GDF15 linked to maternal risk of nausea and vomiting during pregnancy.

GDF15, a hormone acting on the brainstem, has been implicated in the nausea and vomiting of pregnancy, including its most severe form, hyperemesis gravidarum (HG), but a full mechanistic understanding is lacking1-4. Here we report that fetal production of GDF15 and maternal sensitivity to it both contribute substantially to the risk of HG. We confirmed that higher GDF15 levels in maternal blood are associated with vomiting in pregnancy and HG. Using mass spectrometry to detect a naturally labelled GDF15 variant, we demonstrate that the vast majority of GDF15 in the maternal plasma is derived from the feto-placental unit. By studying carriers of rare and common genetic variants, we found that low levels of GDF15 in the non-pregnant state increase the risk of developing HG. Conversely, women with ß-thalassaemia, a condition in which GDF15 levels are chronically high5, report very low levels of nausea and vomiting of pregnancy. In mice, the acute food intake response to a bolus of GDF15 is influenced bi-directionally by prior levels of circulating GDF15 in a manner suggesting that this system is susceptible to desensitization. Our findings support a putative causal role for fetally derived GDF15 in the nausea and vomiting of human pregnancy, with maternal sensitivity, at least partly determined by prepregnancy exposure to the hormone, being a major influence on its severity. They also suggest mechanism-based approaches to the treatment and prevention of HG.

Fetally-encoded GDF15 and maternal GDF15 sensitivity are major determinants of nausea and vomiting in human pregnancy.

Human pregnancy is frequently accompanied by nausea and vomiting that may become severe and life-threatening, as in hyperemesis gravidarum (HG), the cause of which is unknown. Growth Differentiation Factor-15 (GDF15), a hormone known to act on the hindbrain to cause emesis, is highly expressed in the placenta and its levels in maternal blood rise rapidly in pregnancy. Variants in the maternal GDF15 gene are associated with HG. Here we report that fetal production of GDF15, and maternal sensitivity to it, both contribute substantially to the risk of HG. We found that the great majority of GDF15 in maternal circulation is derived from the feto-placental unit and that higher GDF15 levels in maternal blood are associated with vomiting and are further elevated in patients with HG. Conversely, we found that lower levels of GDF15 in the non-pregnant state predispose women to HG. A rare C211G variant in GDF15 which strongly predisposes mothers to HG, particularly when the fetus is wild-type, was found to markedly impair cellular secretion of GDF15 and associate with low circulating levels of GDF15 in the non-pregnant state. Consistent with this, two common GDF15 haplotypes which predispose to HG were associated with lower circulating levels outside pregnancy. The administration of a long-acting form of GDF15 to wild-type mice markedly reduced subsequent responses to an acute dose, establishing that desensitisation is a feature of this system. GDF15 levels are known to be highly and chronically elevated in patients with beta thalassemia. In women with this disorder, reports of symptoms of nausea or vomiting in pregnancy were strikingly diminished. Our findings support a causal role for fetal derived GDF15 in the nausea and vomiting of human pregnancy, with maternal sensitivity, at least partly determined by pre-pregnancy exposure to GDF15, being a major influence on its severity. They also suggest mechanism-based approaches to the treatment and prevention of HG.

Animal and translational models of SARS-CoV-2 infection and COVID-19.

COVID-19 is causing a major once-in-a-century global pandemic. The scientific and clinical community is in a race to define and develop effective preventions and treatments. The major features of disease are described but clinical trials have been hampered by competing interests, small scale, lack of defined patient cohorts and defined readouts. What is needed now is head-to-head comparison of existing drugs, testing of safety including in the background of predisposing chronic diseases, and the development of new and targeted preventions and treatments. This is most efficiently achieved using representative animal models of primary infection including in the background of chronic disease with validation of findings in primary human cells and tissues. We explore and discuss the diverse animal, cell and tissue models that are being used and developed and collectively recapitulate many critical aspects of disease manifestation in humans to develop and test new preventions and treatments.

Which infancy growth parameters are associated with later adiposity? The Cambridge Baby Growth Study.

Background: Highly consistent positive associations are reported between infancy growth and later obesity risk. However, it is unclear whether infancy growth parameters beyond body weight add to the prediction of later obesity risk.Aim: To assess whether infancy length and skinfold thicknesses add to infancy weight in the prediction of childhood adiposity.Subjects and methods: This analysis included 254 children with available data on infant growth from birth to 24 months and childhood adiposity at age 6-11 years measured by DXA. Multilevel linear regression was used to examine the predictors of childhood percent body fat (%BF), with adjustment for sex and age at follow-up visit.Results: Birth weight and weight gain (modelled as changes in z-score) between 0-3 months and 3-24 months showed independent positive relationships with childhood %BF. The addition of gains in infant length and skinfolds between 0-3 months, but not 3-24 months, improved overall model prediction, from 18.7% to 20.7% of the variance in childhood %BF (likelihood ratio test, p < 0.0001), although their independent effect estimates were small (infant length gain: negative trend, partial R-square 0.6%, p = 0.2; skinfolds: positive trend, 1.3%, p = 0.09).Conclusion: Infancy length and skinfolds contribute significantly, but only modestly, to the prediction of childhood adiposity.

Maternal serum concentrations of bisphenol A and propyl paraben in early pregnancy are associated with male infant genital development.

STUDY QUESTION: Are maternal serum phthalate metabolite, phenol and paraben concentrations measured at 10-17 weeks of gestation associated with male infant genital developmental outcomes, specifically cryptorchidism, anogenital distance (AGD), penile length and testicular descent distance, at birth and postnatally? SUMMARY ANSWER: Maternal serum bisphenol A (BPA) concentration at 10-17 weeks of gestation was positively associated with congenital or postnatally acquired cryptorchidism, and n-propyl paraben (n-PrP) concentration was associated with shorter AGD from birth to 24 months of age. WHAT IS KNOWN ALREADY: Male reproductive disorders are increasing in prevalence, which may reflect environmental influences on foetal testicular development. Animal studies have implicated phthalates, BPA and parabens, to which humans are ubiquitously exposed. However, epidemiological studies have generated conflicting results and have often been limited by small sample size and/or measurement of chemical exposures outside the most relevant developmental window. STUDY DESIGN, SIZE, DURATION: Case-control study of cryptorchidism nested within a prospective cohort study (Cambridge Baby Growth Study), with recruitment of pregnant women at 10-17 postmenstrual weeks of gestation from a single UK maternity unit between 2001 and 2009 and 24 months of infant follow-up. Of 2229 recruited women, 1640 continued with the infancy study after delivery, of whom 330 mothers of 334 male infants (30 with congenital cryptorchidism, 25 with postnatally acquired cryptorchidism and 279 unmatched controls) were included in the present analysis. PARTICIPANTS/MATERIALS, SETTING, METHODS: Maternal blood was collected at enrolment, and serum levels of 16 phthalate metabolites, 9 phenols (including BPA) and 6 parabens were measured using liquid chromatography/tandem mass spectrometry. Logistic regression was used to model the association of cryptorchidism with serum chemical concentrations, adjusting for putative confounders. Additionally, offspring AGD, penile length and testicular descent distance were assessed at 0, 3, 12, 18 and 24 months of age, and age-specific Z scores were calculated. Associations between serum chemical levels and these outcomes were tested using linear mixed models. MAIN RESULTS AND THE ROLE OF CHANCE: Maternal serum BPA concentration was associated with offspring all-type cryptorchidism both when considered as a continuous exposure (adjusted odds ratio per log10 µg/l: 2.90, 95% CI 1.31-6.43, P = 0.009) and as quartiles (phet = 0.002). Detection of n-PrP in maternal serum was associated with shorter AGD (by 0.242 standard deviations, 95% CI 0.051-0.433, P = 0.01) from birth to 24 months of age; this reduction was independent of body size and other putative confounders. We did not find any consistent associations with offspring outcomes for the other phenols, parabens, and phthalate metabolites measured. LIMITATIONS, REASONS FOR CAUTION: We cannot discount confounding by other demographic factors or endocrine-disrupting chemicals. There may have been misclassification of chemical exposure due to use of single serum measurements. The cohort was not fully representative of pregnant women in the UK, particularly in terms of smoking prevalence and maternal ethnicity. WIDER IMPLICATIONS OF THE FINDINGS: Our observational findings support experimental evidence that intrauterine exposure to BPA and n-PrP during early gestation may adversely affect male reproductive development. More evidence is required before specific public health recommendations can be made. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by a European Union Framework V programme, the World Cancer Research Fund International, the Medical Research Council (UK), Newlife the Charity for Disabled Children, the Mothercare Group Foundation, Mead Johnson Nutrition and the National Institute for Health Research Cambridge Comprehensive Biomedical Research Centre. Visiting Fellowship (J.M.): Regional Programme 'Jiménez de la Espada' for Research Mobility, Cooperation and Internationalization, Seneca Foundation-Science and Technology Agency for the Region of Murcia (No. 20136/EE/17). K.O. is supported by the Medical Research Council (UK) (Unit Programme number: MC_UU_12015/2). The authors declare no conflict of interest.

Associations between a fetal imprinted gene allele score and late pregnancy maternal glucose concentrations.

AIM: We hypothesised that some of the genetic risk for gestational diabetes (GDM) is due to the fetal genome affecting maternal glucose concentrations. Previously, we found associations between fetal IGF2 gene variants and maternal glucose concentrations in late pregnancy. METHODS: In the present study, we tested associations between SNP alleles from 15 fetal imprinted genes and maternal glucose concentrations in late pregnancy in the Cambridge Baby Growth and Wellbeing cohorts (1160 DNA trios). RESULTS: Four fetal SNP alleles with the strongest univariate associations: paternally-transmitted IGF2 rs10770125 (P-value=2×10-4) and INS rs2585 (P-value=7×10-4), and maternally-transmitted KCNQ1(OT1) rs231841 (P-value=1×10-3) and KCNQ1(OT1) rs7929804 (P-value=4×10-3), were used to construct a composite fetal imprinted gene allele score which was associated with maternal glucose concentrations (P-value=4.3×10-6, n=981, r2=2.0%) and GDM prevalence (odds ratio per allele 1.44 (1.15, 1.80), P-value=1×10-3, n=89 cases and 899 controls). Meta-analysis of the associations including data from 1367 Hyperglycaemia and Adverse Pregnancy Outcome Study participants confirmed the paternally-transmitted fetal IGF2/INS SNP associations (rs10770125, P-value=3.2×10-8, rs2585, P-value=3.6×10-5) and the composite fetal imprinted gene allele score association (P-value=1.3×10-8), but not the maternally-transmitted fetal KCNQ1(OT1) associations (rs231841, P-value=0.4; rs7929804, P-value=0.2). CONCLUSION: This study suggests that polymorphic variation in fetal imprinted genes, particularly in the IGF2/INS region, contribute a small but significant part to the risk of raised late pregnancy maternal glucose concentrations.

Biomonitoring the genotoxic potential of the air on Tradescantia pallida var. purpurea under climatic conditions in the Sinos River basin, Rio Grande do Sul, Brazil.

The present study evaluated the genotoxic effects of the atmospheric air on Tradescantia pallida var. purpurea in urban areas with different intensities of vehicular traffic and in riparian forest fragments in the Sinos River Basin (Rio Grande do Sul, Brazil), considering the influence of climatic conditions prevailing in these environments. Bimonthly, from May 2012 to March 2013, cuttings with flower buds were exposed for 8 h in urban and riparian forest environments in the municipalities of Caraá, Taquara and Campo Bom in the upper, middle and lower sections, respectively, of the Sinos River Basin. Simultaneously, negative controls were made and climatic data were recorded. Micronuclei (MCN) frequencies were determined in young tetrads of pollen mother cells and expressed as MCN/100 tetrads. Significantly higher MCN frequencies were observed in buds exposed in urban and riparian forest environments in Taquara (up to 7.23 and 4.80, respectively) and Campo Bom (up to 4.90 and 4.23, respectively) than in buds exposed in Caraá (up to 2.90 and 2.50, respectively), in the majority of samplings, and in relation to the negative control (up to 1.93) in all months. Over the course of the period monitored, there were significant variations in MCN frequencies at all sampling points, with the exception of the urban environment in Caraá. For the urban environments, relation between the MCN frequency, vehicular traffic and mean temperature was observed. For the riparian forest fragments, there was no association between MCN frequency and climatic factors. Tradescantia pallida var. purpurea can be considered a useful tool to point out areas with increased atmospheric pollution, since the exposure of plants under severe climatic conditions is avoided to minimize their negative influence on the formation of micronuclei.

Biomonitoring the genotoxic potential of the air on Tradescantia pallida var. purpurea under climatic conditions in the Sinos River basin, Rio Grande do Sul, Brazil

Abstract The present study evaluated the genotoxic effects of the atmospheric air on Tradescantia pallida var. purpurea in urban areas with different intensities of vehicular traffic and in riparian forest fragments in the Sinos River Basin (Rio Grande do Sul, Brazil), considering the influence of climatic conditions prevailing in these environments. Bimonthly, from May 2012 to March 2013, cuttings with flower buds were exposed for 8 h in urban and riparian forest environments in the municipalities of Caraá, Taquara and Campo Bom in the upper, middle and lower sections, respectively, of the Sinos River Basin. Simultaneously, negative controls were made and climatic data were recorded. Micronuclei (MCN) frequencies were determined in young tetrads of pollen mother cells and expressed as MCN/100 tetrads. Significantly higher MCN frequencies were observed in buds exposed in urban and riparian forest environments in Taquara (up to 7.23 and 4.80, respectively) and Campo Bom (up to 4.90 and 4.23, respectively) than in buds exposed in Caraá (up to 2.90 and 2.50, respectively), in the majority of samplings, and in relation to the negative control (up to 1.93) in all months. Over the course of the period monitored, there were significant variations in MCN frequencies at all sampling points, with the exception of the urban environment in Caraá. For the urban environments, relation between the MCN frequency, vehicular traffic and mean temperature was observed. For the riparian forest fragments, there was no association between MCN frequency and climatic factors. Tradescantia pallida var. purpurea can be considered a useful tool to point out areas with increased atmospheric pollution, since the exposure of plants under severe climatic conditions is avoided to minimize their negative influence on the formation of micronuclei.

Resumo O presente estudo avaliou os efeitos genotóxicos do ar atmosférico sobre Tradescantia pallida var. purpurea em áreas urbanas com diferentes intensidades de tráfego veicular e em fragmentos de mata ciliar na Bacia do Rio dos Sinos (Rio Grande do Sul, Brasil), considerando a influência de condições climáticas prevalecentes nesses ambientes. Bimensalmente, de maio de 2012 a março de 2013, ramos com botões florais foram expostos por 8 h em ambientes urbanos e de mata ciliar nos municípios de Caraá, Taquara e Campo Bom nos trechos superior, médio e inferior, respectivamente, da Bacia do Rio dos Sinos. Simultaneamente, foram realizados controles negativos e levantados dados climáticos. Frequências de micronúcleos (MCN) foram determinadas em tétrades jovens de células-mãe de grãos de pólen e expressas como MCN/100 tétrades. Frequências de MCN significativamente superiores foram observadas em botões expostos nos ambientes urbanos e de matas ciliares em Taquara (até 7,23 e 4,80, respectivamente) e Campo Bom (até 4,90 e 4,23, respectivamente) do que em botões expostos em Caraá (até 2,90 e 2,50, respectivamente), na maioria das amostragens, e em relação ao controle negativo (até 1,93) em todos os meses. Ao longo do período monitorado, ocorreram variações significativas nas frequências de MCN em todos os pontos amostrais, com exceção do ambiente urbano de Caraá. Para os ambientes urbanos, foi observada relação entre a frequência de MCN, tráfego veicular e temperatura média. Para os fragmentos de mata ciliar, não houve associação entre a frequência de MCN e fatores climáticos. Tradescantia pallida var. purpurea pode ser considerada uma ferramenta útil para apontar áreas com poluição atmosférica aumentada, desde que, sob condições climáticas severas, a exposição das plantas seja evitada, para minimizar o efeito destas sobre a formação de micronúcleos.

Biomonitoring the genotoxic potential of the air on Tradescantia pallida var. purpurea under climatic conditions in the Sinos River basin, Rio Grande do Sul, Brazil / Biomonitoramento do potencial genotóxico do ar em Tradescantia pallida var. purpurea sob condições climáticas na bacia do Rio dos Sinos, Rio Grande do Sul, Brasil

Abstract The present study evaluated the genotoxic effects of the atmospheric air on Tradescantia pallida var. purpurea in urban areas with different intensities of vehicular traffic and in riparian forest fragments in the Sinos River Basin (Rio Grande do Sul, Brazil), considering the influence of climatic conditions prevailing in these environments. Bimonthly, from May 2012 to March 2013, cuttings with flower buds were exposed for 8 h in urban and riparian forest environments in the municipalities of Caraá, Taquara and Campo Bom in the upper, middle and lower sections, respectively, of the Sinos River Basin. Simultaneously, negative controls were made and climatic data were recorded. Micronuclei (MCN) frequencies were determined in young tetrads of pollen mother cells and expressed as MCN/100 tetrads. Significantly higher MCN frequencies were observed in buds exposed in urban and riparian forest environments in Taquara (up to 7.23 and 4.80, respectively) and Campo Bom (up to 4.90 and 4.23, respectively) than in buds exposed in Caraá (up to 2.90 and 2.50, respectively), in the majority of samplings, and in relation to the negative control (up to 1.93) in all months. Over the course of the period monitored, there were significant variations in MCN frequencies at all sampling points, with the exception of the urban environment in Caraá. For the urban environments, relation between the MCN frequency, vehicular traffic and mean temperature was observed. For the riparian forest fragments, there was no association between MCN frequency and climatic factors. Tradescantia pallida var. purpurea can be considered a useful tool to point out areas with increased atmospheric pollution, since the exposure of plants under severe climatic conditions is avoided to minimize their negative influence on the formation of micronuclei.

Resumo O presente estudo avaliou os efeitos genotóxicos do ar atmosférico sobre Tradescantia pallida var. purpurea em áreas urbanas com diferentes intensidades de tráfego veicular e em fragmentos de mata ciliar na Bacia do Rio dos Sinos (Rio Grande do Sul, Brasil), considerando a influência de condições climáticas prevalecentes nesses ambientes. Bimensalmente, de maio de 2012 a março de 2013, ramos com botões florais foram expostos por 8 h em ambientes urbanos e de mata ciliar nos municípios de Caraá, Taquara e Campo Bom nos trechos superior, médio e inferior, respectivamente, da Bacia do Rio dos Sinos. Simultaneamente, foram realizados controles negativos e levantados dados climáticos. Frequências de micronúcleos (MCN) foram determinadas em tétrades jovens de células-mãe de grãos de pólen e expressas como MCN/100 tétrades. Frequências de MCN significativamente superiores foram observadas em botões expostos nos ambientes urbanos e de matas ciliares em Taquara (até 7,23 e 4,80, respectivamente) e Campo Bom (até 4,90 e 4,23, respectivamente) do que em botões expostos em Caraá (até 2,90 e 2,50, respectivamente), na maioria das amostragens, e em relação ao controle negativo (até 1,93) em todos os meses. Ao longo do período monitorado, ocorreram variações significativas nas frequências de MCN em todos os pontos amostrais, com exceção do ambiente urbano de Caraá. Para os ambientes urbanos, foi observada relação entre a frequência de MCN, tráfego veicular e temperatura média. Para os fragmentos de mata ciliar, não houve associação entre a frequência de MCN e fatores climáticos. Tradescantia pallida var. purpurea pode ser considerada uma ferramenta útil para apontar áreas com poluição atmosférica aumentada, desde que, sob condições climáticas severas, a exposição das plantas seja evitada, para minimizar o efeito destas sobre a formação de micronúcleos.

Integrated Environmental Assessment of streams in the Sinos River basin in the state of Rio Grande do Sul, Brazil.

The deterioration of environmental quality in the Sinos River basin is directly associated with the impacts of intense industrialization and urbanization. An integrated environmental assessment (IEA) was conducted in July and September of 2012, in areas along the sources of the EstânciaVelha/Portão, Pampa and Schmidt streams using physical, chemical and biological methods. The water in the three sampling sites was not proper for human consumption, presented a low toxic contamination index (TCI) and mesotrophic characteristics. One site was included in Class 4, and two, in Class 3, according to current legislation. The rapid assessment protocol (RAP) indicated a natural environmental condition for habitat diversity and environmental impact in the three sites. The Tradescantia pallida (Rose) D.R. Hunt var. purpurea Boom biomarker showed water genotoxicity in two of the sites. The integrated diagnosis of water quality in these streams is fundamentally important to ensure the sustainable management of water resources and their multiple uses, as well to estimate their contribution to pollution in this river basin.

The EndoPredict score provides prognostic information on late distant metastases in ER+/HER2- breast cancer patients.

BACKGROUND: ER+/HER2- breast cancers have a proclivity for late recurrence. A personalised estimate of relapse risk after 5 years of endocrine treatment can improve patient selection for extended hormonal therapy. METHODS: A total of 1702 postmenopausal ER+/HER2- breast cancer patients from two adjuvant phase III trials (ABCSG6, ABCSG8) treated with 5 years of endocrine therapy participated in this study. The multigene test EndoPredict (EP) and the EPclin score (which combines EP with tumour size and nodal status) were predefined in independent training cohorts. All patients were retrospectively assigned to risk categories based on gene expression and on clinical parameters. The primary end point was distant metastasis (DM). Kaplan-Meier method and Cox regression analysis were used in an early (0-5 years) and late time interval (>5 years post diagnosis). RESULTS: EP is a significant, independent, prognostic parameter in the early and late time interval. The expression levels of proliferative and ER signalling genes contribute differentially to the underlying biology of early and late DM. The EPclin stratified 64% of patients at risk after 5 years into a low-risk subgroup with an absolute 1.8% of late DM at 10 years of follow-up. CONCLUSION: The EP test provides additional prognostic information for the identification of early and late DM beyond what can be achieved by combining the commonly used clinical parameters. The EPclin reliably identified a subgroup of patients who have an excellent long-term prognosis after 5 years of endocrine therapy. The side effects of extended therapy should be weighed against this projected outcome.

EndoPredict improves the prognostic classification derived from common clinical guidelines in ER-positive, HER2-negative early breast cancer.

BACKGROUND: In early estrogen receptor (ER)-positive/HER2-negative breast cancer, the decision to administer chemotherapy is largely based on prognostic criteria. The combined molecular/clinical EndoPredict test (EPclin) has been validated to accurately assess prognosis in this population. In this study, the clinical relevance of EPclin in relation to well-established clinical guidelines is assessed. PATIENTS AND METHODS: We assigned risk groups to 1702 ER-positive/HER2-negative postmenopausal women from two large phase III trials treated only with endocrine therapy. Prognosis was assigned according to National Comprehensive Cancer Center Network-, German S3-, St Gallen guidelines and the EPclin. Prognostic groups were compared using the Kaplan-Meier survival analysis. RESULTS: After 10 years, absolute risk reductions (ARR) between the high- and low-risk groups ranged from 6.9% to 11.2% if assigned according to guidelines. It was at 18.7% for EPclin. EPclin reassigned 58%-61% of women classified as high-/intermediate-risk (according to clinical guidelines) to low risk. Women reclassified to low risk showed a 5% rate of distant metastasis at 10 years. CONCLUSION: The EPclin score is able to predict favorable prognosis in a majority of patients that clinical guidelines would assign to intermediate or high risk. EPclin may reduce the indications for chemotherapy in ER-positive postmenopausal women with a limited number of clinical risk factors.

RNA-based determination of ESR1 and HER2 expression and response to neoadjuvant chemotherapy.

BACKGROUND: Hormone and human epidermal growth factor receptor 2 (HER2) receptors are the most important breast cancer biomarkers, and additional objective and quantitative test methods such as messenger RNA (mRNA)-based quantitative analysis are urgently needed. In this study, we investigated the clinical validity of RT-PCR-based evaluation of estrogen receptor (ESR1) and HER2 mRNA expression. PATIENTS AND METHODS: A total of 1050 core biopsies from two retrospective (GeparTrio, GeparQuattro) and one prospective (PREDICT) neoadjuvant studies were evaluated by quantitative RT-PCR for ESR1 and HER2. RESULTS: ESR1 mRNA was significantly predictive for reduced response to neoadjuvant chemotherapy in univariate and multivariate analysis in all three cohorts. The complete pathologically documented response (pathological complete response, pCR) rate for ESR1+/HER2- tumors was 7.3%, 8.0% and 8.6%; for ESR1-/HER2- tumors it was 34.4%, 33.7% and 37.3% in GeparTrio, GeparQuattro and PREDICT, respectively (P < 0.001 in each cohort). In the Kaplan-Meier analysis in GeparTrio patients with ESR1+/HER2- tumors had the best prognosis, compared with ESR1-/HER2- and ESR1-/HER2+ tumors [disease-free survival (DFS): P < 0.0005, overall survival (OS): P < 0.0005]. CONCLUSIONS: Our results suggest that mRNA levels of ESR1 and HER2 predict response to neoadjuvant chemotherapy and are significantly associated with long-term outcome. As an additional option to standard immunohistochemistry and gene-array-based analysis, quantitative RT-PCR analysis might be useful for determination of the receptor status in breast cancer.

Estaquia de Ipomoea cairica (L. ) Sweet / Stem cutting of Ipomoea cairica (L. ) Sweet

A Ipomoea cairica (L.) Sweet é uma trepadeira herbácea nativa, amplamente utilizada na medicina popular brasileira e inexistem informações sobre a propagação vegetativa. Em vista disso, objetivou-se avaliar a presença de folhas nas estacas, o substrato e a dose de reguladores vegetais mais adequados para a propagação por estaquia. Foram conduzidos dois experimentos, no primeiro, foram avaliados dois tipos de estacas (com e sem folhas) e quatro substratos (areia, casca de arroz carbonizada, latossolo vermelho distrófico + matéria orgânica - 1:1, latossolo vermelho distrófico + matéria orgânica + areia - 1:1:2), enquanto no segundo foram testadas cinco concentrações diferentes de AIB (0, 250, 500, 750 e 1000 mg L-1). Após 20 dias, obteve-se 86,2% de estacas enraizadas no substrato areia e, no segundo experimento, observou-se que o AIB não influenciou a porcentagem de enraizamento (94% em média). Conclui-se que a presença de folhas melhora a qualidade do enraizamento, que os substratos indicados para a propagação são areia e casca de arroz carbonizada devido ao maior enraizamento, fácil disponibilidade e baixo custo, e que a utilização de AIB na concentração 250 mg L-1 é a mais adequada para propagação por estaquia de I. cairica.

Ipomoea cairica (L.) Sweet is an herbaceous climbing plant widely used in Brazilian folk medicine and there is no information regarding its vegetative propagation. In view of this, the aim of this study was to evaluate the presence of leaves on stem cuttings and the most adequate substrate and level of plant growth regulators for propagation by stem cuttings of this morning glory. Two experiments were conducted, in the first, two types of stem cuttings (with and without leaves) and four substrates (sand; carbonized rice hull; Haplortox + organic matter - 1:1; Haplortox + organic matter + sand - 1:1:2) were evaluated, and in the second experiment five different concentrations of IBA (0, 250, 500, 750 and 1000 mg L-1) were tested. After 20 days, we obtained 86.2% of cuttings rooted in sand substrate and in the second experiment IBA did not affect the rooting percentage (94% on average). We can conclude that the presence of leaves improved the quality of rooting, the substrates indicated for propagation are sand and carbonized rice hull due to greater rooting, easy availability and low cost, and the use of IBA at 250 mg L-1 is more appropriate to propagation by stem cuttings of I. cairica.

[Predictive and prognostic markers of breast cancer. Molecular biological analysis of fixed tumor tissue]. / Prädiktive und prognostische Brustkrebsmarker. Molekularbiologische Analyse von fixiertem Tumorgewebe als Basis.

A multitude of prognostic and predictive multiparameter algorithms based on the analysis of mRNA have been published in recent years. Many of the algorithms require fresh or fresh frozen tissue as a source of the mRNA. However, practical considerations suggest formalin-fixed paraffin-embedded tissue (FFPE tissue) to be a more suitable starting material for routine diagnostic applications. Therefore, Siemens Healthcare Diagnostics is developing a fully automated method to extract mRNA and DNA from FFPE tissue for use in pathology laboratories. Initially, the method will be used as part of a prognosis assay to predict the likelihood of distant metastasis and death for node-negative breast cancer patients.

Association analysis of the IGF1 gene with childhood growth, IGF-1 concentrations and type 1 diabetes.

AIMS/HYPOTHESIS: Insulin-like growth factor-1 is a major childhood growth factor and promotes pancreatic islet cell survival and growth in vitro. We hypothesised that genetic variation in IGF1 might be associated with childhood growth, glucose metabolism and type 1 diabetes risk. We therefore examined the association between common genetic variation in IGF1 and predisposition to type 1 diabetes, childhood growth and metabolism. MATERIALS AND METHODS: Variants in IGF1 were identified by direct resequencing of the exons, exon-intron boundaries and 5' and 3' regions in 32 unrelated type 1 diabetes patients. A tagging subset of these variants was genotyped in a collection of type 1 diabetes families (3,121 parent-child trios). We also genotyped a previously reported CA repeat in the region 5' to IGF1. A subset of seven tag single nucleotide polymorphism (SNPs) that captured variants with minor allele frequency (MAF) > or =0.05 was genotyped in 902 children from the Avon Longitudinal Study of Parents And Children with data on growth, IGF-1 concentrations, insulin secretion and insulin action. RESULTS: Resequencing detected 27 SNPs in IGF1, of which 11 had a MAF > 0.05 and were novel. Variants with MAF > or = 0.10 were captured by a set of four tag-SNPs. These SNPs showed no association with type 1 diabetes. In children, global variation in IGF1 was weakly associated with IGF-1 concentrations, but not with other phenotypes. The CA repeat in the region 5' to IGF1 showed no association with any phenotype. CONCLUSIONS/INTERPRETATION: Common genetic variation in IGF1 alters IGF-1 concentrations but is not associated with growth, glucose metabolism or type 1 diabetes.

Genetic variations and normal fetal growth.

Size at birth is said to be a highly heritable trait, with an estimated 30-70% of the variability a result of genetics. Data from family studies may be confounded, however, by potential interactions between fetal genes and the maternal uterine environment. Overall, the maternal environment tends to restrain fetal growth, and this is most evident in first pregnancies. Restraint of fetal growth appears to be inherited through the maternal line. Potential genetic candidates include the mitochondrial DNA 16189 variant, and common variants of exclusively maternally expressed genes, such as H19, which have been associated with size at birth. Maternal blood glucose levels and blood pressure are also correlated with size at birth, but the degree to which these changes relate to genetic variation in the mother is unclear. Elegant studies in mouse knockout models and rare genetic variants in humans have highlighted the importance of insulin-like growth factor I (IGF-I), IGF-II, insulin and their respective receptors in determining fetal growth. However, data linking common variation in the genes that regulate these proteins and receptors with size at birth are few and inconsistent. Interestingly, common variation in the insulin gene (INS) variable number tandem repeats, which regulates the transcription of insulin and IGF-II, has been associated with size at birth, largely in second and subsequent pregnancies, where maternal restraint is least evident. This suggests that fetal genes, and in particular paternally expressed genes, may have significant effects on fetal growth during pregnancies where maternal restraint of fetal growth is less evident.

Association of aromatase (CYP 19) gene variation with features of hyperandrogenism in two populations of young women.

BACKGROUND: Aromatase catalyses the conversion of androgens to estrogens and thus variation in the aromatase gene could contribute to female syndromes of androgen excess, such as precocious pubarche (PP) and polycystic ovarian syndrome (PCOS). METHODS: Two groups, one case-control containing girls from Barcelona, Spain with PP (n = 186) or healthy controls (n = 71), and the other a population study of young women from Oxford, UK, who volunteered for a study of normal women's health (n = 109), were genotyped at four aromatase gene haplotype-tag single nucleotide polymorphisms (SNP). Clinical features and hormone concentrations relevant to hyperandrogenism were compared across haplotypes or genotypes. RESULTS: Distributions of aromatase haplotypes (P < 0.0001) and aromatase SNP_50 genotype (P = 0.001) were significantly different between PP girls and Spanish controls. The AGGG haplotype was associated with an odds ratio (95% confidence interval) of 0.5 (0.3-0.9) (P = 0.005) for the presence of PP compared to GAGG. In 84 post-pubertal PP girls, aromatase haplotype was associated with functional ovarian hyperandrogenism (P < 0.05), independently of insulin sensitivity. In the Oxford population, SNP_50 was associated with variation in PCOS symptom score (P = 0.008) and circulating testosterone concentrations (P = 0.02). CONCLUSIONS: This study suggests that common variation at the aromatase gene (and not just rare loss-of-function mutations) is associated with androgen excess in girls and young women.

Insulin sensitivity and secretion in normal children related to size at birth, postnatal growth, and plasma insulin-like growth factor-I levels.

AIMS/HYPOTHESIS: Type 2 diabetes risk is associated with low birth weight, rapid weight gain during childhood, and shorter stature and lower circulating IGF-I levels in adults. The largest variations in growth rates occur during the first postnatal years. We hypothesised that early postnatal variations in height and weight gain and IGF-I levels may be associated with risk markers for adult disease. METHODS: We measured the fasting insulin sensitivity (Homeostasis model) and insulin secretion post-oral glucose (insulinogenic index 0-30 min) in 851 normal 8-year-old children from a prospective birth cohort. We examined associations between size at birth, postnatal weight gain and circulating IGF-I levels with insulin sensitivity and secretion at 8 years of age. RESULTS: Fasting insulin sensitivity at 8 years was closely related to current BMI (r= -0.33, p<0.0005). Lower insulin sensitivity and higher BMI and waist circumference were all predicted by greater weight gain between birth to 3 years of age (all p<0.0005); lower birth weight was associated with reduced insulin sensitivity only in the highest current BMI tertile ( r=0.17, p=0.006). In contrast, lower insulin secretion was related to smaller size at birth ( p=0.01), independent of postnatal weight gain and insulin sensitivity. Lower insulin secretion was also independently related to shorter stature at 8 years of age relative to parental height ( p=0.047) and with lower plasma IGF-I levels at 5 years of age ( n=252, p=0.004). CONCLUSIONS/INTERPRETATION: Associations between lower birth weight and insulin resistance may be dependent on rapid weight gain during the early postnatal years. However, irrespective of postnatal weight gain, smaller size at birth, lower IGF-I levels and lower childhood height predicted reduced compensatory insulin secretion.

Sobrevida de 18 meses em cadela com sarcoma indiferenciado submetida à cirurgia radical e quimioterapia antineoplásica

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