de una nueva arquitectura religiosa universitaria. In the third chapter, C3, we study and analyze the most notable elements in which are found those particularities referred to as "genetic" in each of the principal parts, (see above C3.1.1... - C3.1.8), where these influences - sometimes synergies - are traced, helping to justify and form a classification based on four of those principals (see above C3.2), from which, at the end of this chapter may be discerned a matrix pattern, that of the chapel itself (see above. C3.3.), based on concurrent architectural orders. Once the necessary information and order is obtained, we come to the decisive point in the fourth chapter, C4, where the syncretic capacity of the chapel in response to the main hypothesis indicated in the subtitle of the thesis is justified. For this, the chapter beings with the focus and context of the terms "syncretism" and "syncretic", providing justification for their use for this research, going on to assert that the chapel is syncretic from the sum of two fundamental aspects: the first corresponds to the interfaith and non-denominational capacities of the chapel, its ability to transcend both situations and be recognizable by both the religious and the scientific. The second corresponds to the sum of the different syncretic parts, each in themselves, capable of making together a syncretic building with the opposite. Once discerned the keys to the syncretic and epic in the chapel and despite its dual character both SACRED and PROFANE, a comparatison positions the chapel as being unique among interfaith examples built in the 1950s, without being repeated in the same way and with the same result over time or in any other university or centre of technology. So, the exhibition of this work ends with the last chapter, C5, in which from that comparison a number of issues come together and to distance themselves from MIT and bear out the initial proposition, concluding that the hypothesis and its pattern, the pattern of the syncretic which models the "modus operandi" of the architect to contain the ineffable. The research closes ranks around four conclusions for the four main chapters; C2, C3, C4, and C5 The chapel of MIT as a prototypical model is not repeated in time, or any other university and is positioned as the best prototype - a landmark of a new universitary religious architecture.

Bayesian models for finding and grouping junctions

In this paper, we propose two Bayesian methods for detecting and grouping junctions. Our junction detection method evolves from the Kona approach, and it is based on a competitive greedy procedure inspired in the region competition method. Then, junction grouping is accomplished by finding connecting paths between pairs of junctions. Path searching is performed by applying a Bayesian A* algorithm that has been recently proposed. Both methods are efficient and robust, and they are tested with synthetic and real images.

Calspan/Chrysler Research Safety Vehicle - phase III: final technical report. Volume I: executive summary.

National Highway Traffic Safety Administration, Washington, D.C.

Construction of a comprehensive causal network, phase III: final report (volume I).

National Highway Traffic Safety Administration, Washington, D.C.

Design, development and testing of Calspan/Chrysler research safety vehicle - phase II. Volume I. Final technical report.

National Highway Traffic Safety Administration, Washington, D.C.

Research safety vehicle - phase II. Volume I: executive summary. Final report.

National Highway Traffic Safety Administration, Washington, D.C.

Report of the status phase of the school facilities survey authorized by title I: P. L. 815, 81st Congress.

Mode of access: Internet.

Direct and general support and depot maintenance repair parts and special tools list : welding machine, arc, generator, electric motor driven, AC, 220V, 3 phrase [i.e. phase], 60HZ, single operator, remote control, 300 amp DC arc, wheel MTD ....

"December 1968."

Operator, organizational, direct support, and general support maintenance manual for air conditioner, vertical compact : type I, vertical, size C, 18,000 BTU/hr, class I, 208 volt, 3 phase, 50/60 hertz, Keco model F18T-2 : NSN 4120-00-168-1781.

"21 December 1979."