A novel antifolate suppresses growth of FPGS-deficient cells and overcomes methotrexate resistance

Cancer cells make extensive use of the folate cycle to sustain increased anabolic metabolism. Multiple chemotherapeutic drugs interfere with the folate cycle, including methotrexate and 5-fluorouracil that are commonly applied for the treatment of leukemia and colorectal cancer (CRC), respectively. Despite high success rates, therapy-induced resistance causes relapse at later disease stages. Depletion of folylpolyglutamate synthetase (FPGS), which normally promotes intracellular accumulation and activity of natural folates and methotrexate, is linked to methotrexate and 5-fluorouracil resistance and its association with relapse illustrates the need for improved intervention strategies. Here, we describe a novel antifolate (C1) that, like methotrexate, potently inhibits dihydrofolate reductase and downstream one-carbon metabolism. Contrary to methotrexate, C1 displays optimal efficacy in FPGS-deficient contexts, due to decreased competition with intracellular folates for interaction with dihydrofolate reductase. We show that FPGS-deficient patient-derived CRC organoids display enhanced sensitivity to C1, whereas FPGS-high CRC organoids are more sensitive to methotrexate. Our results argue that polyglutamylation-independent antifolates can be applied to exert selective pressure on FPGS-deficient cells during chemotherapy, using a vulnerability created by polyglutamylation deficiency

A novel antifolate suppresses growth of FPGS-deficient cells and overcomes methotrexate resistance

Cancer cells make extensive use of the folate cycle to sustain increased anabolic metabolism. Multiple chemotherapeutic drugs interfere with the folate cycle, including methotrexate and 5-fluorouracil that are commonly applied for the treatment of leukemia and colorectal cancer (CRC), respectively. Despite high success rates, therapy-induced resistance causes relapse at later disease stages. Depletion of folylpolyglutamate synthetase (FPGS), which normally promotes intracellular accumulation and activity of natural folates and methotrexate, is linked to methotrexate and 5-fluorouracil resistance and its association with relapse illustrates the need for improved intervention strategies. Here, we describe a novel antifolate (C1) that, like methotrexate, potently inhibits dihydrofolate reductase and downstream one-carbon metabolism. Contrary to methotrexate, C1 displays optimal efficacy in FPGS-deficient contexts, due to decreased competition with intracellular folates for interaction with dihydrofolate reductase. We show that FPGS-deficient patient-derived CRC organoids display enhanced sensitivity to C1, whereas FPGS-high CRC organoids are more sensitive to methotrexate. Our results argue that polyglutamylation-independent antifolates can be applied to exert selective pressure on FPGS-deficient cells during chemotherapy, using a vulnerability created by polyglutamylation deficiency

Process intensification education contributes to sustainable development goals: Part 2

Achieving the United Nations sustainable development goals requires industry and society to develop tools and processes that work at all scales, enabling goods delivery, services, and technology to large conglomerates and remote regions. Process Intensification (PI) is a technological advance that promises to deliver means to reach these goals, but higher education has yet to totally embrace the program. Here, we present practical examples on how to better teach the principles of PI in the context of the Bloom's taxonomy and summarise the current industrial use and the future demands for PI, as a continuation of the topics discussed in Part 1. In the appendices, we provide details on the existing PI courses around the world, as well as teaching activities that are showcased during these courses to aid students’ lifelong learning. The increasing number of successful commercial cases of PI highlight the importance of PI education for both students in academia and industrial staff.We acknowledge the sponsors of the Lorentz’ workshop on“Educating in PI”: The MESA+Institute of the University of Twente,Sonics and Materials (USA) and the PIN-NL Dutch Process Intensi-fication Network. DFR acknowledges support by The Netherlands Centre for Mul-tiscale Catalytic Energy Conversion (MCEC), an NWO Gravitationprogramme funded by the Ministry of Education, Culture and Sci-ence of the government of The Netherlands. NA acknowledges the Deutsche Forschungsgemeinschaft (DFG)- TRR 63¨Integrierte Chemische Prozesse in flüssigen Mehrphasen-systemen¨(Teilprojekt A10) - 56091768. The participation by Robert Weber in the workshop and thisreport was supported by Laboratory Directed Research and Devel-opment funding at Pacific Northwest National Laboratory (PNNL).PNNL is a multiprogram national laboratory operated for theUS Department of Energy by Battelle under contract DE-AC05-76RL0183

Process intensification education contributes to sustainable development goals : part 1

In 2015 all the United Nations (UN) member states adopted 17 sustainable development goals (UN-SDG) as part of the 2030 Agenda, which is a 15-year plan to meet ambitious targets to eradicate poverty, protect the environment, and improve the quality of life around the world. Although the global community has progressed, the pace of implementation must accelerate to reach the UN-SDG time-line. For this to happen, professionals, institutions, companies, governments and the general public must become cognizant of the challenges that our world faces and the potential technological solutions at hand, including those provided by chemical engineering. Process intensification (PI) is a recent engineering approach with demonstrated potential to significantly improve process efficiency and safety while reducing cost. It offers opportunities for attaining the UN-SDG goals in a cost-effective and timely manner. However, the pedagogical tools to educate undergraduate, graduate students, and professionals active in the field of PI lack clarity and focus. This paper sets out the state-of-the-art, main discussion points and guidelines for enhanced PI teaching, deliberated by experts in PI with either an academic or industrial background, as well as representatives from government and specialists in pedagogy gathered at the Lorentz Center (Leiden, The Netherlands) in June 2019 with the aim of uniting the efforts on education in PI and produce guidelines. In this Part 1, we discuss the societal and industrial needs for an educational strategy in the framework of PI. The terminology and background information on PI, related to educational implementation in industry and academia, are provided as a preamble to Part 2, which presents practical examples that will help educating on Process Intensification

Chemistry and reaction kinetics of biowaste torrefaction

This thesis addresses the question of how the chemistry and reaction kinetics of torrefaction are influenced by reaction conditions and the effects occuring during the reaction. This research question can be specified by questions such as, what controls their kinetics during torrefaction and what does this mean, which products are formed, what are the mass - and energy balances, and what is the endothermal and/or exothermal behaviour. In future energy scenarios an important role in the (renewable) energy supply is given to biomass. The unique position of biomass as the only renewable source for sustainable carbon carrier makes biomass an attractive energy source. Biomass as energy source has some typical characteristics making it a specific, but complicated fuel for the future. Some biomass properties are inconvenient, particularly its high oxygen content, a low calorific value, the hydrophilic nature and there with connected high moisture content. Other disadvantages of biomass are its tenacious and fibrous structure and its inhomogeneous composition. This makes process design and process control complicated. Torrefaction is a technology that can improve biomass properties and therefore offers solutions to the above problems. Torrefaction is a thermal pre-treatment technology to upgrade ligno-cellulosic biomass to a higher quality and more attractive biofuel. The main principle of torrefaction, from a chemical point of view, is the removal of oxygen leading to a final solid product: the torrefied biomass having a lower O/C ratio compared to the original biomass. The heart of the torrefaction technology is the reactor concept. In the development of the torrefaction system knowledge it is important to obtain a good insight into the mechanisms of torrefaction at fundamental level. Torrefaction is a complex process which involves many physical and chemical processes such as heat transfer, moisture evaporation, decomposition kinetics, heat of torrefaction, pressure build up in the solid, changes in material properties all in relation with torrefaction temperature. Further the material is inherently anisotropic. Research at this level can give better information about the quality of the torrefaction. The thesis can be divided into three parts. In the first part a broad literature review about pyrolysis and torrefaction is carried out. The second part gives the experimental section in which the chemistry and reaction kinetics have been studied extensively with the help of different experimental methods. The final part gives an overview on the-state-of-the-art of different commercial torrefaction initiatives to further assist reactor technology. Although pyrolysis and torrefaction operate in a different temperature regime, pyrolysis type research is applied for exploring torrefaction of biowaste resources. The chemical principles and different reaction mechanisms are to get insight into the torrefaction characteristics. Due to the different reaction temperatures differences between pyrolysis and torrefaction are observed in the final product composition and reaction rates. The weight loss kinetics of different biowaste resources and its constituents are determined by thermogravimetric analysis at a milligram scale. The reaction kinetics are modeled based on existing pyrolysis reaction models. On the basis of the mathematical results only, it cannot be stated how the biomass decomposes during torrefaction. Different assumptions on the kinetics lead to identical mathematical formulations. Hence, it is found that biomass torrefaction follows the classical methods of reaction kinetics. During biomass torrefaction two different phases on these categories react independently of each other. The slow reacting phase has high availability and the fast reacting phase has an apparent temperature dependence of the (low) availability. The products formed during torrefaction of different biowaste streams have been determined in a small scale fixed bed reactor (0 – 10 g) and thermogravimetric analysis coupled with mass spectroscopy and Fourier Transformed Infrared. In the fixed bed reactor the torrefied wood, the condensable and non-condensable gases are quantified offline with elemental analysis, gas chromatography/mass spectroscopy and micro gas chromatography. The fast reacting phase with low availability produces small molecular products even as the slow reacting phase with high availability, but this phase also produces higher molecular weight products and aromatic compounds. Finally, the energy balance of the torrefaction of beech wood is determined. The heat of reaction that is found is between 0.7 MJ/kg biomass endothermic and -0.8 MJ/kg biomass exothermic for reaction temperatures between 230 and 280°C. Finally, the influence of torrefaction on large cylindrical wood particles with diameters between 10 and 28 mm for beech and willow wood has been investigated. Fixed bed experiments are carried out at temperatures between 200 - 300°C to determine the product composition and the intra particle temperature profile depending on location, time and temperature. The condensable products are characterized and the exothermal effect is quantified. It is shown that the maximum temperature increase due to this exothermal effect is between 40°C inside a large particle. Also an analytical mathematical model has been developed based on the reaction mechanism found with thermogravimetric analysis and for the kinetic modelling to describe this internal temperature profile. Some modifications are applied to the model found to describe the weight loss kinetics. The model describes the temperature profile in the particle as a function of time, temperature, location and the progress of the reaction. The high number of required numerical parameters limits the numerical validation of the torrefaction model and makes biomass modeling complicated

Process intensification education contributes to sustainable development goals. Part 1

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Process intensification education contributes to sustainable development goals. Part 1

In 2015 all the United Nations (UN) member states adopted 17 sustainable development goals (UN-SDG) as part of the 2030 Agenda, which is a 15-year plan to meet ambitious targets to eradicate poverty, protect the environment, and improve the quality of life around the world. Although the global community has progressed, the pace of implementation must accelerate to reach the UN-SDG time-line. For this to happen, professionals, institutions, companies, governments and the general public must become cognizant of the challenges that our world faces and the potential technological solutions at hand, including those provided by chemical engineering. Process intensification (PI) is a recent engineering approach with demonstrated potential to significantly improve process efficiency and safety while reducing cost. It offers opportunities for attaining the UN-SDG goals in a cost-effective and timely manner. However, the pedagogical tools to educate undergraduate, graduate students, and professionals active in the field of PI lack clarity and focus. This paper sets out the state-of-the-art, main discussion points and guidelines for enhanced PI teaching, deliberated by experts in PI with either an academic or industrial background, as well as representatives from government and specialists in pedagogy gathered at the Lorentz Center (Leiden, The Netherlands) in June 2019 with the aim of uniting the efforts on education in PI and produce guidelines. In this Part 1, we discuss the societal and industrial needs for an educational strategy in the framework of PI. The terminology and background information on PI, related to educational implementation in industry and academia, are provided as a preamble to Part 2, which presents practical examples that will help educating on Process Intensification