Targeting tumour proliferation with a small-molecule inhibitor of AICAR transformylase homodimerization

Aminoimidazole carboxamide ribonucleotide transformylase/ inosine monophosphate cyclohydrolase (ATIC) is a bifunctional homodimeric enzyme that catalyzes the last two steps of de novo purine biosynthesis. Homodimerization of ATIC, a protein–protein interaction with an interface of over 5000 Ų, is required for its aminoimidazole carboxamide ribonucleotide (AICAR) transformylase activity, with the active sites forming at the interface of the interacting proteins. Here, we report the development of a small‐molecule inhibitor of AICAR transformylase that functions by preventing the homodimerization of ATIC. The compound is derived from a previously reported cyclic hexapeptide inhibitor of AICAR transformylase (with a K_i of 17 μM ), identified by high‐throughput screening. The active motif of the cyclic peptide is identified as an arginine‐tyrosine dipeptide, a capped analogue of which inhibits AICAR transformylase with a K_i value of 84 μM . A library of nonnatural analogues of this dipeptide was designed, synthesized, and assayed. The most potent compound inhibits AICAR transformylase with a K_i value of 685 nM , a 25‐fold improvement in activity from the parent cyclic peptide. The potential for this AICAR transformylase inhibitor in cancer therapy was assessed by studying its effect on the proliferation of a model breast cancer cell line. Using a nonradioactive proliferation assay and live cell imaging, a dose‐dependent reduction in cell numbers and cell division rates was observed in cells treated with our ATIC dimerization inhibitor.     

Trends in chemical engineering education: Process, product and sustainable chemical engineering challenges

Teaching chemical engineering has always been faced with a dilemma: either keep in touch with industry needs or incorporate new scientific concepts into the curriculum. In this paper, a short historical analysis of the evolution of chemical engineering teaching is presented and the recent trends of the two previous facets (industry and science) are briefly reviewed. The process vs product engineering concept is proposed as one of the means to achieve a better alignment between the curriculum and industry needs. A chemical engineering teaching framework, based in part on a product and a process oriented component, which has been in place in our department 5 years ago, is described and discussed. The concept of sustainable chemistry, including process and product considerations, which can be seen as the next frontier in chemical engineering education, is finally analysed from the education point of view.     

Integrative chemical product design strategies: Reflecting industry trends and challenges

A review of integrative product design strategies is motivated by current trends and challenges faced by the chemical processing industry. The transition in the chemical process industry towards more complex formulated and structured products challenges existing approaches and scientific tools that are well suited for bulk chemical design and properties estimation (Charpentier and McKenna, 2004, Favre et al., 2002). Moreover, the ensuing market challenges, brought on by dominant global trends, demand efficient product design approaches that seek to balance technical specifications and market requirements with the business performance objectives. Integrative approaches to product design are therefore repositioned as useful strategies that simultaneously enhance technical performance and efficiency in design execution. The discussion of the integrative product design strategies is supported by findings of a recent industry benchmark study involving 15 chemical manufacturers.     

Opportunities and challenges for a Golden Age of chemical engineering

Chemical engineering is entering a new Golden Age of practice, thought, and impact, accompanied by great new opportunities and challenges. Five aspects mark this development: a new abundance of hydrocarbons; the evolution of biology into a molecular science; the ubiquity of powerful computational tools; the trend in manufacturing to be more process-oriented; and the systems approach that is part of ChE education from its first stages. There are important technical challenges, including technology creation and environmental impact, but just as important are new appreciation for and attention to challenges that require societal dialogues about complexity, uncertainty, and evolving and sometimes contradictory requirements. Crucial to all these impacts is enhancing the identity of what the profession is. That must be based on recognizing that the core of chemical engineering is applying molecular sciences to create value and advance the quality of life.     

Targeting Lipocalin-2 in Inflammatory Breast Cancer Cells with Small Interference RNA and Small Molecule Inhibitors

Inflammatory Breast Cancer (IBC) is an aggressive form of invasive breast cancer, highly metastatic, representing 2–4% of all breast cancer cases in the United States. Despite its rare nature, IBC is responsible for 7–10% of all breast cancer deaths, with a 5-year survival rate of 40%. Thus, targeted and effective therapies against IBC are needed. Here, we proposed Lipocalin-2 (LCN2)—a secreted glycoprotein aberrantly abundant in different cancers—as a plausible target for IBC. In immunoblotting, we observed higher LCN2 protein levels in IBC cells than non-IBC cells, where the LCN2 levels were almost undetectable. We assessed the biological effects of targeting LCN2 in IBC cells with small interference RNAs (siRNAs) and small molecule inhibitors. siRNA-mediated LCN2 silencing in IBC cells significantly reduced cell proliferation, viability, migration, and invasion. Furthermore, LCN2 silencing promoted apoptosis and arrested the cell cycle progression in the G0/G1 to S phase transition. We used in silico analysis with a library of 25,000 compounds to identify potential LCN2 inhibitors, and four out of sixteen selected compounds significantly decreased cell proliferation, cell viability, and the AKT phosphorylation levels in SUM149 cells. Moreover, ectopically expressing LCN2 MCF7 cells, treated with two potential LCN2 inhibitors (ZINC00784494 and ZINC00640089) showed a significant decrease in cell proliferation. Our findings suggest LCN2 as a promising target for IBC treatment using siRNA and small molecule inhibitors.     

Therapeutic Targeting of Alternative RNA Splicing in Gastrointestinal Malignancies and Other Cancers

Recent comprehensive genomic studies including single-cell RNA sequencing and characterization have revealed multiple processes by which protein-coding and noncoding RNA processing are dysregulated in many cancers. More specifically, the abnormal regulation of mRNA and precursor mRNA (pre-mRNA) processing, which includes the removal of introns by splicing, is frequently altered in tumors, producing multiple different isoforms and diversifying protein expression. These alterations in RNA processing result in numerous cancer-specific mRNAs and pathogenically spliced events that generate altered levels of normal proteins or proteins with new functions, leading to the activation of oncogenes or the inactivation of tumor suppressor genes. Abnormally spliced pre-mRNAs are also associated with resistance to cancer treatment, and certain cancers are highly sensitive to the pharmacological inhibition of splicing. The discovery of these alterations in RNA processing has not only provided new insights into cancer pathogenesis but identified novel therapeutic vulnerabilities and therapeutic opportunities in targeting these aberrations in various ways (e.g., small molecules, splice-switching oligonucleotides (SSOs), and protein therapies) to modulate alternative RNA splicing or other RNA processing and modification mechanisms. Some of these strategies are currently progressing toward clinical development or are already in clinical trials. Additionally, tumor-specific neoantigens produced from these pathogenically spliced events and other abnormal RNA processes provide a potentially extensive source of tumor-specific therapeutic antigens (TAs) for targeted cancer immunotherapy. Moreover, a better understanding of the molecular mechanisms associated with aberrant RNA processes and the biological impact they play might provide insights into cancer initiation, progression, and metastasis. Our goal is to highlight key alternative RNA splicing and processing mechanisms and their roles in cancer pathophysiology as well as emerging therapeutic alternative splicing targets in cancer, particularly in gastrointestinal (GI) malignancies.     

Optimal control and the Pontryagin's principle in chemical engineering: History,theory, and challenges

In the mid-1950s, Pontryagin et al. published a principle that became a fundamental concept in optimal control (OC) theory. The principle provides theoretical and practical methods to find the solution of OC problems, in particular, open-loop control problems. In chemical engineering, the principle has played an important role as a decision making framework for more than 60 years. This study gathers the main contributions on the application of the Pontryagin's principle to the dynamic optimization of chemical processes. A concise overview of the optimality conditions for a wide class of constrained OC problems is provided. Numerical methods to solve the necessary conditions and strategies to address inequality constraints are summarized. The information and illustrative case study presented in this work can be used as a guide to implement the principle in different settings. Opportunities for further application of the principle in relevant chemical engineering problems are also discussed.     

煤直接液化技术发展的化学脉络及化学工程挑战

从对煤直接液化的化学本质的分析入手,讨论了煤直接液化技术发展的化学脉络及所面临的化学工程挑战。作者认为,煤直接液化技术的化学本质是煤大分子结构在热场中裂解产生自由基碎片的速率和自由基碎片加氢的速率的匹配,这两个速率的差异决定了煤浆预热、煤液化反应,甚至高温条件下产物分离等过程的特征,决定了油收率、系统中物料结焦、物料输送等行为。     

Nanoscale carriers for targeted delivery of drugs and therapeutic biomolecules

This review highlights the recent developments in the area of nanocarrier‐based targeted delivery systems for both conventional drugs and therapeutic agents of increased complexity. A challenging objective of targeted drug delivery is the development of novel nanocarriers for the delivery of protein/peptide drugs via the oral, pulmonary and nasal administration routes. The nanocarriers need to be biocompatible, biodegradable, non‐toxic and stable in biological media, to protect their payload and deliver it to desired sites within the body, preferentially in a temporally regulated manner, and on the other hand to be manufactured in a simple scalable manner, with relatively low cost. © 2012 Canadian Society for Chemical Engineering     

Membranes for Kraft black liquor concentration and chemical recovery: Current progress,challenges, and opportunities

Membranes can significantly reduce energy consumption during concentration of black liquor (BL) in the Kraft papermaking process, but the harsh conditions (pH ~12, 80°C–95°C, ~15 wt% solids) make this challenging. We elucidate challenges and opportunities for membranes in BL applications. We critically review membrane materials, processes, and operational modes investigated in the literature. Future advances will involve fabrication of higher-rejecting (≥95% lignin and inorganics), BL-resistant, NF, and RO membranes. Opportunities exist for molecular sieving and electrically driven membranes to recover other valuable chemicals such as carboxylic acids. We also discuss the economics of BL concentration with a single-stage membrane process.     

流化床化学气相沉积多晶硅的技术进步与挑战

Various methods for production of polysilicon have been proposed for lowering the production cost and energy consumption, and enhancing productivity, which are critical for industrial applications. The fluidized bed chemical vapor deposition (FBCVD) method is a most promising alternative to conventional ones, but the homogeneous reaction of silane in FBCVD results in unwanted formation of fines, which will affect the product quality and output. There are some other problems, such as heating degeneration due to undesired polysilicon deposition on the walls of the reactor and the heater. This article mainly reviews the technological develop-ment on FBCVD of polycrystalline silicon and the research status for solving the above problems. It also identifies a number of chal-lenges to tackle and principles should be followed in the design of a FBCVD reactor.     

木聚糖生物转化药物、能源和化工中间体

介绍了木聚糖的结构与酶糖化机理,综述了国内外对木聚糖生物转化方面的研究.详细介绍了木聚糖转化为低聚木糖和木糖醇等医药食品、燃料乙醇和2,3-丁二醇等能源物质、乳酸和糠醛等化工中间体的研究进展.     

从多尺度到介尺度——复杂化工过程模拟的新挑战

化工过程普遍面对具有多尺度结构的复杂系统,而作为从基本单元相互作用形成系统整体行为与功能的关键环节,介尺度结构对化工过程的定量描述和定向调控具有重要意义。同时,化学、材料、生物、物理和系统科学等领域也都逐步认识到各自的介尺度问题及其共同特性。这表明对介尺度结构与行为共性的深入研究将对科学界产生全局性的影响,同时也表明这样的研究必须通过多学科充分交流、紧密合作才能取得重大进展。本文试图从多尺度研究的背景出发探讨化工及相关过程中介尺度模拟的意义、挑战和方法,并展望其发展。     

WTO过渡期结束后中国石油和化工建设的机遇与挑战

入世三年了,我国石油石化业度过了入世三年过渡期的不平凡岁月,内外环境发生了巨大深刻而又不可逆转的变化,在应对、调整、做强、发展等方面取得了阶段性的成果。挑战与机遇并存,是入世三年的真实写照。以中国石油、中国石化和中国海油为代表的中国石油石化行业抓住机遇,积极应对,以做大做强、深化改革、持续重组、抓紧结构调整、大力提高国际竞争力、实施“走出去”战略为重点大做文章,成效显著,初战告捷。一.油气勘探方面东部油田稳中有降,西部油田产能增加;五大气区格局并举,输气干线东西贯通在油气勘探开发领域,我国三大石油石化公司利…     

In Vitro Evaluation of Bis-3-Chloropiperidines as RNA Modulators Targeting TAR and TAR-Protein Interaction

After a long limbo, RNA has gained its credibility as a druggable target, fully earning its deserved role in the next generation of pharmaceutical R&D. We have recently probed the trans-activation response (TAR) element, an RNA stem–bulge–loop domain of the HIV-1 genome with bis-3-chloropiperidines (B-CePs), and revealed the compounds unique behavior in stabilizing TAR structure, thus impairing in vitro the chaperone activity of the HIV-1 nucleocapsid (NC) protein. Seeking to elucidate the determinants of B-CePs inhibition, we have further characterized here their effects on the target TAR and its NC recognition, while developing quantitative analytical approaches for the study of multicomponent RNA-based interactions.