Design,synthesis and optimization of bis-amide derivatives as CSF1R inhibitors

Signaling via the receptor tyrosine kinase CSF1R is thought to play an important role in recruitment and differentiation of tumor-associated macrophages (TAMs). TAMs play pro-tumorigenic roles, including the suppression of anti-tumor immune response, promotion of angiogenesis and tumor cell metastasis. Because of the role of this signaling pathway in the tumor microenvironment, several small molecule CSF1R kinase inhibitors are undergoing clinical evaluation for cancer therapy, either as a single agent or in combination with other cancer therapies, including immune checkpoint inhibitors. Herein we describe our lead optimization effort that resulted in the identification of a potent, cellular active and orally bioavailable bis-amide CSF1R inhibitor. Docking and biochemical analysis allowed the removal of a metabolically labile and poorly permeable methyl piperazine group from an early lead compound. Optimization led to improved metabolic stability and Caco2 permeability, which in turn resulted in good oral bioavailability in mice.     

Association of age and gender of patients undergoing class V tooth coloured restoration in maxillary teeth

It is of interest to assess the association of age and gender of patients undergoing class V tooth colored restoration in maxillary teeth. Records were collected by reviewing the data of 86,000 patients of which 1580 patients had undergone class V tooth colored restoration in maxillary teeth. Patients were divided into age groups 18-30, 31-40,41-50,71-80 years. The most common age group who had undergone class V restoration was in the age group 41-50 years (30.8%). Cervical abrasions were the most common (79%). Most of the patients underwent direct restoration (87.7%). Direct restoration was found to be more prevalent in the age group 41-50 years due to cervical abrasion.     

Correction to: Combined therapeutic efficacy of carvacrol and X-radiation against 1,2-dimethyl hydrazine-induced experimental rat colon carcinogenesis

Molecular and Cellular Biochemistry -     

Trophoblast differentiation of human embryonic stem cells

Molecular mechanisms regulating human trophoblast differentiation remain poorly understood due to difficulties in obtaining primary tissues from very early developmental stages in humans. Therefore, the use of human embryonic stem cells (hESCs) as a source for generating trophoblast tissues is of significant interest. Trophoblast-like cells have been obtained through treatment of hESCs with bone morphogenetic protein (BMP) or inhibitors of activin/nodal/transforming growth factor-β signaling, or through protocols involving formation of embryoid bodies (EBs); however, there is controversy over whether hESC-derived cells are indeed analogous to true trophoblasts found in vivo. In this review, we provide an overview of previously described efforts to obtain trophoblasts from hESCs. We also discuss the merits and limitations of hESCs as a source of trophoblast derivatives.