Oncolytic herpes viruses, chemotherapeutics, and other cancer drugs

Oncolytic viruses are emerging as a potential new way of treating cancers. They are selectively replication-competent viruses that propagate only in actively dividing tumor cells but not in normal cells and, as a result, destroy the tumor cells by consequence of lytic infection. At least six different oncolytic herpes simplex viruses (oHSVs) have undergone clinical trials worldwide to date, and they have demonstrated an excellent safety profile and intimations of efficacy. The first pivotal Phase III trial with an oHSV, talimogene laherparepvec (T-Vec [OncoVex<sup>GM-CSF</sup>]), is almost complete, with extremely positive early results reported. Intuitively, therapeutically beneficial interactions between oHSV and chemotherapeutic and targeted therapeutic drugs would be limited as the virus requires actively dividing cells for maximum replication efficiency and most anticancer agents are cytotoxic or cytostatic. However, combinations of such agents display a range of responses, with antagonistic, additive, or, perhaps most surprisingly, synergistic enhancement of antitumor activity. When synergistic interactions in cancer cell killing are observed, chemotherapy dose reductions that achieve the same overall efficacy may be possible, resulting in a valuable reduction of adverse side effects. Therefore, the combination of an oHSV with “standard-of-care” drugs makes a logical and reasonable approach to improved therapy, and the addition of a targeted oncolytic therapy with “standard-of-care” drugs merits further investigation, both preclinically and in the clinic. Numerous publications report such studies of oncolytic HSV in combination with other drugs, and we review their findings here. Viral interactions with cellular hosts are complex and frequently involve intracellular signaling networks, thus creating diverse opportunities for synergistic or additive combinations with many anticancer drugs. We discuss potential mechanisms that may lead to synergistic interactions

Mass Spectrometry in the Elucidation of the Glycoproteome of Bacterial Pathogens

Presently some three hundred post-translational modifications are known to occur in bacteria in vivo. Many of these modifications play critical roles in the regulation of proteins and control key biological processes. One of the most predominant modifications, N- and O-glycosylations are now known to be present in bacteria (and archaea) although they were long believed to be limited to eukaryotes. In a number of human pathogens these glycans have been found attached to the surfaces of pilin, flagellin and other surface and secreted proteins where it has been demonstrated that they play a role in the virulence of these bacteria. Mass spectrometry characterization of these glycosylation events has been the enabling key technology for these findings. This review will look at the use of mass spectrometry as a key technology for the detection and mapping of these modifications within microorganisms, with particular reference to the human pathogens, Campylobacter jejuni and Mycobacterium tuberculosis. The overall aim of this review will be to give a basic understanding of the current ‘state-of-the-art’ of the key techniques, principles and technologies, including bioinformatics tools, involved in the analysis of the glycosylation modifications

Modeling Course-Based Undergraduate Research Experiences: An Agenda for Future Research and Evaluation

Course-based undergraduate research experiences (CUREs) are being championed as scalable ways of involving undergraduates in science research. Studies of CUREs have shown that participating students achieve many of the same outcomes as students who complete research internships. However, CUREs vary widely in their design and implementation, and aspects of CUREs that are necessary and sufficient to achieve desired student outcomes have not been elucidated. To guide future research aimed at understanding the causal mechanisms underlying CURE efficacy, we used a systems approach to generate pathway models representing hypotheses of how CURE outcomes are achieved. We started by reviewing studies of CUREs and research internships to generate a comprehensive set of outcomes of research experiences, determining the level of evidence supporting each outcome. We then used this body of research and drew from learning theory to hypothesize connections between what students do during CUREs and the outcomes that have the best empirical support. We offer these models as hypotheses for the CURE community to test, revise, elaborate, or refute. We also cite instruments that are ready to use in CURE assessment and note gaps for which instruments need to be developed.Howard Hughes Medical InstituteScience and Mathematics Educatio

Initial development of an ablative leading edge for the space shuttle orbiter

A state-of-the-art preliminary design for typical wing areas is developed. Seven medium-density ablators (with/without honeycomb, flown on Apollo, Prime, X15A2) are evaluated. The screening tests include: (1) leading-edge models sequentially subjected to ascent heating, cold soak, entry heating, post-entry pressure fluctuations, and touchdown shock, and (2) virgin/charred models subjected to bondline strains. Two honeycomb reinforced 30 pcf elastomeric ablators were selected. Roughness/recession degradation of low speed aerodynamics appears acceptable. The design, including attachments, substructure and joints, is presented

Application of digital particle image velocimetry to insect aerodynamics: measurement of the leading-edge vortex and near wake of a Hawkmoth.

Some insects use leading-edge vortices to generate high lift forces, as has been inferred from qualitative smoke visualisations of the flow around their wings. Here we present the first Digital Particle Image Velocimetry (DPIV) data and quantitative analysis of an insect’s leading-edge vortex and near wake at two flight speeds. This allows us to describe objectively 2D slices through the flow field of a tethered Tobacco Hawkmoth (Manduca sexta). The near-field vortex wake appears to braodly resemble elliptical vortex loops. The presence of a leading-edge vortex towards the end of the downstroke is found to coincide with peak upward force production measured by a six-component force–moment balance. The topology of Manduca’s leading-edge vortex differs from that previously described because late in the downstroke, the structure extends continuously from wingtip across the thorax to the other wingtip

Biomechanical comparison of the track start and the modified one-handed track start in competitive swimming: an intervention study

This study compared the conventional track and a new one-handed track start in elite age group swimmers to determine if the new technique had biomechanical implications on dive performance. Five male and seven female GB national qualifiers participated (mean ± SD: age 16.7 ± 1.9 years, stretched stature 1.76 ± 0.8 m, body mass 67.4 ± 7.9 kg) and were assigned to a control group (n = 6) or an intervention group (n = 6) that learned the new onehanded dive technique. All swimmers underwent a 4-week intervention comprising 12 ± 3 thirty-minute training sessions. Video cameras synchronized with an audible signal and timing suite captured temporal and kinematic data. A portable force plate and load cell handrail mounted to a swim starting block collected force data over 3 trials of each technique. A MANCOVA identified Block Time (BT), Flight Time (FT), Peak Horizontal Force of the lower limbs (PHF) and Horizontal Velocity at Take-off (Vx) as covariates. During the 10-m swim trial, significant differences were found in Time to 10 m (TT10m), Total Time (TT), Peak Vertical Force (PVF), Flight Distance (FD), and Horizontal Velocity at Take-off (Vx) (p < .05). Results indicated that the conventional track start method was faster over 10 m, and therefore may be seen as a superior start after a short intervention. During training, swimmers and coaches should focus on the most statistically significant dive performance variables: peak horizontal force and velocity at take-off, block and flight time