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Immunotoxins are rationally designed cancer targeting and killing agents. Disulfide stabilized antibody Fv portion—toxin conjugates (dsFv-toxin) are third generation immunotoxins containing only the antibody fragment variable portions and a toxin fused to the V H or V L . Pseudomonas exotoxin fragment (PE-38) is a commonly used toxin in immunotoxin clinical trials. dsFv-toxin purification was previously published, but the recovery was not satisfactory. This report describes the development of a cGMP production process of the dsFv-toxin that incorporated a novel purification method. The method has been successfully applied to the clinical manufacturing of two dsFv-PE38 immunotoxins, MR1-1 targeting EGFRvIII and HA22 targeting CD22. The two subunits, V L and V H PE-38 were expressed separately in Escherichia coli using recombinant technology. Following cell lysis, inclusion bodies were isolated from the biomass harvested from fermentation in animal source component-free media. The dsFv-toxin was formed after denaturation and refolding, and subsequently purified to homogeneity through ammonium sulfate precipitation, hydrophobic interaction and ion-exchange chromatography steps. It was shown, in a direct comparison experiment using MR1-1 as model protein, that the recovery from the new purification method was improved three times over that from previously published method. The improved recovery was also demonstrated during the clinical production of two dsFv-PE38 immunotoxins—MR1-1 and HA22.

Bringing together scholars from the fields of musicology and international history, this book investigates the significance of music to foreign relations, and how it affected the interaction of nations since the late 19th century. For more than a century, both state and non-state actors have sought to employ sound and harmony to influence allies and enemies, resolve conflicts, and export their own culture around the world. This book asks how we can understand music as an instrument of power and influence, and how the cultural encounters fostered by music changes our ideas about international history.

Mediator-associated kinases CDK8/19 are context-dependent drivers or suppressors of tumorigenesis. Their inhibition is predicted to have pleiotropic effects, but it is unclear whether this will impact on the clinical utility of CDK8/19 inhibitors. We discovered two series of potent chemical probes with high selectivity for CDK8/19. Despite pharmacodynamic evidence for robust on-target activity, the compounds exhibited modest, though significant, efficacy against human tumor lines and patient-derived xenografts. Altered gene expression was consistent with CDK8/19 inhibition, including profiles associated with super-enhancers, immune and inflammatory responses and stem cell function. In a mouse model expressing oncogenic beta-catenin, treatment shifted cells within hyperplastic intestinal crypts from a stem cell to a transit amplifying phenotype. In two species, neither probe was tolerated at therapeutically-relevant exposures. The complex nature of the toxicity observed with two structurally-differentiated chemical series is consistent with on-target effects posing significant challenges to the clinical development of CDK8/19 inhibitors. Healthy cells in the human body can become cancerous if they gain genetic mutations that allow them to rapidly grow and divide. Some types of cancer respond better to drug treatments than others and tumors often develop resistance to a particular drug treatment after a while. Because of this, researchers are always searching for new molecules to develop into anticancer drugs. Recently, a team of researchers identified some small molecules that could inactivate two closely related proteins called CDK8 and CDK19. CDK8 is essential for the WNT signaling pathway – which enables cells to communicate with one another – and has been extensively studied in various cancers. Previous studies indicate that this protein can either promote or inhibit the growth of tumors, depending on the type and stage of the cancer. Furthermore, CDK8 regulates a type of molecular switch called a “super-enhancer”, which controls the activity of many genes. In contrast, the role of CDK19 in cells was not as well understood. Here Clarke, Ortiz-Ruiz et al. investigated whether two different classes of small molecules that target CDK8 and CDK19 (referred to as “prototype CDK8/19 drugs”) could inhibit the growth of cancers, and whether they have any harmful side effects on healthy cells. For the experiments, human cancer cells were implanted into mice. Treating these mice with prototype CDK8/19 drugs inhibited the activity of CDK8 and CDK19 in the cancer cells and slowed the growth of colorectal tumors. A type of blood cancer called acute myeloid leukaemia was particularly sensitive to the drugs. However, Clarke, Ortiz-Ruiz et al. also observed that the prototype drugs altered the activity of many genes with roles in healthy tissues such as immune, bone and stem cells. Further experiments in mice and cells grown in the laboratory confirmed that these prototype drugs have adverse effects on healthy intestinal and bone marrow stem cells and trigger changes to immune cells. These concerning side effects were also evident when the prototype drugs were tested in rats and dogs. Furthermore, the experiments indicate that there is not a suitable range of doses of these drugs in which the therapeutic benefits outweigh the toxic side effects. Clarke, Ortiz-Ruiz et al. conclude that the clinical development of CDK8/19 drugs will be extremely challenging and that their prototype drugs would not currently be suitable for use as cancer treatments. However, the small molecules they describe will be important probes in research to study exactly how CDK8/19 regulate gene activity in both healthy cells and cancers.

We present a new microstructure dataset consisting of ultrahigh carbon steel (UHCS) micrographs taken over a range of length scales under systematically varied heat treatments. Using the UHCS dataset as a case study, we develop a set of visualization tools for interacting with and exploring large microstructure and metadata datasets. Based on generic microstructure representations adapted from the field of computer vision, these tools enable image-based microstructure retrieval, as well as spatial maps of both microstructure and related metadata, such as processing conditions or properties measurements. We provide the microstructure image data, processing metadata, and source code for these microstructure exploration tools. The UHCS dataset is intended as a community resource for development and evaluation of microstructure data science techniques and for creation of microstructure data science teaching modules.

The Cold War was not simply a duel of superpowers. It took place not just in Washington and Moscow but also in the social and political arenas of geographically far-flung countries emerging from colonial rule. Moreover, Cold War tensions were manifest not only in global political disputes but also in struggles over technology. Technological systems and expertise offered a powerful way to shape countries politically, economically, socially, and culturally. Entangled Geographiesexplores how Cold War politics, imperialism, and postcolonial nation building became entangled in technologies and considers the legacies of those entanglements for today's globalized world. The essays address such topics as the islands and atolls taken over for military and technological purposes by the supposedly non-imperial United States, apartheid-era South Africa's efforts to achieve international legitimacy as a nuclear nation, international technical assistance and Cold War politics, the Saudi irrigation system that spurred a Shi'i rebellion, and the momentary technopolitics of emergency as practiced by Medecins sans Frontières. The contributors to Entangled Geographies offer insights from the anthropology and history of development, from diplomatic history, and from science and technology studies. The book represents a unique synthesis of these three disciplines, providing new perspectives on the global Cold War.

Deforestation remains a prominent contributor to climate change and biodiversity loss. Yet while 76 million hectares of primary tropical forest have been lost since 2000, two thirds of tropical forests remain. What factors have been most important for protecting these forests? Unlike policies, which often have clearly defined spatial and temporal boundaries, the roles played by dynamic underlying political and economic structures, and their interactions with policies and emergent factors, can be challenging to identify. Expert knowledge can bridge this gap by revealing the full range of factors needed to achieve forest protection. Here, we conducted a Delphi study with 36 experts, focusing on the Brazilian Amazon and Indonesia. Our results highlight the importance of political will, civil society advocacy, and intergovernmental diplomacy, and shifts in the importance of different factors over time. These findings illuminate the interactions between international and national structures and policies in generating the conditions for forest protection.

Wikipedia articles about places, OpenStreetMap features, and other forms of peer-produced content have become critical sources of geographic knowledge for humans and intelligent technologies. In this paper, we explore the effectiveness of the peer production model across the rural/urban divide, a divide that has been shown to be an important factor in many online social systems. We find that in both Wikipedia and OpenStreetMap, peer-produced content about rural areas is of systematically lower quality, is less likely to have been produced by contributors who focus on the local area, and is more likely to have been generated by automated software agents (i.e. bots). We then codify the systemic challenges inherent to characterizing rural phenomena through peer production and discuss potential solutions.