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Cancer cells require sustained oncogenic signaling in order to maintain their malignant properties. It is, however, unclear whether they possess other dependencies that can be exploited therapeutically. We report here that in a large fraction of human breast cancers, the gene encoding focal adhesion kinase (FAK), a core component of integrin signaling, was amplified and FAK mRNA was overexpressed. A mammary gland--specific deletion of Fak in mice did not seem to affect normal mammary epithelial cells, and these mice were protected from tumors initiated by the polyoma middle T oncoprotein (PyMT), which activates Ras and PI3K. FAK-deficient PyMT-transformed cells displayed both growth arrest and apoptosis, as well as diminished invasive and metastatic capacity. Upon silencing of Fak, mouse mammary tumor cells transformed by activated Ras became senescent and lost their invasive ability. Further, Neu-transformed cells also underwent growth arrest and apoptosis if integrin [beta]4-dependent signaling was simultaneously inactivated. Human breast cancer cells carrying oncogenic mutations that activate Ras or PI3K signaling displayed similar responses upon silencing of FAK. Mechanistic studies indicated that FAK sustains tumorigenesis by promoting Src-mediated phosphorylation of [p130.sup.Cas]. These results suggest that FAK supports Ras- and PI3K-dependent mammary tumor initiation, maintenance, and progression to metastasis by orchestrating multiple core cellular functions, including proliferation, survival, and avoidance of senescence., Introduction Cancer cells require sustained oncogenic signaling in order to thrive (1). A large fraction of breast tumors carry oncogenic mutations that cause hyperactivation of the Raf/ERK cascade (20%-25% HER2, [...]

Background and Purpose: Excessive brain iron deposition is involved in Parkinson's disease (PD) pathogenesis. However, the correlation of iron accumulation in various brain nuclei is not well‐established in different stages of the disease. This cross‐sectional study aims to evaluate quantitative susceptibility mapping (QSM) as an imaging technique to measure brain iron accumulation in PD patients in different stages compared to healthy controls. Methods: Ninety‐six PD patients grouped by their Hoehn and Yahr (H&Y) stages and 31 healthy controls were included in this analysis. The magnetic susceptibility values of the substantia nigra (SN), red nucleus (RN), caudate, putamen, and globus pallidus were obtained and compared. Results: Iron level was increased in the SN of PD patients in all stages versus controls (p <.001), with no significant difference within stages. Iron in the RN was significantly increased in stage II versus controls (p =.013) and combined stages III and IV versus controls (p <.001). The iron levels in caudate, putamen, and globus pallidus were not different between any groups. Conclusions: Our data suggest iron accumulation occurs early in the disease course and only in the SN and RN of these patients. This is a large cross‐sectional study of brain iron deposition in PD patients according to H&Y staging. Prospective studies are warranted to further validate QSM as a method to follow brain iron, which could serve as a disease biomarker and a therapeutic target. [ABSTRACT FROM AUTHOR]

Purpose: To determine the reproducibility of quantitative susceptibility mapping at multiple sites on clinical and preclinical scanners (1.5 T, 3 T, 7 T, and 9.4 T) from different vendors (Siemens, GE, Philips, and Bruker) for standardization of multicenter studies. Methods: Seven phantoms distributed from the core site, each containing 5 compartments with gadolinium solutions with fixed concentrations between 0.625 mM and 10 mM. Multi‐echo gradient echo scans were performed at 1.5 T, 3 T, 7 T, and 9.4 T on 12 clinical and 3 preclinical scanners. DICOM images from the scans were processed into quantitative susceptibility maps using the Laplacian boundary value (LBV) and MEDI+0 automatic uniform reference algorithm. Region of interest (ROI) analyses were performed by a physicist to determine agreement between results from all sites. Measurement reproducibility was assessed using regression, Bland‐Altman plots, and the intra‐class correlation coefficient (ICC). Results: Quantitative susceptibility mapping (QSM) from all scanners had similar, artifact‐free visual appearance. Regression analysis showed a linear relationship between gadolinium concentrations and average QSM measurements for all phantoms (y = 350x – 0.0346, r2>0.99). The SD of measurements increased almost linearly from 32 ppb to 230 ppb as the measured susceptibility increased from 0.26 ppm to 3.56 ppm. A Bland‐Altman plot showed the bias, upper, and lower limits of agreement for all comparisons were −10, −210, and 200 ppb, respectively. The ICC was 0.991 with a 95% CI (0.973, 0.99). Conclusions: QSM shows excellent multicenter reproducibility for a large range of susceptibility values encountered in cranial and extra‐cranial applications on a diverse set of scanner platforms. [ABSTRACT FROM AUTHOR]

Chronic active multiple sclerosis lesions, characterized by a hyperintense rim of iron-enriched, activated microglia and macrophages, have been linked to greater tissue damage. Post-mortem studies have determined that chronic active lesions are primarily related to the later stages of multiple sclerosis; however, the occurrence of these lesions, and their relationship to earlier disease stages may be greatly underestimated. Detection of chronic active lesions across the patient spectrum of multiple sclerosis requires a validated imaging tool to accurately identify lesions with persistent inflammation. Quantitative susceptibility mapping provides efficient in vivo quantification of susceptibility changes related to iron deposition and the potential to identify lesions harbouring iron-laden inflammatory cells. The PET tracer 11C-PK11195 targets the translocator protein expressed by activated microglia and infiltrating macrophages. Accordingly, this study aimed to validate that lesions with a hyperintense rim on quantitative susceptibility mapping from both relapsing and progressive patients demonstrate a higher level of innate immune activation as measured on 11C-PK11195 PET. Thirty patients were enrolled in this study, 24 patients had relapsing remitting multiple sclerosis, six had progressive multiple sclerosis, and all patients had concomitant MRI with a gradient echo sequence and PET with 11C-PK11195. A total of 406 chronic lesions were detected, and 43 chronic lesions with a hyperintense rim on quantitative susceptibility mapping were identified as rim+ lesions. Susceptibility (relative to CSF) was higher in rim+ (2.42 ± 17.45 ppb) compared to rim- lesions (-14.6 ± 19.3 ppb, P < 0.0001). Among rim+ lesions, susceptibility within the rim (20.04 ± 14.28 ppb) was significantly higher compared to the core (-5.49 ± 14.44 ppb, P < 0.0001), consistent with the presence of iron. In a mixed-effects model, 11C-PK11195 uptake, representing activated microglia/macrophages, was higher in rim+ lesions compared to rim- lesions (P = 0.015). Validating our in vivo imaging results, multiple sclerosis brain slabs were imaged with quantitative susceptibility mapping and processed for immunohistochemistry. These results showed a positive translocator protein signal throughout the expansive hyperintense border of rim+ lesions, which co-localized with iron containing CD68+ microglia and macrophages. In conclusion, this study provides evidence that suggests that a hyperintense rim on quantitative susceptibility measure within a chronic lesion is a correlate for persistent inflammatory activity and that these lesions can be identified in the relapsing patients. Utilizing quantitative susceptibility measure to differentiate chronic multiple sclerosis lesion subtypes, especially chronic active lesions, would provide a method to assess the impact of these lesions on disease progression. [ABSTRACT FROM AUTHOR]