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

Geographic distribution:\u3ci\u3e Acrantophis dumerili\u3c/i\u3e (Duméril’s Madagascan Ground Boa). USA. Florida.

The geographic distribution of Acrantophis dumerili, a nonindigenous introduced species in Florida, with new records, is presented. Acrantophis dumerili is indigenous to southern and southwestern Madagascar. We provide the first vouchers for Miami-Dade and Bay counties, which were likely escaped or released pets. Florida already has three established species of booid snakes (one boa, two pythons), all introduced through the pet trade pathway. Although there is no clear evidence for an established population of A. dumerili in Florida at this time, the Bay County individuals in a rural area in the Florida panhandle are a particular concern given that two propagules were found at the same general site less than one month apart, and Florida has the largest number of introduced herpetofauna in the world with nonindigenous species having a one out of three chance of becoming established (Krysko et al. 2016, op. cit.)

Geographic distribution:\u3ci\u3e Acrantophis dumerili\u3c/i\u3e (Duméril’s Madagascan Ground Boa). USA. Florida.

The geographic distribution of Acrantophis dumerili, a nonindigenous introduced species in Florida, with new records, is presented. Acrantophis dumerili is indigenous to southern and southwestern Madagascar. We provide the first vouchers for Miami-Dade and Bay counties, which were likely escaped or released pets. Florida already has three established species of booid snakes (one boa, two pythons), all introduced through the pet trade pathway. Although there is no clear evidence for an established population of A. dumerili in Florida at this time, the Bay County individuals in a rural area in the Florida panhandle are a particular concern given that two propagules were found at the same general site less than one month apart, and Florida has the largest number of introduced herpetofauna in the world with nonindigenous species having a one out of three chance of becoming established (Krysko et al. 2016, op. cit.)

Flight Acoustic Testing and For the Rotorcraft Noise Data Acquisition Model (RNM)

Two acoustic flight tests have been conducted on a remote test range at Eglin Air Force Base in the panhandle of Florida. The first was the "Acoustics Week" flight test conducted in September 2003. The second was the NASA Heavy Lift Rotorcraft Acoustics Flight Test conducted in October-November 2005. Benchmark acoustic databases were obtained for a number of rotorcraft and limited fixed wing vehicles for a variety of flight conditions. The databases are important for validation of acoustic prediction programs such as the Rotorcraft Noise Model (RNM), as well as for the development of low noise flight procedures and for environmental impact assessments. An overview of RNM capabilities and a detailed description of the RNM/ART (Acoustic Repropagation Technique) process are presented. The RNM/ART process is demonstrated using measured acoustic data for the MD600N. The RNM predictions for a level flyover speed sweep show the highest SEL noise levels on the flight track centerline occurred at the slowest vehicle speeds. At these slower speeds, broadband noise content is elevated compared to noise levels obtained at the higher speeds. A descent angle sweep shows that, in general, ground noise levels increased with increasing descent rates. Vehicle orientation in addition to vehicle position was found to significantly affect the RNM/ART creation of source noise semi-spheres for vehicles with highly directional noise characteristics and only mildly affect those with weak acoustic directionality. Based on these findings, modifications are proposed for RNM/ART to more accurately define vehicle and rotor orientation

The role of ECL2 in CGRP receptor activation: a combined modelling and experimental approach

The calcitonin gene-related peptide (CGRP) receptor is a complex of a calcitonin receptor-like receptor (CLR), which is a family B G-protein-coupled receptor (GPCR) and receptor activity modifying protein 1. The role of the second extracellular loop (ECL2) of CLR in binding CGRP and coupling to Gs was investigated using a combination of mutagenesis and modelling. An alanine scan of residues 271–294 of CLR showed that the ability of CGRP to produce cAMP was impaired by point mutations at 13 residues; most of these also impaired the response to adrenomedullin (AM). These data were used to select probable ECL2-modelled conformations that are involved in agonist binding, allowing the identification of the likely contacts between the peptide and receptor. The implications of the most likely structures for receptor activation are discussed.</jats:p

Muon-fluorine entangled states in molecular magnets

The information accessible from a muon-spin relaxation experiment is often limited since we lack knowledge of the precise muon stopping site. We demonstrate here the possibility of localizing a spin polarized muon in a known stopping state in a molecular material containing fluorine. The muon-spin precession that results from the entangled nature of the muon-spin and surrounding nuclear spins is sensitive to the nature of the stopping site and we use this property to identify three classes of site. We are also able to describe the extent to which the muon distorts its surroundings.Comment: 4 pages, 3 figure

Validation of Ray Tracing Code Refraction Effects

NASA's current predictive capabilities using the ray tracing program (RTP) are validated using helicopter noise data taken at Eglin Air Force Base in 2007. By including refractive propagation effects due to wind and temperature, the ray tracing code is able to explain large variations in the data observed during the flight test

Flight Acoustic Testing and Data Acquisition For the Rotor Noise Model (RNM)

Two acoustic flight tests have been conducted on a remote test range at Eglin Air Force Base in the panhandle of Florida. The first was the Acoustics Week flight test conducted in September 2003. The second was the NASA Heavy Lift Rotorcraft Acoustics Flight Test conducted in October-November 2005. Benchmark acoustic databases were obtained for a number of rotorcraft and limited fixed wing vehicles for a variety of flight conditions. The databases are important for validation of acoustic prediction programs such as the Rotorcraft Noise Model (RNM), as well as for the development of low noise flight procedures and for environmental impact assessments. An overview of RNM capabilities and a detailed description of the RNM/ART (Acoustic Repropagation Technique) process are presented. The RNM/ART process is demonstrated using measured acoustic data for the MD600N. The RNM predictions for a level flyover speed sweep show the highest SEL noise levels on the flight track centerline occurred at the slowest vehicle speeds. At these slower speeds, broadband noise content is elevated compared to noise levels obtained at the higher speeds. A descent angle sweep shows that, in general, ground noise levels increased with increasing descent rates. Vehicle orientation in addition to vehicle position was found to significantly affect the RNM/ART creation of source noise semi-spheres for vehicles with highly directional noise characteristics and only mildly affect those with weak acoustic directionality. Based on these findings, modifications are proposed for RNM/ART to more accurately define vehicle and rotor orientation