Bostwick Autoderm and Implant Technique: Improved Outcomes for Obese Patients in Immediate Breast Reconstruction.

Background: The Bostwick autoderm technique uses the patient's own deepithelialized mastectomy flap for lower pole coverage of an implant, similar to the use of acellular dermal matrix. The skin is closed over the autoderm flap in a Wise pattern. Unlike acellular dermal matrix, autoderm is perfused tissue that offers immediate protection for the implant.

Optimization of GPR40 Agonists for Type 2 Diabetes.

GPR40 (FFA1 and FFAR1) has gained significant interest as a target for the treatment of type 2 diabetes. TAK-875 (1), a GPR40 agonist, lowered hemoglobin A1c (HbA1c) and lowered both postprandial and fasting blood glucose levels in type 2 diabetic patients in phase II clinical trials. We optimized phenylpropanoic acid derivatives as GPR40 agonists and identified AMG 837 (2) as a clinical candidate.

Structure guided design of a series of sphingosine kinase (SphK) inhibitors.

Sphingosine-1-phosphate (S1P) signaling plays a vital role in mitogenesis, cell migration and angiogenesis. Sphingosine kinases (SphKs) catalyze a key step in sphingomyelin metabolism that leads to the production of S1P. There are two isoforms of SphK and observations made with SphK deficient mice show the two isoforms can compensate for each other's loss.

Discovery of AMG 853, a CRTH2 and DP Dual Antagonist.

Prostaglandin D2 (PGD2) plays a key role in mediating allergic reactions seen in asthma, allergic rhinitis, and atopic dermatitis. PGD2 exerts its activity through two G protein-coupled receptors (GPCRs), prostanoid D receptor (DP or DP1), and chemoattractant receptor-homologous molecule expressed on Th2 cells (CRTH2 or DP2). We report the optimization of a series of phenylacetic acid derivatives in an effort to improve the dual activity of AMG 009 against DP and CRTH2.

Lung function and inflammatory responses in healthy young adults exposed to 0.06 ppm ozone for 6.6 hours.

Rationale: Exposure to ozone causes a decrease in spirometric lung function and an increase in airway inflammation in healthy young adults at concentrations as low as 0.08 ppm, close to the National Ambient Air Quality Standard for ground level ozone.

Objectives: To test whether airway effects occur below the current ozone standard and if they are more pronounced in potentially susceptible individuals, such as those deficient in the antioxidant gene glutathione S-transferase mu 1 (GSTM1).

Association of cardiac and vascular changes with ambient PM2.5 in diabetic individuals.

Background And Objective: Exposure to fine airborne particles (PM2.5) has been shown to be responsible for cardiovascular and hematological effects, especially in older people with cardiovascular disease. Some epidemiological studies suggest that individuals with diabetes may be a particularly susceptible population.

Discovery and optimization of CRTH2 and DP dual antagonists.

A series of phenylacetic acid derivatives was discovered as CRTH2 antagonists. Modification of the series led to compounds that are also antagonists of DP. Since activation of CRTH2 and DP are believed to play key roles in mediating responses of asthma and other immune diseases, this series was optimized to increase the dual antagonistic activities and improve pharmacokinetic properties.

Intragenic DNA methylation alters chromatin structure and elongation efficiency in mammalian cells.

Transcriptional silencing in mammals is often associated with promoter methylation. However, a considerable number of genomic methylated CpGs exist in transposable elements, which are frequently found in intronic regions. To determine whether intragenic methylation influences transcription efficiency, we used the Cre/loxP-based system, RMCE, to introduce a transgene, methylated exclusively in a region downstream of the promoter, into a specific genomic site.