Thrombospondin-1 (TSP1) is a matricellular protein that displays both pro-and anti-adhesive activities. Binding to sulfated glycoconjugates mediates most high affinity binding of soluble TSP1 to MDA-MB-435 cells, but attachment and spreading of these cells on immobilized TSP1 is primarily ␤ 1 integrin-dependent. The integrin ␣ 3 ␤ 1 is the major mediator of breast carcinoma cell adhesion and chemotaxis to TSP1. This integrin is partially active in MDA-MB-435 cells but is mostly inactive in MDA-MB-231 and MCF-7 cells, which require ␤ 1 integrin activation to induce spreading on TSP1. Integrinmediated cell spreading on TSP1 is accompanied by extension of filopodia containing ␤ 1 integrins. TSP1 binding activity of the ␣ 3 ␤ 1 integrin is not stimulated by CD47-binding peptides from TSP1 or by protein kinase C activation, which activate ␣ v ␤ 3 integrin function in the same cells. In MDA-MB-231 but not MDA-MB-435 cells, this integrin is activated by pertussis toxin, whereas serum, insulin, insulin-like growth factor-1, and ligation of CD98 increase activity of this integrin in both cell lines. Serum stimulation is accompanied by increased surface expression of CD98, whereas insulinlike growth factor-1 does not increase CD98 expression. Thus, the pro-adhesive activity of TSP1 for breast carcinoma cells is controlled by several signals that regulate activity of the ␣ 3 ␤ 1 integrin. Thrombospondin-1 (TSP1)1 is an extracellular matrix glycoprotein that has diverse effects on cell behavior (reviewed in Refs. 1 and 2). The five known thrombospondin genes display distinct patterns of expression during development and in several disease states. Disruption of the thbs1 gene in mice results in lordosis of the spine and abnormal proliferation and inflammatory responses in the lung (3). Suppression of THBS1 expression by loss of wild type p53, by activated Ras, Myc, nickel, and in metastatic clones of several tumor cell lines suggested that loss of TSP1 expression may contribute to tumor progression (reviewed in Ref. 4). Consistent with this hypothesis, overexpression of THBS1 in breast carcinoma cells (5), a transformed endothelial cell line (6), fibroblasts from Li Fraumini patients (7), and glioblastoma cells (8) decreases tumor growth in animal models. This suppressive activity is due at least in part to the anti-angiogenic activity of TSP1 (reviewed in Refs. 4, 9, and 10). TSP1 antagonizes growth factor-stimulated proliferation and migration of endothelial cells. Its anti-angiogenic activity is thought to be the major mechanism for suppression of tumor growth in THBS1-transfected MDA-MB-435 breast carcinoma cells, because thrombospondin overexpression strongly inhibited tumor growth in vivo but did not significantly alter in vitro proliferation, motility, or the ability of the tumor cells to form colonies in soft agar (5). However, higher doses of exogenous TSP1 and some TSP1 peptides can directly inhibit proliferation of these cells in vitro (11).Defining the receptors that recognize TSP1 on endothelial and tumor cells ...

No abstract

No abstract

No abstract

Type 2 diabetes mellitus (T2DM) is a progressive disease with multifactorial etiology. The first-line therapy includes monotherapy (with metformin), which often fails to provide effective glycemic control, necessitating the addition of add-on therapy. In this regard, multiple single-dose agents formulated as a single-dose form called fixed-dose combinations (FDCs) have been evaluated for their safety, efficacy, and tolerability. The primary objective of this review is to develop practice-based expert group opinion on the current status and the causes of concern regarding the irrational use of FDCs, in Indian settings. After due discussions, the expert group analyzed the results from several clinical evidence in which various fixed combinations were used in T2DM management. The panel opined that FDCs (double or triple) improve patient adherence, reduce cost, and provide effective glycemic control and, thereby, play an important role in the management of T2DM. The expert group strongly recommended that the irrational metformin FDC's, banned by Indian government, should be stopped and could be achieved through active participation from the government, regulatory bodies, and health ministry, and through continuous education of primary care physicians and pharmacists. In T2DM management, FDCs play a crucial role in achieving glycemic targets effectively. However, understanding the difference between rational and irrational FDC combinations is necessary from the safety, efficacy, and tolerability perspective. In this regard, primary care physicians will have to use a multistep approach so that they can take informed decisions.