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Schuyler D.,Ralph H. Johnson Veterans Administration Hospital
Primary Care Companion to the Journal of Clinical Psychiatry

Through this column, we hope that practitioners in general medical settings will gain a more complete knowledge of the many patients who are likely to benefit from brief psychotherapeutic interventions. A close working relationship between primary care and psychiatry can serve to enhance patient outcome. © 2014 Physicians Postgraduate Press, Inc. Source

Sharpton J.,Geriatric Unit | Schuyler D.,Ralph H. Johnson Veterans Administration Hospital
Primary Care Companion to the Journal of Clinical Psychiatry

Each psychotherapy intervention served a major relationship function for Mr A; each encouraged problem-solving and worked hard to not be disputatious. Each emphasized the many ways in which he had successfully adapted to his new environment and noted how a former loner had managed to make multiple new relationships and fulfilled his need to have a productive existence. The act of being present is an important aspect of psychotherapy. Being silent may be uncomfortable for some, but sometimes its positive effect is like no other. Mr A is a good example of this. He does not always want us to explain things to him or to apprise him of facts related to realistic goals. He feels that he has had significant losses, and he is aware that he is living out the end of his life. He sometimes just wants to be heard. We must remember that what he may really want is for us to be quietly and unconditionally present. © 2012 Physicians Postgraduate Press, Inc. Source

Salas A.,Ralph H. Johnson Veterans Administration Hospital | Salas A.,Hollings Cancer Center | Ponnusamy S.,Ralph H. Johnson Veterans Administration Hospital | Ponnusamy S.,Hollings Cancer Center | And 32 more authors.

The mechanisms by which sphingosine kinase-1 (SK-1)/sphingosine 1-phosphate (S1P) activation contributes to imatinib resistance in chronic myeloid leukemia (CML) are unknown. We show herein that increased SK-1/S1P enhances Bcr-Abl1 protein stability, through inhibition of its proteasomal degradation in imatinib-resistant K562/IMA-3 and LAMA-4/IMA human CML cells. In fact, Bcr-Abl1 stability was enhanced by ectopic SK-1 expression. Conversely, siRNA-mediated SK-1 knockdown in K562/IMA-3 cells, or its genetic loss in SK-1-/- MEFs, significantly reduced Bcr-Abl1 stability. Regulation of Bcr-Abl1 by SK-1/S1P was dependent on S1P receptor 2 (S1P2) signaling, which prevented Bcr-Abl1 dephosphorylation, and degradation via inhibition of PP2A. Molecular or pharmacologic interference with SK-1/S1P2 restored PP2A-dependent Bcr-Abl1 dephosphorylation, and enhanced imatinib- or nilotinib-induced growth inhibition in primary CD34+ mononuclear cells obtained from chronic phase and blast crisis CML patients, K562/IMA-3 or LAMA4/IMA cells, and 32Dcl3 murine progenitor cells, expressing the wild-type or mutant (Y253H or T315I) Bcr-Abl1 in situ. Accordingly, impaired SK-1/S1P2 signaling enhanced the growth-inhibitory effects of nilotinib against 32D/T315I-Bcr-Abl1-derived mouse allografts. Since SK-1/S1P/S1P2 signaling regulates Bcr-Abl1 stability via modulation of PP2A, inhibition of SK-1/S1P2 axis represents a novel approach to target wild-type- or mutant-Bcr-Abl1 thereby overcoming drug resistance. © 2011 by The American Society of Hematology. Source

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