Clinical trial designs for rare diseases: Studies developed and discussed by the International Rare Cancers Initiative

BACKGROUND: The past three decades have seen rapid improvements in the diagnosis and treatment of most cancers and the most important contributor has been research. Progress in rare cancers has been slower, not least because of the challenges of undertaking research.

SETTINGS: The International Rare Cancers Initiative (IRCI) is a partnership which aims to stimulate and facilitate the development of international clinical trials for patients with rare cancers. It is focused on interventional--usually randomized--clinical trials with the clear goal of improving outcomes for patients. The key challenges are organisational and methodological. A multi-disciplinary workshop to review the methods used in ICRI portfolio trials was held in Amsterdam in September 2013. Other as-yet unrealised methods were also discussed.

RESULTS: The IRCI trials are each presented to exemplify possible approaches to designing credible trials in rare cancers. Researchers may consider these for use in future trials and understand the choices made for each design.

INTERPRETATION: Trials can be designed using a wide array of possibilities. There is no 'one size fits all' solution. In order to make progress in the rare diseases, decisions to change practice will have to be based on less direct evidence from clinical trials than in more common diseases.

Resiliencia y variables sociodemograficas

En el presente trabajo se aborda la definición de una de las variables dentro de lo que se denomina Capital psicológico positivo, la Resiliencia, sus principales características y algunas de las variables socio demográficas que en el estudio pretenden ver el nivel de relación existente entre cada una de ellas (indirecta o directamente) en el proceso resiliente de una persona para posteriores discusiones y su implicación dentro de la gestión empresarial y sus direcciones futuras.

Nutritional and safety assessments of foods and feeds nutritionally improved through biotechnology: Case studies

During the last 2 decades, the public and private sectors have made substantial international research progress toward improving the nutritional value of a wide range of food and feed crops. Nevertheless, significant numbers of people still suffer from the effects of undernutrition. In addition, the nutritional quality of feed is often a limiting factor in livestock production systems, particularly those in developing countries. As newly developed crops with nutritionally improved traits come closer to being available to producers and consumers, we must ensure that scientifically sound and efficient processes are used to assess the safety and nutritional quality of these crops. Such processes will facilitate deploying these crops to those world areas with large numbers of people who need them. This document describes 5 case studies of crops with improved nutritional value. These case studies examine the principles and recommendations published by the Intl. Life Sciences Inst. (ILSI) in 2004 for the safety and nutritional assessment of foods and feeds derived from nutritionally improved crops (ILSI 2004). One overarching conclusion that spans all 5 case studies is that the comparative safety assessment process is a valid approach. Such a process has been endorsed by many publications and organizations, including the 2004 ILSI publication. The type and extent of data that are appropriate for a scientifically sound comparative safety assessment are presented on a case-by-case basis in a manner that takes into account scientific results published since the 2004 ILSI report. This report will appear in the January issue of Comprehensive Reviews in Food Science and Food Safety.

Construção de vínculos de confiança empresarial

O trabalho apresentado neste relatório tem por objetivo pesquisar a constituição e o desenvolvimento da confiança entre os empresários participantes do programa Cooperar para Competir, o qual compõe o conjunto de treinamentos oferecidos para o Arranjo Produtivo Local de Birigui pelo SEBRAE-SP em parceria com instituições locais como o Sindicato da Indústrias do Calçado e Vestuário de Birigui, o SESI de Birigui, entre outros. Em termos de metodologia, foi escolhido o método qualitativo para desenvolver uma pesquisa exploratória de estudo de caso (o Cooperar para Competir) e foram utilizadas duas técnicas de pesquisa – a entrevista aberta ou não-dirigida e a técnica de história oral. Para o seu desenvolvimento, foram estabelecidas três grandes áreas de investigação que, juntas, ofereceriam uma visão abrangente do tema analisado: a) a primeira grande área é responsável pelo estudo do contexto e da estrutura econômica do APL em geral, bem como de seus agentes presentes naquela região e suas particularidades. Nesta primeira parte são apresentadas discussões sobre clusters, sua importância e representatividade no Brasil e no mundo, bem como uma análise do cluster calçadista de Birigui de acordo com o Modelo Diamante proposto por Porter (1999); b) a segunda área abrange tanto a estrutura formal do Cooperar para Competir em cada uma das turmas quanto o processo dinâmico do curso, seus momentos críticos e as estratégias pedagógicas adotadas a cada momento em vista dos desafios. Esta parte contextualiza o programa, apresenta sua estrutura e reflete a construção das bases de cooperação em sala de aula por uma perspectiva axiológica; c) a terceira área, por fim, é caracterizada pela pesquisa de campo, quando foram investigadas as vivências, experiências e impactos dos e nos participantes do ponto de vista subjetivo e como eles entenderam os efeitos em suas vidas profissional e pessoal. As entrevistas abertas foram realizadas com dois grupos de participantes, o Grupo Graduado e o Grupo Novo, a fim entender o desenvolvimento de ambos os grupos, os resultados alcançados pelo primeiro e o efeito da suspensão do programa no segundo. Todo o processo seguido durante a pesquisa permitiu que se chegasse a inúmeras conclusões, como o porquê do sucesso do programa Cooperar para Competir – o sucesso, neste caso, reside no desenho pedagógico que atende a dimensão axiológica, ou seja, não apenas se falou de cooperação, mas se produziu cooperação ao integrar competências, interesses e valores. O programa serviu, então, como um espaço filosófico e laboratorial. Assim, o conteúdo e a sequência seguidos também tem sua importância relativizada frente as relações e a construção de algo que transcende o caráter utilitarista ou funcionalista das disciplinas. As entrevistas individuais e em grupo mostraram que se reconhecerem como iguais foi um fator gerador de confiança entre os participantes, a qual também é expressa quando estes se abrem para compreenderem o modo como os outros atribuem significados para a relação de desconfiança e confiança e passam a estabelecer um sistema de significação comum. Além disso, a consciência de sua realidade e o reconhecimento de sua responsabilidade junto a si mesmo, à sua empresa, ao projeto desenvolvido no Cooperar para Competir e à comunidade de Birigui marcam, também, a mudança do esquema mental de sapateiro para empresário.

AGRICULTURAL BIRD PROBLEMS IN THE SOUTHEAST

Our chairman has wisely asked that we not spend all of our time here telling each other about our bird problems. In the Southeast, our difficulties with blackbirds are based upon the same bird habits that cause trouble elsewhere: they flock, they roost and they eat, generally taking advantage of the readily available handouts that today's agricul¬tural practices provide. Those of us on the receiving end of these de¬predations of course think that damage in our own particular area must be far the worst, anywhere. Because of the location of our meeting place today, perhaps it is worthwhile to point out that a report prepared by our Bureau's Washington office this year outlined the problem of blackbird damage to corn in the Middle Atlantic States, the Great Lakes Region and in Florida, and then followed with this statement--"An equally serious problem occurs in rice and grain sorghum fields of Arkansas, Mississippi, Texas and Louisiana." The report also men¬tions that the largest winter concentrations of blackbirds are found in the lower Mississippi Valley. Our 1963-64 blackbird-starling survey showed 43 principal roosts totaling approximately 100 million of these birds in Virginia, the Carolinas, Georgia, Alabama, Tennessee and Kentucky. We have our own birds during the summer plus the "tourist" birds from up here and elsewhere during the winter, and all of these birds must eat, so suffice it to say that we, too, have some bird problems in the Southeast. I'm sure you're more interested in what we're doing about them. To keep this in perspective also, please bear in mind that against the magnitude of these problems, our blackbird control research staff at Gainesville consists of 3 biologists, 1 biochemist and one technician. And unfortunately, none of us happens to be a miracle worker. I think, though, we have made great progress toward solving the bird problems in the Southeast for the man-hours that have been expended in this re¬search. My only suggestion to those who are impatient about not having more answers is that they examine the budget that has been set up for this work. Only then could we intelligently discuss what might be expected as a reasonable rate of research progress. When I think about what we have accomplished in a short span of time, with very small expenditure, I can assure you that I am very proud of our small research crew at Gainesville--and I say this quite sincerely. At the Gainesville station, we work under two general research approaches to the bird damage problem. These projects have been assigned to us. The first is research on management of birds, particularly blackbirds and starlings destructive to crops or in feedlots, and, secondly, the development and the adaptation of those chemical compounds found to be toxic to birds but relatively safe to mammals. These approaches both require laboratory and field work that is further subdivided into several specific research projects. Without describing the details of these now, I want to mention some of our recent results. From the results, I'm sure you will gather the general objectives and some of the procedures used.

Membranöse Glomerulopathie-eine Autoimmunerkrankung

Membranous nephropathy is one of the most common glomerular diseases and leading causes of nephrotic syndrome in Caucasian adults. Known as a clinico-pathologic entity for over 50 years, it is defined by thickening of the glomerular capillary membrane with subepithelial immuncomplexes. Secondary forms (e. g. hepatitis B, autoimmune disease or medication-induced) are distinguished from idiopathic forms. Despite spontaneous remissions in about 30 % of cases, one third of idiopathic forms progress to end-stage renal disease after 10 years. Seminal research progress of the last decade has allowed the identification of autoantibodies directed against podocytary elements leading to secondary damage to the filtration barrier. The so-called idiopathic membranous nephropathy has thus become a prototype of autoimmune disease. The autoantibodies detectable in 70 - 80 % of cases of idiopathic membranous nephropathy are directed against the M-type phospholipase A2-receptor on the podocyte membrane and correlate with disease activity. These epochal findings influence on diagnostic and therapeutic strategies establishing a rationale for the use of B cell-directed therapy on top of optimal supportive therapy.

The INO80 chromatin remodeling complex is involved in the nucleotide excision repair pathway

The genomic DNA of eukaryotic cells is well organized into chromatin structures. However, these repressed structures present barriers that block the access of regulatory factors to the genome during various nuclear events. To overcome the obstacle, two major cellular processes, post-modification of histone tails and ATP-dependent chromatin remodeling, are involved in reconfiguring chromatin structure and creating accessible DNA. Despite the current research progress, much remains to be explored concerning the relationship between chromatin remodeling and DNA repair. Recently, one member of the ATP-dependent chromatin remodeling complexes, INO80, has been found to play a crucial role in DNA damage repair. However, the functions of this complex in higher eukaryotes have yet to be determined. The goal of my study is to generate a human somatic INO80 conditional knockout model and investigate the functions of Ino80 in damage repair.^ By homologous targeting of the INO80 locus in human HCT116 colon epithelial cells, I established a human somatic INO80 conditional knockout model. I have demonstrated that the conditional INO80 cells exhibited a sufficiently viable period when the INO80 protein is removed. Moreover, I found that loss of INO80 resulted in deficient UV lesion repair in response to UV while the protein levels of the NER factors such as XPC, XPA, XPD were not affected. And in vitro repair synthesis assay showed that the NER incision and repair synthesis activities were intact in the absence of INO80. Examination on the damage recognition factor XPC showed its recruitment to damage sites was impaired in the INO80 mutant cells. Loss of INO80 also led to reduced enrichment of XPA at the site of UV lesions. Despite the reduced recruitment of XPC and XPA observed in INO80 mutants, no direct interaction was detected. Meanwhile, direct interaction between INO80 and DDB1, the initial UV lesion detector, was detected by coimmunoprecipitation. UV-induced chromosome relaxation was reduced in cells devoid of INO80. These results demonstrate the INO80 complex may participates in the NER by interacting with DDB1 and having a critical role of in creating DNA accessibility for the nucleotide excision pathway. ^

The Annual bulletin of the Beach Erosion Board

Mode of access: Internet.

The spatial patterns of the tau immunopositive neuronal cytoplasmic inclusions (NCI) in the tauopathies

Tau positive neuronal cytoplasmic inclusions (NCI) are the ‘hallmark’ pathological feature of several neurodegenerative diseases collectively known as the tauopathies. This study compared the spatial patterns of various types of NCI in selected tauopathies including the neurofibrillary tangles (NFT) in Alzheimer's disease (AD) and progressive supranuclear palsy (PSP), Pick bodies (PB) in Pick’s disease (PiD), and the tau positive (tau+) neurons in corticobasal degeneration (CBD). In the cerebral cortex of these disorders, the tau+ NCI were distributed in clusters and in a significant proportion of analyses, the clusters were distributed with a regular periodicity parallel to the pia mater. The inclusions in AD, PiD and CBD exhibited a similar range of spatial patterns but in PSP were less frequently clustered and more frequently randomly distributed. In gyri where the NCI were clustered, there was a significant difference in mean cluster size between disorders. Hence, clusters of NFT in AD were larger than those in PSP and the tau+ neurons in CBD and clusters of PB in PiD were larger than the tau+ neurons in CBD and the NFT in PSP. The cluster size of the tau+ neurons in CBD was similar to the NFT in PSP. The data suggest that the formation of clusters of NCI, regularly distributed parallel to the pia mater, is a common feature of the tauopathies indicating similar patterns of cortical degeneration and pathogenic mechanisms across different diseases. Furthermore, the data suggest that cortical degeneration affecting the short and long cortico-cortical pathways may be a characteristic of the tauopathies.

The visual cortex in Alzheimer disease:laminar distribution of the pathological changes in visual areas V1 and V2

Alzheimer’s disease (AD) is an important neurodegenerative disorder causing visual problems in the elderly population. The pathology of AD includes the deposition in the brain of abnormal aggregates of ?-amyloid (A?) in the form of senile plaques (SP) and abnormally phosphorylated tau in the form of neurofibrillary tangles (NFT). A variety of visual problems have been reported in patients with AD including loss of visual acuity (VA), colour vision and visual fields; changes in pupillary responses to mydriatics, defects in fixation and in smooth and saccadic eye movements; changes in contrast sensitivity and in visual evoked potentials (VEP); and disturbances in complex visual tasks such as reading, visuospatial function, and in the naming and identification of objects. In addition, pathological changes have been observed to affect the eye, visual pathway, and visual cortex in AD. To better understand degeneration of the visual cortex in AD, the laminar distribution of the SP and NFT was studied in visual areas V1 and V2 in 18 cases of AD which varied in disease onset and duration. In area V1, the mean density of SP and NFT reached a maximum in lamina III and in laminae II and III respectively. In V2, mean SP density was maximal in laminae III and IV and NFT density in laminae II and III. The densities of SP in laminae I of V1 and NFT in lamina IV of V2 were negatively correlated with patient age. No significant correlations were observed in any cortical lamina between the density of NFT and disease onset or duration. However, in area V2, the densities of SP in lamina II and lamina V were negatively correlated with disease duration and disease onset respectively. In addition, there were several positive correlations between the densities of SP and NFT in V1 with those in area V2. The data suggest: (1) NFT pathology is greater in area V2 than V1, (2) laminae II/III of V1 and V2 are most affected by the pathology, (3) the formation of SP and NFT in V1 and V2 are interconnected, and (4) the pathology may spread between visual areas via the feed-forward short cortico-cortical connections.

Quantitative neuropathology:data collection and statistical analysis

The use of quantitative methods has become increasingly important in the study of neuropathology and especially in neurodegenerative disease. Disorders such as Alzheimer's disease (AD) and the frontotemporal dementias (FTD) are characterized by the formation of discrete, microscopic, pathological lesions which play an important role in pathological diagnosis. This chapter reviews the advantages and limitations of the different methods of quantifying pathological lesions in histological sections including estimates of density, frequency, coverage, and the use of semi-quantitative scores. The sampling strategies by which these quantitative measures can be obtained from histological sections, including plot or quadrat sampling, transect sampling, and point-quarter sampling, are described. In addition, data analysis methods commonly used to analysis quantitative data in neuropathology, including analysis of variance (ANOVA), polynomial curve fitting, multiple regression, classification trees, and principal components analysis (PCA), are discussed. These methods are illustrated with reference to quantitative studies of a variety of neurodegenerative disorders.

The neuropathology of the occipital cortex and its significance in the visual problems of patients with variant Creutzfeldt-Jakob Disease (vCJD)

The occipital lobe is one of the cortical areas most affected by the pathology of variant Creutzfeldt-Jakob disease (vCJD). To understand the visual problems of vCJD patients, neuropathological changes were studied in striate (B17, V1) and extrastriate (B18, V2) regions of the occipital cortex in eleven cases of vCJD. No differences in the density of vacuoles or surviving neurons were observed in B17 and B18 but densities of glial cell nuclei and deposits of the protease resistant form of prion protein (PrPsc) were greater in B18. The density of PrPsc deposits in B17 was positively correlated with their density in B18. The density of the diffuse PrPsc deposits in B17 was negatively correlated with the density of the surviving neurons in B18. In B17 and B18, the vacuoles either exhibited density peaks in laminae II/III and V/VI or were more uniformly distributed across the laminae. Diffuse PrPsc deposits were most frequent in laminae II/III and florid PrPsc deposits more generally distributed. In B18, the surviving neurons were more consistently bimodally distributed and the glial cell nuclei most abundant in laminae V/VI compared with B17. Hence, both striate and extrastriate areas of the occipital cortex are affected by the pathology of vCJD, the pathological changes being most severe in B18. Neuronal degeneration in B18 may be associated with the development of diffuse PrPsc deposits in B17. These data suggest that the short cortico-cortical connections between B17 and B18 and the pathways to subcortical visual areas are compromised in vCJD. Pathological changes in striate and extrastriate regions of the occipital cortex may contribute to several of the visual problems identified in patients with vCJD including oculomotor and visuo-spatial function. © 2012 Nova Science Publishers, Inc. All rights reserved.