Sequence-based BRCA testing can identify variants of unknown significance (VUS). Relatively little is known about how well a test outcome of VUS is understood by patients and referring physicians, ...and whether genetic counselors have an interest in the development of VUS management guidelines.
Self-administered questionnaires were completed by 36 VUS counselees, 75 women with a BRCA mutation and 33 with no mutation found (NMF). We also surveyed 24 genetic counselors and 22 referring family physicians.
One-third of VUS failed to recall the clinical significance of their result. Incorrect recall was significantly higher among VUS with high-school-only education (70% versus 19%, P = 0.02). Risk perception, cancer worry and uptake of surveillance and risk-reducing surgeries among VUS counselees were more similar to NMF than to mutation carriers. Genetic counselors accurately predicted the difficulties counselees would have with a VUS result and identified the need for VUS management guidelines. Referring physicians unanimously stated that genetic testing was indicated for unaffected siblings of VUS carriers.
While VUS seems to be correctly perceived by counselees as more similar to NMF than to a pathogenic mutation, miscomprehension of VUS is more common, particularly in counselees with lower education. VUS-related educational interventions for both VUS counselees and their referring physicians are needed. We encourage the development of national VUS-related guidelines for genetic counselors.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Reactive distillation (RD) is an efficient process intensification technique that integrates chemical reaction and distillation in a single apparatus. The process is also known as catalytic ...distillation when a solid catalyst is used. RD technology has many key advantages such as reduced capital investment and significant energy savings, as it can surpass equilibrium limitations, simplify complex processes, increase product selectivity, and improve separation efficiency. However, RD is also constrained by thermodynamic requirements (related to volatility differences and heat of reaction), the need to align the reaction and distillation operating conditions, and the availability of catalysts that are active, selective, and with sufficient longevity. This paper is the first to provide an overview and insights into novel integrated reactive distillation technologies that combine RD principles with other intensified distillation technologiese.g., dividing-wall column (DWC), cyclic distillation, HiGee distillation, heat-integrated distillation column (HIDiC), and membrane-, microwave-, or ultrasound-assisted distillationpotentially leading to the development of new processes and applications.
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IJS, KILJ, NUK, PNG, UL, UM
Kaposi's sarcoma herpesvirus (KSHV) is the etiologic agent of Kaposi's sarcoma (KS), a hyperplasia consisting of enlarged malformed vasculature and spindle-shaped cells, the main proliferative ...component of KS. While spindle cells express markers of lymphatic and blood endothelium, the origin of spindle cells is unknown. Endothelial precursor cells have been proposed as the source of spindle cells. We previously identified two types of circulating endothelial colony forming cells (ECFCs), ones that expressed markers of blood endothelium and ones that expressed markers of lymphatic endothelium. Here we examined both blood and lymphatic ECFCs infected with KSHV. Lymphatic ECFCs are significantly more susceptible to KSHV infection than the blood ECFCs and maintain the viral episomes during passage in culture while the blood ECFCs lose the viral episome. Only the KSHV-infected lymphatic ECFCs (K-ECFCLY) grew to small multicellular colonies in soft agar whereas the infected blood ECFCs and all uninfected ECFCs failed to proliferate. The K-ECFCLYs express high levels of SOX18, which supported the maintenance of high copy number of KSHV genomes. When implanted subcutaneously into NSG mice, the K-ECFCLYs persisted in vivo and recapitulated the phenotype of KS tumor cells with high number of viral genome copies and spindling morphology. These spindle cell hallmarks were significantly reduced when mice were treated with SOX18 inhibitor, SM4. These data suggest that KSHV-infected lymphatic ECFCs can be utilized as a KSHV infection model for in vivo translational studies to test novel inhibitors representing potential treatment modalities for KS.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Dysfunction of the androgen receptor (AR) signalling axis plays a pivotal role in the development and progression of prostate cancer (PCa). Steroidal and non-steroidal AR antagonists can ...significantly improve the survival of PCa patients by blocking the action of the endogenous ligand through binding to the hormone receptor and preventing its activation. Herein, we report two synthetic strategies, each utilizing the advantages of microwave irradiation, to modify the A-ring of natural androgen 5α-dihydrotestosterone (DHT) with pyridine scaffolds. Treatment of DHT with appropriate Mannich salts led to 1,5-diketones, which were then converted with hydroxylamine to A-ring-fused 6′-substituted pyridines. To extend the compound library with 4′,6′-disubstituted analogues, 2-arylidene derivatives of DHT were subjected to ring closure reactions according to the Kröhnke’s pyridine synthesis. The crystal structure of a monosubstituted pyridine product was determined by single crystal X-ray diffraction. AR transcriptional activity in a reporter cell line was investigated for all novel A-ring-fused pyridines and a number of previously synthesized DHT-based quinolines were included to the biological study to obtain information about the structure-activity relationship. It was shown that several A-ring-fused quinolines acted as AR antagonists, in comparison with the dual or agonist character of the majority of A-ring-fused pyridines. Derivative 1d (A-ring-fused 6′-methoxyquinoline) was studied in detail and showed to be a low-micromolar AR antagonist (IC50 = 10.5 µM), and it suppressed the viability and proliferation of AR-positive PCa cell lines. Moreover, the candidate compound blocked the AR downstream signalling, induced moderate cell-cycle arrest and showed to bind recombinant AR and to target AR in cells. The binding mode and crucial interactions were described using molecular modelling.
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•Novel A-ring fused pyridines of 5α-dihydrotestosterone have been synthesized.•The crystal structure of a representative pyridine derivative was determined.•32 compounds were investigated as AR modulators.•Lead compound 1d showed to be a low-micromolar AR antagonist.•The binding mode and interaction of 1d with the AR-LBD was described.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
► Dimethyl ether (DME) synthesis by methanol dehydration. ► Novel DME process based on a reactive dividing-wall column (R-DWC). ► High-purity DME product in one unit, with minimal footprint and lower ...costs. ► Optimized design using state of the art sequential quadratic programming (SQP). ► Significant energy savings of 12–58% and up to 30% lower capital investment costs.
Dimethyl ether (DME) is of great industrial interest due to its use as clean fuel for diesel engines or in combustion cells, as a precursor to other organic compounds, as well as a green aerosol propellant that can effectively replace chloro-fluoro-carbons. Conventionally, high purity DME is synthesized by dehydration of methanol produced from syngas, in a process involving a catalytic fixed-bed reactor and a direct sequence of two distillation columns.
The key problem of this classic process is the high investment costs for several units that require a large overall plant footprint, as well as the associated high energy requirements. To solve these problems, we propose in this work an innovative DME process based on a reactive dividing-wall column (R-DWC) that effectively integrates in one shell a reactive distillation (RD) unit with the DWC technology. The double integrated system allows the production of high-purity DME in only one unit, with minimal footprint and significantly lower costs.
This study also makes a fair comparison between the reported conventional DME process and the optimally designed process alternatives based on RD and R-DWC, respectively. All processes are optimized in terms of minimal energy requirements, using the state of the art sequential quadratic programming (SQP) method implemented in AspenTech Aspen Plus. The results clearly demonstrate that the R-DWC process has superior performances as compared to the conventional or RD process: significant energy savings of 12–58%, up to 60% reduced CO2 emissions, as well as up to 30% lower capital investment costs.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK
The article describes a new interferometric system for measuring the coil displacement in the BIPM Kibble balance. The system has led to a significant reduction in both the type A and type B ...uncertainty of the Kibble balance measurement. Compared to the previous version, the new instrument doubles the measurement signal thanks to a novel design. The optical and mechanical setup is more compact, more stable, and less sensitive to vibration noise. It is also more easily aligned, particularly for adjusting the interferometer beams vertically.
The need for greater sustainability for the production of fuels and chemicals has spurred significant research to rethink energy use in the chemical industry, and eventually substitute fossil fuel ...sources by renewable sources. Nowadays, the chemical industry is responsible for about one third of the total energy used - and the associated CO2 emissions - in the industrial sector. Among the energy intensive operations, distillation alone is responsible for about 40% of the energy used in the chemical industry, but there is clearly much room for improvement. This paper aims to provide an informative perspective on the current energy use in the chemical industry, with a focus on distillation – the undisputed king of industrial separation processes – and potential improvements for a more sustainable future. There is clearly an increasing need and scope for advanced distillation technologies (e.g. reactive distillation, dividing-wall columns, thermal coupling, cyclic distillation, heat pump assisted distillation, and heat integrated distillation columns) that can significantly reduce the energy usage and the carbon footprint of modern chemical plants. However, these advanced distillation technologies must be considered, along with conventional distillation operations, in the context of the process as a whole. Based on the overview provided, several challenges and opportunities for research directions are highlighted towards rethinking the energy use in distillation processes, for a more sustainable chemical industry.
•Addresses the energy use in the chemical industry and identifies the main issues.•Proposes effective ways to reduce the energy use in distillation for better sustainability.•Case study on complex column sequencing for a sub-ambient distillation system.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Communication in cancer care has become a major topic of interest. Since there is evidence that ineffective communication affects both patients and oncology clinicians (physicians and nurses), ...so-called communication skills trainings (CSTs) have been developed over the last decade. While these trainings have been demonstrated to be effective, there is an important heterogeneity with regard to implementation and with regard to evidence of different aspects of CST.
In order to review and discuss the scientific literature on CST in oncology and to formulate recommendations, the Swiss Cancer League has organised a consensus meeting with European opinion leaders and experts in the field of CST, as well as oncology clinicians, representatives of oncology societies and patient organisations. On the basis of a systematic review and a meta-analysis, recommendations have been developed and agreed upon.
Recommendations address (i) the setting, objectives and participants of CST, (ii) its content and pedagogic tools, (iii) organisational aspects, (iv) outcome and (v) future directions and research.
This consensus meeting, on the basis of European expert opinions and a systematic review and meta-analysis, defines key elements for the current provision and future development and evaluation of CST in oncology.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Currently furfural production has been the subject of increased interest because it is a biobased chemical able to compete with fossil-based chemicals. Furfural is characterized by flammability, ...explosion, and toxicity properties. Improper handling and process design can lead to catastrophic accidents. Hence it is of most importance to use inherent safety concepts during the design stage. This work is the first to present several new downstream separation processes for furfural purification, which are designed using an optimization approach that simultaneously considers safety criteria in addition to the total annual cost and the eco-indicator 99. The proposed schemes include thermally coupled configuration, thermodynamic equivalent configuration, dividing-wall column, and a heat integrated configuration. These are compared with the traditional separation process of furfural known as the Quaker Oats Process. The results show that because of a large amount of water present in the feed, similar values are obtained for total annual cost and eco-indicator 99 in all cases. Moreover, the topology of the processes has an important role in the safety criteria. The thermodynamic equivalent configuration resulted as the safest alternative with a 40% reduction of the inherent risk with respect to the Quaker Oats Process, and thus it is the safest option to purify furfural.
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IJS, KILJ, NUK, PNG, UL, UM
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•Novel 2-arylidene derivatives of 5α-dihydrotestosterone have been synthesized.•Heterocyclizations of the α,β-enones were performed with binucleophilic reagents.•Crystal structures of ...representative compounds were determined.•The transcription activity of the androgen receptor was found to be diminished.•A flexible docking study was performed.
One of the main directions of steroid research is the preparation of modified derivatives in which, in addition to changes in physicochemical properties, receptor binding is significantly altered, thus a bioactivity different from that of the parent compound predominates. In the frame of this work, 2-arylidene derivatives were first synthesized by regioselective modification of the A-ring of natural sex hormone, 5α-dihydrotestosterone (DHT). After Claisen-Schmidt condensations of DHT with (hetero)aromatic aldehydes in alkaline EtOH, heterocyclizations of the α,β-enones were performed with 3-amino-1,2,4-triazole, 3-aminopyrazole and 3-amino-5-methylpyrazole in the presence of t-BuOK in DMF to afford 7′-epimeric mixtures of A-ring-fused azolo-dihydropyrimidines, respectively. Depending on the electronic demand of the substituents of the arylidene moiety, spontaneous or 2,3-dichloro-5,6-dicyanobenzoquinone (DDQ)-induced oxidation of the heteroring led to triazolo1,5-apyrimidines and pyrazolo1,5-apyrimidines in good yields, while, using the Jones reagent as a strong oxidant, 17-oxidation also occurred. The crystal structures of an arylidene and a triazolopyrimidine product have been determined by single crystal X-ray diffraction and both were found to crystallize in the monoclinic crystal system at P21 space group. Most derivatives were found to diminish the transcriptional activity of androgen receptor (AR) in reporter cell line. The candidate compound (17β-hydroxy-2-(4-chloro)benzylidene-5α-androstan-3-one, 2f) showed to suppress androgen-mediated AR transactivation in a dose-dependent manner. We confirmed the cellular interaction of 2f with AR, described the binding in AR-binding cavity by the flexible docking and showed the ability of the compound to suppress the expression of AR-regulated genes in two prostate cancer cell lines.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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