Ectromelia Virus Infections of Mice as a Model to Support the Licensure of Anti-Orthopoxvirus Therapeutics

The absence of herd immunity to orthopoxviruses and the concern that variola or monkeypox viruses could be used for bioterroristic activities has stimulated the development of therapeutics and safer prophylactics. One major limitation in this process is the lack of accessible human orthopoxvirus infections for clinical efficacy trials; however, drug licensure can be based on orthopoxvirus animal challenge models as described in the “Animal Efficacy Rule”. One such challenge model uses ectromelia virus, an orthopoxvirus, whose natural host is the mouse and is the etiological agent of mousepox. The genetic similarity of ectromelia virus to variola and monkeypox viruses, the common features of the resulting disease, and the convenience of the mouse as a laboratory animal underscores its utility in the study of orthopoxvirus pathogenesis and in the development of therapeutics and prophylactics. In this review we outline how mousepox has been used as a model for smallpox. We also discuss mousepox in the context of mouse strain, route of infection, infectious dose, disease progression, and recovery from infection

Caltech: Using our IR with Campus Research Groups

We have expanded the IR into a service that meets the needs of groups and centers on campus. As research dollars become scarce, research support often comes with a requirement to demonstrate a return on investment (ROI). The IR can help groups and centers meet this requirement by assisting with publications lists

Development of CMX001 for the Treatment of Poxvirus Infections

CMX001 (phosphonic acid, [[(S)-2-(4-amino-2-oxo-1(2H)-pyrimidinyl)-1-(hydroxymethyl)ethoxy]methyl]mono[3-(hexadecyloxy)propyl] ester) is a lipid conjugate of the acyclic nucleotide phosphonate, cidofovir (CDV). CMX001 is currently in Phase II clinical trials for the prophylaxis of human cytomegalovirus infection and under development using the Animal Rule for smallpox infection. It has proven effective in reduction of morbidity and mortality in animal models of human smallpox, even after the onset of lesions and other clinical signs of disease. CMX001 and CDV are active against all five families of double-stranded DNA (dsDNA) viruses that cause human morbidity and mortality, including orthopoxviruses such as variola virus, the cause of human smallpox. However, the clinical utility of CDV is limited by the requirement for intravenous dosing and a high incidence of acute kidney toxicity. The risk of nephrotoxicity necessitates pre-hydration and probenecid administration in a health care facility, further complicating high volume CDV use in an emergency situation. Compared with CDV, CMX001 has a number of advantages for treatment of smallpox in an emergency including greater potency in vitro against all dsDNA viruses that cause human disease, a high genetic barrier to resistance, convenient oral administration as a tablet or liquid, and no evidence to date of nephrotoxicity in either animals or humans. The apparent lack of nephrotoxicity observed with CMX001 in vivo is because it is not a substrate for the human organic anion transporters that actively secrete CDV into kidney cells. The ability to test the safety and efficacy of CMX001 in patients with life-threatening dsDNA virus infections which share many basic traits with variola is a major advantage in the development of this antiviral for a smallpox indication

Sequential simulation (SqS) of clinical pathways: a tool for public and patient engagement in point-of-care diagnostics

Objectives: Public and patient engagement (PPE) is fundamental to healthcare research. To facilitate effective engagement in novel point-of-care tests (POCTs), the test and downstream consequences of the result need to be considered. Sequential simulation (SqS) is a tool to represent patient journeys and the effects of intervention at each and subsequent stages. This case study presents a process evaluation of SqS as a tool for PPE in the development of a volatile organic compound-based breath test POCT for the diagnosis of oesophagogastric (OG) cancer. Setting: Three 3-hour workshops in central London. Participants: 38 members of public attended a workshop, 26 (68%) had no prior experience of the OG cancer diagnostic pathway. Interventions: Clinical pathway SqS was developed from a storyboard of a patient, played by an actor, noticing symptoms of oesophageal cancer and following a typical diagnostic pathway. The proposed breath testing strategy was then introduced and incorporated into a second SqS to demonstrate pathway impact. Facilitated group discussions followed each SqS. Primary and secondary outcome measures: Evaluation was conducted through pre-event and postevent questionnaires, field notes and analysis of audiovisual recordings. Results: 38 participants attended a workshop. All participants agreed they were able to contribute to discussions and like the idea of an OG cancer breath test. Five themes emerged related to the proposed new breath test including awareness of OG cancer, barriers to testing and diagnosis, design of new test device, new clinical pathway and placement of test device. 3 themes emerged related to the use of SqS: participatory engagement, simulation and empathetic engagement, and why participants attended. Conclusions: SqS facilitated a shared immersive experience for participants and researchers that led to the coconstruction of knowledge that will guide future research activities and be of value to stakeholders concerned with the invention and adoption of POCT

Efficacy of CMX001 as a Prophylactic and Presymptomatic Antiviral Agent in New Zealand White Rabbits Infected with Rabbitpox Virus, a Model for Orthopoxvirus Infections of Humans

CMX001, a lipophilic nucleotide analog formed by covalently linking 3-(hexdecyloxy)propan-1-ol to cidofovir (CDV), is being developed as a treatment for smallpox. CMX001 has dramatically increased potency versus CDV against all dsDNA viruses and, in contrast to CDV, is orally available and has shown no evidence of nephrotoxicity in healthy volunteers or severely ill transplant patients to date. Although smallpox has been eliminated from the environment, treatments are urgently being sought due to the risk of smallpox being used as a bioterrorism agent and for monkeypox virus, a zoonotic disease of Africa, and adverse reactions to smallpox virus vaccinations. In the absence of human cases of smallpox, new treatments must be tested for efficacy in animal models. Here we first review and discuss the rabbitpox virus (RPV) infection of New Zealand White rabbits as a model for smallpox to test the efficacy of CMX001 as a prophylactic and early disease antiviral. Our results should also be applicable to monkeypox virus infections and for treatment of adverse reactions to smallpox vaccination

Evolving library services in the ever-​changing world of chemical information: From printed to electronic to networked

Access to chem. information has evolved dramatically over the past 50 years, from printed to electronic to networked. Channeling and focusing this torrent of information to meet the specific needs of researchers has increased exponentially over time, and has required librarians to become beta testers, instructors, and negotiators. Dana Roth's contributions to chem. information, and to the field of librarianship as a whole, cannot be overestimated. This talk will highlight key contributions that Roth has made to the relationships between the Caltech Library and publishers, and between the Library and the campus research community. These relationships continue to flourish and expand, and examples of past efforts and current projects from across the Caltech Library will be discussed

Pressed for Space: The Effects of Justification and the Printing Process on Fifteenth-Century Orthography

There is a long-held belief that, prior to the standardisation of written English, printers altered spellings to justify their type. I investigate this claim through an analysis of spelling changes in William Caxton’s two editions of the Canterbury Tales—by examining text within one book, written by one author, and set by one compositor, the only difference between the sections of verse and the sections of prose should be the requirement for justification within the latter. Were the compositors altering spellings to justify their type, we would expect to see a greater number of altered spellings in the prose sections of text. This is not what the results of this study show—instead there is no statistically significant difference between the frequency of spelling changes in justified and non-justified text. However, there is a significantly higher number of abbreviations introduced into the justified text. These results suggest that the compositor of Caxton’s second edition Canterbury Tales did not change spellings to justify his type