Breast cancer specific survival in Kaplan-Meier univariate analysis according to the expression levels of presenilins.

<p>Low (N = 28) and high (N = 27) mRNA levels of PS1 (A and B) and low (N = 32) and high (N = 23) mRNA levels of PS2 (C and D) at 5 years (A and C) and the whole follow-up time (B and D).</p

γ-Secretase Components as Predictors of Breast Cancer Outcome

<div><p>γ-secretase is a large ubiquitously expressed protease complex composed of four core subunits: presenilin, Aph1, PEN-2, and nicastrin. The function of γ-secretase in the cells is to proteolytically cleave various proteins within their transmembrane domains. Presenilin and Aph1 occur as alternative variants belonging to mutually exclusive γ-secretase complexes and providing the complexes with heterogeneous biochemical and physiological properties. γ-secretase is proposed to have a role in the development and progression of cancer and γ-secretase inhibitors are intensively studied for their probable anti-tumor effects in various types of cancer models. Here, we for the first time determined mRNA expression levels of presenilin-1, presenilin-2, Aph1a, Aph1b, PEN-2, and nicastrin in a set of breast cancer tissue samples (N = 55) by quantitative real-time PCR in order to clarify the clinical significance of the expression of different γ-secretase complex components in breast cancer. We found a high positive correlation between the subunit expression levels implying a common regulation of transcription. Our univariate Kaplan-Meier survival analyses established low expression level of γ-secretase complex as a risk factor for breast cancer specific mortality. The tumors expressing low levels of γ-secretase complex were characterized by high histopathological tumor grade, low or no expression of estrogen and progesterone receptors and consequently high probability to fall into the class of triple negative breast cancer tumors. These results may provide novel tools to further categorize breast cancer tumors, especially the highly aggressive and poorly treatable breast cancer type of triple negative cases, and suggest a significant role for γ-secretase in breast cancer.</p> </div

Breast cancer specific survival in Kaplan-Meier univariate analysis according to the expression levels of Aph1 variants.

<p>Low (N = 34) and high (N = 21) mRNA levels of Aph1a (A and B) and low (N = 34) and high (N = 21) mRNA levels of Aph1b (C and D) at 5 years (A and C) and the whole follow-up time (B and D).</p

Breast cancer specific survival in Kaplan-Meier univariate analysis according to the expression levels of PEN-2 and nicastrin.

<p>Low (N = 33) and high (N = 22) mRNA levels of PEN-2 (A and B) and low (N = 33) and high (N = 21) mRNA expression levels of NCT (C and D) at 5 years (A and C) and the whole follow-up time (B and D).</p

Rodent β-amyloid (Aβ) staining following cortical photothrombosis.

<p>Digital photomicrographs showed atypical, Aβ deposits in the thalamus ipsilateral to the cortical lesion (<b>A–D</b>). The inserts <b>A1–D1</b> at higher magnification are taken from the same brain sections. The genotype had a significant effect on rodent Aβ load (two-way ANOVA, <i>P</i><0.05) being more pronounced in non-transgenic mice (<b>E</b>). Values are presented as mean±s.e.m. Scale bar: 500 µm (<b>A–D</b>), 20 µm (<b>A1–D1</b>).</p

Rose Bengal induced cortical photothrombosis.

<p>(<b>A</b>) The cold light was positioned to illuminate the skull 2.4 mm right from Bregma. (<b>B</b>) Nissl-stained sections show a typical photothrombotic lesion in the right sensorimotor cortex (arrows). (<b>C</b>) The genotype had a significant effect on lesion size (two-way ANOVA, <i>P</i><0.05) with smaller lesions in transgenic mice. Values are presented as mean±s.e.m. Scale bar: 1 mm (<b>B</b>).</p

Confirmation of the transgenic Aβ phenotype.

<p>Human specific W0-2 staining against Aβ showed a relative high staining intensity in transgenic mice due to intracellular Aβ typical to young transgenic animals (A). A few plaques were observed (arrows). Only some non-specific staining was observed in non-transgenic mice due to degenerative processes (<b>B</b>). Scale bar: 400 µm.</p

Calcium staining (Alizarin Red) following cortical photothrombosis.

<p>Digital photomicrographs showed atypical, calcium deposits in the thalamus ipsilateral to the cortical lesion (<b>A–D</b>). The inserts <b>A1–D1</b> at higher magnification are taken from the same brain sections. Treatment had a significant effect on calcium accumulation (two-way ANOVA, <i>P</i><0.001) (<b>E</b>). Values are presented as mean±s.e.m. Scale bar: 500 µm (<b>A–D</b>), 20 µm (<b>A1–D1</b>).</p

Cellular localization of rodent Aβ deposits in the thalamus following cortical photothrombosis.

<p>Double immunofluorescence staining for rodent Aβ and NeuN <b>(A)</b> or rodent Aβ and GFAP <b>(B)</b> did not show co-localization in AD transgenic mice (arrows).</p

Behavioral testing of mice exposed to intermediate frequency magnetic fields indicates mild memory impairment

<div><p>Human exposure to intermediate frequency magnetic fields (MF) is increasing due to applications like electronic article surveillance systems and induction heating cooking hobs. However, limited data is available on their possible health effects. The present study assessed behavioral and histopathological consequences of exposing mice to 7.5 kHz MF at 12 or 120 μT for 5 weeks. No effects were observed on body weight, spontaneous activity, motor coordination, level of anxiety or aggression. In the Morris swim task, mice in the 120 μT group showed less steep learning curve than the other groups, but did not differ from controls in their search bias in the probe test. The passive avoidance task indicated a clear impairment of memory over 48 h in the 120 μT group. No effects on astroglial activation or neurogenesis were observed in the hippocampus. The mRNA expression of brain-derived neurotrophic factor did not change but expression of the proinflammatory cytokine tumor necrosis factor alpha mRNA was significantly increased in the 120 μT group. These findings suggest that 7.5 kHz MF exposure may lead to mild learning and memory impairment, possibly through an inflammatory reaction in the hippocampus.</p></div