Estrogen receptor beta-subtype selective tetrahydrofluorenones: use of a fused pyrazole as a phenol bioisostere.

Synthesis of a series of fused pyrazole tetrahydrofluorenone analogs which are potent, ERbeta subtype selective ligands is described. Analogs possessing subnanomolar ERbeta binding, greater than 100-fold ERbeta-selectivity, and oral bioavailability are reported.

The discovery of tetrahydrofluorenones as a new class of estrogen receptor beta-subtype selective ligands.

Synthesis and derivatization of a series of substituted tetrahydrofluorenone analogs giving potent, ERbeta subtype selective ligands are described. Several analogs possessing ERbeta binding affinities comparable to 17beta-estradiol but with greater than 75-fold selectivity over ERalpha are reported.

Stability, change, and correlates of the peer relationships of young children with mild developmental delays.

The peer relationships of young children with mild developmental (cognitive) delays recruited at 4-6 years of age were examined in a longitudinal study across a 2-year period. Results revealed only modest increases in children's peer interactions, a high degree of intraindividual stability, and the existence of a poorly organized and conflict-prone pattern of peer interactions. Child cognitive and language levels as well as family stress and support were associated with children's peer interactions.

Software studies for germanium detectors data analysis.

Efficiency calibrations of multiple high-purity germanium (HPGe) detectors are being maintained at the National Institute of Standards and Technology (NIST). Four generally available software packages for HPGe detector gamma-ray spectrum analysis, including the one currently used at NIST, were tested on spectra collected from two HPGe detectors at different source-to-detector distances and using point sources and ampoules as calibration geometries. The resulting efficiency curves were inter-compared.

Assessing the 210At impurity in the production of 211At for radiotherapy by 210Po analysis via isotope dilution alpha spectrometry.

A method for assessing the impurity 210At in cyclotron-produced 211At via isotope dilution alpha spectrometry is presented. The activity of 210At is quantified by measuring the activity of daughter nuclide 210Po. Counting sources are prepared by spontaneous deposition of Po on a silver disc.

6H-Benzo[c]chromen-6-one derivatives as selective ERbeta agonists.

A series of 6H-benzo[c]chromen-6-one and 6H-benzo[c]chromene derivatives were prepared, and the affinity and selectivity for ERalpha and ERbeta was measured. Many of the analogs were found to be potent and selective ERbeta agonists. Bis hydroxyl at positions 3 and 8 is essential for activity in a HTRF coactivator recruitment assay.

Tricuspid valve replacement after cardiac transplantation.

Background: Tricuspid valve insufficiency (TI) is common after orthotopic heart transplantation. However, tricuspid valve replacement or repair (TVR) is rare. The aim of this study is to evaluate our experience with TVR in cardiac transplant recipients.

Ensembl 2006.

The Ensembl (http://www.ensembl.org/) project provides a comprehensive and integrated source of annotation of large genome sequences.

Utility of histologic parameters in screening for antibody-mediated rejection of the cardiac allograft: a study of 3,170 biopsies.

Background: Diagnostic criteria for antibody-mediated rejection (AMR) of the cardiac allograft have recently been proposed as part of the International Society for Heart and Lung Transplantation (ISHLT) biopsy grading scheme. Histologic features of vascular adherence of macrophages (VASC) and endothelial activation or swelling in capillaries (ENDO) are proposed as criteria to prompt the immunohistochemical investigation of biopsies for AMR. The aim of this study was to determine whether VASC and ENDO are adequate to act as screening parameters to trigger further AMR investigation.

Androstenediol analogs as ER-beta-selective SERMs.

A series of 19-substituted androstenediol derivatives was prepared. Some of the novel analogs were surprisingly potent and selective ligands for ER-beta.

Periocular routes for retinal drug delivery.

Despite numerous scientific efforts, delivery of therapeutic amounts of a drug to the retina remains a challenge. This challenge is compounded if chronic therapy is desired. The inability or inefficiency of topical and systemic routes for retinal delivery of existing drugs is now widely accepted.

Alveolar bone grafting: achieving the organisational standards determined by CSAG, a baseline audit at the Birmingham Children's Hospital.

Introduction: Birmingham Children's Hospital (BCH) is the centre for a regional comprehensive cleft service attempting to implement the national guidelines for minimum standards of care. A national audit of cleft management (CSAG) found that 58% of alveolar bone grafts were successful; published series suggest that success rates can be of the order of 95%. We present the results of an audit of alveolar bone grafting over a 33-month period, after implementation.

Group 4 salicyloxazolines are potent polymerization catalysts.

Octahedral titanium and zirconium complexes based on salicyloxazoline ligands with sterically demanding ortho-substituents provide a new family of extremely active ethene polymerization catalysts [up to 10(8) g PE (mol bar h)(-1)] which are in some cases "single site".

Antagonist-induced, activation function-2-independent estrogen receptor alpha phosphorylation.

Estrogen receptor alpha (ERalpha) serine 118 (Ser118) phosphorylation modulates activation function-1 (AF1) function. Correct positioning of helix 12 promotes agonist-dependent recruitment of cyclin-dependent kinase-7 to catalyze this event. In this study we show robust cyclin-dependent kinase-7-independent, AF2 antagonist-induced Ser118 phosphorylation.

Estrogen receptor ligands. Part 14: application of novel antagonist side chains to existing platforms.

Two novel side chains which had previously been found to enhance antagonist activity in the dihydrobenzoxathiin SERM series were applied to three existing platforms. The novel side chains did not improve the antagonist activity of the existing platforms.

Functionally diverse complement of large conductance calcium- and voltage-activated potassium channel (BK) alpha-subunits generated from a single site of splicing.

The pore-forming alpha-subunits of large conductance calcium- and voltage-activated potassium (BK) channels are encoded by a single gene that undergoes extensive alternative pre-mRNA splicing. However, the extent to which differential exon usage at a single site of splicing may confer functionally distinct properties on BK channels is largely unknown. Here we demonstrated that alternative splicing at site of splicing C2 in the mouse BK channel C terminus generates five distinct splice variants: ZERO, e20, e21(STREX), e22, and a novel variant deltae23.

MDM2 as a predictor of prostate carcinoma outcome: an analysis of Radiation Therapy Oncology Group Protocol 8610.

Background: The MDM2 oncoprotein promotes p53 degradation via ubiquitin, establishing negative feedback control of p53 and consequently affecting cell cycle arrest and apoptosis. The authors evaluated the association between MDM2 expression and local failure, distant metastasis (DM), cause-specific mortality, and overall mortality in men treated in Radiation Therapy Oncology Group 8610 with radiotherapy, with or without androgen deprivation.

Methods: Of the 456 eligible and analyzable patients (parent cohort), adequate archival diagnostic tissue specimens from 108 patients were available for MDM2 analysis (MDM2 cohort).

Estrogen receptor ligands. Part 13: Dihydrobenzoxathiin SERAMs with an optimized antagonist side chain.

An optimized side chain for dihydrobenzoxathiin SERAMs was discovered and attached to four dihydrobenzoxathiin platforms. The novel SERAMs show exceptional estrogen antagonist activity in uterine tissue and an MCF-7 breast cancer cell assay.

Neuropeptide Y receptor antagonists.

A review of the patent literature for neuropeptide Y (NPY) antagonists is presented for the period of January 2000 to March 2001. This review focuses on antagonists of the Y(1) and Y(5) receptor subtypes, which have been of primary interest as anti-obesity agents. In contrast to the Y(5) receptor, there have been only a limited number of new chemical entities claimed as antagonists at the Y(1) receptor.

Novel ketal ligands for the glucocorticoid receptor: in vitro and in vivo activity.

A novel series of selective ligands for the human glucocorticoid receptor is described. Structure-activity studies focused on variation of B-ring size, ketal ring size, and ketal substitution. These analogs were found to be potent and selective ligands for GR and have partial agonist profiles in functional assays for transactivation (TAT, GS) and transrepression (IL-6).

Haplotype structure and phylogenetic shadowing of a hypervariable region in the CAPN10 gene.

It has been proposed that variation in calpain 10 (CAPN10) contributes to the risk of type 2 diabetes (T2D). A previous survey of CAPN10 in ethnically diverse populations revealed an intronic region with a significant excess of polymorphism levels relative to inter-species sequence divergence, suggesting that this region was the target of long-standing balancing selection. Based on the thrifty genotype hypothesis, variation that increases risk to T2D in contemporary humans at one time conferred a survival advantage in ancestral populations.

Limits on gravitational-wave emission from selected pulsars using LIGO data.

We place direct upper limits on the amplitude of gravitational waves from 28 isolated radio pulsars by a coherent multidetector analysis of the data collected during the second science run of the LIGO interferometric detectors. These are the first direct upper limits for 26 of the 28 pulsars. We use coordinated radio observations for the first time to build radio-guided phase templates for the expected gravitational-wave signals.

Addressing the maintenance of certification challenge: the College of American Pathologists response.

Context: The American Board of Medical Specialties Maintenance of Certification (MOC) process will become effective in 2006. The College of American Pathologists (CAP) Education Committee defined pathology-specific competencies within MOC categories and used data from a survey of pathologists to create education courses targeted to each MOC category.

Objective: To define pathology-specific competencies within MOC categories and to identify priority learning needs for pathologists.

In vitro bioactivation of dihydrobenzoxathiin selective estrogen receptor modulators by cytochrome P450 3A4 in human liver microsomes: formation of reactive iminium and quinone type metabolites.

Estrogens and selective estrogen receptor modulators (SERMs) are prescribed widely in the clinic to alleviate symptoms in postmenopausal women, and they are metabolized to reactive intermediates, which may elicit adverse effects. As part of our efforts to develop safer SERMs, in vitro covalent protein binding of (2S,3R)-(+)-3-(4-hydroxyphenyl)-2-[4-(2-piperidin-1-ylethoxy)phenyl]-2,3-dihydro-1,4-benzoxathiin-6-ol (I) was evaluated. Radioactivity from [3H]I became covalently bound to proteins in a fashion that was both time- and NADPH-dependent in human liver microsomes and reached a value of 1106 pmol equiv/mg protein following a 45 min incubation.

Novel heterocyclic glucocorticoids: in vitro profile and in vivo efficacy.

A series of novel ligands for the glucocorticoid receptor containing two heterocycles were synthesized. These compounds were investigated for a dissociative profile using transrepression and transactivation assays. Several compounds were tested in vivo and showed the ability to reduce inflammation in a mouse.