Cochlear signal alterations using pseudo-color perceptual enhancement for patients with sensorineural hearing loss.

BACKGROUND: Neuroimaging detection of sensorineural hearing loss (SNHL)-related temporal bone abnormalities is limited (20-50%). We hypothesize that cochlear signal differences in gray-scale data may exceed the threshold of human eye detection. Gray-scale images can be post-processed to enhance perception of tonal difference using "pseudo-color" schemes. OBJECTIVE: To compare patients with unilateral SNHL to age-matched normal magnetic resonance imaging (MRI) exams for "labyrinthine color differences" employing pseudo-color post-processing. MATERIALS AND METHODS: The MRI database at an academic children's hospital was queried for "hearing loss." Only unilateral SNHL cases were analyzed. Sixty-nine imaging exams were reviewed. Thirteen age-matched normal MR exams in children without hearing loss were chosen for comparison. Pseudo-color was applied with post-processing assignment of specific hues to each gray-scale intensity value. Gray-scale and pseudo-color images were qualitatively evaluated for signal asymmetries by a board-certified neuroradiologist blinded to the side of SNHL. RESULTS: Twenty-six SNHL (mean: 7.6±3 years) and 13 normal control exams (mean: 7.3±4 years) were included. All patients had normal gray-scale cochlear signal and all controls had symmetrical pseudo-color signal. However, pseudo-color images revealed occult asymmetries localizing to the SNHL ear with lower values in 38%. Ninety-one percent of these cases showed concordance between the side of pseudo-color positivity and the side of hearing loss. CONCLUSION: Pseudo-color perceptual image enhancement reveals intra-labyrinthine fluid alterations on MR exams in children with unilateral SNHL. Pseudo-color image enhancement techniques improve detection of cochlear pathology and could have therapeutic implications.

Adult human mesenchymal stem cells enhance breast tumorigenesis and promote hormone independence.

Adult human mesenchymal stem cells (hMSCs) have been shown to home to sites of breast cancer and integrate into the tumor stroma. We demonstrate here the effect of hMSCs on primary breast tumor growth and the progression of these tumors to hormone independence. Co-injection of bone marrow-derived hMSCs enhances primary tumor growth of the estrogen receptor-positive, hormone-dependent breast carcinoma cell line MCF-7 in the presence or absence of estrogen in SCID/beige mice. We also show hormone-independent growth of MCF-7 cells when co-injected with hMSCs. These effects were found in conjunction with increased immunohistochemical staining of the progesterone receptor in the MCF-7/hMSC tumors as compared to MCF-7 control tumors. This increase in PgR expression indicates a link between MCF-7 cells and MSCs through ER-mediated signaling. Taken together, our data reveal the relationship between tumor microenvironment and tumor growth and the progression to hormone independence. This tumor stroma-cell interaction may provide a novel target for the treatment of estrogen receptor-positive, hormone-independent, and endocrine-resistant breast carcinoma.

Pharmacology and anti-tumor activity of RWJ67657, a novel inhibitor of p38 mitogen activated protein kinase.

Endocrine therapy resistance is a primary cause of clinical breast cancer treatment failure. The p38 mitogen activated protein kinase (MAPK) signaling pathway is known to promote ligand independent tumor growth and resistance to endocrine therapy. In this study, we investigated the therapeutic potential of the p38 inhibitor RWJ67657 in the treatment of tamoxifen resistant MDA-MB-361 cells. RWJ67657 dose-dependently decreased both basal and stimulated activation of p38 MAPK signaling in this drug resistant cell system. Decreased activation of p38 by RWJ67657 resulted in inhibition of the downstream p38 targets hsp27 and MAPKAPK. Diminished p38 signaling resulted in inhibition of p38-medated gene transcription. Furthermore, pharmacological inhibition of p38 by RWJ67657 decreased biological effects of p38, including ER-mediated gene expression and clonogenic survival in a dose-dependent manner. Animal studies revealed significantly decreased p38 signaling in vivo following exposure to RWJ67657. Treatment with the inhibitor markedly decreased phosphorylation of p38 in MDA-MB-361 tumors, leading to decreased transcription of both Fra-1 and progesterone receptor. Utilizing well-established xenograft tumor models, we demonstrated that RWJ67657 exhibits potent anti-tumor properties. Treatment with RWJ67657 markedly decreased tamoxifen resistant tumor growth, both in the presence and absence of estrogen. Taken together, our findings demonstrate the therapeutic potential of targeting the p38-MAPK signaling cascade in the treatment of endocrine resistant breast cancer.

Inhibition of p38-MAPK alters SRC coactivation and estrogen receptor phosphorylation.

The p38 mitogen activated protein kinase pathway (MAPK) is known to promote cell survival, endocrine therapy resistance and hormone independent breast cancer cell proliferation. Therefore, we utilized the novel p38 inhibitor RWJ67657 to investigate the relevance of targeting this pathway in the ER (+) breast cancer cell line MCF-7. Our results show that RWJ67657 inhibits both basal and estrogen stimulated phosphorylation of p38α, resulting in decreased activation of the downstream p38α targets hsp27 and MAPAPK. Furthermore, inhibition of p38α by RWJ67657 blocks clonogenic survival of MCF-7 cells with little effect on non-cancerous breast epithelial cells. Even though p38α is known to phosphorylate ERα at residue within ER's hinge region at Thr311, resulting in increased ERα transcriptional activation, our results suggest RWJ67657 inhibits the p38α-induced activation of ER by targeting both the AF-1 and AF-2 activation domains within ERα. We further show that RWJ67657 decreases the transcriptional activity of the ER coactivators SRC-1, SRC-2 and SRC-3. Taken together, our results strongly suggest that in addition to phosphorylating Thr311 within ERα, p38α indirectly activates the ER by phosphorylation and stimulation of the known ERα coactivators, SRC-1, -2 and-3. Overall, our data underscore the therapeutic potential of targeting the p38 MAPK pathway in the treatment of ER (+) breast cancer.