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High-power Femtosecond Optical Parametric Amplification at 1 kHz in BiB 3 O 6 pumped at 800 nm
No full textAbstract: Substantial power scaling of a travelling-wave femtosecond optical parametric amplifier, pumped near 800 nm by a 1 kHz Ti:sapphire laser amplifier, is demonstrated using monoclinic BiB 3 O 6 in a two stage scheme with continuum seeding. Total energy output (signal plus idler) exceeding 1 mJ is achieved, corresponding to an intrinsic conversion efficiency of ≈32% for the second stage. The tunability extends from 1.1 to 2.9 µm. The high parametric gain and broad amplification bandwidth of this crystal allowed the maintenance of the pump pulse duration, leading to pulse lengths less than 140 fs, both for the signal and idler pulses, even at such high output levels
Provisioning of Complex Adaptive Services
No full textABSTRACT Service oriented computing is becoming the standard paradigm to support the creation of applications composed of eservices selected from a registry. Nowadays, we are assisting to the proliferation of standardized approaches to describe such services, but there is the general agreement of distinguishing the general characteristics of services from the characteristics linked to service invocation. In many case, the selection of services is static and based on matching techniques to retrieve the most appropriate service. The paper presents the MAIS architecture to provide highly adaptive e-services in a mobile and interactive environment. It focuses on service selection and invocation, contextaware orchestration, and mechanisms for managing user interaction in a service oriented architecture. We propose adaptivity at different levels: at the process level, but also at the level of the selection of a concrete service given an abstract description. Selection is based on suitable ontologies and can consider the actual context and user characteristics to retrieve the most suitable services. The paper describes the main components of the architecture and exemplifies them on a simply process for a shipping company
); and Pfizer Global Research and Development
No full textABSTRACT: During the development of any PEGylated protein or peptide, toxicology in relevant species will be conducted prior to human exposure. Normally, comprehensive metabolism data accompany the toxicity studies for a small molecule. We have examined whether such studies would be relevant in the safety assessment of PEGylated material. Literature data indicate that the polyethylene glycol (PEG) associated with a biological molecule should provide no extra concern because the exposure-toxicity relationship of PEG in animals and humans has been thoroughly investigated and metabolism/excretion of PEG is well understood. Based on the comparisons of PEG exposure from PEGylated biological products and the exposure of PEG associated with toxicity in humans, the therapeutic index is large (approximately 600-fold or greater). Therefore, assuming that toxicological evaluation of a biological molecule of interest is complete and satisfactory therapeutic windows are achieved, the data contained in this review indicate that the PEG associated with a protein or other biological molecule does not represent an additional unquantified risk to humans. The conjugation of small proteins, peptides, and oligonucleotides with polyethylene glycol (PEG), or PEGylation, has become an increasingly common method of improving the half-life of biological products, mainly through reducing the urinary excretion of the molecule PEG is a polymer made up of identical ethylene glycol subunits. PEGs have a descriptor associated with them that represents the mean molecular weight of the molecule (i.e., PEG200 has a molecular weight of 200) To couple the PEG to the protein, peptide, or oligonucleotide, the PEG (generally monomethoxy PEG) is first activated. Several methods can be used to achieve this activation and coupling, including cyanuric chloride, 1,1Ј-carbonyldiimidazole, phenylchloroformate, or succidinimidyl active ester Toxicology studies with the PEGylated proteins are normally carried out before studies in humans, and these provide excellent evidence of the safety of these PEG-containing molecules. Such safety studies, when performed on small organic molecules, are normally accompanied with corresponding metabolism studies exploring the biological fate of the molecule in the various toxicology species and human. These studies are very difficult to conduct on the PEGylated material, and this leaves a possible concern about the PEGylated portion of the molecule and its impact on human safety. In their nonconjugated form, polyethylene glycols are widely used as excipients for a large variety of drugs and are also regularly used in children for the treatment of pediatric constipation or for colonoscopy 9 The purpose of this review is to consider the toxicology (animal and human), metabolism, excretion, and exposures of humans to PEG and to evaluate the safety of the PEG on PEGylated proteins to those exposed to these biological products. The feasibility of conducting ADME studies will also be considered, as well as any value they would bring to the risk assessment. Toxicology of Polyethylene Glycol in Animals Acute, short-, and long-term toxicology studies with PEGs administered by the oral, intraperitoneal, and intravenous routes in a wide range of animal species have been carried out with PEGs with molecular weights of up to 10,000. The toxicity of PEG has been thoroughly reviewed In chronic oral toxicology studies in the rat, PEG1500 (0.06 g/kg/ day) and PEG4000 (0.02 g/kg/day) did not cause any significant adverse effects after 2 years' administration In chronic toxicology studies in nonrodent species there were no adverse events in dogs that received PEGs ranging from 400 to 4000 molecular weight (2% in diet) for a year Toxicology of PEGylated Molecules in Animals Preclinical toxicology studies performed with PEGylated proteins have also not revealed any PEG-specific toxic findings. For example, with PEG-interferon, the toxicity profile was evaluated in cynomolgus monkeys dosed subcutaneously for 4 weeks either twice weekly (dose up to 562.5 g/kg) or daily (doses up to 600 g/kg) and for 13 weeks administered twice weekly (doses up to 150 g/kg). PEG-interferon was well tolerated. The characteristic pattern of interferon ␣ toxicity was observed with PEG-interferon. These effects included suppressive effects on the hematopoietic system and increases in liver enzymes [Pegasys (peginterferon ␣ 2a ); EPAR]. With Peg-Intron (PEGylated interferon ␣ 2a ), repeated dose toxicity studies were performed in cynomolgus monkeys using subcutaneous doses administered every other day for 1 month. Important findings included decreases in all types of blood cells, serum proteins, calcium, phosphorus, and potassium. The findings observed in PEG-Intron-dosed monkeys were similar to those produced by Intron A. There was no unique toxicity due to the PEGylation. Greater incidence and/or severity of the findings were noted in the high-dosed monkeys given PEG-Intron compared with those given Intron A. This is in accordance with the prolonged exposure and higher AUC values obtained using PEG-Intron (PEG-Intron; EPAR). Treatments with PEGylated proteins such as PEG-interferon ␣ 2a (40 kDa; Pegasys) and PEGylated asparaginase do not reveal any specific adverse events linked to the PEG moiety Overall, the acute or chronic administration of PEG with a range of molecular weights by a range of routes has not led to any major toxicities, and signs of toxicity that do occur are only apparent at high dose. In light of this information, PEG can be considered to have a toxicological profile of very low concern in animals. Clearance of Polyethylene Glycol by Metabolism The metabolism of PEG has been investigated in animals and in humans. A summary of the results is presented in Metabolism of PEG. The metabolism of PEG itself is simple and involves the oxidation of the alcohol groups present on the PEG to a carboxylic acid. For example, the diacid and hydroxyl acid metabolites of PEG have been observed in the plasma and urine of burn patients and rabbits and in the bile of cats The phase 1 metabolism of PEG in mammalian systems is mediated by alcohol dehydrogenase Impact of Molecular Weight on PEG Metabolic Clearance. Excretion balance studies have been carried out in humans with PEG. Assuming that any PEG that has not been recovered intact in these studies has been metabolized prior to secretion, it is apparent that PEG mol. wt
Parsing German: How Much Morphology Do We Need?
No full textAbstract We investigate how the granularity of POS tags influences POS tagging, and furthermore, how POS tagging performance relates to parsing results. For this, we use the standard "pipeline" approach, in which a parser builds its output on previously tagged input. The experiments are performed on two German treebanks, using three POS tagsets of different granularity, and six different POS taggers, together with the Berkeley parser. Our findings show that less granularity of the POS tagset leads to better tagging results. However, both too coarse-grained and too fine-grained distinctions on POS level decrease parsing performance
Surgical Safety Checklist: considerations on institutional policies Lista de verificação de segurança cirúrgica: Considerações a partir da micropolítica institucional Lista de Verificación de Seguridad Quirúrgica: Consideraciones sobre las políticas insti
No full textAbstrAct Objective: To reflexive analysis on aspects of institutional micro that can influence the use of surgical safety checklist for health services. Methods: It is an article of reflection, based on scientific evidence available on the subject surgical safety checklist, available in the PubMed database. Results: There are aspects of the institutional micro that need to be considered in the implementation process of the surgical safety checklist, namely: management of health, planning, education process, audit, feedback to those involved, special situations of the labor process, beyond the subjectivity of health professionals. Conclusion: Recognize factors of institutional micro influencing the use of the checklist can contribute to the creation of mechanisms to ensure the successful implementation of the list for the safety of the patient. resumen Objetivo: Análisis reflexivo sobre aspectos de micro institucional que pueden influir en el uso de la lista de verificación de seguridad quirúrgica para los servicios de salud. Métodos: Es un artículo de reflexión, basada en la evidencia científica disponible sobre el tema lista de verificación de seguridad quirúrgica, disponible en la base de datos PubMed. Resultados: Hay aspectos de la micro institucional que deben ser considerados en el proceso de aplicación de la lista de verificación de seguridad quirúrgica, a saber: la gestión de la salud, la planificación, el proceso de la educación, la auditoría, la retroalimentación de los participantes, las situaciones especiales del proceso de trabajo, más allá de la subjetividad de los profesionales de la salud. Conclusión: Reconocer factores de micro institucional que influyen en el uso de la lista de verificación puede contribuir a la creación de mecanismos para asegurar la implementación exitosa de la lista para la seguridad del paciente. Palabras clave: Seguridad del Paciente; Lista de Verificación; Servicios de Salud
2007: CHALLENGES IN MENTORING INDIVIDUALS IN BIOMEDICAL ENGINEERING TEAM DESIGN PROJECTS Challenges in Mentoring Individuals in Biomedical Engineering Team Design Projects
No full textAbstract The undergraduate curriculum in biomedical engineering at Purdue University allows students to practice design and teamwork skills each semester, culminating in the capstone design experience in the senior year. The capstone course is a unique opportunity for students to experience real-world projects and for instructors to carry out assessment and mentoring practices that prepare students for professional practice. Our approach is unique, in that assessment and mentoring are directly related to one another. Assessment is built into the course through measurement of student performance using detailed rubrics. Mentoring occurs in many formats: detailed critiques of student work, formal team or one-on-one conversations, informal conversations at workstations, etc. We have found these practices essential to the transformation of students to practicing engineers; without them, many students would not have made the transformation. Ultimately, the course is time intensive for both students and instructors, but the processes we employ provide experience in a real-world industrial design process as a means to complete the students' professional training and allows for mentoring which impacts and assesses students in a way that no other courses currently include. The details presented in this paper might easily be incorporated into other design courses as a means to enhance learning and the design experience
Formal Verification of Cognitive Models
No full textAbstract Cognitive modeling has outgrown the toy problems of the research labs and is increasingly tackling Industrial size applications. This growth is not matched in terms of software tools and methodologies. In this paper, we propose a systematic automated approach for verifying the correctness of cognitive models. We present a modular specification language, define model correctness, and present algorithms for automatically checking that a model meets its specifications
Obstructive Sleep Apnea and Coronary Artery Disease: From Pathophysiology to Clinical Implications
No full text2010
No full textMultiple myeloma (MM) is a clonal plasma cell disorder, which remains incurable. The t(4;14) translocation is present in 15% of patients with symptomatic disease and, despite recent therapeutic improvements such as bortezomib treatment, still indicates a poor prognosis. 1,2 However, t(4;14) MM is a heterogeneous group, containing both "high risk" and "good risk" patients. 3 In addition, the translocation is also detected in some cases of indolent (stage I) MM and even in monoclonal gammopathy of undetermined significance (MGUS). 4,5 Prognostic tools capable of predicting the evolution of the different forms of t(4;14) monoclonal gammopathies are currently lacking. The t(4;14) translocation deregulates two potential oncogenes, FGFR3 and MMSET/WHSC1. Previous studies have shown that FGFR3 expression, which is lost in a subset of t(4;14) MM, does not have a significant impact on patients' survival. 6-9 The MMSET gene, which is overexpressed in all t(4;14) MM, encodes for a histone methyltransferase which is involved in tumor progression and genomic instability. 8,10-12 Three major breakpoints within the 5'coding region of MMSET (MB4-1, MB4-2 and MB4-3) have been observed at 4p16 on chromosome der(4). 7,11 Each breakpoint overexpresses a specific IGH/MMSET fusion transcript. While MB4-1 produces a full length MMSET protein, MB4-2 and MB4-3 give different truncated proteins. The aim of this study was to clarify the prognostic significance of each MB4 breakpoint in a large cohort of patients. We investigated the MB4 breakpoint distribution and prognostic value in a cohort of 294 patients with t(4;14) monoclonal gammopathies including 38 asymptomatic patients (MGUS or stage I MM according to the Durie and Salmon classification) and 256 symptomatic MM patients diagnosed at the Hematology Laboratory of Paris Saint Louis and Nantes. In all cases, quantitative reverse transcriptase polymerase chain reaction (RT-PCR) was performed using cDNA from purified CD138 + bone marrow plasma cells at diagnosis to analyze expression of FGFR3 and the IGH-MMSET fusion transcripts resulting from the three different breakpoints MB4-1, MB4-2 and MB4-3, as described previously. 13 Among the 38 asymptomatic (MGUS/stage I MM) patients [(14 males and 24 females; median age 61 years (range, 35-78) with a median follow-up since diagnosis of 56 months)], RT-PCR analysis of the different IGH/MMSET fusion transcripts revealed a low percentage of the MB4-2 subtype (5%), compared to the MB4-1 and MB4-3 subtypes (74% and 21%, respectively). In contrast, among the patients with symptomatic MM, MB4-2 transcripts were expressed in 21% of cases, as compared to 62% for MB4-1, and 17% for MB4-3. Thus, the MB4-2 breakpoint is rarely observed in t(4;14) indolent monoclonal gammopathy, while it is significantly more frequent in t(4;14) symptomatic MM (P=0.0228) ( In each subgroup, about two-thirds of patients received haematologica 2015; 100:e471 LETTERS TO THE EDITOR © F e r r a t a S t o r t i F o u n d a t i o n a bortezomib-containing regimen in frontline therapy and two-thirds of patients had an autologous stem cell transplant. Only four patients received such a transplant after relapse. A combined immunomodulator-bortezomib regimen was used more frequently in MB4-2 patients (32%) than in MB4-1 (18%) (P=0.026) or MB4-3 (10%) patients (P=0.0014). Overall response rates to the first-line therapy, according to International Myeloma Working Group statements 12 were 78%, 89% and 76% in the MB4-1, MB4-2 and MB4-3 sub-groups, respectively. Interestingly, 70% of MB4-2 patients achieved a very good partial response or better, as compared to 49% and 44% of patients with MB4-1 and MB4-3, respectively (P=0.049). Thus, MB4-2 breakpoint was associated with a better quality of response to the front-line treatment, possibly as a result of a more frequent use of a combination of immunomodulatory drugs plus bortezomib. The prognostic impact of each breakpoint (MB4-1, MB4-2 or MB4-3) was analyzed by comparing patients' outcome (event-free survival, overall survival, survival after the first relapse) using Kaplan-Meier analysis. As shown in To further investigate the impact of WHSC1 breakpoints on the outcome of patients with t(4;14), deletion of chromosome 17 at p13 [del(17p)], which is associated with high-risk MM, was analyzed by fluorescence in situ hybridization at diagnosis in 162/256 cases for which tumor plasma cells were available. Overall, del(17p) was detected in 34 out of 162 cases (21%). Only 5/34 patients (2 MB4-1, 1 MB4-2 and 2 MB4-3) had a del(17p) in less than 60% of plasma cells (31-45%). The presence of del(17p) was associated with a shortened survival (median survival: 21 versus 40 months, P=0.00766) (data not shown). The del(17p) was statistically more frequently found in tumor cells with MB4-2 (14/41, 34%) as compared to MB4-1 breakpoint (13/90, 14%) (P=0.0216) but was found at a similar rate in plasma cells with MB4-3 breakpoints (7/31, 28%) (P=0.292). The frontline therapy was similar in the del(17p)-positive and -negative MB4 groups. Interestingly, among patients with del(17p), those with the MB4-2 breakpoint had a shorter overall survival than those with the MB4-1 or MB4-3 breakpoint with a median overall survival of 18.6 months (P<0.0001) 11 . However, in that study, survival analysis was performed on a smaller number of patients (n=43). In addition, the survival analysis compared patients with MB4-1 (n=30) to the pooled MB4-2 and MB4-3 subgroup (n=13), according to their ability to encode a full length or a truncated MMSET protein. Pooling MB4-2 and MB4-3 cases may have masked the specific prognostic value of the MB4-2 breakpoint. At present, the molecular basis for the particularly poor prognosis associated with the MB4-2 breakpoint is not clear. Recent studies have shown that over-expression of MMSET triggers a genome-wide increase of H3K36 dimethylation and drives oncogenic properties in vitro. 9-13 In addition, increased H3K36 dimethylation was reported in a series of children with pediatric acute lymphoblastic leukemia expressing mutated or MB4-2-like truncated MMSET. 14,15 Thus, it is possible that the higher genomewide level of H3K36me2 resulting from over-expression of a truncated MB4-2 MMSET protein could render tumor plasma cells more sensitive to first-line therapy, but could eventually drive the emergence of chemoresistant clones that could shorten patients' survival. MMSET has also been implicated in the cellular response to DNA damage through its H4K20 histone methyltransferase activity. 10 This function requires the phosphorylation of serine 102 by the ATM protein, which facilitates the binding of MMSET at DNA doublestrand breaks and the recruitment of 53BP1. 10 The removal of Ser102 in truncated MMSET isoforms might therefore enhance genomic instability and promote the emergence of resistant clones in patients. However, Ser102 is deleted in the forms derived from both MB4-2 and MB4-3, and so differential effects on DNA damage are unlikely to account for the different clinical outcomes observed for these two breakpoints. One potentially important difference between MB4-2 and MB4-3 could relate to the position of these breakpoints relative to the 5' PWWP domain involved in protein-protein interactions. While the MB4-3 breakpoint leads to a truncated MMSET protein lacking the entire PWWP domain, the product expressed from MB4-2 product retains part of this domain. 11 Future studies will need to address whether these truncated MMSET proteins could interact with different partner proteins and exert different activities on histone H3 and H4, with specific impact on patients' outcome. In our study, a high frequency of del(17p) was observed in plasma cells overexpressing the MB4-2-derived truncated form of MMSET. The combination of both genetic abnormalities severely impairs patients' outcome. In this retrospective study, del(17p) was specifically included as it was the only poor prognostic marker which had been determined in a large proportion of patients. It is now important to investigate the clinical interactions between the different MMSET breakpoints and other genetic markers associated with poor prognosis, including gain of 1q, del(12p) and del(17p), in prospective studies. Together, our results indicate that the breakpoint within the MMSET locus may explain, in part, the prognostic heterogeneity of t(4;14) gammopathies. Thus, a systematic identification of the MB4 breakpoint, along with screening for a del(17p), may be useful in the management of patients with t(4;14) MM and may pave the way for specific therapies targeting MMSET activity. LETTERS TO THE EDITOR © F e r r a t a S t o r t i F o u n d a t i o
