Incorporating bazedoxifene/conjugated estrogens into the current paradigm of menopausal therapy

Many women experience bothersome vasomotor and vaginal symptoms during the menopausal transition. Decreasing levels of estrogens during menopause are also associated with reduced bone density and an increased risk of osteoporosis. Combined estrogen/progestin therapy (hormone therapy) effectively treats menopausal symptoms and prevents bone loss, but has been associated with some safety and tolerability concerns. A novel menopausal therapy is the tissue selective estrogen complex, which pairs a selective estrogen receptor modulator with one or more estrogens. In preclinical studies, the tissue selective estrogen complex partnering bazedoxifene (BZA) with conjugated estrogens (CE) antagonized stimulation of breast and endometrial tissue, reduced vasomotor instability, and preserved bone mass in rat and mouse models. The specific attributes seen with BZA/CE were different from those observed with other selective estrogen receptor modulator/estrogen pairings. BZA/CE has undergone clinical evaluation in the Phase III Selective estrogens, Menopause, And Response to Therapy (SMART) trials in postmenopausal women with an intact uterus. Of the various doses of BZA/CE evaluated, BZA 20 mg/CE 0.45 mg and 0.625 mg were associated with a low incidence of endometrial hyperplasia (<1%) similar to placebo, and showed significant improvements in hot flushes and vulvar/vaginal symptoms and increases in bone mineral density. BZA 20 mg/CE 0.45 mg and 0.625 mg were associated with a low incidence of breast-related adverse events and demonstrated no difference from placebo in age-related changes in mammographic breast density. Both BZA/ CE doses showed a favorable tolerability profile, with no increases in uterine bleeding or breast tenderness, and had positive effects on metabolic parameters and quality of life. BZA/CE may be a promising alternative to hormone therapy for the treatment of menopausal symptoms and prevention of osteoporosis in nonhysterectomized postmenopausal women

Electrical Conductance of Molecular Wires

Molecular wires (MW) are the fundamental building blocks for molecular electronic devices. They consist of a molecular unit connected to two continuum reservoirs of electrons (usually metallic leads). We rely on Landauer theory as the basis for studying the conductance properties of MW systems. This relates the lead to lead current to the transmission probability for an electron to scatter through the molecule. Two different methods have been developed for the study of this scattering. One is based on a solution of the Lippmann-Schwinger equation and the other solves for the {\bf t} matrix using Schroedinger's equation. We use our methodology to study two problems of current interest. The first MW system consists of 1,4 benzene-dithiolate (BDT) bonded to two gold nanocontacts. Our calculations show that the conductance is sensitive to the chemical bonding between the molecule and the leads. The second system we study highlights the interesting phenomenon of antiresonances in MW. We derive an analytic formula predicting at what energies antiresonances should occur in the transmission spectra of MW. A numerical calculation for a MW consisting of filter molecules attached to an active molecule shows the existence of an antiresonance at the energy predicted by our formula.Comment: 14 pages, 5 figure

Dynamic Trans Interactions in Yeast Chromosomes

Three-dimensional organization of the genome is important for regulation of gene expression and maintenance of genomic stability. It also defines, and is defined by, contacts between different chromosomal loci. Interactions between loci positioned on different chromosomes, i.e. “trans” interactions are one type of such contacts. Here, we describe a case of inducible trans interaction in chromosomes of the budding yeast S. cerevisiae. Special DNA sequences, inserted in two ectopic chromosomal loci positioned in trans, pair with one another in an inducible manner. The spatial proximity diagnostic of pairing is observable by both chromosome capture analysis (3C) and epifluorescence microscopy in whole cells. Protein synthesis de novo appears to be required for this process. The three-dimensional organization of the yeast nucleus imposes a constraint on such pairing, presumably by dictating the probability with which the two sequences collide with one another

Integration of Tobacco Treatment Services into Cancer Care at Stanford.

As part of a National Cancer Institute Moonshot P30 Supplement, the Stanford Cancer Center piloted and integrated tobacco treatment into cancer care. This quality improvement (QI) project reports on the process from initial pilot to adoption within 14 clinics. The Head and Neck Oncology Clinic was engaged first in January 2019 as a pilot site given staff receptivity, elevated smoking prevalence, and a high tobacco screening rate (95%) yet low levels of tobacco cessation treatment referrals (&lt;10%) and patient engagement (&lt;1% of smokers treated). To improve referrals and engagement, system changes included an automated "opt-out" referral process and provision of tobacco cessation treatment as a covered benefit with flexible delivery options that included phone and telemedicine. Screening rates increased to 99%, referrals to 100%, 74% of patients were reached by counselors, and 33% of those reached engaged in treatment. Patient-reported abstinence from all tobacco products at 6-month follow-up is 20%. In July 2019, two additional oncology clinics were added. In December 2019, less than one year from initiating the QI pilot, with demonstrated feasibility, acceptability, and efficacy, the tobacco treatment services were integrated into 14 clinics at Stanford Cancer Center

Chemical probing of the homopurine·homopyrimidine tract in supercoiled DNA at single-nucleotide resolution

AbstractLocal structure of the homopurine·homopyrimidine tract in a supercoiled plasmid pEJ4 was studied using chemical probes at single-nucleotide resolution. The conformation of the homopyrimidine strand was probed by osmium tetroxide, pyridine (Os,py) while that of the homopurine strand was tested by diethyl pyrocarbonate (DEPC), i.e. by probes reacting preferentially with single-stranded DNA. At weakly acidic pH values, a strong Os,py attack on three nucleotides at the centre of the (dC-dT)16 block and a weaker attack on two nucleotides at the end of the block were observed. DEPC modified adenines in the 5′-half of the homopurine strand. Os,py modification at the centre of the block corresponded to the loop of the hairpin formed by the homopyrimidine tract, while DEPC modification corresponded to the unstructured half of the homopurine strand in the model of protonated triplex H form of DNA

Theory of Melting and the Optical Properties of Gold/DNA Nanocomposites

We describe a simple model for the melting and optical properties of a DNA/gold nanoparticle aggregate. The optical properties at fixed wavelength change dramatically at the melting transition, which is found to be higher and narrower in temperature for larger particles, and much sharper than that of an isolated DNA link. All these features are in agreement with available experiments. The aggregate is modeled as a cluster of gold nanoparticles on a periodic lattice connected by DNA bonds, and the extinction coefficient is computed using the discrete dipole approximation. Melting takes place as an increasing number of these bonds break with increasing temperature. The melting temperature corresponds approximately to the bond percolation threshold.Comment: 5 pages, 4 figure. To be published in Phys. Rev.

Analysis of Collectivism and Egoism Phenomena within the Context of Social Welfare

Comparative benefits provided by the basic social strategies including collectivism and egoism are investigated within the framework of democratic decision-making. In particular, we study the mechanism of growing "snowball" of cooperation.Comment: 12 pages, 5 figures. Translated from Russian. Original Russian Text published in Problemy Upravleniya, 2008, No. 4, pp. 30-3

The multiple gene duplication problem revisited

Motivation: Deciphering the location of gene duplications and multiple gene duplication episodes on the Tree of Life is fundamental to understanding the way gene families and genomes evolve. The multiple gene duplication problem provides a framework for placing gene duplication events onto nodes of a given species tree, and detecting episodes of multiple gene duplication. One version of the multiple gene duplication problem was defined by Guigó et al. in 1996. Several heuristic solutions have since been proposed for this problem, but no exact algorithms were known

Field-effect transistors assembled from functionalized carbon nanotubes

We have fabricated field effect transistors from carbon nanotubes using a novel selective placement scheme. We use carbon nanotubes that are covalently bound to molecules containing hydroxamic acid functionality. The functionalized nanotubes bind strongly to basic metal oxide surfaces, but not to silicon dioxide. Upon annealing, the functionalization is removed, restoring the electronic properties of the nanotubes. The devices we have fabricated show excellent electrical characteristics.Comment: 5 pages, 6 figure