The mechanism of resistance to human epidermal growth factor receptor 2 (HER2)-targeted agents has not been fully understood. We investigated the influence of PIK3CA mutations on sensitivity to ...HER2-targeted agents in naturally derived breast cancer cells.
We examined the effects of Calbiochem (CL)-387,785, HER2 tyrosine kinase inhibitor, and trastuzumab on cell growth and HER2 signaling in eight breast cancer cell lines showing HER2 amplification and trastuzumab-conditioned BT474 (BT474-TR).
Four cell lines with PIK3CA mutations (E545K and H1047R) were more resistant to trastuzumab than the remaining four without mutations (mean percentage of control with 10 μg/ml trastuzumab: 58% versus 92%; P=0.010). While PIK3CA-mutant cells were more resistant to CL-387,785 than PIK3CA-wild-type cells (mean percentage of control with 1μm CL-387,785: 21% versus 77%; P=0.001), CL-387,785 retained activity against BT474-TR. Growth inhibition by trastuzumab and CL-387,785 was more closely correlated with changes in phosphorylation of S6K (correlation coefficient, 0.811) than those of HER2, Akt, or ERK1/2. Growth of most HER2-amplified cells was inhibited by LY294002, regardless of PIK3CA genotype.
Conclusions:PIK3CA mutations are associated with resistance to HER2-targeted agents. PI3K inhibitors are potentially effective in overcoming trastuzumab resistance caused by PIK3CA mutations. S6K phosphorylation is a possibly useful pharmacodynamic marker in HER2-targeted therapy.
An optical cavity consisting of optically trapped mirrors makes a resonant bar that can be stiffer than diamond. A limitation of the stiffness arises in the length of the optical bar as a consequence ...of the finite light speed. High laser power and light mass mirrors are essential for realization of a long and stiff optical bar that can be useful for example in the gravitational-wave detector aiming at the observation of a signal from neutron-star collisions, supernovae, etc. In this letter, we introduce a parametric signal amplification scheme that realizes the long and stiff optical bar with a non-linear crystal inside the signal-recycling cavity.
•A stiff optical spring bar is a way to detect gravitational waves at high frequencies.•A parametric amplification technique realizes the stiff optical bar without increasing the circulating laser power.•This letter introduces our theoretical work on a new interferometric configuration with the parametric amplifier.
Summary
Background
Dupilumab, a human monoclonal antibody, blocks the shared receptor unit for interleukin‐4 and interleukin‐13. International phase II and III studies have evaluated the efficacy and ...safety of dupilumab in adults with moderate‐to‐severe atopic dermatitis (AD), but the effects of dupilumab in Japanese patients have not been reported.
Objectives
To evaluate the efficacy and safety of dupilumab in Japanese patients with moderate‐to‐severe AD.
Methods
We analysed the efficacy and safety of dupilumab in the Japanese cohorts of a 16‐week, phase IIb dose‐finding trial (AD‐1021; NCT01859988); a 16‐week, phase III, placebo‐controlled monotherapy trial (LIBERTY AD SOLO 1; NCT02277743) and a 52‐week, phase III, placebo‐controlled study of dupilumab with topical corticosteroids (LIBERTY AD CHRONOS; NCT02260986).
Results
Twenty‐seven, 106 and 117 Japanese patients were enrolled in AD‐1021, SOLO 1 and CHRONOS, respectively. Baseline disease severity was numerically higher in the Japanese cohort than in the overall study population. Generally, dupilumab significantly improved signs and symptoms of AD, including pruritus and patient quality of life, compared with placebo in the Japanese cohort, consistent with the overall study population. The combined safety profile of dupilumab in the Japanese cohort was similar to that in the total study populations; dupilumab was associated with an increased incidence of injection‐site reactions and conjunctivitis compared with placebo. Dupilumab was associated with rapid reduction in thymus and activation‐regulated chemokine and gradual IgE reductions.
Conclusions
Dupilumab alone or with topical corticosteroids improved signs and symptoms of AD, had an acceptable safety profile, and suppressed biomarkers of type 2 inflammation compared with placebo in Japanese adult patients with moderate‐to‐severe AD.
What's already known about this topic?
Differences in atopic dermatitis (AD) pathology have been reported between Asian and Western populations, in which distinct helper T‐cell activation profiles have been observed.
International clinical studies in adults with moderate‐to‐severe AD have evaluated the efficacy and safety of dupilumab, which blocks interleukin‐4 and interleukin‐13, key molecules in type 2 inflammation.
The effects of dupilumab in Japanese patients specifically have not yet been reported.
What does this study add?
Dupilumab alone or with topical corticosteroids improved signs and symptoms of AD and had an acceptable safety profile compared with placebo in Japanese patients with moderate‐to‐severe AD.
The effects were comparable with those observed in the overall study population.
Reported immunological differences in AD pathology in Asian patients may be secondary to type 2 immune activation.
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Abstract Photo-functionalized radical reactions on TiO2 have been correlated with adsorption of organic impurities and decreasing hydrophilicity of titanium-based biomaterials. Such reactive oxygen ...species (ROS) spontaneously generated on oxidized titanium surfaces may also have important roles against time-dependent degradation of biological ability and adherent micro-organisms. This study examined in vitro biological ability as a function of time and antimicrobial activity on oxidized titanium surfaces without photo-functionalization. Mechanically polished titanium and thermally oxidized titanium surfaces that had been stored for 4 wks showed adsorbed organic impurities with decreased surface hydrophilicity. Even after the storage period, anodically oxidized titanium surfaces enabled super-hydrophilicity without adsorption of organic impurities, because of the ROS and the hydrophilic functional groups generated on the surfaces. The osteogenic gene expressions of osteoblasts cultured on anodically oxidized titanium surfaces with or without storage were significantly higher than those on thermally oxidized titanium and polished titanium surfaces. Titanium surfaces anodically oxidized in a solution with chloride achieved antimicrobial activity against an oral microorganism due to the amount of ROS generated on the surface. Thus, titanium anodically oxidized in solution with chloride may have potential use for titanium-based internal fixation devices.
To investigate the role of multiparametric magnetic resonance (MR) imaging in the evaluation of response to platinum-based neoadjuvant chemotherapy in advanced ovarian cancer and to compare imaging ...parameters between primary ovarian mass and metastatic disease.
Evaluable patients suspected of having advanced ovarian carcinoma were enrolled in a prospective protocol-driven study. Research ethics committee approval and written informed consent were obtained. Multiparametric MR imaging (diffusion-weighted MR imaging, dynamic contrast material-enhanced DCE MR imaging, and hydrogen 1 MR spectroscopy) was performed with a 3.0-T wholebody MR imaging system. Three marker lesions-primary ovarian mass, omental cake, and peritoneal deposit-were outlined by a radiologist on apparent diffusion coefficient (ADC) and vascular signal fraction (VSF) maps and on DCE MR images. Comparisons of mean ADC, mean VSF, DCE MR imaging parameters, and choline concentration between responders and nonresponders were based on Response Evaluation Criteria in Solid Tumors and CA-125 criteria.
Twenty-two patients were evaluable. The mean ADC for peritoneal metastases was lower than that for ovarian (P = .015) and omental (P = .006) sites. There were no differences in pretreatment DCE MR imaging parameters between tumor sites. After treatment, responders showed a significantly larger increase in ADC (P = .021) and fractional volume of the extravascular extracellular space (v(e)) (P = .025) of ovarian lesions compared with nonresponders, but there was no change in ADC at other sites. Pre- and posttreatment values of choline concentration of ovarian lesions were lower in responders (P = .025) than in nonresponders (P = .010).
The significant differences in baseline ADCs among primary ovarian cancer, omental cake, and peritoneal deposits indicate that diffusivity profiles may be tumor-site dependent, suggesting biologic heterogeneity of disease. ADC and v(e) parameters correlated with the cytotoxic effects of platinum-based therapy and may be useful response markers, while choline concentration predicted but did not reflect response.
In this paper, a new nodal loading model for use in voltage stability assessment of electric power systems is proposed, and the formulation of worst cases based on this model, as well as related ...numerical methods, are described. In this nodal loading model, called the "hyper-cone" model, a set of future operating points in a load parameter space is modeled. That is, the "vertex" of the hyper-cone is taken to be the current operating point, and the "thickness" of the hyper-cone represents the uncertainty of future loading. The worst loading case is the point, among the set of transfer limit points on or within the hyper-cone, at which the total load is smallest. In other words, in terms of the uncertainty of future loading, the worst case corresponds to the most conservative transfer limit. Efficient numerical methods to compute this worst case are shown, and these methods are demonstrated on some sample power systems including IEEE 118-node system.
The impact of baseline coronary plaque burden on the clinical outcome in patients receiving aggressive low-density lipoprotein cholesterol (LDL-C) lowering therapy to levels <70 mg/dL is unknown. We ...assessed the prognostic significance of baseline coronary plaque burden following high-intensity statin therapy.
SATURN used serial intravascular ultrasound (IVUS) to measure coronary atheroma volume in 1039 patients before and after 24 months of treatment with rosuvastatin 40 mg or atorvastatin 80 mg. This post hoc analysis compared the relationship between baseline percent atheroma volume (PAV) and major adverse cardiovascular events (MACE: death, myocardial infarction, stroke, coronary revascularization, hospitalization for unstable angina) in patients with baseline PAV less than (n = 519) or greater than (n = 520) the median. Patients with a higher baseline PAV had a similar LDL-C compared with those with a lower baseline PAV at baseline (119.0 ± 29 vs. 121.0 ± 27 mg/dL, P = 0.09) and at follow-up (65.3 ± 23 vs. 65.8 ± 22 mg/dL, P = 0.47). In multivariable analysis, each standard deviation increase in baseline PAV was associated with a 28% increase in MACE HR 1.28 (1.05, 1.57), P = 0.01. Those with the highest quartile of baseline PAV (>41.8%) had a 2-year cumulative MACE rate of 12%, which was significantly higher (log-rank P = 0.001) than MACE rates of all lower PAV quartiles (MACE: quartile 3, 2, and 1 were 5.7, 7.9, and 5.1%, respectively). LDL-C levels at baseline HR 0.96 (0.79, 1.18), P = 0.73 and on-treatment HR 1.19 (0.83, 1.73), P = 0.35 were not associated with MACE.
Following 2 years of high-intensity statin therapy, a baseline coronary atheroma volume predicted MACE, despite the achievement of very low on-treatment LDL-C levels.
To evaluate the effect of long-term maximally intensive statin therapy on indices of coronary atheroma composition in a randomized trial, and how these changes relate to modifications of serum ...lipoproteins and systemic inflammation.
The Study of coronary Atheroma by inTravascular Ultrasound: the effect of Rosuvastatin vs. atorvastatiN (SATURN) employed serial intravascular ultrasound (IVUS) measures of coronary atheroma in patients treated with rosuvastatin 40 mg or atorvastatin 80 mg daily for 24 months. Seventy-one patients underwent serial assessment of indices of plaque composition by spectral analysis of the radiofrequency IVUS signal. Changes in low-density lipoprotein cholesterol LDL-C; -52 (-72, -33) mg/dL, P < 0.001, C-reactive protein CRP -0.2 (-1, 0.1) mg/L, P = 0.01, and high-density lipoprotein cholesterol HDL-C; +2.8 (-0.3, 7.8) mg/dL, P < 0.001 were associated with regression of percent atheroma volume (PAV: -1.6 ± 3.6%, P < 0.001). A reduction in estimated fibro-fatty tissue volume accompanied atheroma regression (P < 0.001), while dense calcium tissue volume increased (P = 0.002). There were no changes in fibrous or necrotic core tissue volumes. Volumetric changes in necrotic core tissue correlated with on-treatment HDL-C (r = -0.27, P = 0.03) and CRP (r = 0.25, P = 0.03) levels. A per-lesion analysis showed a reduction in the number of pathological intimal thickening lesions (defined by ≥3 consecutive IVUS frames containing PAV of ≥40%, predominantly fibro-fatty plaque, with <10% confluent necrotic core and <10% confluent dense calcium) at follow-up (67 vs. 38, P = 0.001). Fibroatheromas and fibrotic lesions remained static in number.
Changes in indices of atheroma composition accompany regression of coronary atheroma with maximally intensive statin therapy, and associate with anti-inflammatory effects of statins.
NCT000620542.
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