Recent gene profiling studies have identified a new breast cancer subtype, the basal-like group, which expresses genes characteristic of basal epithelial cells and is associated with poor clinical ...outcomes. However, the genes responsible for the aggressive behavior observed in this group are largely unknown. Here we report that the small heat shock protein alpha-basic-crystallin (alphaB-crystallin) was commonly expressed in basal-like tumors and predicted poor survival in breast cancer patients independently of other prognostic markers. We also demonstrate that overexpression of alphaB-crystallin transformed immortalized human mammary epithelial cells (MECs). In 3D basement membrane culture, alphaB-crystallin overexpression induced luminal filling and other neoplastic-like changes in mammary acini, while silencing alphaB-crystallin by RNA interference inhibited these abnormalities. alphaB-Crystallin overexpression also induced EGF- and anchorage-independent growth, increased cell migration and invasion, and constitutively activated the MAPK kinase/ERK (MEK/ERK) pathway. Moreover, the transformed phenotype conferred by alphaB-crystallin was suppressed by MEK inhibitors. In addition, immortalized human MECs overexpressing alphaB-crystallin formed invasive mammary carcinomas in nude mice that recapitulated aspects of human basal-like breast tumors. Collectively, our results indicate that alphaB-crystallin is a novel oncoprotein expressed in basal-like breast carcinomas that independently predicts shorter survival. Our data also implicate the MEK/ERK pathway as a potential therapeutic target for these tumors.
CONTEXTSelection for trastuzumab therapy depends on a companion diagnostic assessment of HER2 by either immunohistochemistry (IHC) for protein overexpression or fluorescence in situ hybridization ...(FISH) to detect gene amplification. Although many studies have compared IHC to FISH, few have compared the tests to the true gold standard, tumor response. OBJECTIVETo compare HER2 testing by FISH and IHC along with a third immunofluorescence-based assay (automated quantitative analysis-tissue microarray AQUA-TMA) and to assess the value of each test for prediction of response to trastuzumab. DESIGNImmunohistochemistry and FISH assays were done on both whole slides (IHC-WS and FISH-WS) and on TMAs (IHC-TMA and FISH-TMA). AQUA was only done on TMAs (AQUA-TMA). Response was assessed according to modified Response Evaluation Criteria in Solid Tumors. RESULTSAQUA-TMA scores showed a significant linear relationship to both the FISH signal ratio and IHC scores on whole sections and TMAs. Assay assessment by outcome showed no association between response and FISH-WS ratio (P = .96), FISH-TMA (P = .55), IHC-WS (P = .75), or IHC-TMA (P = .06), but a significant relationship between AQUA score and categoric response was observed (P = .01). Assessed as a function of outcome using models of logistic regression, both AQUA-TMA and IHC-TMA were equally significant (P = .01). FISH-WS was the most sensitive assay, with a significantly higher true-positive fraction than all other tests except AQUA-TMA, although it was the least specific. IHC-TMA was the most specific assay. The lowest misclassification rate was achieved using AQUA-TMA (0.30). CONCLUSIONSBoth AQUA-TMA and IHC-TMA were substantially more predictive than the FISH or IHC-WS tests. Although these results are derived from a small retrospective series, they suggest that accurate measurement of protein expression and unbiased selection of tissue for measurement may be key factors in prediction of response.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, OILJ, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK, VSZLJ
The results of practical use of a POS-4 vector magnetometer, developed by the Research Laboratory of Quantum Magnetometry, UrFU (Yekaterinburg) and based on POS Overhauser sensors, are presented. ...Continuous measurements by POS-4 have been carried out at the Paratunka observatory (IKIR FEB RAS, Kamchatka) since 2015, were done at the Saint Petersburg observatory (GC RAS / IZMIRAN SPb Branch, Leningrad Region) in 2017-2018 and have been performed at the Arti observatory (Institute of Geophysics, UB RAS, Sverdlovsk Region) since 2020. On the new high-latitude observatory White Sea (IAGA code WSE, GC RAS / MSU, Nikolai Pertsov White Sea Biological Station , Karelia), POS-4 is used as a main variometer for magnetic measurements. In April 2019, the magnetometer was successfully used for field measurements on ice during the TRANSARCTIC expedition in the Barents Sea (AARI, Roshydromet). At the beginning of 2021 IZMIRAN started testing two POS-4 magnetometers at the Moskow observatory. According to the results of field and observatory measurements it was possible to identify the advantages and disadvantages of the magnetometer and provide the information for its developers for further modernization in order to improve its efficiency and reliability. Many years of experience in POS-4 application determine the areas where its scientific and applied usage will provide important results, for example, for magnetic measurements in the Arctic regions or for monitoring of active zones around volcanoes.
PDF