Research on stabilization of coupled hyperbolic PDEs has been dominated by the focus on pairs of counter-convecting ("heterodirectional") transport PDEs with distributed local coupling and with ...controls at one or both boundaries. A recent extension allows stabilization using only one control for a system containing an arbitrary number of coupled transport PDEs that convect at different speeds against the direction of the PDE whose boundary is actuated. In this paper we present a solution to the fully general case, in which the number of PDEs in either direction is arbitrary, and where actuation is applied on only one boundary (to all the PDEs that convect downstream from that boundary). To solve this general problem, we solve, as a special case, the problem of control of coupled "homodirectional" hyperbolic linear PDEs, where multiple transport PDEs convect in the same direction with arbitrary local coupling. Our approach is based on PDE backstepping and yields solutions to stabilization, by both full-state and observer-based output feedback, and trajectory tracking problems.
In MONALEESA-2, ribociclib plus letrozole showed improved progression-free survival compared with letrozole alone as first-line treatment for postmenopausal patients with hormone receptor ...(HR)-positive, HER2-negative, advanced breast cancer. MONALEESA-7 aimed to assess the efficacy and safety of ribociclib plus endocrine therapy in premenopausal women with advanced, HR-positive breast cancer.
This phase 3, randomised, double-blind, placebo-controlled trial was done at 188 centres in 30 countries. Eligible patients were premenopausal women aged 18–59 years who had histologically or cytologically confirmed HR-positive, HER2-negative, advanced breast cancer; an Eastern Cooperative Oncology Group performance status of 0 or 1; measurable disease as per Response Evaluation Criteria in Solid Tumors version 1.1 criteria, or at least one predominantly lytic bone lesion; and had not received previous treatment with cyclin-dependent kinases 4 and 6 inhibitors. Endocrine therapy and chemotherapy in the adjuvant or neoadjuvant setting was permitted, as was up to one line of chemotherapy for advanced disease. Patients were randomly assigned (1:1) via interactive response technology to receive oral ribociclib (600 mg/day on a 3-weeks-on, 1-week-off schedule) or matching placebo with either oral tamoxifen (20 mg daily) or a non-steroidal aromatase inhibitor (letrozole 2·5 mg or anastrozole 1 mg, both oral, daily), all with goserelin (3·6 mg administered subcutaneously on day 1 of every 28-day cycle). Patients and investigators were masked to treatment assignment. Efficacy analyses were by intention to treat, and safety was assessed in all patients who received at least one dose of any study treatment. The primary endpoint was investigator-assessed progression-free survival. MONALEESA-7 is registered with ClinicalTrials.gov, NCT02278120 and is ongoing, but no longer enrolling patients.
Between Dec 17, 2014, and Aug 1, 2016, 672 patients were randomly assigned: 335 to the ribociclib group and 337 to the placebo group. Per investigator's assessment, median progression-free survival was 23·8 months (95% CI 19·2–not reached) in the ribociclib group compared with 13·0 months (11·0–16·4) in the placebo group (hazard ratio 0·55, 95% CI 0·44–0·69; p<0·0001). Grade 3 or 4 adverse events reported in more than 10% of patients in either group were neutropenia (203 61% of 335 patients in the ribociclib group and 12 4% of 337 in the placebo group) and leucopenia (48 14% and four 1%). Serious adverse events occurred in 60 (18%) of 335 patients in the ribociclib group and 39 (12%) of 337 in the placebo group, of which 15 (4%) and six (2%), respectively, were attributed to the study regimen. 12 (4%) of 335 patients in the ribociclib group and ten (3%) of 337 in the placebo group discontinued treatment because of adverse events. No treatment-related deaths occurred. 11 deaths occurred (five 1% in the ribociclib group and six 2% in the placebo group) during or within 30 days after treatment, most of which were due to progression of the underlying breast cancer (three 1% and six 2%). The remaining two deaths in the ribociclib group were due to an intracranial haemorrhage in an anticoagulated patient, and a pre-existing wound haemorrhage in another patient.
Ribociclib plus endocrine therapy improved progression-free survival compared with placebo plus endocrine therapy, and had a manageable safety profile in patients with premenopausal, HR-positive, HER2-negative, advanced breast cancer. The combination could represent a new first-line treatment option for these patients.
Novartis.
Huntington's disease (HD) is an inherited, dominant neurodegenerative disorder caused by an abnormal expansion of CAG triplets in the huntingtin gene (htt). Despite extensive efforts to modify the ...progression of HD thus far only symptomatic treatment is available. Recent work suggests that treating invertebrate and mice HD models with metformin, a well-known AMPK activator which is used worldwide to treat type 2-diabetes, reduces mutant huntingtin from cells and alleviates many of the phenotypes associated to HD. Herein we report statistical analyses of a sample population of participants in the Enroll-HD database, a world-wide observational study on HD, to assess the effect of metformin intake in HD patients respect to cognitive status using linear models. This cross-sectional study shows for the first time that the use of metformin associates with better cognitive function in HD patients.
Ribociclib plus endocrine therapy (ET) demonstrated a statistically significant progression-free survival and overall survival (OS) benefit in the phase III MONALEESA-7 trial of pre-/perimenopausal ...patients with hormone receptor (HR)-positive (HR+), HER2-negative (HER2-) advanced breast cancer (ABC). The median OS was not reached in the ribociclib arm in the protocol-specified final analysis; we hence performed an exploratory OS and additional outcomes analysis with an extended follow-up (median, 53.5 months).
Patients were randomized to receive ET goserelin plus nonsteroidal aromatase inhibitor (NSAI) or tamoxifen with ribociclib or placebo. OS was evaluated with a stratified Cox proportional hazard model and summarized with Kaplan-Meier methods.
The intent-to-treat population included 672 patients. Median OS was 58.7 months with ribociclib versus 48.0 months with placebo hazard ratio = 0.76; 95% confidence interval (CI), 0.61-0.96. Kaplan-Meier estimated OS at 48 months was 60% and 50% with ribociclib and placebo, respectively. Subgroup analyses were generally consistent with the OS benefit, including patients who received NSAI and patients aged less than 40 years. Subsequent antineoplastic therapies following discontinuation were balanced between the ribociclib (77%) and placebo (78%) groups. Use of cyclin-dependent kinase 4/6 inhibitors after discontinuation was higher with placebo (26%) versus ribociclib (13%). Time to first chemotherapy was significantly delayed with ribociclib versus placebo. No drug-drug interactions were observed between ribociclib and either NSAI.
Ribociclib plus ET continued to show significantly longer OS than ET alone in pre-/perimenopausal patients, including patients aged less than 40 years, with HR+/HER2- ABC with 53.5 months of median follow-up (ClinicalTrials.gov, NCT02278120).
On the 60th anniversary of the celebration of the Second Vatican Council, we would like to take up again a statement from the constitution Lumen gentium, which was a source of controversy from the ...moment it was proposed in the schema De Ecclesia during the Council: «The Church is in Christ, like a sacrament, a sign and instrument of intimate union with God and of the unity of the entire humankind» (Lumen gentium, 1). In this article, we want to take up the concept of the Church as a sacrament, which emerged from the conciliar constitution on the Church, as a first step, although the conception of the Church as a sacrament is found in ecclesiology before the Second Vatican Council. Second, we will focus on the reception of this concept and its development after the Council. We will conclude with a third part devoted to its implications for ecumenical dialogue and the difficulties and possibilities for convergence it offers, with particular reference to the document of the Faith and Order Commission: The Church towards a Common Vision (2013).
Within the cellular microenvironment of organisms, the surface‐ and volume‐ enclosed multiple enzymes perform highly complex series of chemical reactions for very selective and efficient synthesis of ...biomolecules. Several efforts have been carried out to mimic these timely and spatially defined natural enzyme cascade reactions onto the artificial multienzyme nano‐assemblies via immobilization of two or more enzymes on nanosupport, while maintaining the catalytic activity. These biocatalytic systems undergo cascade reactions for the efficient production of chemicals and materials of interest. Their increasing interest is based on their numerous potential applications in the area of environmental, biomedical and applied chemistry. A variety of nanosupports and multienzyme immobilization techniques have been optimized and reported. Nanoreactors usually show molecular crowding and anomalous diffusion of substances that modify the mass action kinetic laws. Thus, the kinetics is different than those shown by free diluted enzymes. Consequently, the catalytic activity considerations in cascade reactions on nanoassemblies are of great importance. Thus, in this work, important parameters of enzyme kinetics in cascade reaction and the molecular tools for the design and optimization of bi‐ and multi‐enzymatic nanobioreactors reactions are discussed.
Multienzyme cascades: Nanoreactors usually show molecular crowding and anomalous diffusion of substances that modify the mass action kinetic laws. Thus, the kinetics is different than those shown by free diluted enzymes. Consequently, the catalytic activity considerations in cascade reactions on nanoassemblies are of great importance. Thus, in this work, important parameters of enzyme kinetics in cascade reaction and the molecular tools for the design and optimization of bi‐ and multi‐enzymatic nanobioreactors reactions are discussed.
Highly stable and reusable magnetic crosslinked enzyme aggregates (m‐CLEAS) of laccase are synthesized with simultaneous improved enzymatic activity. Magnetic copper ferrite nanoparticles (CFNPs) ...were synthesized by solvothermal procedure with an average size of ~8 nm. The nanometric m‐CLEAS were formed by co‐aggregation of enzyme with CFNPs and crosslinked using glutaraldehyde. Different mass ratios of CFNPs:Laccase were assayed (1 : 2, 1 : 3, and 1 : 6), where 1 : 6 resulted in the highest activity recovery (97 %). The m‐CLEAS showed an average size of ~239 nm, ~24 % enzyme immobilization efficiency, and loading as high as 1.75 g of protein per g of support. As expected, m‐CLEAS oxidized the substrate with a higher transformation rate (kcat) and catalytic efficiency (kcat/Km) than the free enzyme. m‐CLEAS showed superior storage and thermostability compared to free enzyme and non‐magnetic CLEAS. In particular, the m‐CLEAS showed ~150 % and ~100 % residual activity after 30 days of storage at 4 °C and room temperature, respectively. Furthermore, m‐CLEAS showed good recyclability, retaining ~78 % and ~54 % laccase activity after 5 and 10 cycles of reuse, respectively. This work highlights the facile and cost‐effective synthesis of nanometric m‐CLEAS with exceptional storage stability and simultaneously improved laccase activity, making them suitable for a range of green industrial processes.
This work demonstrates the facile and cost‐effective synthesis of magnetic crosslinked laccase aggregates (m‐CLEAS) on CuFe2O4. m‐CLEAS showed high enzyme loading, improved catalytic performance and thermal stability with exceptional storage stability than free enzyme and CLEAS. The results highlight the promise of m‐CLEAS for green industrial processes.
Overexpression of sirtuins (NAD(+)-dependent protein deacetylases) has been reported to increase lifespan in budding yeast (Saccharomyces cerevisiae), Caenorhabditis elegans and Drosophila ...melanogaster. Studies of the effects of genes on ageing are vulnerable to confounding effects of genetic background. Here we re-examined the reported effects of sirtuin overexpression on ageing and found that standardization of genetic background and the use of appropriate controls abolished the apparent effects in both C. elegans and Drosophila. In C. elegans, outcrossing of a line with high-level sir-2.1 overexpression abrogated the longevity increase, but did not abrogate sir-2.1 overexpression. Instead, longevity co-segregated with a second-site mutation affecting sensory neurons. Outcrossing of a line with low-copy-number sir-2.1 overexpression also abrogated longevity. A Drosophila strain with ubiquitous overexpression of dSir2 using the UAS-GAL4 system was long-lived relative to wild-type controls, as previously reported, but was not long-lived relative to the appropriate transgenic controls, and nor was a new line with stronger overexpression of dSir2. These findings underscore the importance of controlling for genetic background and for the mutagenic effects of transgene insertions in studies of genetic effects on lifespan. The life-extending effect of dietary restriction on ageing in Drosophila has also been reported to be dSir2 dependent. We found that dietary restriction increased fly lifespan independently of dSir2. Our findings do not rule out a role for sirtuins in determination of metazoan lifespan, but they do cast doubt on the robustness of the previously reported effects of sirtuins on lifespan in C. elegans and Drosophila.
The adenosine monophosphate activated kinase protein (AMPK) is an evolutionary-conserved protein important for cell survival and organismal longevity through the modulation of energy homeostasis. ...Several studies suggested that AMPK activation may improve energy metabolism and protein clearance in the brains of patients with vascular injury or neurodegenerative disease. However, in Huntington's disease (HD), AMPK may be activated in the striatum of HD mice at a late, post-symptomatic phase of the disease, and high-dose regiments of the AMPK activator 5-aminoimidazole-4-carboxamide ribonucleotide may worsen neuropathological and behavioural phenotypes. Here, we revisited the role of AMPK in HD using models that recapitulate the early features of the disease, including Caenorhabditis elegans neuron dysfunction before cell death and mouse striatal cell vulnerability. Genetic and pharmacological manipulation of aak-2/AMPKα shows that AMPK activation protects C. elegans neurons from the dysfunction induced by human exon-1 huntingtin (Htt) expression, in a daf-16/forkhead box O-dependent manner. Similarly, AMPK activation using genetic manipulation and low-dose metformin treatment protects mouse striatal cells expressing full-length mutant Htt (mHtt), counteracting their vulnerability to stress, with reduction of soluble mHtt levels by metformin and compensation of cytotoxicity by AMPKα1. Furthermore, AMPK protection is active in the mouse brain as delivery of gain-of-function AMPK-γ1 to mouse striata slows down the neurodegenerative effects of mHtt. Collectively, these data highlight the importance of considering the dynamic of HD for assessing the therapeutic potential of stress-response targets in the disease. We postulate that AMPK activation is a compensatory response and valid approach for protecting dysfunctional and vulnerable neurons in HD.
•DEHP and MEHP induced the migration and enlargement of A549 cells.•Phthalates decreased the surfactant proteins suggesting a change in the epithelial phenotype of A459 cells.•Phthalates changed the ...levels of fibronectin and E- cadherin suggesting an epithelial-mesenchymal-transition.•The change on the epithelial phenotype can be a mechanism of DEHP and MEHP toxicity.
Di(2-ethylhexyl) phthalate (DEHP) is a widely used plasticizer that is metabolized to mono(2-ethylhexyl) phthalate (MEHP). Inhalation is an important exposure route for both phthalates, and their effects on lungs include inflammation, alteration of postnatal maturation (alveolarization), enlarged airspaces and cell differentiation changes, suggesting that alveolar epithelial cells-2 (AEC) are targets of phthalates. This study evaluated the cell progression, epithelial and mesenchymal markers, including surfactant secretion in A549 cells (AEC) that were exposed to DEHP (1–100 μM) or MEHP (1–50 μM) for 24–72 h. The results showed an increased cell proliferation at all concentrations of each phthalate at 24 and 48 h. Cell migration showed a concentration-dependent increase at 24 and 48 h of exposure to either phthalate and enlarged structures were seen. Decreased levels of both surfactants (SP-B/SP-C) were observed after the exposure to either phthalate at 48 h, and of SP-C positive cells exposed to MEHP, suggesting a loss of the epithelial phenotype. While a decrease in the epithelial marker E-cadherin and an increase in the mesenchymal marker fibronectin were observed following exposure to either phthalate. Our results showed that DEHP and MEHP altered the structure and migration of A549 cells and promoted the loss of the epithelial phenotype.
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