Cancers du sein chez l'homme: quatre cas avec différenciation neuroendocrine.

Introduction: Les cancers du sein (CS) chez l'homme sont rares (1% des CS) et relativement mal connus. La répartition des types histologiques diffère dans ce groupe par rapport aux CS de la femme. Objectif: Nous rapportons quatre cas de carcinomes mammaires invasifs à différenciation neuroendocrine diagnostiqués chez des patients de sexe masculin de 1992 à 2012. Cas: Les patients étaient âgés de 80, 77, 59 et 56 ans. La tumeur s'est révélée par une masse palpable (2 cas) ou une douleur (2 cas). Le geste chirurgical a été une tumorectomie chez un patient, une mastectomie chez 3 patients (un an après le diagnostic pour l'un d'entre eux). Ces quatre CS correspondaient à des carcinomes invasifs de grade 1 ou 2 selon Elston et Ellis, avec composante de carcinome papillaire solide dans 2 cas, hormonosensibles, de statut HER2 négatif, avec expression de la chromogranine ou/et de la synaptophysine dans plus de 50% des cellules tumorales. Le statut ganglionnaire axillaire était positif dans 2 cas, non évalué dans 2 cas. Les dossiers cliniques (traitement adjuvant, survie) sont en cours d'analyse. Discussion: Les CS sont rares chez l'homme, en majorité hormonosensibles, de stade relativement avancé dans les grandes séries disponibles (1). Une différenciation neuroendocrine n'a été qu'exceptionnellement rapportée dans les CS de l'homme (2). Dans 2 des 4 cas rapportés ici elle est associée à une composante de carcinome papillaire solide. En l'absence de composante in situ, l'hypothèse d'une métastase est à considérer. Conclusion: L'incidence et les spécificités éventuelles de ce sous-groupe de CS, quant au pronostic et à la réponse aux traitements, restent à déterminer. Références : 1. Anderson WF et al. JCO 2010;28:232-9 ; 2. Potier B et al. Ann Chirur Plast 2010.

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.

A regulatory network for coordinated flower maturation.

For self-pollinating plants to reproduce, male and female organ development must be coordinated as flowers mature. The Arabidopsis transcription factors AUXIN RESPONSE FACTOR 6 (ARF6) and ARF8 regulate this complex process by promoting petal expansion, stamen filament elongation, anther dehiscence, and gynoecium maturation, thereby ensuring that pollen released from the anthers is deposited on the stigma of a receptive gynoecium. ARF6 and ARF8 induce jasmonate production, which in turn triggers expression of MYB21 and MYB24, encoding R2R3 MYB transcription factors that promote petal and stamen growth. To understand the dynamics of this flower maturation regulatory network, we have characterized morphological, chemical, and global gene expression phenotypes of arf, myb, and jasmonate pathway mutant flowers. We found that MYB21 and MYB24 promoted not only petal and stamen development but also gynoecium growth. As well as regulating reproductive competence, both the ARF and MYB factors promoted nectary development or function and volatile sesquiterpene production, which may attract insect pollinators and/or repel pathogens. Mutants lacking jasmonate synthesis or response had decreased MYB21 expression and stamen and petal growth at the stage when flowers normally open, but had increased MYB21 expression in petals of older flowers, resulting in renewed and persistent petal expansion at later stages. Both auxin response and jasmonate synthesis promoted positive feedbacks that may ensure rapid petal and stamen growth as flowers open. MYB21 also fed back negatively on expression of jasmonate biosynthesis pathway genes to decrease flower jasmonate level, which correlated with termination of growth after flowers have opened. These dynamic feedbacks may promote timely, coordinated, and transient growth of flower organs.

Geographic variation in the frequency of isolation and fluconazole and voriconazole susceptibilities of Candida glabrata: an assessment from the ARTEMIS DISK Global Antifungal Surveillance Program.

Geographic differences in frequency and azole resistance among Candida glabrata may impact empiric antifungal therapy choice. We examined geographic variation in isolation and azole susceptibility of C. glabrata. We examined 23 305 clinical isolates of C. glabrata during ARTEMIS DISK global surveillance. Susceptibility testing to fluconazole and voriconazole was assessed by disk diffusion, and the results were grouped by geographic location: North America (NA) (2470 isolates), Latin America (LA) (2039), Europe (EU) (12 439), Africa and the Middle East (AME) (728), and Asia-Pacific (AP) (5629). Overall, C. glabrata accounted for 11.6% of 201 653 isolates of Candida and varied as a proportion of all Candida isolated from 7.4% in LA to 21.1% in NA. Decreased susceptibility (S) to fluconazole was observed in all geographic regions and ranged from 62.8% in AME to 76.7% in LA. Variation in fluconazole susceptibility was observed within each region: AP (range, 50-100% S), AME (48-86.9%), EU (44.8-88%), LA (43-92%), and NA (74.5-91.6%). Voriconazole was more active than fluconazole (range, 82.3-84.2% S) with similar regional variation. Among 22 sentinel sites participating in ARTEMIS from 2001 through 2007 (84 140 total isolates, 8163 C. glabrata), the frequency of C. glabrata isolation increased in 14 sites and the frequency of fluconazole resistance (R) increased in 11 sites over the 7-year period of study. The sites with the highest cumulative rates of fluconazole R were in Poland (22% R), the Czech Republic (27% R), Venezuela (27% R), and Greece (33% R). C. glabrata was most often isolated from blood, normally sterile body fluids and urine. There is substantial geographic and institutional variation in both frequency of isolation and azole resistance among C. glabrata. Prompt species identification and fluconazole susceptibility testing are necessary to optimize therapy for invasive candidiasis.

ESPÉCIES DO GÉNERO CURVULARIA (FUNGOS ANAMÓRFICOS: HYPHOMYCETES) NA ILHA DE SANTIAGO, CABO VERDE

Nos estudos sobre a micoflora de muitos ecossistemas os fungos do género Curvularia Boedijn 1933, constituem um dos mais fascinantes grupos, devido à frequência com que são observados especímenes do género e ao elevado número de espécies que são normalmente identificadas. Apesar da maioria dos táxones do género ser conhecida como saprófita em diferentes substratos vegetais e no solo, podendo ainda ser isolada a partir do solo e do ar, muitas espécies são fitopatogénicas, sobretudo em gramíneas e em regiões de clima tropical e subtropical (SIVANESAN 1987). Um pequeno número de espécies pode raramente originar doenças em animais, incluindo humanos, surgindo como agentes de onicomicoses, sinusite alérgica, pneumonia, endocardite e alergia broncopulmonar (CARTER & BOUDREAUX 2004). Descrito com a espécie tipo C. lunata (Wakker) Boedijn, o género Curvularia permitiu acomodar espécies da família Dematiaceae que possuíam conidióforos macronematosos, mononematosos, direitos ou flexuosos, frequentemente geniculados, por vezes nodosos, células conidiogénicas politétricas, integradas, terminais e simpodiais, fragmoconídios solitários, acropleurógenos por proliferação subterminal do conidióforo, oliváceos a castanhos, elipsóides, cilíndricos, obovóides ou piriformes, três ou mais septos transversais, terceira célula ou segunda e terceira distintamente maiores e escuras, muitas vezes desigualmente curvos devido ao alargamento de uma ou duas células centrais, raramente direitos, septos rígidos, hilo truncado ou protuberante (ELLIS 1971). O género actualmente é composto por mais de 40 táxones que se distinguem por diferenças mais ou menos evidentes na morfologia dos conídios, número de septos e aspectos culturais (SIVANESAN 1987, HOSOKAWA et al. 2003, SIVANESAN et al. 2003, ZHANG-MENG & ZHANG 2003, ZHANG-MENG et al. 2004, CHUNG 2005). Algumas espécies possuem teleomorfo conhecido no género Cochliobolus Drechsler 1934, formando ascósporos filiformes paralelos ou frouxamente enrolados em espiral, característica não evidenciada pela espécie tipo do género, C. heterostrophus (Drechsler) Drechsler, teleomorfo de Bipolaris maydis (Nisik. & Miyake) Shoem., na qual os ascósporos se mostram enrolados formando uma espiral fechada. Por isso, teleomorfos dos fungos do género Curvularia são considerados por alguns autores como sendo do género Pseudocochliobolus Tsuda, Ueyama & Nishih. 1978, que é tido como uma sinonímia de Cochliobolus (ALCORN 1983, SIVANESAN 1987). De notar, no entanto, que sendo filogeneticamente próximo do género Bipolaris Shoem. 1959, as suas espécies apresentam semelhanças morfológicas com espécies do género Bipolaris que têm conídios pequenos e direitos e estudos com análise de sequências ITS e com o marcador enzimático gliceraldeído-3-P desidrogenase mostraram que partilham teleomorfo no grupo 2 do género Cochliobolus (BERBEE et al. 1999). A variabilidade morfológica observada nos fungos enquadrados em Curvularia levou a que ao ser criado o género as espécies fossem separadas em três grupos, ‘geniculata’, com a espécie-tipo C. geniculata (Tracy & Earle) Boedijn, ‘lunata’, com a espécie-tipo C. lunata (Tracy & Earle) Boedijn, e ‘maculans’, com a espécie-tipo C. maculans (Bancroft) Boedijn (=C. eragrostidis (Henn.) Mey.), que se diferenciaram pela forma dos conídios e número de septos (CORBETTA 1964). Nos grupos ‘lunata’ e ‘maculans’ ficaram colocadas as espécies com conídios 3-septados e no grupo ‘geniculata’ as espécies que tinham conídios 4- septados ou com maior número de septos. As espécies do grupo ‘lunata’ distinguiram-se das do grupo ‘maculans’ principalmente por apresentarem curvatura mais pronunciada, célula mediana mais volumosa e habitual presença de estroma em cultura. O reconhecimento das características principais do género Curvularia é relativamente fácil, o que permite que seja normalmente possível a identificação ao género de um qualquer espécimen. No entanto, a identificação em espécie é por vezes complicada pelas descrições vagas e ausência de ilustrações em trabalhos mais antigos, inconstância de características morfológicas e biométricas dos esporos, causada por diferentes condições em que ocorre o crescimento, e sobreposição dos valores das medidas apresentadas por diferentes autores (TSUDA & UEYAMA 1982, HOSOKAWA et al. 2003). Contudo, esta situação não impede que a identificação das espécies continue a ser feita numa aproximação fenotípica, com base em características morfológicas e culturais. Recentemente, as espécies C. fallax Boedijn, C. geniculata (Tracy & Earle) Boedijn e C. senegalensis (Speg.) Subram., do grupo ‘geniculata’, que eram aceites como táxones válidos em monografias clássicas do género (ELLIS 1971, SIVANESAN 1987) mostraram-se interférteis (HOSOKAWA et al. 2003), vindo a ser consideradas, com base em características morfológicas e análise de DNA total por RFLP (HOSOKAWA et al. 2003) e na análise da sequência do gene Brn1 (SUN et al. 2003), como espécie única e sinonimizadas com C. geniculata. Sabido que a diversidade dos fungos que ocorrem nos diferentes ecossistemas de Cabo Verde tem sido pouco estudada, iniciou-se um levantamento da micoflora associada a gramíneas, tendo-se obtido uma colecção de Magnaporthe grisea (Hebert) Barr (LIMA & DUCLOS 2001) e de espécies dos géneros Bipolaris, Exserohilum Leonard & Suggs e Curvularia. O presente trabalho tem como objectivo descrever e ilustrar as espécies de Curvularia identificadas na ilha de Santiago e contribuir para o melhor conhecimento do género naquele país. Na bibliografia consultada não foram encontradas referências a fungos do género Curvularia para Cabo Verde.

An Automatic Approach for Learning and Tuning Gaussian Interval Type-2 Fuzzy Membership Functions Applied to Lung CAD Classification System

The potential of type-2 fuzzy sets for managing high levels of uncertainty in the subjective knowledge of experts or of numerical information has focused on control and pattern classification systems in recent years. One of the main challenges in designing a type-2 fuzzy logic system is how to estimate the parameters of type-2 fuzzy membership function (T2MF) and the Footprint of Uncertainty (FOU) from imperfect and noisy datasets. This paper presents an automatic approach for learning and tuning Gaussian interval type-2 membership functions (IT2MFs) with application to multi-dimensional pattern classification problems. T2MFs and their FOUs are tuned according to the uncertainties in the training dataset by a combination of genetic algorithm (GA) and crossvalidation techniques. In our GA-based approach, the structure of the chromosome has fewer genes than other GA methods and chromosome initialization is more precise. The proposed approach addresses the application of the interval type-2 fuzzy logic system (IT2FLS) for the problem of nodule classification in a lung Computer Aided Detection (CAD) system. The designed IT2FLS is compared with its type-1 fuzzy logic system (T1FLS) counterpart. The results demonstrate that the IT2FLS outperforms the T1FLS by more than 30% in terms of classification accuracy.

A new highly penetrant form of obesity due to deletions on chromosome 16p11.2.

Obesity has become a major worldwide challenge to public health, owing to an interaction between the Western 'obesogenic' environment and a strong genetic contribution. Recent extensive genome-wide association studies (GWASs) have identified numerous single nucleotide polymorphisms associated with obesity, but these loci together account for only a small fraction of the known heritable component. Thus, the 'common disease, common variant' hypothesis is increasingly coming under challenge. Here we report a highly penetrant form of obesity, initially observed in 31 subjects who were heterozygous for deletions of at least 593 kilobases at 16p11.2 and whose ascertainment included cognitive deficits. Nineteen similar deletions were identified from GWAS data in 16,053 individuals from eight European cohorts. These deletions were absent from healthy non-obese controls and accounted for 0.7% of our morbid obesity cases (body mass index (BMI) >or= 40 kg m(-2) or BMI standard deviation score >or= 4; P = 6.4 x 10(-8), odds ratio 43.0), demonstrating the potential importance in common disease of rare variants with strong effects. This highlights a promising strategy for identifying missing heritability in obesity and other complex traits: cohorts with extreme phenotypes are likely to be enriched for rare variants, thereby improving power for their discovery. Subsequent analysis of the loci so identified may well reveal additional rare variants that further contribute to the missing heritability, as recently reported for SIM1 (ref. 3). The most productive approach may therefore be to combine the 'power of the extreme' in small, well-phenotyped cohorts, with targeted follow-up in case-control and population cohorts.

Definition of clinically distinct molecular subtypes in estrogen receptor-positive breast carcinomas through genomic grade.

PURPOSE: A number of microarray studies have reported distinct molecular profiles of breast cancers (BC), such as basal-like, ErbB2-like, and two to three luminal-like subtypes. These were associated with different clinical outcomes. However, although the basal and the ErbB2 subtypes are repeatedly recognized, identification of estrogen receptor (ER) -positive subtypes has been inconsistent. Therefore, refinement of their molecular definition is needed. MATERIALS AND METHODS: We have previously reported a gene expression grade index (GGI), which defines histologic grade based on gene expression profiles. Using this algorithm, we assigned ER-positive BC to either high-or low-genomic grade subgroups and compared these with previously reported ER-positive molecular classifications. As further validation, we classified 666 ER-positive samples into subtypes and assessed their clinical outcome. RESULTS: Two ER-positive molecular subgroups (high and low genomic grade) could be defined using the GGI. Despite tracking a single biologic pathway, these were highly comparable to the previously described luminal A and B classification and significantly correlated to the risk groups produced using the 21-gene recurrence score. The two subtypes were associated with statistically distinct clinical outcome in both systemically untreated and tamoxifen-treated populations. CONCLUSION: The use of genomic grade can identify two clinically distinct ER-positive molecular subtypes in a simple and highly reproducible manner across multiple data sets. This study emphasizes the important role of proliferation-related genes in predicting prognosis in ER-positive BC.

Genomewide association study using a high-density single nucleotide polymorphism array and case-control design identifies a novel essential hypertension susceptibility locus in the promoter region of endothelial NO synthase.

Essential hypertension is a multifactorial disorder and is the main risk factor for renal and cardiovascular complications. The research on the genetics of hypertension has been frustrated by the small predictive value of the discovered genetic variants. The HYPERGENES Project investigated associations between genetic variants and essential hypertension pursuing a 2-stage study by recruiting cases and controls from extensively characterized cohorts recruited over many years in different European regions. The discovery phase consisted of 1865 cases and 1750 controls genotyped with 1M Illumina array. Best hits were followed up in a validation panel of 1385 cases and 1246 controls that were genotyped with a custom array of 14 055 markers. We identified a new hypertension susceptibility locus (rs3918226) in the promoter region of the endothelial NO synthase gene (odds ratio: 1.54 [95% CI: 1.37-1.73]; combined P=2.58 · 10(-13)). A meta-analysis, using other in silico/de novo genotyping data for a total of 21 714 subjects, resulted in an overall odds ratio of 1.34 (95% CI: 1.25-1.44; P=1.032 · 10(-14)). The quantitative analysis on a population-based sample revealed an effect size of 1.91 (95% CI: 0.16-3.66) for systolic and 1.40 (95% CI: 0.25-2.55) for diastolic blood pressure. We identified in silico a potential binding site for ETS transcription factors directly next to rs3918226, suggesting a potential modulation of endothelial NO synthase expression. Biological evidence links endothelial NO synthase with hypertension, because it is a critical mediator of cardiovascular homeostasis and blood pressure control via vascular tone regulation. This finding supports the hypothesis that there may be a causal genetic variation at this locus.

Strong time dependence of the 76-gene prognostic signature for node-negative breast cancer patients in the TRANSBIG multicenter independent validation series.

PURPOSE: Recently, a 76-gene prognostic signature able to predict distant metastases in lymph node-negative (N(-)) breast cancer patients was reported. The aims of this study conducted by TRANSBIG were to independently validate these results and to compare the outcome with clinical risk assessment. EXPERIMENTAL DESIGN: Gene expression profiling of frozen samples from 198 N(-) systemically untreated patients was done at the Bordet Institute, blinded to clinical data and independent of Veridex. Genomic risk was defined by Veridex, blinded to clinical data. Survival analyses, done by an independent statistician, were done with the genomic risk and adjusted for the clinical risk, defined by Adjuvant! Online. RESULTS: The actual 5- and 10-year time to distant metastasis were 98% (88-100%) and 94% (83-98%), respectively, for the good profile group and 76% (68-82%) and 73% (65-79%), respectively, for the poor profile group. The actual 5- and 10-year overall survival were 98% (88-100%) and 87% (73-94%), respectively, for the good profile group and 84% (77-89%) and 72% (63-78%), respectively, for the poor profile group. We observed a strong time dependence of this signature, leading to an adjusted hazard ratio of 13.58 (1.85-99.63) and 8.20 (1.10-60.90) at 5 years and 5.11 (1.57-16.67) and 2.55 (1.07-6.10) at 10 years for time to distant metastasis and overall survival, respectively. CONCLUSION: This independent validation confirmed the performance of the 76-gene signature and adds to the growing evidence that gene expression signatures are of clinical relevance, especially for identifying patients at high risk of early distant metastases.

Validation and clinical utility of a 70-gene prognostic signature for women with node-negative breast cancer.

BACKGROUND: A 70-gene signature was previously shown to have prognostic value in patients with node-negative breast cancer. Our goal was to validate the signature in an independent group of patients. METHODS: Patients (n = 307, with 137 events after a median follow-up of 13.6 years) from five European centers were divided into high- and low-risk groups based on the gene signature classification and on clinical risk classifications. Patients were assigned to the gene signature low-risk group if their 5-year distant metastasis-free survival probability as estimated by the gene signature was greater than 90%. Patients were assigned to the clinicopathologic low-risk group if their 10-year survival probability, as estimated by Adjuvant! software, was greater than 88% (for estrogen receptor [ER]-positive patients) or 92% (for ER-negative patients). Hazard ratios (HRs) were estimated to compare time to distant metastases, disease-free survival, and overall survival in high- versus low-risk groups. RESULTS: The 70-gene signature outperformed the clinicopathologic risk assessment in predicting all endpoints. For time to distant metastases, the gene signature yielded HR = 2.32 (95% confidence interval [CI] = 1.35 to 4.00) without adjustment for clinical risk and hazard ratios ranging from 2.13 to 2.15 after adjustment for various estimates of clinical risk; clinicopathologic risk using Adjuvant! software yielded an unadjusted HR = 1.68 (95% CI = 0.92 to 3.07). For overall survival, the gene signature yielded an unadjusted HR = 2.79 (95% CI = 1.60 to 4.87) and adjusted hazard ratios ranging from 2.63 to 2.89; clinicopathologic risk yielded an unadjusted HR = 1.67 (95% CI = 0.93 to 2.98). For patients in the gene signature high-risk group, 10-year overall survival was 0.69 for patients in both the low- and high-clinical risk groups; for patients in the gene signature low-risk group, the 10-year survival rates were 0.88 and 0.89, respectively. CONCLUSIONS: The 70-gene signature adds independent prognostic information to clinicopathologic risk assessment for patients with early breast cancer.

Years of valor,1969.

This book was written by Edith Wasson McElroy and published by the Iowa Civil War Centennial Commission. It follows the Meigs, a fictitious family from the late 1680's in England to 1865 in Iowa. The Meigs personify the way of life, in a typical Iowa home during this period. Their experiences are those of many early Iowa pioneers and brings to life and into reality, early Iowa life and the Civil War in its climax.

Clinical usefulness of temporal artery biopsy.

To assess the diagnostic usefulness of temporal artery biopsy in temporal arteritis (TA) and establish clinical features capable of predicting its positivity we have retrospectively studied the biopsy specimens and the clinical features of 103 patients who had undergone temporal artery biopsy. Temporal artery biopsy reached a positive predictive value of 90.2% with respect to the final diagnosis based on the criteria proposed by Ellis and Ralston and the clinical course. The simultaneous presence of recent onset headache, jaw claudication, and abnormalities of the temporal arteries on physical examination had a specificity of 94.8% with respect to the histological diagnosis and of 100% with respect to final diagnosis. The presence of any of these clinical features, though of little specificity (34.4%), had a sensitivity of 100% with respect to histological diagnosis, selecting a group of patients in whom temporal artery biopsy has more discriminative value.

Padrões de comportamento de busca e uso de informação por pesquisadores de biologia molecular e biotecnologia

O comportamento de busca e uso de informação dos pesquisadores da área de biologia molecular e biotecnologia foi analisado com base no modelo de David Ellis, verificando como a informação científica em meio digital altera este comportamento. Constituiu-se de pesquisa qualitativa, que, para a coleta de dados, utilizou questões abertas, com entrevista aos pesquisadores do Departamento de Biologia Molecular e Biotecnologia da Universidade Federal do Rio Grande do Sul. Os dados foram trabalhados em uma base de dados desenvolvida no software de análise qualitativa Nvivo versão 2.0, em conformidade com técnicas de codificação o método comparativo constante. Os resultados mostraram um perfil de comportamento de busca e uso de informação do grupo de pesquisadores, com suas principais características, em vários aspectos, geradas pelo uso das tecnologias, destacando a não-linearidade da busca e obtenção da informação. Constatou-se que os periódicos científicos eletrônicos são a principal fonte de informação destes pesquisadores, e que são amplamente utilizados e aceitos, mas o mesmo não acontece com aqueles de acesso livre, ainda usados de modo restrito. Conclui, também, que o modelo de Ellis é válido, com ampliações e modificações. Sugere novos temas de estudo relacionados ao enfoque pesquisado.