A phase I/II trial of vorinostat in combination with 5-fluorouracil in patients with metastatic colorectal cancer who previously failed 5-FU-based chemotherapy

PURPOSE: We conducted a phase I/II clinical trial to determine the safety and feasibility of combining vorinostat with 5-fluorouracil (5-FU) in patients with metastatic colorectal cancer (mCRC) and elevated intratumoral thymidylate synthase (TS).

METHODS: Patients with mCRC who had failed all standard therapeutic options were eligible. Intratumoral TS mRNA expression and peripheral blood mononuclear cell (PBMC) histone acetylation were measured before and after 6 consecutive days of vorinostat treatment at 400 mg PO daily. 5-FU/LV were given on days 6 and 7 and repeated every 2 weeks, along with continuous daily vorinostat. Dose escalation occurred in cohorts of three to six patients.

RESULTS: Ten patients were enrolled. Three dose levels were explored in the phase I portion of the study. Two dose-limiting toxicities (DLTs) were observed at the starting dose level, which resulted in dose de-escalation to levels -1 and -2. Given the occurrence of two DLTs at each of the dose levels, we were unable to establish a maximum tolerated dose (MTD). Two patients achieved significant disease stabilization for 4 and 6 months. Grade 3 and 4 toxicities included fatigue, thrombocytopenia and mucositis. Intratumoral TS downregulation > or = 50% was observed in one patient only. Acetylation of histone 3 was observed in PBMCs following vorinostat treatment.

CONCLUSIONS: The study failed to establish a MTD and was terminated. The presence of PBMC histone acetylation indicates biological activity of vorinostat, however, consistent reductions in intratumoral TS mRNA were not observed. Alternate vorinostat dose-scheduling may alleviate the toxicity and achieve optimal TS downregulation.

The cyclin D1 (CCND1) rs9344 G>A polymorphism predicts clinical outcome in colon cancer patients treated with adjuvant 5-FU-based chemotherapy

Recent evidence indicates a potential prognostic and predictive value for germline polymorphisms in genes involved in cell cycle control. We investigated the effect of cyclin D1 (CCND1) rs9344 G>A in stage II/III colon cancer patients and validated the findings in an independent study cohort. For evaluation and validation set, a total of 264 and 234 patients were included. Patients treated with 5-fluorouracil-based chemotherapy, carrying the CCND1 rs9344 A/A genotype had significantly decreased time-to-tumor recurrence (TTR) in univariate analysis and multivariate analysis (hazard ratio (HR) 2.47; 95% confidence interval (CI) 1.16-5.29; P=0.019). There was no significant association between CCND1 rs9344 G>A and TTR in patients with curative surgery alone. In the validation set, the A allele of CCND1 rs9344 G>A remained significantly associated with decreased TTR in univariate and multivariate analyses (HR 1.94; 95% CI 1.05-3.58; P=0.035). CCND1 rs9344 G>A may be a predictive and/or prognostic biomarker in stage II/III colon cancer patients, however, prospective trials are warranted to confirm our findings.

A comparative study of Type II-P and II-L supernova rise times as exemplified by the case of LSQ13cuw

We report on our findings based on the analysis of observations of the Type II-L supernova LSQ13cuw within the framework of currently accepted physical predictions of core-collapse supernova explosions. LSQ13cuw was discovered within a day of explosion, hitherto unprecedented for Type II-L supernovae. This motivated a comparative study of Type II-P and II-L supernovae with relatively well-constrained explosion epochs and rise times to maximum (optical) light. From our sample of twenty such events, we find evidence of a positive correlation between the duration of the rise and the peak brightness. On average, SNe II-L tend to have brighter peak magnitudes and longer rise times than SNe II-P. However, this difference is clearest only at the extreme ends of the rise time versus peak brightness relation. Using two different analytical models, we performed a parameter study to investigate the physical parameters that control the rise time behaviour. In general, the models qualitatively reproduce aspects of the observed trends. We find that the brightness of the optical peak increases for larger progenitor radii and explosion energies, and decreases for larger masses. The dependence of the rise time on mass and explosion energy is smaller than the dependence on the progenitor radius. We find no evidence that the progenitors of SNe II-L have significantly smaller radii than those of SNe II-P.

A Compositional and Interpretable Semantic Space

Vector Space Models (VSMs) of Semantics are useful tools for exploring the semantics of single words, and the composition of words to make phrasal meaning. While many methods can estimate the meaning (i.e. vector) of a phrase, few do so in an interpretable way. We introduce a new method (CNNSE) that allows word and phrase vectors to adapt to the notion of composition. Our method learns a VSM that is both tailored to support a chosen semantic composition operation, and whose resulting features have an intuitive interpretation. Interpretability allows for the exploration of phrasal semantics, which we leverage to analyze performance on a behavioral task.

Real-space grids and the Octopus code as tools for the development of new simulation approaches for electronic systems

Real-space grids are a powerful alternative for the simulation of electronic systems. One of the main advantages of the approach is the flexibility and simplicity of working directly in real space where the different fields are discretized on a grid, combined with competitive numerical performance and great potential for parallelization. These properties constitute a great advantage at the time of implementing and testing new physical models. Based on our experience with the Octopus code, in this article we discuss how the real-space approach has allowed for the recent development of new ideas for the simulation of electronic systems. Among these applications are approaches to calculate response properties, modeling of photoemission, optimal control of quantum systems, simulation of plasmonic systems, and the exact solution of the Schrödinger equation for low-dimensionality systems.

Migration, Space and Transnational Identities: The British in South Africa

This timely text explores the lives, histories and identities of white British-born immigrants in South Africa, twenty years after the post-apartheid Government took office. Drawing on over sixty in depth biographical interviews and ethnographic work in Johannesburg, Pietermaritzburg and Cape Town, Daniel Conway and Pauline Leonard analyse how British immigrants' relate to, participate in and embody South Africa's complex racial and political history. Through their everyday lives, political and social attitudes, relationships with the places and spaces of South Africa, as well as their expectations of the future, the complexities of their transnational, raced and classed identities and senses of belonging are revealed. Migration, Space and Transnational Identities makes an important contribution to sociological, geographical, political and anthropological debates on transnational migration, whiteness, Britishness and lifestyle, tourism and labour migration.

New York City: "gilt cage" or "promised land" ? : representations of urban space in Edith Wharton and Anzia Yezierska

This thesis explores the importance of literary New York City in the urban narratives of Edith Wharton and Anzia Yezierska. It specifically looks at the Empire City of the Progressive Period when the concept of the city was not only a new theme but also very much a typical American one which was as central to the American experience as had been the Western frontier. It could be argued, in fact, that the American city had become the new frontier where modern experiences like urbanization, industrialization, immigration, and also women's emancipation and suffrage, caused all kinds of sensations on the human scale from smoothly lived assimilation and acculturation to deeply felt alienation because of the constantly shifting urban landscape. The developing urban space made possible the emergence of new female literary protagonists like the working girl, the reformer, the prostitute, and the upper class lady dedicating her life to 'conspicuous consumption'. Industrialization opened up city space to female exploration: on the one hand, upper and middle class ladies ventured out of the home because of the many novel urban possibilities, and on the other, lower class and immigrant girls also left their domestic sphere to look for paid jobs outside the home. New York City at the time was not only considered the epicenter of the world at large, it was also a city of great extremes. Everything was constantly in flux: small brownstones made way for ever taller skyscrapers and huge waves of immigrants from Europe pushed native New Yorkers further uptown on the island, adding to the crowdedness and intensity of the urban experience. The city became a polarized urban space with Fifth Avenue representing one end of the spectrum and the Lower East Side the other. Questions of space and the urban home greatly mattered. It has been pointed out that the city setting functions as an ideal means for the display of human nature as well as social processes. Narrative representations of urban space, therefore, provide a similar canvas for a protagonist's journey and development. From widely diverging vantage points both Edith Wharton and Anzia Yezierska thus create a polarized city where domesticity is a primal concern. Looking at all of their New York narratives by close readings of exterior and interior city representations, this thesis shows how urban space greatly affects questions of identity, assimilation, and alienation in literary protagonists who cannot escape the influence of their respective urban settings. Edith Wharton's upper class "millionaire" heroines are framed and contained by the city interiors of "old" New York, making it impossible for them to truly participate in the urban landscape in order to develop outside of their 'Gilt Cages'. On the other side are Anzia Yezierska's struggling "immigrant" protagonists who, against all odds, never give up in their urban context of streets, rooftops, and stoops. Their New York City, while always challenging and perpetually changing, at least allows them perspectives of hope for a 'Promised Land' in the making. Central for both urban narrative approaches is the quest for a home as an architectural structure, a spiritual resting place, and a locus for identity forming. But just as the actual city embraces change, urban protagonists must embrace change also if they desire to find fulfillment and success. That this turns out to be much easier for Anzia Yezierska's driven immigrants rather than for Edith Wharton's well established native New Yorkers is a surprising conclusion to this urban theme.

A musculoskeletal shoulder model based on pseudo-inverse and null-space optimization.

The goal of the present work was assess the feasibility of using a pseudo-inverse and null-space optimization approach in the modeling of the shoulder biomechanics. The method was applied to a simplified musculoskeletal shoulder model. The mechanical system consisted in the arm, and the external forces were the arm weight, 6 scapulo-humeral muscles and the reaction at the glenohumeral joint, which was considered as a spherical joint. The muscle wrapping was considered around the humeral head assumed spherical. The dynamical equations were solved in a Lagrangian approach. The mathematical redundancy of the mechanical system was solved in two steps: a pseudo-inverse optimization to minimize the square of the muscle stress and a null-space optimization to restrict the muscle force to physiological limits. Several movements were simulated. The mathematical and numerical aspects of the constrained redundancy problem were efficiently solved by the proposed method. The prediction of muscle moment arms was consistent with cadaveric measurements and the joint reaction force was consistent with in vivo measurements. This preliminary work demonstrated that the developed algorithm has a great potential for more complex musculoskeletal modeling of the shoulder joint. In particular it could be further applied to a non-spherical joint model, allowing for the natural translation of the humeral head in the glenoid fossa.

眞福直指Zhen fu zhi zhi.

Guide de la vraie béatitude.Par le P. Lobelli, avec autorisation de Wan Duo ma si. Préface de l'auteur ; préface par Kang Ting huai, de Yin (1670). Édition portant divers sceaux.2 livres.

« Les Croniques des roys de France, depuis le temps des premiers roys qui I furent dusques au temps du roy Phelippe, qui fu filz Phelippe li biaux, et frère le roy Looys, lesqueles Pierres Honnorez du Nuef Chastel, en Normendie, fist escrire et ordoner,... selon l'ordenance des Croniques de Saint-Denis, à maistre Thommas de Maubuege, demeurant en rue nueve Nostre-Dame de Paris, l'an... 1318... ».

Ce ms. contient : 1° les Grandes Chroniques, jusqu'à la mort de Philippe-Auguste ; 2° la Chronique française de GUILLAUME DE NANGIS, de 1223 à 1316 (fol. 362-400) ; 3° une continuation de 1316 à 1330. Cf. L. Delisle, Mém. sur les ouvrages de G. de Nangis, dans les Mém. de l'Acad. des Inscriptions (1873), t. XXVII, II, p. 355.

Ethical space in a secondary school: a case study /

Discourse in the provincial education system that includes Aboriginal peoples is a convoluted one-sided affair. This has contributed to the limited academic success for Aboriginal secondary students in the provincial school system. The Office of the Auditor General (2004) announced a 27-28 year gap in Academic success compared to non- Aboriginal students (p. I). Both Aboriginal and non-Aboriginal stakeholders are fiiistrated and confused with the lack of support for long-term solutions to address academic success for Aboriginal students. The boundaries in education that exist between the dominant society of Canada and Aboriginal peoples in education are hindering the development of ethical space in which to negotiate and apply "concrete arguments and concepts" (Ermine, 2000, p. 140) for 'best' solutions across the cultural divide. Recent literature suggests a gap in knowledge to address this cultural divide. This study reveals racism is still prevalent and the problem lies in the fallacy of Euro-Western pedagogical beliefs. There is a need to design ethical space that will assist transformation of cross-relations in education for inclusion of Aboriginal voices and content. I submit that ethical space involves physical and abstract space. This report is a qualitative, exploratory, and single case study of one northern Ontario secondary school attended by First Nations and Metis peoples who comprise 35% of the school population. Twenty-six stakeholders volunteered to participate in six interviews. The volunteers in this study are Aboriginal and non-Aboriginal. Aboriginal peoples are firom two First Nations, and Metis peoples. It is an Aboriginal designed and delivered study that a) describes an Aboriginally-designed research method to gather data across cultural divides in a secondary school, b) reviews Tri-Council Policy Section 6 (TCPS) regarding 'good practices' in ethical research involving Aboriginal peoples, and c) summarizes stakeholder perspectives of the 'best educational environment' for one secondary school.

El peregrino septentrional atlante : delineado en la exemplarissima vida del venerable padre Antonio Margil de Jesús, fruto de la floridiffima ciudad de Valencia, hijo de fu seraphica obfervante provincia, predicador miffionero, notario apoftolico, camiffario del Santo Officio, fundador y ex-guardián de tres colegios, piefecto de las miffiones de propaganda fde en todas las Indias Occidentales y acalamado de la piedad por Nuevo Apostol de Guatemala.

UANL

Quién fué el verdadero responsable de la muerte del General Vicente Guerrero?

UANL

Informe rendido por el Sr. Manuel Vivanco Llano presidente de la Sociedad de Salubridad y Beneficiencia de Linares N. León, al terminar el objeto con que fué fundada dicha corporación.

UANL

Defensa legal de D. Antonio de la Campa, vecino que fué de esta ciudad en los autos pendientes en esta real audiencia con el albacea de María Luciana Villavicencio y de don Joaquín Zuazueta, marido de Ana Joaquina sobre nulidad de la disposición testamentaría en que aplicó su caudal á obras piadosas

UANL