Linear motor motion control using a learning feedforward controller

The design and realization of an online learning motion controller for a linear motor is presented, and its usefulness is evaluated. The controller consists of two components: (1) a model-based feedback component, and (2) a learning feedforward component. The feedback component is designed on the basis of a simple second-order linear model, which is known to have structural errors. In the design, an emphasis is placed on robustness. The learning feedforward component is a neural-network-based controller, comprised of a one-hidden-layer structure with second-order B-spline basis functions. Simulations and experimental evaluations show that, with little effort, a high-performance motion system can be obtained with this approach

Dopamine D-2 up-regulation in psychosis patients after antipsychotic drug treatment

Purpose of reviewRecently, it has been questioned whether the re-emergence of psychotic symptoms following antipsychotic discontinuation or dose reduction is attributable to underlying psychotic vulnerability or to rebound effects of chronic use of antipsychotic medication. It was repeatedly shown that relapse rates are high after discontinuation of maintenance treatment. A potential contributing factor could be the increase in density of postsynaptic dopamine D2 receptors in the striatum and the higher affinity of D2 receptors for dopamine after chronic blockade.Recent findingsTo date, little clinical evidence is available for the mechanisms involved in postsynaptic striatal D2 receptor up-regulation after use of antipsychotic medication, and most knowledge comes from animal studies.SummaryFurther research is needed to investigate whether antipsychotic medication causes neuroadaptations leading to a dopamine supersensitive state in humans, how long such hypersensitive states may last and what differences exist between high and low D2 affinity antipsychotic drugs. Further, information is needed on discontinuation schedules that provide optimal protection for relapse during hypersensitive periods

The dual hit hypothesis of schizophrenia:evidence from animal models

Schizophrenia is a heterogeneous psychiatric disorder, which can severely impact social and professional functioning. Epidemiological and clinical studies show that schizophrenia has a multifactorial aetiology comprising genetic and environmental risk factors. Although several risk factors have been identified, it is still not clear how they result in schizophrenia. This knowledge gap, however, can be investigated in animal studies. In this review, we summarise animal studies regarding molecular and cellular mechanisms through which genetic and environmental factors may affect brain development, ultimately causing schizophrenia. Preclinical studies suggest that early environmental risk factors can affect the immune, GABAergic, glutamatergic, or dopaminergic system and thus increase the susceptibility to another risk factor later in life. A second insult, like social isolation, stress, or drug abuse, can further disrupt these systems and the interactions between them, leading to behavioural abnormalities. Surprisingly, first insults like maternal infection and early maternal separation can also have protective effects. Single gene mutations associated with schizophrenia did not have a major impact on the susceptibility to subsequent environmental hits

Positron emission tomography of tumour [18F]fluoroestradiol uptake in patients with acquired hormone-resistant metastatic breast cancer prior to oestradiol therapy

Purpose Whereas anti-oestrogen therapy is widely applied to treat oestrogen receptor (ER) positive breast cancer, paradoxically, oestrogens can also induce tumour regression. Upregulation of ER expression is a marker for oestrogen hypersensitivity. We, therefore, performed an exploratory study to evaluate positron emission tomography (PET) with the tracer 16 alpha-[F-18] fluoro-17 beta-oestradiol (F-18-FES) as potential marker to select breast cancer patients for oestradiol therapy. Methods Eligible patients had acquired endocrine-resistant metastatic breast cancer that progressed after >= 2 lines of endocrine therapy. All patients had prior ER-positive histology. Treatment consisted of oestradiol 2 mg, three times daily, orally. Patients underwent F-18-FES-PET/CT imaging at baseline. Tumour F-18-FES-uptake was quantified for a maximum of 20 lesions and expressed as maximum standardised uptake value (SUVmax). CT-scan was repeated every 3 months to evaluate treatment response. Clinical benefit was defined as time to radiologic or clinical progression >= 24 weeks. Results F-18-FES uptake, quantified for 255 lesions in 19 patients, varied greatly between lesions (median 2.8; range 0.6-24.3) and between patients (median 2.5; range 1.1-15.5). Seven (37 %) patients experienced clinical benefit of oestrogen therapy, eight progressed (PD), and four were non-evaluable due to side effects. The positive and negative predictive value PPV/NPV) of F-18-FES-PET for response to treatment were 60 % (95 % CI: 31-83 %) and 80 % (95 % CI: 38-96 %), respectively, using SUVmax >1.5. Conclusion F-18-FES-PET may aid identification of patients with acquired antihormone resistant breast cancer that are unlikely to benefit from oestradiol therapy

Pharmacokinetic and Pharmacodynamic Studies of Elacestrant, A Novel Oral Selective Estrogen Receptor Degrader, in Healthy Post-Menopausal Women

BACKGROUND AND OBJECTIVES: Advanced estrogen receptor-positive (ER+) breast cancer is currently treated with endocrine therapy. Elacestrant is a novel, nonsteroidal, selective estrogen receptor degrader with complex dose-related ER agonist/antagonist activity that is being developed as a treatment option for ER+ breast cancer. METHODS: Two first-in-human phase 1 studies of elacestrant in healthy postmenopausal women (Study 001/Study 004) were conducted to determine its pharmacokinetic and pharmacodynamic profile as well as its safety and maximum tolerated dose. RESULTS: In total, 140 postmenopausal subjects received at least one dose of study drug (114 received elacestrant and 26 received placebo). Single-ascending dose and multiple-ascending dose assessments showed that doses up to 1000 mg daily were safe and well tolerated, and the maximum tolerated dose was not reached. Oral administration of elacestrant had an absolute bioavailability of 10% and a mean half-life ranging from 27 to 47 h, reaching steady state after 5-6 days. Mean occupancy of the ER in the uterus after seven daily doses was 83% for 200 mg and 92% for 500 mg daily. The median ratio of elacestrant concentrations in the cerebral spinal fluid vs. plasma was 0.126% (500 mg dose) and 0.205% (200 mg dose). Most adverse events were related to the upper gastrointestinal tract. CONCLUSIONS: These data demonstrate that elacestrant has good bioavailability when administered orally with a half-life that supports once-daily administration. Engagement of the ER and some ability to cross the blood-brain barrier was demonstrated in addition to an acceptable safety profile

Supercharges, Quantum States and Angular Momentum for N=4 Supersymmetric Monopoles

We revisit the moduli space approximation to the quantum mechanics of monopoles in N=4 supersymmetric Yang-Mills-Higgs theory with maximal symmetry breaking. Starting with the observation that the set of fermionic zero-modes in N=4 supersymmetric Yang-Mills-Higgs theory can be viewed as two copies of the set of fermionic zero-modes in the N=2 version, we build a model to describe the quantum mechanics of N=4 supersymmetric monopoles, based on our previous paper [1] on the N=2 case, in which this doubling of fermionic zero-modes is manifest throughout. Our final picture extends the familiar result that quantum states are described by differential forms on the moduli space and that the Hamiltonian operator is the Laplacian acting on forms. In particular, we derive a general expression for the total angular momentum operator on the moduli space which differs from the naive candidate by the adjoint action of the complex structures. We also express all the supercharges in terms of (twisted) Dolbeault operators and illustrate our results by discussing, in some detail, the N=4 supersymmetric quantum dynamics of monopoles in a theory with gauge group SU(3) broken to U(1) x U(1).Comment: Updated references, included a derivation of the angular momentum operator, 32 page

Correction to:Pharmacokinetic and Pharmacodynamic Studies of Elacestrant, A Novel Oral Selective Estrogen Receptor Degrader, in Healthy Post-Menopausal Women (European Journal of Drug Metabolism and Pharmacokinetics, (2020), 45, 5, (675-689), 10.1007/s13318-020-00635-3)

Authors would like to correct the errors in table 2

Application of PET Tracers in Molecular Imaging for Breast Cancer

Purpose of Review: Molecular imaging with positron emission tomography (PET) is a powerful tool to visualize breast cancer characteristics. Nonetheless, implementation of PET imaging into cancer care is challenging, and essential steps have been outlined in the international “imaging biomarker roadmap.” In this review, we identify hurdles and provide recommendations for implementation of PET biomarkers in breast cancer care, focusing on the PET tracers 2-[18F]-fluoro-2-deoxyglucose ([18F]-FDG), sodium [18F]-fluoride ([18F]-NaF), 16α-[18F]-fluoroestradiol ([18F]-FES), and [89Zr]-trastuzumab. Recent Findings: Technical validity of [18F]-FDG, [18F]-NaF, and [18F]-FES is established and supported by international guidelines. However, support for clinical validity and utility is still pending for these PET tracers in breast cancer, due to variable endpoints and procedures in clinical studies. Summary: Assessment of clinical validity and utility is essential towards implementation; however, these steps are still lacking for PET biomarkers in breast cancer. This could be solved by adding PET biomarkers to randomized trials, development of imaging data warehouses, and harmonization of endpoints and procedures

Detection of Dural Metastases Before the Onset of Clinical Symptoms by 16 alpha-[F-18]Fluoro-17 beta-Estradiol PET in a Patient With Estrogen Receptor-Positive Breast Cancer

We offer an illustrative case about estrogen receptor (ER) imaging (also known as 16 alpha-[F-18]fluoro-17 beta-estradiol ([F-18]-FES) PET) and the detection of metastatic lesions in the dural region. We present a case of a woman with ER-positive metastatic breast cancer and high [F-18]-FES uptake in the dural region on PET imaging, without associated clinical symptoms. These lesions were missed on [F-18]-FDG PET because of physiological [F-18]-FDG uptake in the brain. This case highlighted some difficulties in the interpretation of imaging of brain metastases and demonstrated the added value of [F-18]-FES PET imaging. [F-18]-FES PET could be used to prove the presence of ER-positive metastases in the brain