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Aberrant NF-κB activity drives oncogenesis and cell survival in multiple myeloma (MM) and many other cancers. However, despite an aggressive effort by the pharmaceutical industry over the past 30 years, no specific IκBα kinase (IKK)β/NF-κB inhibitor has been clinically approved, due to the multiple dose-limiting toxicities of conventional NF-κB-targeting drugs. To overcome this barrier to therapeutic NF-κB inhibition, we developed the first-in-class growth arrest and DNA-damage-inducible (GADD45)β/mitogen-activated protein kinase kinase (MKK)7 inhibitor, DTP3, which targets an essential, cancer-selective cell-survival module downstream of the NF-κB pathway. As a result, DTP3 specifically kills MM cells, ex vivo and in vivo , ablating MM xenografts in mice, with no apparent adverse effects, nor evident toxicity to healthy cells. Here, we report the results from the preclinical regulatory pharmacodynamic (PD), safety pharmacology, pharmacokinetic (PK), and toxicology programmes of DTP3, leading to the approval for clinical trials in oncology. These results demonstrate that DTP3 combines on-target-selective pharmacology, therapeutic anticancer efficacy, favourable drug-like properties, long plasma half-life and good bioavailability, with no target-organs of toxicity and no adverse effects preclusive of its clinical development in oncology, upon daily repeat-dose administration in both rodent and non-rodent species. Our study underscores the clinical potential of DTP3 as a conceptually novel candidate therapeutic selectively blocking NF-κB survival signalling in MM and potentially other NF-κB-driven cancers.

International differences in practices and attitudes regarding pet cats' interactions with wildlife were assessed by surveying citizens from at least two cities in Australia, New Zealand, the UK, the USA, China and Japan. Predictions tested were: (i) cat owners would agree less than non-cat owners that cats might threaten wildlife, (ii) cat owners value wildlife less than non-cat owners, (iii) cat owners are less accepting of cat legislation/restrictions than non-owners, and (iv) respondents from regions with high endemic biodiversity (Australia, New Zealand, China and the USA state of Hawaii) would be most concerned about pet cats threatening wildlife. Everywhere non-owners were more likely than owners to agree that pet cats killing wildlife were a problem in cities, towns and rural areas. Agreement amongst non-owners was highest in Australia (95%) and New Zealand (78%) and lowest in the UK (38%). Irrespective of ownership, over 85% of respondents from all countries except China (65%) valued wildlife in cities, towns and rural areas. Non-owners advocated cat legislation more strongly than owners except in Japan. Australian non-owners were the most supportive (88%), followed by Chinese non-owners (80%) and Japanese owners (79.5%). The UK was least supportive (non-owners 43%, owners 25%). Many Australian (62%), New Zealand (51%) and Chinese owners (42%) agreed that pet cats killing wildlife in cities, towns and rural areas was a problem, while Hawaiian owners were similar to the mainland USA (20%). Thus high endemic biodiversity might contribute to attitudes in some, but not all, countries. Husbandry practices varied internationally, with predation highest where fewer cats were confined. Although the risk of wildlife population declines caused by pet cats justifies precautionary action, campaigns based on wildlife protection are unlikely to succeed outside Australia or New Zealand. Restrictions on roaming protect wildlife and benefit cat welfare, so welfare is a better rationale.

Following the arrival of Cassini at Titan in 2004, the Titan atmosphere has been shown to contain large complex polycyclic-aromatic hydrocarbons. Since Cassini has provided a great deal of data, there exists a need for kinetic rate data to help with modeling this atmosphere. One type of kinetic data needed is electron-ion dissociative recombination (e-IDR) rate constants. These data are not readily available for larger compounds, such as naphthalene, or oxygen containing compounds, such as 1,4 dioxane or furan. Here, the rate constants for naphthalene, 1,4 dioxane, and furan have been measured and their temperature dependencies are determined when possible, using the University of Georgia's Variable Temperature Flowing Afterglow. The rate constants are compared with those previously published for other compounds; these show trends which illustrate the effects which multi-rings and oxygen heteroatoms substitutions have upon e-IDR rate constants.

Lethal control is used extensively in New Zealand to control nonnative nonhuman mammals. Respondents were surveyed about 8 mammal groups considered pests and their attitudes toward their control and pest status. They also identified the most appropriate method of control for the 8 different mammals. Information was gathered from 3 groups of respondents: nonhuman animal protectionists, conservationists, and the general public. Conservationists routinely rated all animal groups as more severe pests than the general public or animal protectionists, who provided the lowest scores. Rats, stoats, brushtail possums, and rabbits were identified as the 4 most serious pests by all 3 groups. Conservationists were 5.7 and 2.6 times more likely to prefer a lethal method of control than protectionists and the general public, respectively. For all 3 groups an increase in pest score for a given animal saw a decline in importance placed upon the animal's welfare. This relationship was strong for the general public but weak for conservationists and animal protectionists. Understanding aspects of potentially opposing viewpoints may be invaluable in supporting the development of new welfare-focused control methods.

In gas phase ion chemistry, the growth of larger molecules is known to occur through association of ions and neutrals. Where the ion attaches to the neutral is important because it can influence the possibility of additional associations, effectively enabling or terminating further molecular growth. This was investigated by using a Selected Ion Flow Tube (SIFT) at 300 K to study the reactions of CH(3)(+) with the following series of single-ring homocyclic and heterocyclic molecules: benzene (C(6)H(6)), cyclohexane (C(6)H(12)), pyridine (C(5)H(5)N), pyrimidine (C(4)H(4)N(2)), piperidine (C(5)H(11)N), 1,4-dioxane (C(4)H(8)O(2)), furan (C(4)H(4)O), pyrrole (C(4)H(5)N), and pyrrolidine (C(4)H(9)N). Most of the reactions, except for 1,4-dioxane, pyrrole, and pyrrolidine, proceed at the gas kinetic rate. In the ion product distributions, charge transfer, hydride ion abstraction, proton transfer, fragmentation, and association were observed. In particular, proton transfer is seen to be small in all cases even though these channels are energetically favorable. Association is appreciable when the molecules are aromatic (except for furan) and nonexistent when there are no pi electrons in the ring. CH(3)(+) ions are an important intermediate in molecular synthesis in interstellar clouds and in the Titan ionosphere and ring molecules have also been detected in these media. The significance of the studied reactions to these media is discussed.

The selected ion flow tube (SIFT) technique has been used to investigate the ion-molecule reactions of several ions with the neutral molecules ethylene oxide, CH(2)OCH(2)-c, and propenal, CH(2)CHCHO. Both molecules have been identified in hot-core star forming regions [] and have significance to astrochemical models of the interstellar (ISM) and circumstellar medium (CSM). Moreover, the molecules contain functional groups, such as the epoxide group (ethylene oxide) and an aldehyde group, which are part of a conjugated pi-electron system (propenal) whose reactivities have not been studied in detail in gas-phase ion-molecule reactions. The larger recombination energy ions, Ar(+) and N(2)(+), were reacted with the neutrals to give insight into general fragmentation tendencies. These reactions proceeded via dissociative charge-transfer yielding major fragmentation products of CH(3)(+) and HCO(+) for ethylene oxide and CH(2)CH(+) and HCO(+) for propenal. The amino acids glycine and alanine are of particular interest to astrobiology, especially if they can be synthesized in the gas phase. In an attempt to synthesize amino acid precursors, ethylene oxide and propenal were reacted with NH(n)(+) (n = 1-4) and HCNH(+). As might be expected from the proton detachment energies, NH(+), NH(2)(+), and HCNH(+) reacted via proton transfer. NH(3)(+) reacted with each molecule via H-atom abstraction to produce NH(4)(+), and NH(4)(+) reacted via a ternary association. All binary reactions proceeded near the gas kinetic rate. Several associated molecule switching reactions were performed and implications of these reactions to the structures of the association products are discussed Ikeda et al. and Hollis et al.

Background: The authors evaluated temporomandibular disorder (TMD) outcomes in general dental practice one year after treatment with stabilizing splints (SS) or nonoccluding control splints (CS)., Methods: Seventy-two randomly allocated subjects completed initial treatment. The outcomes measures were a pain visual analog scale (VAS), muscle tenderness, temporomandibular joint (TMJ) tenderness, interincisal opening, TMJ clicks and headaches. After initial treatment, 81 percent of the subjects were found to have been treated satisfactorily. The dentists referred the remaining subjects to a dental hospital. At one year, the authors recalled 52 of the original subjects for evaluation., Results: Improvements after initial treatment were maintained at one year for all outcomes, except for TMJ clicking, which returned to pretreatment levels. Eighty-one percent of the subjects rated their treatment as either good or excellent in reducing jaw pain. The authors found that subjects were aware of more of their TMJ clicks than dentists observed at the one-year clinical examination, but most subjects thought their clicking or the associated pain had been reduced. Fifty-five percent subjects had used their splints in the previous six months, but only 31 percent of these had done so daily. There were no significant differences between splint groups., Conclusion: At one year, a good response to TMD treatment in general practice had been maintained, but many subjects still had clicking TMJs., Clinical Implications: Trained dentists can manage TMD satisfactorily, with only a small proportion of patients needing specialist attention.

The temperature dependencies of the rate coefficients, alpha(e), for electron-ion dissociative recombination (DR) of N2H+/N2D+ and HCO+/DCO+ ions with electrons have been measured over the range 100-500 K. Also, optical emissions have been detected at approximately 100 K from the N2(B3(pi)g) electronically excited products of N2H+/N2D+ recombination. The measurements were carried out using the classic FALP technique combined with an optical monochromator. For N2H+, there was no variation of alpha(e) with temperature above 200 K, with an average value of alpha(e)(N2H+) = 2.8 x 10(-7) cm3 s(-1). The temperature variation for T approximately 100-300 K observed for alpha(e)(HCO+) is similar to that of N2H+ ions for T approximately 300-500 K. The smaller rate coefficient measured for DCO+ and N2D+ ions shows the influence of an isotope effect. The substantial enhancement of the vibrational level, upsilon' = 6, from the N2B state for N2H+ recombination over N2D+ recombination is consistent with previous result at 300 K and implies the influence of a tunneling mechanism of DR.