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A new stream of research and development responds to changes in life expectancy across the world. It includes technologies which enhance well-being of individuals, specifically for older people. The ACCOMPANY project focuses on home companion technologies and issues surrounding technology development for assistive purposes. The project responds to some overlooked aspects of technology design, divided into multiple areas such as empathic and social human-robot interaction, robot learning and memory visualisation, and monitoring persons’ activities at home. To bring these aspects together, a dedicated task is identified to ensure technological integration of these multiple approaches on an existing robotic platform, Care-O-Bot®3 in the context of a smart-home environment utilising a multitude of sensor arrays. Formative and summative evaluation cycles are then used to assess the emerging prototype towards identifying acceptable behaviours and roles for the robot, for example role as a butler or a trainer, while also comparing user requirements to achieved progress. In a novel approach, the project considers ethical concerns and by highlighting principles such as autonomy, independence, enablement, safety and privacy, it embarks on providing a discussion medium where user views on these principles and the existing tension between some of these principles, for example tension between privacy and autonomy over safety, can be captured and considered in design cycles and throughout project developments.

Small molecule IAP antagonists - SMAC mimetics (SM) - are being developed as an anticancer therapy. SM therapy was demonstrated not only to sensitize tumor cells to TNFα-mediated cell death but also to exert immunostimulatory properties. Their good safety and tolerability profile, plus promising preclinical data, warrants further investigation into their various effects within the tumor microenvironment. Using in vitro models of human tumor cells and fibroblast spheroids co-cultured with primary immune cells, we investigated the effects of SM on immune cell activation. SM treatment induces the maturation of human PBMC- and patient-derived dendritic cells (DC), and modulates cancer-associated fibroblasts towards an immune interacting phenotype. Finally, SM-induced tumor necroptosis further enhances DC activation, leading also to higher T-cell activation and infiltration into the tumor site. These results highlight the relevance of using heterotypic in vitro models to investigate the effects of targeted therapies on different components of the tumor microenvironment., Competing Interests: All authors were employees of Boehringer Ingelheim RCV GmbH & Co KG at the time the study was conducted. The SMAC mimetic compound used in this work is included in a patent filed by Boehringer Ingelheim International GmbH. The authors declare no other competing interests., (© 2023 The Author(s).)

Here, we report the fragment-based discovery of BI-9321, a potent, selective and cellular active antagonist of the NSD3-PWWP1 domain. The human NSD3 protein is encoded by the WHSC1L1 gene located in the 8p11-p12 amplicon, frequently amplified in breast and squamous lung cancer. Recently, it was demonstrated that the PWWP1 domain of NSD3 is required for the viability of acute myeloid leukemia cells. To further elucidate the relevance of NSD3 in cancer biology, we developed a chemical probe, BI-9321, targeting the methyl-lysine binding site of the PWWP1 domain with sub-micromolar in vitro activity and cellular target engagement at 1 µM. As a single agent, BI-9321 downregulates Myc messenger RNA expression and reduces proliferation in MOLM-13 cells. This first-in-class chemical probe BI-9321, together with the negative control BI-9466, will greatly facilitate the elucidation of the underexplored biological function of PWWP domains.

The transcription factor BCL6 is a known driver of oncogenesis in lymphoid malignancies, including diffuse large B cell lymphoma (DLBCL). Disruption of its interaction with transcriptional repressors interferes with the oncogenic effects of BCL6. We used a structure-based drug design to develop highly potent compounds that block this interaction. A subset of these inhibitors also causes rapid ubiquitylation and degradation of BCL6 in cells. These compounds display significantly stronger induction of expression of BCL6-repressed genes and anti-proliferative effects than compounds that merely inhibit co-repressor interactions. This work establishes the BTB domain as a highly druggable structure, paving the way for the use of other members of this protein family as drug targets. The magnitude of effects elicited by this class of BCL6-degrading compounds exceeds that of our equipotent non-degrading inhibitors, suggesting opportunities for the development of BCL6-based lymphoma therapeutics., (Copyright © 2017 Boehringer Ingelheim RCV GmbH & Co KG. Published by Elsevier Inc. All rights reserved.)

Although the MAPK pathway is frequently deregulated in cancer, inhibitors targeting RAF or MEK have so far shown clinical activity only in BRAF- and NRAS-mutant melanoma. Improvements in efficacy may be possible by combining inhibition of mitogenic signal transduction with inhibition of cell-cycle progression. We have studied the preclinical pharmacology of BI 847325, an ATP-competitive dual inhibitor of MEK and Aurora kinases. Potent inhibition of MEK1/2 and Aurora A/B kinases by BI 847325 was demonstrated in enzymatic and cellular assays. Equipotent effects were observed in BRAF-mutant cells, whereas in KRAS-mutant cells, MEK inhibition required higher concentrations than Aurora kinase inhibition. Daily oral administration of BI 847325 at 10 mg/kg showed efficacy in both BRAF- and KRAS-mutant xenograft models. Biomarker analysis suggested that this effect was primarily due to inhibition of MEK in BRAF-mutant models but of Aurora kinase in KRAS-mutant models. Inhibition of both MEK and Aurora kinase in KRAS-mutant tumors was observed when BI 847325 was administered once weekly at 70 mg/kg. Our studies indicate that BI 847325 is effective in in vitro and in vivo models of cancers with BRAF and KRAS mutation. These preclinical data are discussed in the light of the results of a recently completed clinical phase I trial assessing safety, tolerability, pharmacokinetics, and efficacy of BI 847325 in patients with cancer. Mol Cancer Ther; 15(10); 2388-98. ©2016 AACR., (©2016 American Association for Cancer Research.)

Clusterin is overexpressed in pancreas during the acute phase of pancreatitis. We intended to clarify the role of clusterin expression in stressed exocrine pancreas. We performed in vitro experiments in transfected AR4-2J cells with modified expression levels of clusterin and in vivo studies in clusterin-deficient mice. AR4-2J cells were exposed to agents mimicking cell-stress during pancreatitis (cerulein, hydrogen peroxide, staurosporine or lysophosphatidylcholine). Clusterin-overexpressing AR4-2J cells showed higher viability after cell stress and accordingly reduced rates of apoptosis and lessened caspase-3 activation. Blockage of endogenous clusterin expression reduced viability and enhanced apoptosis. Presence of clusterin reduced NF-kappaB activation and expression of the NF-kappaB target genes TNF-alpha and MOB-1 under cell stress. Clusterin-deficient mice showed a more severe course of acute experimental pancreatitis with enhanced rates of apoptosis and inflammatory cell infiltration. We concluded that clusterin was protective during inflammation of exocrine pancreas because of its anti-apoptotic and anti-inflammatory functions.

Success of epidermal growth factor receptor (EGFR) targeting agents in different cancer types is related to EGFR gene mutations and/or copy number gains. We investigated the EGFR gene status and protein expression by DNA mutational analysis, fluorescence in situ hybridization (FISH), and immunohistochemistry in tumor tissues from 80 patients with primary and corresponding recurrent ovarian serous carcinomas. The patients were classified into six groups with ascending EGFR gene copy numbers. EGFR amplification and high polysomy (FISH+) was present in a significant fraction of the primary (20%) and recurrent (22%) ovarian carcinomas. On mutational analysis, only one tumor with a silent EGFR mutation was observed, and this was the only carcinoma with high-level amplification. EGFR protein immunoexpression was seen in 28% of primary and 33% of recurrent carcinomas and correlated to amplification in the primary tumors (P = 0.003). In recurrent carcinoma, moderate and strong EGFR expression was associated with amplification (P = 0.034). These molecular events potentially have impact on the responsiveness to EGFR targeting agents in ovarian cancer.

Quantitative CT (QCT) studies of trabecular vertebral bone tissue have been carried out in vitro on a GE CT/T 9800 scanner. Results of both single energy (SE) 80 kVp and dual energy (DE) 80/140 kVp QCT data are compared with chemical mineral analysis to determine accuracy. We examined 62 vertebral specimens, from 28 cadavers (19 male and 9 female with an age range of 19-93 years, mean = 60.4). Averaging the results of all vertebral bodies of the same individual for SEQCT versus ashweight, we found a correlation coefficient (r) of 0.94 (p less than 0.0001), a standard error of the estimate (SEE) of 12.2 mg/cm3 (calibrated to K2HPO4), with a coefficient of variation (CV) of 13.2% and an average underestimation of bone mineral content of 18.7 mg/cm3. The corresponding DEQCT results were r = 0.98 (p less than 0.0001), SEE = 7.4 mg/cm3, CV = 7.0%, and an average underestimation of 4.9 mg/cm3. The SE and DE results are correlated with r = 0.98 (p less than 0.0001), SEE = 8.0 mg/cm3, and CV = 8.7%. From our SEQCT data and the results of the chemical analysis of bone mineral and fat content we calculated a fat sensitivity of 7.7 mg/cm3 K2HPO4 per 100 mg/cm3 fat change for our scanner. Using an average fat variability of 87.5 mg/cm3, this leads to a fat-related uncertainty for the normative SEQCT data of 6.7 mg/cm3, which is far lower than the normal biological variation of 29.4 mg/cm3. Using tabulated normative data on fat content versus age and versus mineral content of 188 vertebral specimens from five collaborating centers, we derived a correction algorithm for QCT measurement that reduces our average underestimation to 0.88 mg/cm3 with an SEE of 12.1 mg/cm3. Hence, this correction procedure can be used to estimate the fat corrected absolute mineral density for research purposes or for scanners with high fat sensitivity. For the GE CT/T 9800 scanner, with a relatively low fat to mineral sensitivity at 80 kVp, the correction procedure is generally not recommended for clinical studies since it minimizes the average fat induced error but does not reduce the residual, partially fat related uncertainty. Finally, since the fat related uncertainty is small compared to biological variation, the correlation is high between SEQCT and DEQCT, and the radiation dose is lower and the precision higher for SEQCT, we suggest that most clinical diagnostic studies using the GE CT/T 9800 scanner for bone mineral determination employ SEQCT at 80 kVp.

An X-ray computed tomographic (CT) scanner was used to measure and image transmission profiles of a single 8 mm thick object slice digitally with a high temporal (up to 20 ms), spatial (1.1 mm), and density (0.5%) resolution. This special digital radiography imaging mode is called a Chronogram. It produces a time-history of measured attenuation values but not a normal anatomical image. After intravenous bolus injection of contrast medium, bolus shape as a function of time and bolus passage times can be imaged. Absolute iodine concentrations in blood vessels and soft tissue can be evaluated at any time in all body regions. The Chronogram has the potential to quantify physiological parameters such as enhancement, passage times, and relative blood flow through pairs of arteries or symmetrically arranged organs and to measure absolute iodine concentrations. As a disadvantage, patient motion can prevent quantitative evaluation. This drawback can, however, be turned into an advantage in that all kinds of motion can be measured, for example, movement and pulsation of the heart.

Initially, the hitherto existing radiographic methods of investigating the adrenal gland are demonstrated. Whole body CT opens a third dimension--in addition to being a non invasive method without risk. The normal CT findings of the adrenal gland are described, as well as the normal variants in shape and position. With help of morphometry and image manipulation, measurements of the size of the adrenal gland in 20 healthy patients were made and are being listed; and the respective normal variants as well as hypo- and hyperplasia are pointed out. Some examples serve to illustrate pathologic conditions, such as inflammation and benign and malignant primary and secondary neoplasia. Finally, the value of adrenal gland CT is discussed in reference to the other existing respective radiographic methods.

The effect of respiratory movement of abdominal organs on computer tomography is illustrated. Methods for an objective evaluation of the reproducibility of tomograms are presented. A procedure for the quantitative determination of the respiratory movement of abdominal organs using computer tomography is described.

A method for the in vivo investigation of the mineral distribution in human vertebral bodies by the aid of computed tomography is presented. The attenuation coefficients resulting from transversal tomograms of vertebral spongiosa are compared with the results of bone ashing from in vitro investigations. Computed tomography values, ash weights and photodensitometric values show a high degree of correlation.

Several cases selected from a group of 67 patients with bony lesions (primary benign and malignant neoplasia, secondary neoplasia and metabolic disorders) serve to demonstrate the significant information gained by CT compared to that gained by conventional radiographic methods including angiography and bone scanning. CT is advantageous in showing the exact intra- and extraosseous extent of the lesion--helpful for further diagnosis and therapy. Measurements of length, area, volume and density can help to narrow down the differential diagnosis and they aid in follow-up examinations. CT supplements conventional radiographic methods and in some cases may even replace them, e.g. angiography.

Whole body CT opens a third dimension-in addition with the advantage of being a non-invasive method with relatively negligible risk. Both, the normal CT findings of the adrenal gland and the normal variants in shape and position are described. With help of morphometry and image processing measurements of the size of the adrenal gland of 20 healthy patients were made and are listed; not only the respective normal variants but also hypo-hyperplasia are pointed out. Some examples are suitable for the illustration of pathologic conditions, such as inflammation and benign and malignant primary and secondary neoplasis. Finally, the value of adrenal gland CT is discussed with reference to the other radiologic methods.

The results presented in this article indicate that quantitative computed tomography provides a reliable means of evaluating and monitoring the many forms of osteoporosis and its various treatments. The greatest advantages of spinal QCT for noninvasive bone mineral measurement are its high precision, the high sensitivity of the vertebral spongiosa measurement site, and the potential for widespread application.