IBS Precision Engineering (Netherlands)

Bronchopulmonary dysplasia, the most prevalent chronic lung disease of prematurity, is often treated with glucocorticoids (GCs) such as dexamethasone (DEX), but their use is encumbered with several adverse somatic, metabolic, and neurologic effects. We previously reported that systemic delivery of the GC prodrug ciclesonide (CIC) in neonatal rats activated glucocorticoid receptor (GR) transcriptional responses in lung but did not trigger multiple adverse effects caused by DEX. To determine whether limited systemic metabolism of CIC was solely responsible for its enhanced safety profile, we treated neonatal rats with its active metabolite desisobutyryl-ciclesonide (Des-CIC). DEX but not Des-CIC caused a reduction in body weight as well as reduced insulin-like growth factor-1 serum levels and chronic hyperglycemia in neonatal rats. However, Des-CIC was as effective as DEX in reducing the expression of various bleomycin-induced proinflammatory cytokine mRNAs. In vitro studies with various cell types demonstrate the potent GR transactivation and transrepression activity of Des-CIC, although genome-wide transcriptomic analyses reveal differences in DEX vs. Des-CIC responses in neonatal rat lung and liver tissue. Des-CIC is a GR super-agonist as revealed by an in vitro coregulator peptide binding assay. In addition, molecular dynamics simulations revealed unique Des-CIC-dependent allosteric signaling pathways between specific residues in the GR ligand-binding domain and receptor surfaces interacting with coregulator peptides. Thus, Des-CIC is a potential novel selective GR modulator that could impart a favorable therapeutic index for CIC use for even modest durations of GC exposure which could have long-lasting adverse somatic, metabolic, or neurologic effects.

The chopper is a cryogenic tip-tilt mechanism in the Common Fore Optics (CFO) of METIS, the mid-infrared imager and spectrograph for ESO's Extremely Large Telescope (ELT). In this paper we delve into the milling process of the mirror of the chopper mechanism, denominated as CM5. This highly accurate mirror is fully integrated into a tip-tilt mechanism and operates to reduce the background noise by shifting between the target object and the background, this happens with a frequency of 5Hz. We will primarily focus on the challenges encountered during the mirror-mechanism fabrication. Notably, the tip/tilt mechanism in the chopper requires precision levels that surpass the accuracy of the 5-axis milling machine that is used. The general accuracy of the used machine on a multi sided part is typically 20 to 30 microns, and is dominated by thermal drift of the machine itself. This significantly increases the manufacturing complexity, therefore a specialized production methodology was devised to ensure the achievement of the micron-level tolerances. In the next paragraphs we will describe how the critical tolerances of down to 5 microns in the mechanism features have been achieved. The use of a so-called Golden Sample provides a known and stable reference during manufacturing, allowing to bypass the drift and static errors of the machine. The usage of CMM measurements proves that the developed production method delivers excellent results overcoming the limitations of the machine accuracy. This monolithic aluminium cryogenic mirror has been produced through in-house CNC programming, milling, and thermal ageing followed by thermal cycling, Single point diamond turning (SPDT) and Wire Electrical Discharging Machining (Wire EDM) by external suppliers. After SPDT of the optical surface, the surface is polished to optical quality and finally a gold coating layer is applied to increase the reflectivity in the desired wavelength.

Efforts to improve estrogen receptor-α (ER)-targeted therapies in breast cancer have relied upon a single mechanism, with ligands having a single side chain on the ligand core that extends outward to determine antagonism of breast cancer growth. Here, we describe inhibitors with two ER-targeting moieties, one of which uses an alternate structural mechanism to generate full antagonism, freeing the side chain to independently determine other critical properties of the ligands. By combining two molecular targeting approaches into a single ER ligand, we have generated antiestrogens that function through new mechanisms and structural paradigms to achieve antagonism. These dual-mechanism ER inhibitors (DMERIs) cause alternate, noncanonical structural perturbations of the receptor ligand-binding domain (LBD) to antagonize proliferation in ER-positive breast cancer cells and in allele-specific resistance models. Our structural analyses with DMERIs highlight marked differences from current standard-of-care, single-mechanism antiestrogens. These findings uncover an enhanced flexibility of the ER LBD through which it can access nonconsensus conformational modes in response to DMERI binding, broadly and effectively suppressing ER activity.

Six degree of freedom manipulation provides full control over position and orientation, essential for many applications. However, six degree of freedom parallel kinematic manipulators (e.g. hexapods) either have a limited range of motion combined with a good repeatability when comprising flexure joints, or they have limited repeatability with a large workspace when using traditional rolling- or sliding-element bearings. In this paper, the design and optimization of a fully flexure-based large range of motion precision hexapod robot is presented. The flexure joints have been specifically developed for the purpose of large range of motion and high support stiffness for this manipulator. The obtained system allows for ±100 mm of translational and more than ±10° of rotational range of motion in each direction combined with a footprint of 0.6 m2 and a height of 0.4 m. Furthermore, a dedicated flexure-based design for the actuated joints combines high actuation forces with the absence of play and friction, allowing for accelerations exceeding 10 g. Experiments on a prototype validate the sub-micron repeatability, which is merely limited by the selected electronics.

Simple SummaryHormonal treatments, especially those used to treat menopause symptoms are known to increase breast cancer risk. It is thus necessary to identify new formulations with a better benefit/risk profile. The aim of this translational study was to evaluate the breast cancer risk associated with a combination of a natural estrogen named estetrol, with progestogens such as natural progesterone and drospirenone. Since the assessment of breast cancer risk in patients during drug development is not possible given the requirement of long-term studies in large populations, this study provides new evidence that a therapeutic dose of estetrol for menopause treatment or contraception, combined with progesterone or drospirenone, may provide a better benefit/risk profile toward breast cancer risk compared to the hormonal treatments currently available for patients.Given the unequivocal benefits of menopause hormone therapies (MHT) and combined oral contraceptives (COC), there is a clinical need for new formulations devoid of any risk of breast cancer promotion. Accumulating data from preclinical and clinical studies support that estetrol (E4) is a promising natural estrogen for MHT and COC. Nevertheless, we report here that E4 remains active on the endometrium, even under a dose that is neutral on breast cancer growth and lung metastasis dissemination. This implies that a progestogen should be combined with E4 to protect the endometrium of non-hysterectomized women from hyperplasia and cancer. Through in vivo observations and transcriptomic analyses, our work provides evidence that combining a progestogen to E4 is neutral on breast cancer growth and dissemination, with very limited transcriptional impact. The assessment of breast cancer risk in patients during the development of new MHT or COC is not possible given the requirement of long-term studies in large populations. This translational preclinical research provides new evidence that a therapeutic dose of E4 for MHT or COC, combined with progesterone or drospirenone, may provide a better benefit/risk profile towards breast cancer risk compared to hormonal treatments currently available for patients.

Abstract Phospholipids are ligands for nuclear hormone receptors (NRs) and regulate transcriptional programs relevant to normal physiology and disease. Here, we demonstrate that mimicking phospholipid-NR interactions greatly improves agonists of liver receptor homolog-1 (LRH-1), a promising therapeutic target for diabetes and colitis. Conventional LRH-1 modulators partially occupy the binding pocket, leaving vacant a region important for phospholipid binding and allostery. Therefore, we constructed a set of hybrid molecules with elements of natural phospholipids appended to a synthetic LRH-1 agonist. The phospholipid-mimicking group improves binding affinity, increases LRH-1 transcriptional activity, promotes coregulator recruitment, and interacts with the targeted LRH-1 residues in crystal structures. The best new agonist markedly improves colonic histopathology and disease-related weight loss in a humanized LRH-1 murine T-cell transfer model of colitis. This is the first evidence of in vivo efficacy for an LRH-1 modulator in colitis, a leap forward in agonist development.

Abstract Purpose The majority of ‘low-risk’ (grade I/II) Ductal Carcinoma In Situ (DCIS) lesions do not progress to invasive breast cancer during a woman’s lifetime. Therefore, the safety of active surveillance versus standard surgical treatment for grade I/II DCIS is being evaluated in several clinical trials. If active surveillance is proven safe and implemented in clinical practice, a significant group of women with low-risk DCIS may forego surgery and radiotherapy. To further reduce their risks, there is an urgent need to identify potentially modifiable risk factors. Nonetheless, non-modifiable risk factors are also of great importance to gain clear understanding of the overall risk for developing a subsequent event (invasive breast cancer, in situ recurrences, distant metastases) following untreated DCIS. A systematic literature review was performed to evaluate the impact of established breast cancer risk factors on the risk of developing in situ or invasive disease after treatment of primary pure DCIS. Methods A systematic literature search was performed in PUBMED, EMBASE and Web of Science. PRISMA methodology was applied for the selection of studies. We only included studies that were published after the review by Shamliyan et al in 2010. Results Nine out of the 3,852 articles retrieved were included for final data extraction and evaluation. These nine studies included a total of 11,602 patients with primary pure DCIS. The sample size of these studies ranged from 50 to 4,131 patients. Across the studies, a total of 979 (range: 2-239) subsequent events, such as ipsilateral invasive, ipsilateral in situ events, and distant metastases, were reported. The median follow-up varied between four and nine years. There was limited information published and limited evidence in the selected studies especially on modifiable factors; and all studies except one, were in women of European-descent. Of the modifiable factors only a high BMI (≥25) in mainly postmenopausal women seemed to be associated with a lower risk of a subsequent event. There was some evidence for several non-modifiable predictors, i.e. younger age at diagnosis of DCIS, positive family history of breast cancer, premenopausal status, and high breast density. Age was associated with a two to threefold risk for experiencing a subsequent event. A positive family history had an almost two-fold increased risk, and pre-menopausal status increased the risk for a subsequent event between 46 to 89%. Furthermore, the highest quintile for breast density was associated with a 70% increase in risk for a subsequent event. See table 1 for effect sizes with 95% confidence intervals. Conclusion There is a limited number of studies published on the impact of risk factors on subsequent events after pure DCIS. Moreover, the available evidence is insufficient to identify potential targets for risk reduction strategies, due to the relatively small numbers and the lack of long term follow-up in a low-event disease such as DCIS. Traditional risk factors for primary invasive breast cancer showed, in general, also to be associated with the risk for a subsequent event after primary pure DCIS. The single study that reported on BMI showed a direction of association that was contrary to expectations. In conclusion large scale, well-designed, studies with specific attention to lifestyle factors are necessary to enable identification of DCIS who are at low and high risk for a subsequent event after primary pure DCIS. Table 1. Overview of published effect sizes of risk of a subsequent event after pure DCISIncluded articlesVariableHR/OR (95% CI)Moran et al. 2017 Age (≥50 vs < 50 years) HR(Multivariate) 0.54 (0.41-0.71)Alvarado et al. 2012Age (<40 vs ≥ 40 years)HR(Univariate) 2.70 (1.06–6.93) Baglia et al. 2018Family history (>2 relatives with Breast Cancer)OR(Multivariate) 1.78 (1.02–3.10)De Lorenzi et al. 2018BMI (high ≥ 25 vs low)HR(Multivariate)0.48(0.26-0.90)De Lorenzi et al. 2018Menopausal state (pre vs post)HR(Multivariate)1.89 (0.37-0.77)Shurell et al. 2017Menopausal state (post vs pre)HR(Multivariate)0.54 (0.37-0.77)Habel et al. 2010Breast density (highest quintile)HR(Multivariate)1.70 (1.00–2.39) Citation Format: Sena Alaeikhanehshir, Ellen G Engelhardt, Frederieke H van Duijnhoven, Maartje van Seijen, Patrick A Bhairosing, Donna Pinto, Deborah Collyar, Jelle Wesseling, Esther H Lips, Marjanka K Schmidt. The impact of patient characteristics and lifestyle factors on the risk of an ipsilateral event after a primary DCIS: A systematic review [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P5-08-15.