Predictors of primary breast cancers responsiveness to preoperative Epirubicin/Cyclophosphamide-based chemotherapy: translation of microarray data into clinically useful predictive signatures

BACKGROUND: Our goal was to identify gene signatures predictive of response to preoperative systemic chemotherapy (PST) with epirubicin/cyclophosphamide (EC) in patients with primary breast cancer. METHODS: Needle biopsies were obtained pre-treatment from 83 patients with breast cancer and mRNA was profiled on Affymetrix HG-U133A arrays. Response ranged from pathologically confirmed complete remission (pCR), to partial remission (PR), to stable or progressive disease, "No Change" (NC). A primary analysis was performed in breast tissue samples from 56 patients and 5 normal healthy individuals as a training cohort for predictive marker identification. Gene signatures identifying individuals most likely to respond completely to PST-EC were extracted by combining several statistical methods and filtering criteria. In order to optimize prediction of non responding tumors Student's t-test and Wilcoxon test were also applied. An independent cohort of 27 patients was used to challenge the predictive signatures. A k-Nearest neighbor algorithm as well as two independent linear partial least squares determinant analysis (PLS-DA) models based on the training cohort were selected for classification of the test samples. The average specificity of these predictions was greater than 74% for pCR, 100% for PR and greater than 62% for NC. All three classification models could identify all pCR cases. RESULTS: The differential expression of 59 genes in the training and the test cohort demonstrated capability to predict response to PST-EC treatment. Based on the training cohort a classifier was constructed following a decision tree. First, a transcriptional profile capable to distinguish cancerous from normal tissue was identified. Then, a "favorable outcome signature" (31 genes) and a "poor outcome signature" (26 genes) were extracted from the cancer specific signatures. This stepwise implementation could predict pCR and distinguish between NC and PR in a subsequent set of patients. Both PLS-DA models were implemented to discriminate all three response classes in one step. CONCLUSION: In this study signatures were identified capable to predict clinical outcome in an independent set of primary breast cancer patients undergoing PST-EC

Geosciences / Miocene Slănic Tuff, Eastern Carpathians, Romania, in the context of Badenian salinity crisis

New geochronological investigations for the Slănic Formation, correlated with previous bio- and lithostratigaphical information, allow for a better succession of events for the Middle Miocene, including the absolute age of the Badenian salinity crisis in the bend sector of the Eastern Carpathians. Within the green Slănic Tuff, white tuff layers were in evidence. The main element distribution of the white and green tuffs indicates a dacitic composition, with higher SiO2 content for the white tuff. The white tuff has a distinct mineralogical composition with quartz, plagioclase, biotite and clinoptilolite. From such a tuff layer a biotite concentrate gives a 40Ar/39Ar age of 13.7 0.2 Ma. As above these tuff layers discrete levels of gypsum occur, the age documents the beginning of the restrictive circulation and formation of evaporites in this sector of Carpathians during Badenian times.(VLID)251000

Complete Clinical Remission of Stage IV Triple-Negative Breast Cancer Lung Metastasis Administering Low-Dose Immune Checkpoint Blockade in Combination With Hyperthermia and Interleukin-2

The prognosis of triple-negative breast cancer with metastases after chemotherapy remains dismal. We report the case of a 50-year-old female with first disease recurrence at the axillary lymph node and, later on, bilateral pulmonary metastases with severe shortness of breath. The patient received low-dose immune checkpoint blockade (concurrent nivolumab and ipilimumab) weekly over 3 weeks with regional hyperthermia 3 times a week, followed by systemic fever-range hyperthermia induced by interleukin-2 for 5 days. She went into complete remission of her pulmonary metastases with transient WHO I-II diarrhea and skin rash. The patient remained alive for 27 months after the start of treatment, with recurrence of metastases as a sternal mass, and up to 3 cm pleural metastases. This exceptional response should instigate further research efforts with this protocol, which consists only of approved drugs and treatments

Gene expression in acute Stanford type A dissection: a comparative microarray study

BACKGROUND: We compared gene expression profiles in acutely dissected aorta with those in normal control aorta. MATERIALS AND METHODS: Ascending aorta specimen from patients with an acute Stanford A-dissection were taken during surgery and compared with those from normal ascending aorta from multiorgan donors using the BD Atlas™ Human1.2 Array I, BD Atlas™ Human Cardiovascular Array and the Affymetrix HG-U133A GeneChip(®). For analysis only genes with strong signals of more than 70 percent of the mean signal of all spots on the array were accepted as being expressed. Quantitative real-time polymerase chain reaction (RT-PCR) was used to confirm regulation of expression of a subset of 24 genes known to be involved in aortic structure and function. RESULTS: According to our definition expression profiling of aorta tissue specimens revealed an expression of 19.1% to 23.5% of the genes listed on the arrays. Of those 15.7% to 28.9% were differently expressed in dissected and control aorta specimens. Several genes that encode for extracellular matrix components such as collagen IV α2 and -α5, collagen VI α3, collagen XIV α1, collagen XVIII α1 and elastin were down-regulated in aortic dissection, whereas levels of matrix metalloproteinases-11, -14 and -19 were increased. Some genes coding for cell to cell adhesion, cell to matrix signaling (e.g., polycystin1 and -2), cytoskeleton, as well as several myofibrillar genes (e.g., α-actinin, tropomyosin, gelsolin) were found to be down-regulated. Not surprisingly, some genes associated with chronic inflammation such as interleukin -2, -6 and -8, were up-regulated in dissection. CONCLUSION: Our results demonstrate the complexity of the dissecting process on a molecular level. Genes coding for the integrity and strength of the aortic wall were down-regulated whereas components of inflammatory response were up-regulated. Altered patterns of gene expression indicate a pre-existing structural failure, which is probably a consequence of insufficient remodeling of the aortic wall resulting in further aortic dissection

Preanalytical variables and performance of diagnostic RNA-based gene expression analysis in breast cancer

Prognostic multigene expression assays have become widely available to provide additional information to standard clinical parameters and to support clinicians in treatment decisions. In this study, we analyzed the impact of variations in tissue handling on the diagnostic EndoPredict test results. EndoPredict is a quantitative reverse transcription PCR assay conducted on RNA from formalin-fixed, paraffin-embedded (FFPE) tissue that predicts the likelihood of distant recurrence in patients with ER-positive/HER2-negative breast cancer. In this study, we performed a total of 138 EndoPredict assays to study the effects of preanalytical variables such as time to fixation, fixation time, tumor cell content, and section storage time on the EndoPredict test results. A time to fixation of up to 12 h and fixation of up to 5 days did not affect the results of the gene expression test. Paired samples of FFPE sections with tumor cell content ranging from 15 to 95 % and tumor-enriched samples showed a correlation coefficient of 0.97. Test results of tissue sections that have been stored for 12 months at +4 or +20 °C showed a correlation of 0.99 when compared to results of nonstored sections. In conclusion, preanalytical tissue handling is not a critical factor for diagnostic gene expression analysis with the EndoPredict assay. The test can therefore be easily integrated into the standard workflow of molecular pathology

Multiple isotope tracers from Permian-Triassic hydrated sulfates: Implications for fluid-mineral interaction

Isotopic compositions of water of crystallization and sulfate anionic group in gypsum and polyhalite were used as tracers for events related to their formation and subsequent evolution, as for example origin of crystallization water and extent of thermal overprint. For this purpose, gypsum and polyhalite from the Permo-Triassic evaporites of the Eastern Alps, were analysed for isotope composition of sulfate anionic group (δ34S and δ18OSO4) and water of crystallization (δD and δ18O). For comparison, water of crystallisation of polyhalite samples of similar age from New Mexico (USA), Kłodawa (Poland) and Hattberg, Hesse (Germany) were also investigated. Estimated δ18O and δD values of polyhalite formation brines vary from 14.4 to 3.4‰ and 42.5 to −6.1‰, respectively. Gypsum formation brines show different δ18O and δD values, from −5.7 to −15‰ and −30.9 to −88.8‰, respectively. The measured δ18OSO4 values of sulfate group are compatible with a thermal overprint at 100°–200°C for both minerals. The thermal overprint documented for the Eastern Alps led to gypsum but not to polyhalite dehydration. The isotopic composition of water of crystallization suggests that polyhalite is preserving the isotopic signature of an enriched brine. During a subsequent event, anhydrite rehydrated to gypsum, with the isotopic composition of water of crystallisation indicating lower (δD and δ18O) values than the present-day meteoric water ones. Due to their distinct mineral structure and, as a result, different temperature of dehydratation, gypsum and polyhalite record different histories following precipitation in an evaporative system

Ecophysiology of the hydrothermal vent snail Ifremeria nautilei and barnacle Eochionelasmus ohtai manusensis , Manus Basin, Papua New Guinea: Insights from shell mineralogy and stable isotope geochemistry

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Abbott monoclonal enzyme immunoassay measurement of estrogen receptors in human breast cancer: A European multicenter study

SCOPUS: ar.jinfo:eu-repo/semantics/publishe