Bisphosphonates are the mainstay of therapy worldwide for osteoporosis. They inhibit the activities of the osteoclasts, the bone resorption cells. While bisphosphonates are known to block farnesyl pyrophsophate synthase to exert their anti-resorptive action, the detailed mechanism is not well understood. Examining the change in expression profile before and after bisphosphonate treatment in the osteoclasts might shed some light on the biological pathways that are perturbed.
Bisphosphonates inactivate human EGFRs to exert antitumor actions.
Specimen part
View SamplesIn this study we investigated changes in gene expression induced by 2cPE (a non-selective isopeptidase inhibitor) in leukemia cells isolated from 10 different patients suffering of B-cell chronic lymphocytic leukemia. We compared 2cPE induced changes in mRNA levels with those induced by bortezomib, another well characterized proteasome inhibitor. Both inhibitors trigger apoptosis in leukemia cells.
The isopeptidase inhibitor 2cPE triggers proteotoxic stress and ATM activation in chronic lymphocytic leukemia cells.
Specimen part, Subject
View SamplesAlveolar epithelial type II (ATII)-like cells can be generated from murine embryonic stem cells (ESCs), although to date, no robust protocols applying specific differentiation factors are established. We hypothesized that the keratinocyte growth factor (KGF), an important mediator of lung organogenesis and primary ATII cell maturation and proliferation, together with dexamethasone, 8-bromoadenosine-cAMP, and isobutylmethylxanthine (DCI), which induce maturation of primary fetal ATII cells, also support the alveolar differentiation of murine ESCs. Here we demonstrate that the above stimuli synergistically potentiate the alveolar differentiation of ESCs as indicated by increased expression of the surfactant proteins (SP-) C and SP-B. This effect is most profound if KGF is supplied not only in the late stage, but at least also during the intermediate stage of differentiation. Our results indicate that KGF most likely does not enhance the generation of (mes)endodermal or NK2 homeobox 1 (Nkx2.1) expressing progenitor cells but rather, supported by DCI, accelerates further differentiation/maturation of respiratory progeny in the intermediate phase and maturation/proliferation of emerging ATII cells in the late stage of differentiation. Ultrastructural analyses confirmed the presence of ATII-like cells with intracellular composite and lamellar bodies. Finally, induced pluripotent stem cells (iPSCs) were generated from transgenic mice with ATII cell-specific lacZ reporter expression. Again, KGF and DCI synergistically increased SP-C and SP-B expression in iPSC cultures, and lacZ expressing ATII-like cells developed. In conclusion, ATII cell-specific reporter expression enabled the first reliable proof for the generation of murine iPSC-derived ATII cells. In addition, we have shown KGF and DCI to synergistically support the generation of ATII-like cells from ESCs and iPSCs. Combined application of these factors will facilitate more efficient generation of stem cell-derived ATII cells for future basic research and potential therapeutic application.
Keratinocyte growth factor and dexamethasone plus elevated cAMP levels synergistically support pluripotent stem cell differentiation into alveolar epithelial type II cells.
Specimen part, Treatment
View SamplesTo understand differences between resting and activated memory CD8+ T cells, we compared the global gene expression of ex vivo isolated naive and spleen and BM memory cells to in vitro activated spleen and BM memory cells.
Memory CD8(+) T cells colocalize with IL-7(+) stromal cells in bone marrow and rest in terms of proliferation and transcription.
Sex, Specimen part
View Samples