hMENA11a contributes to HER3-mediated resistance to PI3K inhibitors in HER2-overexpressing breast cancer cells.

Human Mena (hMENA), an actin regulatory protein of the ENA/VASP family, cooperates with ErbB receptor family signaling in breast cancer. It is overexpressed in high-risk preneoplastic lesions and in primary breast tumors where it correlates with HER2 overexpression and an activated status of AKT and MAPK. The concomitant overexpression of hMENA and HER2 in breast cancer patients is indicative of a worse prognosis. hMENA is expressed along with alternatively expressed isoforms, hMENA11a and hMENAΔv6 with opposite functions. A novel role for the epithelial-associated hMENA11a isoform in sustaining HER3 activation and pro-survival pathways in HER2-overexpressing breast cancer cells has been identified by reverse phase protein array and validated in vivo in a series of breast cancer tissues. As HER3 activation is crucial in mechanisms of cell resistance to PI3K inhibitors, we explored whether hMENA11a is involved in these resistance mechanisms. The specific hMENA11a depletion switched off the HER3-related pathway activated by PI3K inhibitors and impaired the nuclear accumulation of HER3 transcription factor FOXO3a induced by PI3K inhibitors, whereas PI3K inhibitors activated hMENA11a phosphorylation and affected its localization. At the functional level, we found that hMENA11a sustains cell proliferation and survival in response to PI3K inhibitor treatment, whereas hMENA11a silencing increases molecules involved in cancer cell apoptosis. As shown in three-dimensional cultures, hMENA11a contributes to resistance to PI3K inhibition because its depletion drastically reduced cell viability upon treatment with PI3K inhibitor BEZ235. Altogether, these results indicate that hMENA11a in HER2-overexpressing breast cancer cells sustains HER3/AKT axis activation and contributes to HER3-mediated resistance mechanisms to PI3K inhibitors. Thus, hMENA11a expression can be proposed as a marker of HER3 activation and resistance to PI3K inhibition therapies, to select patients who may benefit from these combined targeted treatments. hMENA11a activity could represent a new target for antiproliferative therapies in breast cancer

The anticipation, perception of affective touch in women with, recovered from Anorexia Nervosa

Disruptions in reward processing and anhedonia have long been observed in Anorexia Nervosa (AN). Interoceptive deficits have also been observed in AN, including reduced tactile pleasure. However, the extent to which this tactile anhedonia is specifically liked to an impairment in a specialized, interoceptive C-tactile system originating at the periphery, or a more top-down mechanism in the processing of tactile pleasantness remains debated. Here, we investigated differences between patients with and recovered from AN and healthy controls in the perception of pleasantness of touch delivered in a CT-optimal versus a CT-non-optimal manner, and in their top-down, anticipatory beliefs about the perceived pleasantness of touch. To this end, we measured the anticipated pleasantness of various materials touching the skin and the perceived pleasantness of light, dynamic touch applied to theforearmof 27 women with AN, 24 women who have recovered and 30 healthy controls using C Tactile (CT) afferents-optimal (slow) and non-optimal (fast) velocities. Our results showed that both clinical groups anticipated tactile experiences and rated delivered tactile stimuli as less pleasant than healthy controls, but the latter difference was not related to the CT optimality of the stimulation. Instead, differences in the perception of CT-optimal touch were predicted by differences in top-down beliefs, alexithymia and interoceptive sensibility. Thus, tactile anhedonia in AN might persist as a trait even after otherwise successful recovery of AN and it is not linked to a bottom-up interoceptive deficit in the CT system, but rather to a learned, defective top-down anticipation of tactile pleasantness

Observing the corona and inner heliosphere with Parker Solar Probe

The recently launched Parker Solar Probe (PSP) mission is expected to provide unprecedented views of the solar corona and inner heliosphere. In addition to instruments devoted to taking measurements of the local solar wind, the spacecraft carries a visible imager: the Wide-field Imager for Solar PRobe (WISPR). WISPR will take advantage of the proximity of the spacecraft to the Sun to perform local imaging of the near-Sun environment. WISPR will observe coronal structures at high spatial and time resolutions, although the observed plane-of-sky will rapidly change because of the fast transit at the perihelia. We present a concise description of the PSP mission, with particular regard to the WISPR instrument, discussing its main scientific goals, targets of observations, and outlining the possible synergies with current and upcoming space missions

progression free survival pfs benefit from first line endocrine based therapies in postmenopausal women with hr her2 metastatic breast cancer mbc according to different prognostic subgroups a combined analysis of data from paloma 2 monaleesa 2 monarch 3 falcon swog and fact trials

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Clinical significance of PTEN and p-Akt co-expression in HER2-positive metastatic breast cancer patients treated with trastuzumab-based therapies

Objective: The phosphatase and tensine homologue gene (PTEN) plays a crucial role in proliferation and survival of cancer cells by antagonizing the function of phosphatidylinositol 3'-kinase (PI3K), which, in turn, results in decreased Akt activity. We investigated the clinical impact of the expression of PTEN, p-Akt and PI3K in HER2-positive metastatic breast cancer (MBC) patients treated with trastuzumab-based therapies. Methods: Seventy-three patients treated with trastuzumab-based therapies were included and followed prospectively. PTEN, p-Akt and PI3K expression was determined by immunohistochemistry. Results: PTEN, p-Akt and PI3K resulted positive in 48%, 71% and 46.5% of patients, respectively. A significant correlation between PTEN and p-Akt (kappa 0.22, p = 0.03) and p-Akt and PI3K (kappa 0.20, p = 0.05) was observed. PTEN-positive patients had a progression-free survival (PFS) longer than PTEN-negative ones (p = 0.06). When grouped together, patients co-expressing PTEN and p-Akt had a statistically significant longer PFS as compared to the rest of patients (p = 0.01). At the multivariate analysis, PTEN and p-Akt co-expression was an independent predictor of lower risk of progression (hazard ratio 0.53, p = 0.05). Conclusion: In HER2-positive MBC, basal co-expression of PTEN and p-Akt might identify those patients who are more likely to benefit from trastuzumab-based therapies

Toxicity and activity of docetaxel in anthracycline-pretreated breast cancer patients: a phase II study

: Docetaxel has proven effective in advanced breast cancer. Myelosuppression and cumulative fluid retention syndrome are troublesome, potentially avoidable toxicities. In this consecutive cohort study, docetaxel (100 mg/m2 by 1 hour i.v. infusion, q3 weeks) activity and toxicity was explored in 56 anthracycline-pretreated patients (eligible: 55: median age: 51 years [range: 28-68 years]; median performance status: 0 [range: 0-3]) with metastatic breast cancer, using two different granulocyte colony-stimulating factor and steroid pre- and postmedication schedules. Twenty-nine patients (group A) received a 5-day oral prednisone premedication, and 26 (group B) received 4-day low-dose i.m. dexamethasone; group B patients also received prophylactic granulocyte colony-stimulating factor. All patients were evaluable for toxicity and 53 for response. Prophylactic granulocyte colony-stimulating factor significantly lowered the incidence of grade III-IV neutropenia and neutropenic fever (p = 0.0001 and 0.01, respectively). The incidence of moderate-severe fluid retention syndrome was lower in patients receiving i.m. dexamethasone (p = 0.08). Overall response rate was 53% (4 complete responses/24 partial responses, 95% confidence interval 39.4-66.2%); 32% have stable disease and 15% progressive disease. In 21 anthracycline-refractory/resistant patients, as well as in 10 paclitaxel-pretreated patients, the overall response rate was 50%. Docetaxel is highly active in anthracycline- and paclitaxel-pretreated metastatic breast cancer, with manageable toxicity. Optimal use of both granulocyte colony-stimulating factor support and steroid premedication deserves further investigation

Magnetohydrodynamic oscillations in the solar corona and Earth's magnetosphere : towards consolidated understanding

Magnetohydrodynamic (MHD) oscillatory processes in different plasma systems, such as the corona of the Sun and the Earth’s magnetosphere, show interesting similarities and differences, which so far received little attention and remain underexploited. The successful commissioning within the past ten years of THEMIS, Hinode, STEREO and SDO spacecraft, in combination with matured analysis of data from earlier spacecraft (Wind, SOHO, ACE, Cluster, TRACE and RHESSI) makes it very timely to survey the breadth of observations giving evidence for MHD oscillatory processes in solar and space plasmas, and state-of-the-art theoretical modelling. The paper reviews several important topics, such as Alfv´enic resonances and mode conversion; MHD waveguides, such as the magnetotail, coronal loops, coronal streamers; mechanisms for periodicities produced in energy releases during substorms and solar flares, possibility of Alfv´enic resonators along open field lines; possible drivers of MHD waves; diagnostics of plasmas with MHD waves; interaction of MHD waves with partlyionised boundaries (ionosphere and chromosphere). The review is mainly oriented to specialists in magnetospheric physics and solar physics, but not familiar with specifics of the adjacent research fields

Breast cancer and timing of surgery during menstrual cycle: a 5-year analysis of 248 premenopausal women

: In the present report, we retrospectively analyzed the impact of the timing of surgery during menstrual cycle on disease-free and overall survival of 248 premenopausal patients with stage I/II breast cancer who underwent surgery followed by anthracycline-containing adjuvant chemotherapy. With a median follow-up of 5 years, no statistically significant differences were observed in disease-free or overall survival between women operated upon during the follicular (days 0-14) and the luteal (days 15-32) phase of the menstrual cycle. The impact on disease-free and overall survival of lymph-node status, tumor size and hormone receptor expression, but not of the phase of the menstrual cycle at the time of surgery, was confirmed by univariate and multivariate analysis. However, when combined with hormone receptor status, the phase of the menstrual cycle at the time of surgery proved useful to better define the prognosis of primary breast cancer patients, with significantly longer disease-free and overall survival for patients operated upon during the follicular phase and with positive hormone receptors

Multiwavelength Observations of Supersonic Plasma Blob Triggered by Reconnection Generated Velocity Pulse in AR10808

Using multi-wavelength observations of Solar and Heliospheric Observatory (SoHO)/Michelson Doppler Imager (MDI), Transition Region and Coronal Explorer (TRACE) 171 \AA, and H$\alpha$ from Culgoora Solar Observatory at Narrabri, Australia, we present a unique observational signature of a propagating supersonic plasma blob before an M6.2 class solar flare in AR10808 on 9th September 2005. The blob was observed between 05:27 UT to 05:32 UT with almost a constant shape for the first 2-3 minutes, and thereafter it quickly vanished in the corona. The observed lower bound speed of the blob is estimated as $\sim$215 km s$^{-1}$ in its dynamical phase. The evidence of the blob with almost similar shape and velocity concurrent in H$\alpha$ and TRACE 171 \AA\ supports its formation by multi-temperature plasma. The energy release by a recurrent 3-D reconnection process via the separator dome below the magnetic null point, between the emerging flux and pre-existing field lines in the lower solar atmosphere, is found to be the driver of a radial velocity pulse outwards that accelerates this plasma blob in the solar atmosphere. In support of identification of the possible driver of the observed eruption, we solve the two-dimensional ideal magnetohydrodynamic equations numerically to simulate the observed supersonic plasma blob. The numerical modelling closely match the observed velocity, evolution of multi-temperature plasma, and quick vanishing of the blob found in the observations. Under typical coronal conditions, such blobs may also carry an energy flux of 7.0$\times10^{6}$ ergs cm$^{-2}$ s$^{-1}$ to re-balance the coronal losses above active regions.Comment: Solar Physics; 22 Pages; 8 Figure

Genetic variation in the myeloperoxidase gene and cognitive impairment in Multiple Sclerosis

There is evidence that multiple sclerosis (MS) may associated with cognitive impairment in 25 to 40% of cases. The gene encoding myeloperoxidase (MPO) is involved in molecular pathways leading to β-amyloid deposition. We investigated a functional biallelic (G/A) polymorphism in the promoter region (-463) of the MPO gene in 465 patients affected by MS, divided into 204 cognitively normal and 261 impaired. We did not find significant differences in allele or genotype distributions between impaired and preserved MS patients. Our findings suggest that MPO polymorphism is not a risk factor for cognitive impairment in MS