Discovery of a macrocyclic o-aminobenzamide Hsp90 inhibitor with heterocyclic tether that shows extended biomarker activity and in vivo efficacy in a mouse xenograft model.

A novel series of macrocyclic ortho-aminobenzamide Hsp90 inhibitors is reported. In continuation of our research, heterocycle-containing tethers were explored with the intent to further improve potency and minimize hERG liabilities. This effort culminated in the discovery of compound 10, which efficiently suppressed proliferation of HCT116 and U87 cells.

Macrocyclic lactams as potent Hsp90 inhibitors with excellent tumor exposure and extended biomarker activity.

A novel series of macrocyclic ortho-aminobenzamide Hsp90 inhibitors is reported. In continuation of our research in this area, macrocyclic amides and lactams were explored to reduce the risk of hERG liabilities. This effort culminated in the discovery of compound 38, which showed a favorable in vitro profile, and efficiently suppressed proliferation of several relevant cell lines.

Design and SAR of macrocyclic Hsp90 inhibitors with increased metabolic stability and potent cell-proliferation activity.

A novel series of macrocyclic ortho-aminobenzamide Hsp90 inhibitors is reported. A basic nitrogen within the tether linking the aniline nitrogen atom to a tetrahydroindolone moiety allowed access to compounds with good physical properties. Important structure-activity relationship information was obtained from this series which led to the discovery of a soluble and stable compound which is potent in an Hsp90 binding and cell-proliferation assay.

An enzyme-coupled ultrasensitive luminescence assay for protein methyltransferases.

Epigenetic regulation through protein posttranslational modifications is essential in development and disease. Among the key chemical modifications is protein methylation carried out by protein methyltransferases (PMTs). Quantitative and sensitive PMT activity assays can provide valuable tools to investigate PMT functions.

A pilot study of the efficacy of a 1,064 and 1,320 nm sequentially firing Nd:YAG laser device for lipolysis and skin tightening.

Background: Laser-assisted lipolysis with a medium pulsed 1,064 nm Neodymium:Yttrium-Aluminum-Garnet (Nd:YAG) system has been used since FDA approval in October 2006 [1]. Since then, this technology has been advanced to include an additional wavelength (1,320 nm) and an accelerometer designed to improve efficacy and safety.

Objective: (1) Evaluate the efficacy and safety of a sequentially firing 1,064 and 1,320 nm Nd:YAG laser device for lipolysis.

Laser-assisted lipolysis: a report on complications.

Background: As reported elsewhere, there are several drawbacks associated with traditional liposuction: increased blood loss, ecchymoses, long recovery times with increased postoperative discomfort, and skin laxity. Laser-assisted lipolysis (LAL) is an emerging technology, but the level of safety associated with this device has not been reported. In October 2006, a 1064-nm Nd:YAG laser was approved by the United States Food and Drug Administration for the surgical incision, excision, vaporization, ablation, and coagulation of all soft tissues and has been used for LAL as well as improvement of areas of flaccidity.

Incorporating a medical spa into a physician-run practice.

The age-old spa concept is no less valuable today than it was during the time of Julius Caesar. Over the centuries, there have been many iterations of the concept of the spa. The most recent is the medical spa, which has become the fastest-growing segment of the spa industry.

The new laser liposuction for men.

Laser-assisted lipolysis with a medium-pulsed 1064-nanometer neodymium-doped yttrium aluminum garnet (Nd:YAG) system is a new FDA-approved method of removing localized areas of fat with the added benefit of skin tightening. This new method is particularly useful in treating the lower abdomen and submental areas where skin laxity may occur after the removal of adipose tissue. In addition, decreased bruising and scrotal edema after treating men is possible with use of the tumescent technique and the added benefit of coagulation produced by the laser.

Electromyography-controlled exoskeletal upper-limb-powered orthosis for exercise training after stroke.

Objective: Robot-assisted exercise shows promise as a means of providing exercise therapy for weakness that results from stroke or other neurological conditions. Exoskeletal or "wearable" robots can, in principle, provide therapeutic exercise and/or function as powered orthoses to help compensate for chronic weakness. We describe a novel electromyography (EMG)-controlled exoskeletal robotic brace for the elbow (the active joint brace) and the results of a pilot study conducted using this brace for exercise training in individuals with chronic hemiparesis after stroke.

Alpha1-antitrypsin deficiency panniculitis.

Alpha1-antitrypsin deficiency panniculitis (A1ADP) is a rare form of panniculitis that affects children and adults. Clinical and histologic features, precipitating factors, and treatments are discussed.

Steroid and cytokine regulation of matrix metalloproteinase expression in endometriosis and the establishment of experimental endometriosis in nude mice.

The cyclic expression of matrix metalloproteinases (MMPs) by human endometrium has been suggested to play a role in the invasive process necessary to establish endometriosis. The ability of progesterone exposure to inhibit endometrial MMP-3 and MMP-7 expression requires the local action of TGF beta and may also be linked to the local production of retinoic acid by stromal cells. A continuous expression of several MMPs in endometriotic lesions has been reported, indicating a failure of progesterone or locally produced factors to suppress these enzymes.

In vivo estrogen regulation of epidermal growth factor receptor in human endometrium.

The effects of estrogen and progesterone on the expression of epidermal growth factor receptor (EGFR) in human endometrium were studied in hypogonadal women under conditions that simulated a normal menstrual cycle. All women received the same regimen of estrogen and progesterone and underwent serial biopsies. In one group of women (group I), a biopsy was obtained before receiving estrogen (CD0) and after 11 days (CD11) of estrogen replacement.

The association of intrauterine filling defects on hysterosalpingogram with endometriosis.

Objective: To determine whether there is a significant association between the presence of polyps or polypoid endometrium on hysterosalpingogram (HSG) with the presence of pelvic or peritoneal endometriosis.

Design: Retrospective chart review.

Setting: Department of Reproductive Endocrinology and Infertility at the University of Vermont, College of Medicine.

Septate uterus with cervical duplication: a rare malformation.

This previously unreported case of complete uterine septum, cervical duplication, and a longitudinal vaginal septum is best explained by the theory of Muller et al. (5), not by classically held views of unidirectional müllerian development. According to their theory, this anomaly could develop from failure of fusion of the most caudad müllerian ducts, resulting in a normal uterine fundus, with a complete septum, cervical duplication, and a longitudinal vaginal septum.

Pregnancy after laparoscopic neosalpingostomy in a patient with atresia of the distal fallopian tubes.

Structural congenital anomalies of the fallopian tube are interesting clinical problems that are infrequently reported in the literature. We report a patient with congenital absence of the distal fallopian tubes. After surgical correction by laparoscopic neosalpingostomies using a new intussusception technique, a normal IUP occurred and was delivered at term.

In vitro CA-125 secretion by endometrium from women with advanced endometriosis.

Objective: To determine if the endometrium of women with endometriosis is a potential source of the elevated serum concentrations of CA-125 associated with endometriosis.

Design: Secretion of CA-125 by the endometrium in tissue culture was documented and measured in response to treatment with progesterone (P), 17 beta-estradiol (E2), and progesterone and estradiol (E2+P). Sequential biopsies of the endometrium from the early and late luteal phase were obtained from women with laparoscopically documented normal anatomy or moderate to severe endometriosis.

Evaluation of fetal growth by estimation of neonatal body composition.

To characterize the variation in normal fetal growth by body composition analysis, 188 neonates from uncomplicated singleton term pregnancies were evaluated within 24 hours of birth. Anthropometric measures used to estimate lean body mass and body fat included the following: birth weight 3553 +/- 462 g, lean body mass 3060 +/- 377 g (86.3%), fat mass 495 +/- 196 g (13.

CA-125 secretion by luteal phase endometrium in vitro.

The source of CA-125 in normal women and the mechanisms which control CA-125 production remain to be defined. This study was initiated to examine the pattern of secretion of CA-125 from luteal phase endometrium. Endometrial samples were obtained during the early luteal phase (histological days 16-18) and late luteal phase (histological days 25-27) from ovulatory women with a laparoscopically normal pelvis.