Predicting response and survival in chemotherapy-treated triple-negative breast cancer.

BACKGROUND In this study, we evaluated the ability of gene expression profiles to predict chemotherapy response and survival in triple-negative breast cancer (TNBC). METHODS Gene expression and clinical-pathological data were evaluated in five independent cohorts, including three randomised clinical trials for a total of 1055 patients with TNBC, basal-like disease (BLBC) or both. Previously defined intrinsic molecular subtype and a proliferation signature were determined and tested. Each signature was tested using multivariable logistic regression models (for pCR (pathological complete response)) and Cox models (for survival). Within TNBC, interactions between each signature and the basal-like subtype (vs other subtypes) for predicting either pCR or survival were investigated. RESULTS Within TNBC, all intrinsic subtypes were identified but BLBC predominated (55-81%). Significant associations between genomic signatures and response and survival after chemotherapy were only identified within BLBC and not within TNBC as a whole. In particular, high expression of a previously identified proliferation signature, or low expression of the luminal A signature, was found independently associated with pCR and improved survival following chemotherapy across different cohorts. Significant interaction tests were only obtained between each signature and the BLBC subtype for prediction of chemotherapy response or survival. CONCLUSIONS The proliferation signature predicts response and improved survival after chemotherapy, but only within BLBC. This highlights the clinical implications of TNBC heterogeneity, and suggests that future clinical trials focused on this phenotypic subtype should consider stratifying patients as having BLBC or not.

BAFF, a novel ligand of the tumor necrosis factor family, stimulates B cell growth.

Members of the tumor necrosis factor (TNF) family induce pleiotropic biological responses, including cell growth, differentiation, and even death. Here we describe a novel member of the TNF family, designated BAFF (for B cell activating factor belonging to the TNF family), which is expressed by T cells and dendritic cells. Human BAFF was mapped to chromosome 13q32-34. Membrane-bound BAFF was processed and secreted through the action of a protease whose specificity matches that of the furin family of proprotein convertases. The expression of BAFF receptor appeared to be restricted to B cells. Both membrane-bound and soluble BAFF induced proliferation of anti-immunoglobulin M-stimulated peripheral blood B lymphocytes. Moreover, increased amounts of immunoglobulins were found in supernatants of germinal center-like B cells costimulated with BAFF. These results suggest that BAFF plays an important role as costimulator of B cell proliferation and function.

Lethal skeletal dysplasia in mice and humans lacking the golgin GMAP-210.

BACKGROUND: Establishing the genetic basis of phenotypes such as skeletal dysplasia in model organisms can provide insights into biologic processes and their role in human disease. METHODS: We screened mutagenized mice and observed a neonatal lethal skeletal dysplasia with an autosomal recessive pattern of inheritance. Through genetic mapping and positional cloning, we identified the causative mutation. RESULTS: Affected mice had a nonsense mutation in the thyroid hormone receptor interactor 11 gene (Trip11), which encodes the Golgi microtubule-associated protein 210 (GMAP-210); the affected mice lacked this protein. Golgi architecture was disturbed in multiple tissues, including cartilage. Skeletal development was severely impaired, with chondrocytes showing swelling and stress in the endoplasmic reticulum, abnormal cellular differentiation, and increased cell death. Golgi-mediated glycosylation events were altered in fibroblasts and chondrocytes lacking GMAP-210, and these chondrocytes had intracellular accumulation of perlecan, an extracellular matrix protein, but not of type II collagen or aggrecan, two other extracellular matrix proteins. The similarities between the skeletal and cellular phenotypes in these mice and those in patients with achondrogenesis type 1A, a neonatal lethal form of skeletal dysplasia in humans, suggested that achondrogenesis type 1A may be caused by GMAP-210 deficiency. Sequence analysis revealed loss-of-function mutations in the 10 unrelated patients with achondrogenesis type 1A whom we studied. CONCLUSIONS: GMAP-210 is required for the efficient glycosylation and cellular transport of multiple proteins. The identification of a mutation affecting GMAP-210 in mice, and then in humans, as the cause of a lethal skeletal dysplasia underscores the value of screening for abnormal phenotypes in model organisms and identifying the causative mutations.

TACI, an enigmatic BAFF/APRIL receptor, with new unappreciated biochemical and biological properties.

BAFF is a B cell survival factor that binds to three receptors BAFF-R, TACI and BCMA. BAFF-R is the receptor triggering naïve B cell survival and maturation while BCMA supports the survival of plasma cells in the bone marrow. Excessive BAFF production leads to autoimmunity, presumably as the consequence of inappropriate survival of self-reactive B cells. The function of TACI has been more elusive with TACI(-/-) mice revealing two sides of this receptor, a positive one driving T cell-independent immune responses and a negative one down-regulating B cell activation and expansion. Recent work has revealed that the regulation of TACI expression is intimately linked to the activation of innate receptors on B cells and that TACI signalling in response to multimeric BAFF and APRIL provides positive signals to plasmablasts. How TACI negatively regulates B cells remains elusive but may involve an indirect control of BAFF levels. The discovery of TACI mutations associated with common variable immunodeficiency (CVID) in humans not only reinforces its important role for humoral responses but also suggests a more complex role than first anticipated from knockout animals. TACI is emerging as an unusual TNF receptor-like molecule with a sophisticated mode of action.

Association of BAFF/BLyS overexpression and altered B cell differentiation with Sjögren's syndrome.

BAFF (BLyS, TALL-1, THANK, zTNF4) is a member of the TNF superfamily that specifically regulates B lymphocyte proliferation and survival. Mice transgenic (Tg) for BAFF develop an autoimmune condition similar to systemic lupus erythematosus. We now demonstrate that BAFF Tg mice, as they age, develop a secondary pathology reminiscent of Sjögren's syndrome (SS), which is manifested by severe sialadenitis, decreased saliva production, and destruction of submaxillary glands. In humans, SS also correlates with elevated levels of circulating BAFF, as well as a dramatic upregulation of BAFF expression in inflamed salivary glands. A likely explanation for disease in BAFF Tg mice is excessive survival signals to autoreactive B cells, possibly as they pass through a critical tolerance checkpoint while maturing in the spleen. The marginal zone (MZ) B cell compartment, one of the enlarged B cell subsets in the spleen of BAFF Tg mice, is a potential reservoir of autoreactive B cells. Interestingly, B cells with an MZ-like phenotype infiltrate the salivary glands of BAFF Tg mice, suggesting that cells of this compartment potentially participate in tissue damage in SS and possibly other autoimmune diseases. We conclude that altered B cell differentiation and tolerance induced by excess BAFF may be central to SS pathogenesis.

On the use of the likelihood ratio for forensic evaluation: response to Fenton et al.

This letter to the Editor comments on the article When 'neutral' evidence still has probative value (with implications from the Barry George Case) by N. Fenton et al. [[1], 2014].

ILS-ESP An efficient, simple, and parameter-free algorithm for solving the permutation flow-shop problem

From a managerial point of view, the more effcient, simple, and parameter-free (ESP) an algorithm is, the more likely it will be used in practice for solving real-life problems. Following this principle, an ESP algorithm for solving the Permutation Flowshop Sequencing Problem (PFSP) is proposed in this article. Using an Iterated Local Search (ILS) framework, the so-called ILS-ESP algorithm is able to compete in performance with other well-known ILS-based approaches, which are considered among the most effcient algorithms for the PFSP. However, while other similar approaches still employ several parameters that can affect their performance if not properly chosen, our algorithm does not require any particular fine-tuning process since it uses basic "common sense" rules for the local search, perturbation, and acceptance criterion stages of the ILS metaheuristic. Our approach defines a new operator for the ILS perturbation process, a new acceptance criterion based on extremely simple and transparent rules, and a biased randomization process of the initial solution to randomly generate different alternative initial solutions of similar quality -which is attained by applying a biased randomization to a classical PFSP heuristic. This diversification of the initial solution aims at avoiding poorly designed starting points and, thus, allows the methodology to take advantage of current trends in parallel and distributed computing. A set of extensive tests, based on literature benchmarks, has been carried out in order to validate our algorithm and compare it against other approaches. These tests show that our parameter-free algorithm is able to compete with state-of-the-art metaheuristics for the PFSP. Also, the experiments show that, when using parallel computing, it is possible to improve the top ILS-based metaheuristic by just incorporating to it our biased randomization process with a high-quality pseudo-random number generator.

Análise e Desenvolvimento Institucional do Sector de Ambiente em Cabo Verde

Tendo em conta a importância do ambiente qualificado como um elemento crítico no desenvolvimento em Cabo Verde, o pais vem implementando esforços no sentido da definição e implementação de uma política de ambiente compreensiva. Encontra-se na fase de finalização do Plano de Acção Nacional para o Ambiente 2004 – 2014 (PANA II). O PANA II caracteriza-se pela elaboração participativa de planos de acção municipais e intersectoriais numa perspectiva integrada. Trata-se pois de uma acção que deve dar um impulso novo ao sector do ambiente por introduzir uma abordagem inter-sectorial e descentralizada ao nível dos municípios. O PANA II, na sua totalidade, será um documento orientador de um processo contínuo caracterizado por uma dinâmica própria. Será o instrumento que, nos próximos 10 anos, servirá de base de trabalho permitindo que os diversos sectores directa ou indirectamente relacionados com as questões ambientais se desenvolvam de forma harmoniosa, garantindo um ambiente sadio. Nesta âmbito é necessário analisar os requisitos institucionais para uma implementação sucedida da estratégia e das políticas ambientais no contexto de Cabo Verde. Em conformidade com os métodos aplicados para a elaboração do PANA II, procurou-se a participação dos vários parceiros visando assegurar o envolvimento deles no processo de realização de um diagnóstico qualitativo do sector do ambiente e a compreensão e a apropriação das propostas. O presente estudo sobre a análise e o desenvolvimento institucional do sector do ambiente foi elaborado no período de 28 de julho a 22 de Setembro pelo consultor internacional Ben van Baren e o consultor nacional Edgard Pinto. Os Termos de Referência indicam como elementos que devem ser identificados e analisados no âmbito da consultoria: A clarificação do quadro institucional necessário e desejável para o processo de implementação do PANA II; A definição clara e sistematizada das funções, regras de procedimento e responsabilidades de cada estrutura orgânica envolvida na implementação do PANA II; A capacidade - em termos dos meios humanos, técnicos e logísticos - das estruturas orgânicas existentes (p.e. da Direcção Geral do Ambiente) para assumir essas responsabilidades; A afectação adequada dos meios financeiros, técnicos e humanos nas várias estruturas. A abordagem utilizada foi então a análise de documentos, a realização de entrevistas e a colheita de informações através da realização de um inquérito. Os consultores animaram três sessões de trabalho e um atelier para aprofundar o entendimento das questões e a avaliação das alternativas para o enquadramento institucional do sector do ambiente. As sessões de trabalho foram realizadas com a equipa de Coordenação de PANA II, o Núcleo Municipal, criado no quadro da elaboração dos Planos Ambientais Municipais pela Associação Nacional dos Municípios de Cabo Verde, e com o Comité de Pilotagem, composto por os directores de estruturas directamente envolvidas nas questões de ambiente. O atelier com um grupo alargado, incluindo os parceiros como representantes da administração central, do poder local, do sector privado e da sociedade civil. O modelo do inquérito realizado, a lista dos encontros e entrevistas efectuados, os termos de referência bem como a lista dos documentos consultados encontram-se nos Anexos 1, 2, 3 e 4. Os consultores deixam expresso o seu agradecimento pela colaboração e as informações prestadas por essas diversas entidades, muito particularmente o Director do GEP, Eng.º. Jorge Fernando Leal Andrade e os membros da equipa de coordenação, Dr. Isildo Gomes, Dr.ª Maria Helena Santa Rita Vieira, Engª Oumar Barry, Engª. Margarida Varela e Engª Petra Penninkhoff, bem como a Sra. Paula Bettencourt, pelo apoio logístico.

Plano Ambiental Inter-Sectorial Ambiente e Agricultura, Silvicultura e Pecuária

Cabo Verde é um país ecologicamente frágil e de fracos recursos naturais. A satisfação das necessidades básicas do Homem exige que sejam bem definidas orientações estratégicas de aproveitamento e uma aplicação optimizada dos recursos naturais a favor do desenvolvimento de actividades económicas. Desde a independência, os sucessivos Governos Cabo-verdianos têm-se mostrado preocupados com a questão da preservação dos ecossistemas e com o enquadramento dos organismos vocacionados para a gestão ambiental. Na estratégia expressa nas Grandes Opções para do Desenvolvimento (2002), o ambiente é um dos temas mais importantes. Projecta-se uma sociedade dotada de um sentimento profundo para o ambiente e de uma consciência ecológica desenvolvida sendo as medidas de preservação encaradas de forma sistémica e transversal, pretendendo-se que sejam equitativas. O segundo Plano de Acção Nacional para o Ambiente (PANA II) constitui a concretização destas políticas e define as orientações estratégicas de aproveitamento dos recursos naturais bem como os seus efeitos sobre a gestão sustentável das actividades económicas. É um documento orientador de um processo continuo caracterizado por uma dinâmica própria e que nos próximos 10 anos (2004-2014), servirá de base de trabalho, permitindo um desenvolvimento Cabo-verdiano sustentável e harmonioso, garantindo um ambiente sadio. A elaboração do PANA II foi um processo complexo com o objectivo de assegurar o envolvimento dos parceiros e estabelecer as respectivas interligações entre os vários níveis. Incluído neste processo esteve a elaboração dos nove Planos Ambientais Inter-sectoriais (PAIS). Esses PAIS incluem as preocupações e planos de todos os ministérios e agências envolvidas em sub-sectores específicos. Assim resultarão em programas e actividades coerentes, transversais e com uma visão clara sobre o desenvolvimento sustentável. Este documento apresenta os resultados dos trabalhos e planificação dos parceiros no sector Ambiente e Agricultura.

Avaliação do projeto Final - Recursos Hídrico do Tarrafal – Cabo Verde

A avaliacão do projecto do recursos hidricos do Tarrafal (Cabo Verde ) tem por base dois objectivos: 1) Cumprir as obrigag8es do contrato, o qual roquor uwa avaliação.o final, a 2) Sujeitar-se aon requisitos da CID pars a avaliação final. Desta formal a extenslo deta avaliaqlo 6 male quo ura simples rovialo, reopondendo a obrigaqos do contracto. Esta avaliagKot tern por fim estimar a forma coo o projecto atinglu ou doixou do atingir os objectivos propostos. An recomendaga4s quo safram desta avalia qio dovem sorvir para melhorar os projectos om andamento quo integram no sistema da CID. Ambos o fundos da CID o do contracto foram utilizados nesta avaliaqlo Os pontos apresentados nests documento slo da equipe do avaliaqlo o n~o representan necessariamente 0s da Administraqlo o/ou do Executivo da CID. B. A.VLICrUi)Z DA Ai1ALIAj!O Todo o projecto do Recurnos Hfdricos do Tarrafal eat inserido dontro do pris1m desta avalia.lo. Zbora outrou relatdrios tenham servido do fontes do infor=qlo, a proeantj oxamina o projecto dead. o porfodo da preparaqEo at o trmino C. EQU!!' DE AYALIACKO A equioe roi Joloeada polo Dean ( tipo do reitor do faculdads )# Director da Cemara don Adminintradoras da CID Dr. drnont Briskoyp o polo Director do Executivo, Dr. John L. Fiecher. A avaliaqgo foi orientada pole repartiglo do Executivo da CID. 0 Dr. Barry Re. Baintonp agents director do projectop coordenou o processo do avaliaqEo. 0 Dr. Gerald 3stlockq director do programus Internacionais do agricultura na Universidade do Arizonap foi selocionado coo lider da equips . 0 Dr. Howard Peterson, professor do agriculture • ongenharia do irrgaqIo da Universidade do Utah, foi selecionado coma segundo mumbro da equips. 0 Dr. Peterson ji tinha cumprido dues misses no projecto em Cabo Verde. 0 Dr. Jean Ruley Kearns, conselheiro director da CID no poriodo do 1982-83p fot selecionado comc sondo o tarceiro membro da equipe. D. ATODO DE AVALIAQXO Os pianos proliminares para conduzir a avaliaqo foram feitos numa rounibo inicial em Tucson ( Arizona ) a 5 do novembro do 1982. Nessa rounilo foi deci dido quo o Dr. Matlock visitaria o projecto durante o afs do novembro do 1982. A visita fot planojada do forma a coincidir com a presenga do Kern Stutlor, director coordenador do projectop quo devoria astar am Cabo lirde nessa data co.mpletando os trabalho a preparando o relat6rio final. Uma c6pia do Procasio do Avaliaglo pola AID assim como cdpias do relatdrios anteriores a outros docunontos rolevantea foram diatribufdos aos membros da equips duranto a reunigo inicial. Oa docu ientos examinados polos membros da equip. encontram-se listados na secção /III, Referiencias

BAFF AND APRIL: a tutorial on B cell survival.

BAFF, a member of the TNF family, is a fundamental survival factor for transitional and mature B cells. BAFF overexpression leads to an expanded B cell compartment and autoimmunity in mice, and elevated amounts of BAFF can be found in the serum of autoimmune patients. APRIL is a related factor that shares receptors with BAFF yet appears to play a different biological role. The BAFF system provides not only potential insight into the development of autoreactive B cells but a relatively simple paradigm to begin considering the balancing act between survival, growth, and death that affects all cells.

Predicting the potential for lightning activity in mediterranean storms based on the WRF model dynamic and microphysical fields

A new parameter is introduced: the lightning potential index (LPI), which is a measure of the potential for charge generation and separation that leads to lightning flashes in convective thunderstorms. The LPI is calculated within the charge separation region of clouds between 0 C and 20 C, where the noninductive mechanism involving collisions of ice and graupel particles in the presence of supercooled water is most effective. As shown in several case studies using the Weather Research and Forecasting (WRF) model with explicit microphysics, the LPI is highly correlated with observed lightning. It is suggested that the LPI may be a useful parameter for predicting lightning as well as a tool for improving weather forecasting of convective storms and heavy rainfall.