Binding characteristics of novel nonsteroidal antiestrogens to the rat uterine estrogen receptors

Tamoxifen (TAM), the only antiestrogen currently available for the endocrine therapy of breast cancer behaves as a mixed agonist/antagonist of estrogen action, thus limiting its therapeutic potential. We report the binding characteristics of a novel series of nonsteroidal antiestrogens to the rat uterine estrogen receptor. As measured by competition studies, the affinity of EM-652, the active metabolite of the prodrug EM-800, for the estrogen receptor is 7-11 times higher than that of 17beta-estradiol (E2), ICI 182780, and hydroxy-tamoxifen (OH-TAM), the active metabolite of Tamoxifen. EM-652 is 20x more potent than ICI 164384 and Droloxifene while it is 400 times more potent than Toremifene in displacing [3H]E2 from the rat uterine estrogen receptor. On the other hand, the prodrug EM-800 and Tamoxifen have respectively 150-fold and 410-fold less affinity for the estrogen receptor than the pure antiestrogen EM-652. No significant binding of EM-652, EM-800, TAM or OH-TAM was observed to the rat uterine progesterone receptor at concentrations up to 10,000 nM except for TAM that caused a 50% displacement of labeled R5020 at 4000 nM. No significant binding of EM-652 or EM-800 was observed on the rat ventral prostate androgen receptor or the rat uterine progesterone receptor. The present data demonstrate the high affinity and specificity of the new antiestrogen, EM-652, for the rat uterine estrogen receptor. The antiestrogen EM-652 thus becomes the compound having the highest known affinity for the estrogen receptor. Due to its unique potency and its pure antiestrogenic activity already demonstrated in many systems, this antiestrogen could well offer an important advance for the endocrine therapy of breast cancer, uterine cancer, and other estrogen-sensitive diseases in women.     

Conical array studies

Present requirements for wide-band spread-spectrum techniques for many applications offer attractive potential uses for circular symmetric arrays. Since rigorous analytical techniques are not available to investigate conical array characteristics, experimental techniques can be used to simulate scanning of the conical array. This paper describes techniques that give some insight into the behavior of conical arrays of dipoles. A projected distribution is used to simulate array properties such as beamwidth, sidelobe level, and polarization. Comparisons with a similar cylindrical array are made. Element patterns are examined to determine if behavior is similar to known behavior of element patterns for the cylindrical array. Finally, a conical sector experimental array is used to simulate selected "scanned" beam positions to determine array behavior, i.e., beamwidth, scan limits, polarization, and sidelobe level. Experimental and calculated array patterns, element patterns, and polarization data are given.     

Endothelial Colony-Forming Cells Dysfunctions Are Associated with Arterial Hypertension in a Rat Model of Intrauterine Growth Restriction

Infants born after intrauterine growth restriction (IUGR) are at risk of developing arterial hypertension at adulthood. The endothelium plays a major role in the pathogenesis of hypertension. Endothelial colony-forming cells (ECFCs), critical circulating components of the endothelium, are involved in vasculo-and angiogenesis and in endothelium repair. We previously described impaired functionality of ECFCs in cord blood of low-birth-weight newborns. However, whether early ECFC alterations persist thereafter and could be associated with hypertension in individuals born after IUGR remains unknown. A rat model of IUGR was induced by a maternal low-protein diet during gestation versus a control (CTRL) diet. In six-month-old offspring, only IUGR males have increased systolic blood pressure (tail-cuff plethysmography) and microvascular rarefaction (immunofluorescence). ECFCs isolated from bone marrow of IUGR versus CTRL males displayed a decreased proportion of CD31+ versus CD146+ staining on CD45− cells, CD34 expression (flow cytometry, immunofluorescence), reduced proliferation (BrdU incorporation), and an impaired capacity to form capillary-like structures (Matrigel test), associated with an impaired angiogenic profile (immunofluorescence). These dysfunctions were associated with oxidative stress (increased superoxide anion levels (fluorescent dye), decreased superoxide dismutase protein expression, increased DNA damage (immunofluorescence), and stress-induced premature senescence (SIPS; increased beta-galactosidase activity, increased p16^INK4a, and decreased sirtuin-1 protein expression). This study demonstrated an impaired functionality of ECFCs at adulthood associated with arterial hypertension in individuals born after IUGR.     

The future of HPV testing in clinical laboratories and applied virology research

BACKGROUND: Human papillomaviruses (HPV) are now considered etiologic agents of cancer of the uterine cervix. Adjunctive diagnostic procedures for the detection of HPV infection could increase the sensitivity of primary and secondary screening of cervical cancer. HPV testing could also improve the specificity of screening programs resulting in avoidance of overtreatment and saving of costs for confirmatory procedures. OBJECTIVES: To review the rationale of HPV testing in genital diseases and the potential applications of HPV DNA detection methods for clinical and epidemiological purposes. RESULTS: Progression of HPV infection is associated with the persistence of HPV infection, involvement of high-risk HPV types, high HPV viral load in specimens, integration of viral DNA and possibly the presence of cofactors. The design of HPV diagnostic tests will need to take into account these parameters of disease progression. HPV DNA detection techniques based on signal-amplification are standardized, commercially available and detect several high-risk HPV types. They increase the sensitivity of screening for high-grade and low-grade lesions. Although they may yield false-negative results in the presence of significant HPV-related disease, new test formats could resolve this weakness. Amplification techniques are ideal instruments for epidemiologic purposes since they minimize misclassification of HPV infection status and allow for the detection of low viral burden infections. They are currently not readily applicable to diagnostic laboratories. CONCLUSIONS: Before recommending HPV testing, prospective trials of untreated LSIL with HPV testing as well as the determination of the efficacy and cost-effectiveness of novel HPV tests, need to be completed.     

Elasticity of nanocrystalline kyanite at high pressure and temperature from ultrasonic and synchrotron X-ray techniques

Material properties, such as elasticity data at wide-ranging conditions of pressure and temperature, attract increasing attention for material and earth sciences. In particular, polycrystalline ceramics for next-generation photonic applications are nowadays fabricated by advanced syntheses techniques operating under elevated pressures and temperatures. Herein, the elastic properties of a synthetic transparent and reinforced aluminosilicate nanoceramic composed of triclinic kyanite with minor amounts of trigonal α-alumina crystals are investigated using in situ synchrotron X-ray diffraction and ultrasonic techniques at high-pressure (up to 11 GPa) and high-temperature (300-1500 K) conditions. This not only enables the determination of the equation of state (EoS) parameters by applying the pressure-volume-temperature (P-V-T) data to the high-temperature Birch-Murnaghan EoS but also yields the elastic moduli together with their P and T derivatives from the fit of the compressional and shear wave velocities to a finite strain EoS: K_S0,300 = 186(2) GPa, K′_S0,300 = 7.2(6), (∂K_S0,300/∂T)_P = −0.023(2) GPa K⁻¹, G_0,300 = 125(1) GPa G′_0,300 = 2.3(2), (∂G_0,300/∂T)_P = −0.017(1) GPa K⁻¹. On the basis of our acquired results, we propose to predict the elastic moduli of aluminosilicate ceramics by a linear function of the ratio of AlO₆ octahedra and SiO₄ tetrahedra within the constituting phases.     

A Keratin 7 and E-Cadherin Signature Is Highly Predictive of Tubo-Ovarian High-Grade Serous Carcinoma Prognosis

During tubo-ovarian high-grade serous carcinoma (HGSC) progression, tumoral cells undergo phenotypic changes in their epithelial marker profiles, which are essential for dissemination processes. Here, we set out to determine whether standard epithelial markers can predict HGSC patient prognosis. Levels of E-CADH, KRT7, KRT18, KRT19 were quantified in 18 HGSC cell lines by Western blot and in a Discovery cohort tissue microarray (TMA) (n = 101 patients) using immunofluorescence. E-CADH and KRT7 levels were subsequently analyzed in the TMA of the Canadian Ovarian Experimental Unified Resource cohort (COEUR, n = 1158 patients) and in public datasets. Epithelial marker expression was highly variable in HGSC cell lines and tissues. In the Discovery cohort, high levels of KRT7 and KRT19 were associated with an unfavorable prognosis, whereas high E-CADH expression indicated a better outcome. Expression of KRT7 and E-CADH gave a robust combination to predict overall survival (OS, p = 0.004) and progression free survival (PFS, p = 5.5 × 10⁻⁴) by Kaplan–Meier analysis. In the COEUR cohort, the E-CADH-KRT7 signature was a strong independent prognostic biomarker (OS, HR = 1.6, p = 2.9 × 10⁻⁴; PFS, HR = 1.3, p = 0.008) and predicted a poor patient response to chemotherapy (p = 1.3 × 10⁻⁴). Our results identify a combination of two epithelial markers as highly significant indicators of HGSC patient prognosis and treatment response.     

A numerical scheme for modeling wavefront propagation on a monolayer of arbitrary geometry

The majority of models of wavefront propagation in cardiac tissue have assumed relatively simple geometries. Extensions to complicated three-dimensional (3-D) representations are computationally challenging due to issues related both to problem size and to the correct implementation of flux conservation. In this paper, we present a generalized finite difference scheme (GDFS) to simulate the reaction-diffusion system on a 3-D monolayer of arbitrary shape. GDFS is a vertex-centered variant of the finite-volume method that ensures local flux conservation. Owing to an effectively lower dimensionality, the overall computation time is reduced compared to full 3-D models at the same spatial resolution. We present the theoretical background to compute both the wavefront conduction and local electrograms using a matrix formulation. The same matrix is used for both these quantities. We then give some results of simulation for simple monolayers and complex monolayers resembling a human atria.     

Mutual coupling on a cylindrical array of waveguide elements

This communication presents a modal approach for investigating mutual coupling on a cylindrical array of waveguide elements. Computed results are given in the form of element patterns and are compared with measured patterns.     

A lens feed for a ring array

A method of feeding a 128-element circular array by means of anR-2Rparallel plate lens is presented. The method uses the lens fed by three or four probes at the periphery to excite 32 or 33 elements with the proper amplitude and phase to produce low sidelobe patterns over a broad frequency band. Experimental results are given.