2008 Condition of the State Address as Delivered, January 15, 2008

State of address from Governor Culver.

Effects of a treatment gap during adjuvant chemotherapy in node-positive breast cancer: results of International Breast Cancer Study Group (IBCSG) Trials 13-93 and 14-93.

BACKGROUND: The International Breast Cancer Study Group (IBCSG) conducted two complementary randomized trials to assess whether a treatment-free gap during adjuvant chemotherapy influenced outcome. PATIENTS AND METHODS: From 1993 to 1999, IBCSG Trials 13-93 and 14-93 enrolled 2215 premenopausal and postmenopausal women with axillary node-positive, operable breast cancer. All patients received cyclophosphamide (Cytoxan, C) plus either doxorubicin (Adriamycin, A) or epirubicin (E) for four courses followed immediately (No Gap) or after a 16-week delay (Gap) by classical cyclophosphamide, methotrexate, and fluorouracil (CMF) for three courses. The median follow-up was 7.7 years. RESULTS: The Gap and No-Gap groups had similar disease-free survival (DFS) and overall survival (OS). No identified subgroup showed a statistically significant difference, but exploratory subgroup analysis noted a trend towards decreased DFS for Gap compared with No Gap for women with estrogen receptor (ER)-negative tumors not receiving tamoxifen, especially evident during the first 2 years. CONCLUSIONS: A 16-week gap between adjuvant AC/EC and CMF provided no benefit and may have increased early recurrence rates in patients with ER-negative tumors.

Cancer du sein : la pathologie, pierre angulaire de la décision therapeutique [Breast cancer: pathology, the cornerstone of therapeutic decision]

Tailoring adjuvant therapy in breast cancer patients relies on prognostic and predictive factors, most of which are currently established by histopathological analysis of tumors. The quality of the assessment of the former (i.e.: tumor size, lymph node status, tumor grade, HER2 status, and lymphovascular invasion) and the latter (estrogen and progesteron receptors expression, HER2 overexpression or amplification) is an essential prerequisite for an optimal therapeutic decision. If the prognostic and predictive values of multigenes signatures are confirmed by on-going clinical studies, this approach could enter the clinical practice in the coming years and result in improved accuracy of adjuvant therapies in breast cancer patients. This approach might especially allow avoiding overtreatment in patients at low risk of recurrence.

Recent decrease in the prevalence of congenital heart defects in europe.

OBJECTIVES: To examine trends in the prevalence of congenital heart defects (CHDs) in Europe and to compare these trends with the recent decrease in the prevalence of CHDs in Canada (Quebec) that was attributed to the policy of mandatory folic acid fortification. STUDY DESIGN: We used data for the period 1990-2007 for 47 508 cases of CHD not associated with a chromosomal anomaly from 29 population-based European Surveillance of Congenital Anomalies registries in 16 countries covering 7.3 million births. We estimated trends for all CHDs combined and separately for 3 severity groups using random-effects Poisson regression models with splines. RESULTS: We found that the total prevalence of CHDs increased during the 1990s and the early 2000s until 2004 and decreased thereafter. We found essentially no trend in total prevalence of the most severe group (group I), whereas the prevalence of severity group II increased until about 2000 and decreased thereafter. Trends for severity group III (the most prevalent group) paralleled those for all CHDs combined. CONCLUSIONS: The prevalence of CHDs decreased in recent years in Europe in the absence of a policy for mandatory folic acid fortification. One possible explanation for this decrease may be an as-yet-undocumented increase in folic acid intake of women in Europe following recommendations for folic acid supplementation and/or voluntary fortification. However, alternative hypotheses, including reductions in risk factors of CHDs (eg, maternal smoking) and improved management of maternal chronic health conditions (eg, diabetes), must also be considered for explaining the observed decrease in the prevalence of CHDs in Europe or elsewhere.

Composición bioquímica y distribución de la materia orgánica sedimentaria y sus efectos sobre la estructura comunitaria de la meiofauna en la plataforma continental frente a Callao.

Se estudió la composición y distribución de la materia orgánica sedimentaria en términos de Carbohidratos, Lípidos y Proteínas, así como sus repercusiones sobre la estructura comunitaria de la meiofauna metazoaria (abundancia, biomasa y diversidad a nivel de grandes grupos), además, se estima su rol en el flujo de energía del sub-sistema bentónico mediante el cálculo de la producción secundaria y respiración frente a las costas de Perú Central, Callao (12ºS). Las muestras se recolectaron en el mes de Abril del año 2010, en un gradiente batimétrico en cinco estaciones: Estación E1 (48m) y E2 (93m) correspondiente a la plataforma interna, estación E3 (117m) correspondiente a la plataforma intermedia y la estación E4 (143m) y E5 (148m) correspondiente a la plataforma externa. En cada estación se determinaron parámetros fisicoquímicos como oxígeno disuelto, salinidad y temperatura. Asimismo se determinó el contenido de pigmentos fotosintéticos (clorofila- a y feopigmentos) en la columna de sedimento.

Modelo de control viable para el manejo sostenible del stock de anchoveta peruana (Engraulis ringens)

El manejo sostenible de pesquerías es todavía un problema abierto y la teoría de viabilidad ofrece una alternativa para determinar políticas de manejo de los recursos que garanticen la sostenibilidad, una vez definidas las restricciones que determinan los estados sostenibles del sistema. La dinámica poblacional de la anchoveta peruana se modeló usando un modelo estructurado por edades tipo Thomson–Bell con capturas discretas acoplado con el modelo de reclutamiento de Ricker, con pasos semestrales entre los años 1963–1984. Se definió además un conjunto deseable de estados sostenibles, asociado a los niveles del stock y capturas que satisfacen restricciones ecológicas, económicas y sociales previamente definidas. En base a esto se calculó el conjunto de los estados del stock para los que existe un sucesión de capturas que permiten mantenerlo en un estado sostenible (conjunto denominado núcleo de viabilidad) y una familia de conjuntos de capturas viables, que corresponden a todos los niveles de captura que se puedan aplicar sobre cada estado del stock de manera tal que éste se mantenga dentro del núcleo de viabilidad, es decir, permanezca en un estado sostenible. Se encontró una condición suficiente para la existencia de un núcleo de viabilidad no vacío: que la cuota social (captura mínima para mantener en funcionamiento la pesquería) sea menor a un desembarque de 915 800 t semestrales. Se comparó la serie histórica de capturas con las obtenidas a partir de la teoría de viabilidad para el periodo 1963 - 1984, encontrándose que hubo sobrepesca desde finales de 1968, lo que conllevó al colapso de la pesquería durante El Niño de 1972-1973. A partir de los resultados de viabilidad, se definieron 5 estrategias de manejo pesquero (E1–E5) para la anchoveta peruana, concluyéndose que la estrategia precautoria viable media (E5) hubiera podido evitar el colapso de la pesquería de anchoveta, manteniendo además niveles aceptables de pesca. Además, la estrategia precautoria del ICES (E2) no aseguró la sostenibilidad del stock durante los periodos El Niño. Además, se concluye que hubiera sido necesaria una veda de un año después del colapso de la pesquería para que el stock regresara al núcleo de viabilidad, posibilitando un manejo sostenible en adelante. La teoría de la viabilidad, con el núcleo de viabilidad y las capturas viables asociadas, resultaron ser herramientas útiles para el diseño de estrategias de manejo que aseguran la sostenibilidad de los recursos pesqueros.

Efecto de la inyección de un análogo de GnRH sobre la maduración final ovocitaria y los perfiles plasmáticos de esteroides gonadales en anchoveta peruana (Engraulis ringens)

Se determinó el efecto de un análogo de GnRH sobre la maduración final ovocitaria y los perfiles plasmáticos de testosterona (T), 17β Estradiol (E2) y 17α, 20β dihidroxiprogesterona (17α, 20β DP) en ejemplares de E. ringens. Para ello, individuos de esta especie fueron capturados en la Bahía del Callao fueron acondicionados al cautiverio en tanques de 10 m3 con aeración constante, temperatura del agua de 16 ºC, recirculación de agua de mar y alimentación ad libitum durante un periodo de un mes. Una vez que los peces alcanzaron la madurez gonadal, fueron tomados al azar y anestesiados con tricaína (80 mg L-1) para luego inyectarles 0,005 μg GnRHa g-1 de peso corporal; 0,005 μg GnRHa g-1 de peso corporal + 0,01 mg DOM g-1 de peso corporal y 0,9 % de solución salina. Como GnRHa se empleo acetato de buserelina y como antidopaminérgico se empleó domperidona. Transcurridas 0, 12, 24 y 48 h post inyección (pi) grupos de peces fueron sacrificados mediante sobre exposición de tricaína con la finalidad de extraer las gónadas y colectar la sangre en tubos Eppendorf. El efecto de la hormona sobre la maduración final ovocitaria fue determinado en base al análisis histológico de las gónadas, mientras que su efecto sobre los perfiles de los esteroides mencionados se determinó en base a la cuantificación plasmática mediante radioinmunoanálisis. Los resultados sugieren que la inyección de acetato de buserelina a 0,005 μg g-1 de peso corporal induce la maduración final ovocitaria en hembras maduras de E. ringens 12 horas pi, culminando con el desove entre las 24 y 48 horas pi. Por otro lado, la combinación de esta hormona con domperidona tendría un efecto retardante sobre la activación de dicho proceso. Se determinó además, que los niveles plasmáticos de E2 disminuyen durante la maduración final ovocitaria y luego de producirse el desove se incrementan. Finalmente, se sugiere que el 17α, 20β DP podría estar implicado en la activación de la maduración final ovocitaria sin llegar a ser el principal MIS de la anchoveta.

Sports-related chronic repetitive head trauma as a cause of pituitary dysfunction.

Traumatic brain injury (TBI) is recognized as a cause of hypopituitarism even after mild TBI. Although over the past decade, a growing body of research has detailed neuroendocrine changes induced by TBI, the mechanisms and risk factors responsible for this pituitary dysfunction are still unclear. Around the world, sports-especially combative sports-are very popular. However, sports are not generally considered as a cause of TBI in most epidemiological studies, and the link between sports-related head trauma and hypopituitarism has not been investigated until recently. Thus, there is a paucity of data regarding this important concern. Because of the large number of young sports participants with near-normal life expectancy, the implications of undiagnosed or untreated postconcussion pituitary dysfunction can be dramatic. Understanding the pathophysiological mechanisms and risk factors of hypopituitarism caused by sports injuries is thus an important issue that concerns both medical staff and sponsors of sports. The aim of this paper was to summarize the best evidence for understanding the pathophysiological mechanisms and to discuss the current data and recommendations on sports-related head trauma as a cause of hypopituitarism.

A liver protein fraction regulating hormone-dependent in vitro transcription from the vitellogenin genes induces their expression in Xenopus oocytes.

Xenopus laevis oocytes were used to assay for trans-acting factors shown previously to be involved in the liver-specific regulation of the vitellogenin genes in vitro. To this end, crude liver nuclear extracts obtained from adult estrogen-induced Xenopus females were fractionated by heparin-Sepharose chromatography using successive elutions with 0.1, 0.35, 0.6, and 1.0 M KCl. When these four fractions were injected into oocytes, only the 0.6-M KCl protein fraction significantly stimulated mRNA synthesis from the endogenous B class vitellogenin genes. This same fraction induced estrogen-dependent in vitro transcription from the vitellogenin B1 promoter, suggesting that it contains at least a minimal set of basal transcription factors as well as two positive factors essential for vitellogenin in vitro transcription, i.e. the NF-I-like liver factor B and the estrogen receptor (ER). The presence of these two latter factors was determined by footprinting and gel retardation assays, respectively. In contrast, injection of an expression vector carrying the sequence encoding the ER was unable to activate transcription from the oocyte chromosomal vitellogenin genes. This suggests that the ER alone cannot overcome tissue-specific barriers and that one or several additional liver components participate in mediating tissue-specific expression of the vitellogenin genes. In this respect, we present evidence that the oocyte germinal vesicles contain an NF-I-like activity different from that found in hepatocytes of adult frogs. This observation might explain the lack of vitellogenin gene activation in oocytes injected with the ER cDNA only.

Interaction of alpha-melanotropin with central dopamine systems: role of hormonal state and molecular structure

The tubero-infundibular and nigrostriatal DA neurone systems of rats respond to systemic (i.p.) injection of alpha-MSH (2-100 microgram/kg). The response of the tubero-infundibular (arcuate) DA neurones, an increase in cellular fluorescence intensity which can be interpreted as a sign of increased neuronal activity, is essentially the same in males, estrogen-progesterone-pretreated ovariectomized females and hypophysectomized males, whereas the type of response elicited by alpha-MSH in the nigral DA neurones depends upon the hormonal state of the animal. Differences between the two DA neurone groups exist also with regard to the effects of peptide fragments containing the two active sites of the alpha-MSH molecule. Results of lesion experiments in the lower brainstem (area postrema) and of blockade of muscarinic mechanisms by atropine further point to differences in the mechanisms underlying the peptide effects on the two neurone systems. The reaction of the tubero-infundibular DA system (which controls the pars intermedia of the pituitary) can be considered to reflect the activation of a feedback mechanism on MSH secretion, while the functional counterpart of the changes observed in the nigral system remains unknown at the present time.

Multifactorial ERβ and NOTCH1 control of squamous differentiation and cancer.

Downmodulation or loss-of-function mutations of the gene encoding NOTCH1 are associated with dysfunctional squamous cell differentiation and development of squamous cell carcinoma (SCC) in skin and internal organs. While NOTCH1 receptor activation has been well characterized, little is known about how NOTCH1 gene transcription is regulated. Using bioinformatics and functional screening approaches, we identified several regulators of the NOTCH1 gene in keratinocytes, with the transcription factors DLX5 and EGR3 and estrogen receptor β (ERβ) directly controlling its expression in differentiation. DLX5 and ERG3 are required for RNA polymerase II (PolII) recruitment to the NOTCH1 locus, while ERβ controls NOTCH1 transcription through RNA PolII pause release. Expression of several identified NOTCH1 regulators, including ERβ, is frequently compromised in skin, head and neck, and lung SCCs and SCC-derived cell lines. Furthermore, a keratinocyte ERβ-dependent program of gene expression is subverted in SCCs from various body sites, and there are consistent differences in mutation and gene-expression signatures of head and neck and lung SCCs in female versus male patients. Experimentally increased ERβ expression or treatment with ERβ agonists inhibited proliferation of SCC cells and promoted NOTCH1 expression and squamous differentiation both in vitro and in mouse xenotransplants. Our data identify a link between transcriptional control of NOTCH1 expression and the estrogen response in keratinocytes, with implications for differentiation therapy of squamous cancer.

Macrophage migration inhibitory factor is involved in a positive feedback loop increasing aromatase expression in endometriosis.

Immune-endocrine interplay may play a major role in the pathogenesis of endometriosis. In the present study, we have investigated the interaction between macrophage migration inhibitory factor (MIF), a major pro-inflammatory and growth-promoting factor markedly expressed in active endometriotic lesions, and estradiol (E(2)) in ectopic endometrial cells. Our data showed a significant increase of MIF protein secretion and mRNA expression in endometriotic cells in response to E(2). MIF production was blocked by Fulvestrant, an estrogen receptor (ER) antagonist, and induced by ERα and ERβ selective agonists propyl-pyrazole-triol (PPT) and diarylpropionrile (DPN), respectively, thus demonstrating a specific receptor-mediated effect. Cell transfection with MIF promoter construct showed that E(2) significantly stimulates MIF promoter activity. Interestingly, our data further revealed that MIF reciprocally stimulates aromatase protein and mRNA expression via a posttranscriptional mRNA stabilization mechanism, that E(2) itself can upregulate aromatase expression, and that inhibition of endogenous MIF, using MIF specific siRNA, significantly inhibits E(2)-induced aromatase. Thus, the present study revealed the existence of a local positive feedback loop by which estrogen acts directly on ectopic endometrial cells to upregulate the expression of MIF, which, in turn, displays the capability of inducing the expression of aromatase, the key and rate-limiting enzyme for estrogen synthesis. Such interplay may have a considerable impact on the development of endometriosis.

p27 and Skp2 immunoreactivity and its clinical significance with endocrine and chemo-endocrine treatments in node-negative early breast cancer.

BACKGROUND: Low p27 and high Skp2 immunoreactivity are associated with a poor prognosis and other poor prognostic features including resistant phenotypes and antiestrogen drug resistance. We investigated these proteins in two International Breast Cancer Study Group trials studying node-negative early breast cancer. PATIENTS AND METHODS: Trial VIII compared chemotherapy followed by goserelin with either modality alone in premenopausal patients. Trial IX compared chemotherapy followed by tamoxifen with tamoxifen alone in postmenopausal patients. Central Pathology Office assessed p27 and Skp2 expression in the primary tumor by immunohistochemistry among 1631 (60%) trial patients. RESULTS: p27 and Skp2 were inversely related; 13% of tumors expressed low p27 and high Skp2. Low p27 and high Skp2 were associated with unfavorable prognostic factors including larger size and higher grade tumors, absence of estrogen receptor and progesterone receptor, human epidermal growth factor receptor 2 overexpression and high Ki-67 (each P < 0.05). Low p27 and high Skp2 were not associated with disease-free survival (P = 0.42 and P = 0.48, respectively). The relative effects of chemo-endocrine versus endocrine therapy were similar regardless of p27 or Skp2. CONCLUSIONS: We confirm the association of low p27 and high Skp2 with other poor prognostic features, but found no predictive or prognostic value, and therefore do not recommend routine determination of p27 and Skp2 for node-negative breast cancer.

Compartmentalized secretory leukocyte protease inhibitor expression and hormone responses along the reproductive tract of postmenopausal women

Immunity and hormonal responses in the reproductive tissues of postmenopausal women are poorly understood. Secretory leukocyte protease inhibitor (SLPI), a multifunctional antimicrobial protein expressed at mucosal surfaces, is thought to play a key role in infectious and inflammatory contexts. The aim of this study was to measure SLPI production along the female reproductive tract in postmenopausal women with and without hormonal treatment. We additionally quantified estrogen receptor alpha (ERα) and progesterone receptor A (PRA) in these tissues. Expression of SLPI was decreased in the vagina and ectocervix of women under hormonal treatment. Endocervical ERα mRNA expression was increased while this did not reach significance at the protein level. SLPI expression in the endometrium was not influenced by hormonal treatment. We observed attenuated ERα expression in the cervix and endometrium of hormonally treated women, whereas vaginal expression was increased. PRA expression was augmented in the cervix and endometrium and unchanged in the vagina. Taken together, our results indicate that hormonal responses and receptor expression are differentially regulated in vaginal tissue compared with the cervix and endometrium.

Integrin-mediated adhesion and soluble ligand binding stabilize COX-2 protein levels in endothelial cells by inducing expression and preventing degradation.

Cyclooxygenase-2 (COX-2), a key enzyme in prostaglandin synthesis, is highly expressed during inflammation and cellular transformation and promotes tumor progression and angiogenesis. We have previously demonstrated that endothelial cell COX-2 is required for integrin alphaVbeta3-dependent activation of Rac-1 and Cdc-42 and for endothelial cell spreading, migration, and angiogenesis (Dormond, O., Foletti, A., Paroz, C., and Ruegg, C. (2001) Nat. Med. 7, 1041-1047; Dormond, O., Bezzi, M., Mariotti, A., and Ruegg, C. (2002) J. Biol. Chem. 277, 45838-45846). In this study, we addressed the question of whether integrin-mediated cell adhesion may regulate COX-2 expression in endothelial cells. We report that cell detachment from the substrate caused rapid degradation of COX-2 protein in human umbilical vein endothelial cells (HUVEC) independent of serum stimulation. This effect was prevented by broad inhibition of cellular proteinases and by neutralizing lysosomal activity but not by inhibiting the proteasome. HUVEC adhesion to laminin, collagen I, fibronectin, or vitronectin induced rapid COX-2 protein expression with peak levels reached within 2 h and increased COX-2-dependent prostaglandin E2 production. In contrast, nonspecific adhesion to poly-L-lysine was ineffective in inducing COX-2 expression. Furthermore, the addition of matrix proteins in solution promoted COX-2 protein expression in suspended or poly-L-lysine-attached HUVEC. Adhesion-induced COX-2 expression was strongly suppressed by pharmacological inhibition of c-Src, phosphatidylinositol 3-kinase, p38, extracellular-regulated kinase 1/2, and, to a lesser extent, protein kinase C and by the inhibition of mRNA or protein synthesis. In conclusion, this work demonstrates that integrin-mediated cell adhesion and soluble integrin ligands contribute to maintaining COX-2 steady-state levels in endothelial cells by the combined prevention of lysosomal-dependent degradation and the stimulation of mRNA synthesis involving multiple signaling pathways.