Prolyl Isomerase Pin1 is Highly Expressed in Her2-Positive Breast Cancer and Regulates erbB2 Protein Stability

Overexpression of HER-2/Neu occurs in about 25–30% of breast cancer patients and is indicative of poor prognosis. While Her2/Neu overexpression is primarily a result of erbB2 amplification, it has recently been recognized that erbB2 levels are also regulated on the protein level. However, factors that regulate Her2/Neu protein stability are less well understood. The prolyl isomerase Pin1 catalyzes the isomerization of specific pSer/Thr-Pro motifs that have been phosphorylated in response to mitogenic signaling. We have previously reported that Pin1-catalyzed postphosphorylational modification of signal transduction modulates the oncogenic pathways downstream from c-neu. The goal of this study was to examine the expression of prolyl isomerase Pin1 in human Her2+ breast cancer, and to study if Pin1 affects the expression of Her2/Neu itself. Methods: Immunohistochemistry for Her2 and Pin1 were performed on two hundred twentythree human breast cancers, with 59% of the specimen from primary cancers and 41% from metastatic sites. Pin1 inhibition was achieved using siRNA in Her2+ breast cancer cell lines, and its effects were studied using cell viability assays, immunoblotting and immunofluorescence. Results: Sixty-four samples (28.7%) stained positive for Her2 (IHC 3+), and 54% (122/223) of all breast cancers stained positive for Pin1. Of the Her2-positive cancers 40 (62.5%) were also Pin1-positive, based on strong nuclear or nuclear and cytoplasmic staining. Inhibition of Pin1 via RNAi resulted in significant suppression of Her2-positive tumor cell growth in BT474, SKBR3 and AU565 cells. Pin1 inhibition greatly increased the sensitivity of Her2-positive breast cancer cells to the mTOR inhibitor Rapamycin, while it did not increase their sensitivity to Trastuzumab, suggesting that Pin1 might act on Her2 signaling. We found that Pin1 interacted with the protein complex that contains ubiquitinated erbB2 and that Pin1 inhibition accelerated erbB2 degradation, which could be prevented by treatments with the proteasome inhibitor ALLnL. Conclusion: Pin1 is a novel regulator of erbB2 that modulates the ubiquitin-mediated degradation of erbB2. The overexpression of Pin1 in a majority of Her2-overexpressing breast cancer may contribute to maintain erbB2 levels. Pin1 inhibition alone and in conjunction with mTOR inhibition suppresses the growth of Her2+ breast cancer cells

Prolyl isomerase Pin1 is highly expressed in Her2-positive breast cancer and regulates erbB2 protein stability

Overexpression of HER-2/Neu occurs in about 25–30% of breast cancer patients and is indicative of poor prognosis. While Her2/Neu overexpression is primarily a result of erbB2 amplification, it has recently been recognized that erbB2 levels are also regulated on the protein level. However, factors that regulate Her2/Neu protein stability are less well understood. The prolyl isomerase Pin1 catalyzes the isomerization of specific pSer/Thr-Pro motifs that have been phosphorylated in response to mitogenic signaling. We have previously reported that Pin1-catalyzed post-phosphorylational modification of signal transduction modulates the oncogenic pathways downstream from c-neu. The goal of this study was to examine the expression of prolyl isomerase Pin1 in human Her2+ breast cancer, and to study if Pin1 affects the expression of Her2/Neu itself

Inverse association between cancer and Alzheimer’s disease: results from the Framingham Heart Study

Objectives: To relate cancer since entry into the Framingham Heart Study with the risk of incident Alzheimer’s disease and to estimate the risk of incident cancer among participants with and without Alzheimer’s disease. Design: Community based prospective cohort study; nested age and sex matched case-control study. Setting: Framingham Heart Study, USA. Participants: 1278 participants with and without a history of cancer who were aged 65 or more and free of dementia at baseline (1986-90). Main outcome measures Hazard ratios and 95% confidence intervals for the risks of Alzheimer’s disease and cancer. Results: Over a mean follow-up of 10 years, 221 cases of probable Alzheimer’s disease were diagnosed. Cancer survivors had a lower risk of probable Alzheimer’s disease (hazard ratio 0.67, 95% confidence interval 0.47 to 0.97), adjusted for age, sex, and smoking. The risk was lower among survivors of smoking related cancers (0.26, 0.08 to 0.82) than among survivors of non-smoking related cancers (0.82, 0.57 to 1.19). In contrast with their decreased risk of Alzheimer’s disease, survivors of smoking related cancer had a substantially increased risk of stroke (2.18, 1.29 to 3.68). In the nested case-control analysis, participants with probable Alzheimer’s disease had a lower risk of subsequent cancer (0.39, 0.26 to 0.58) than reference participants, as did participants with any Alzheimer’s disease (0.38) and any dementia (0.44). Conclusions: Cancer survivors had a lower risk of Alzheimer’s disease than those without cancer, and patients with Alzheimer’s disease had a lower risk of incident cancer. The risk of Alzheimer’s disease was lowest in survivors of smoking related cancers, and was not primarily explained by survival bias. This pattern for cancer is similar to that seen in Parkinson’s disease and suggests an inverse association between cancer and neurodegeneration

Development of Shanghai satellite laser ranging station

The topics covered include the following: improvement of the system hardware; upgrading of the software; the observation status; preliminary daylight tracking capability; testing the new type of laser; and future plans

Cis P-tau is induced in clinical and preclinical brain injury and contributes to post-injury sequelae

Traumatic brain injury (TBI) is characterized by acute neurological dysfunction and asso- ciated with the development of chronic traumatic encephalopathy (CTE) and Alzheimer’s disease. We previously showed that cis phosphorylated tau (cis P-tau), but not the trans form, contributes to tau pathology and functional impairment in an animal model of severe TBI. Here we found that in human samples obtained post TBI due to a variety of causes, cis P-tau is induced in cortical axons and cerebrospinal fluid and positively correlates with axonal injury and clinical outcome. Using mouse models of severe or repetitive TBI, we showed that cis P-tau elimination with a specific neutralizing antibody administered immediately or at delayed time points after injury, attenuates the development of neuropathology and brain dysfunction during acute and chronic phases including CTE-like pathology and dysfunction after repetitive TBI. Thus, cis P-tau contributes to short-term and long-term sequelae after TBI, but is effectively neutralized by cis antibody treatment

First observation of the M1 transition ψ(3686)→γηc(2S)\psi(3686)\to \gamma\eta_c(2S)

Using a sample of 106 million \psi(3686) events collected with the BESIII detector at the BEPCII storage ring, we have made the first measurement of the M1 transition between the radially excited charmonium S-wave spin-triplet and the radially excited S-wave spin-singlet states: \psi(3686)\to\gamma\eta_c(2S). Analyses of the processes \psi(2S)\to \gamma\eta_c(2S) with \eta_c(2S)\to \K_S^0 K\pi and K^+K^-\pi^0 gave an \eta_c(2S) signal with a statistical significance of greater than 10 standard deviations under a wide range of assumptions about the signal and background properties. The data are used to obtain measurements of the \eta_c(2S) mass (M(\eta_c(2S))=3637.6\pm 2.9_\mathrm{stat}\pm 1.6_\mathrm{sys} MeV/c^2), width (\Gamma(\eta_c(2S))=16.9\pm 6.4_\mathrm{stat}\pm 4.8_\mathrm{sys} MeV), and the product branching fraction (\BR(\psi(3686)\to \gamma\eta_c(2S))\times \BR(\eta_c(2S)\to K\bar K\pi) = (1.30\pm 0.20_\mathrm{stat}\pm 0.30_\mathrm{sys})\times 10^{-5}). Combining our result with a BaBar measurement of \BR(\eta_c(2S)\to K\bar K \pi), we find the branching fraction of the M1 transition to be \BR(\psi(3686)\to\gamma\eta_c(2S)) = (6.8\pm 1.1_\mathrm{stat}\pm 4.5_\mathrm{sys})\times 10^{-4}.Comment: 7 pages, 1 figure, 1 tabl

Study of J/ψ→ppˉJ/\psi\to p\bar{p} and J/ψ→nnˉJ/\psi\to n\bar{n}

The decays $J/\psi\to p\bar{p}$ and $J/\psi\to n\bar{n}$ have been investigated with a sample of 225.2 million $J/\psi$ events collected with the BESIII detector at the BEPCII $e^+e^-$ collider. The branching fractions are determined to be $\mathcal{B}(J/\psi\to p\bar{p})=(2.112\pm0.004\pm0.031)\times10^{-3}$ and $\mathcal{B}(J/\psi\to n\bar{n})=(2.07\pm0.01\pm0.17)\times10^{-3}$. Distributions of the angle $\theta$ between the proton or anti-neutron and the beam direction are well described by the form $1+\alpha\cos^2\theta$, and we find $\alpha=0.595\pm0.012\pm0.015$ for $J/\psi\to p\bar{p}$ and $\alpha=0.50\pm0.04\pm0.21$ for $J/\psi\to n\bar{n}$. Our branching-fraction results suggest a large phase angle between the strong and electromagnetic amplitudes describing the $J/\psi\to N\bar{N}$ decay.Comment: 16 pages, 13 figures, the 2nd version, submitted to PR

Observation of the exceptional-point-enhanced Sagnac effect

Exceptional points (EPs) are special spectral degeneracies of non-Hermitian Hamiltonians that govern the dynamics of open systems. At an EP, two or more eigenvalues, and the corresponding eigenstates, coalesce. Recently, it was predicted that operation of an optical gyroscope near an EP results in improved response to rotations. However, the performance of such a system has not been examined experimentally. Here we introduce a precisely controllable physical system for the study of non-Hermitian physics and nonlinear optics in high-quality-factor microresonators. Because this system dissipatively couples counter-propagating lightwaves within the resonator, it also functions as a sensitive gyroscope for the measurement of rotations. We use our system to investigate the predicted EP-enhanced Sagnac effect and observe a four-fold increase in the Sagnac scale factor by directly measuring rotations applied to the resonator. The level of enhancement can be controlled by adjusting the system bias relative to the EP, and modelling results confirm the observed enhancement. Moreover, we characterize the sensitivity of the gyroscope near the EP. Besides verifying EP physics, this work is important for the understanding of optical gyroscopes