Human Tissue in the Evaluation of Safety and Efficacy of New Medicines: A Viable Alternative to Animal Models?

The pharma Industry's ability to develop safe and effective new drugs to market is in serious decline. Arguably, a major contributor to this is the Industry's extensive reliance on nonhuman biology-based test methods to determine potential safety and efficacy, objective analysis of which reveals poor predictive value. An obvious alternative approach is to use human-based tests, but only if they are available, practical, and effective. While in vivo (phase 0 microdosing with high sensitivity mass spectroscopy) and in silico (using established human biological data), technologies are increasingly being used, in vitro human approaches are more rarely employed. However, not only are increasingly sophisticated in vitro test methods now available or under development, but the basic ethically approved infrastructure through which human cells and tissues may be acquired is established. Along with clinical microdosing and in silico approaches, more effective access to and use of human cells and tissues in vitro provide exciting and potentially more effective opportunities for the assessment of safety and efficacy of new medicines

The present and future of serum diagnostic tests for testicular germ cell tumours

Testicular germ cell tumours (GCTs) are the most common malignancy occurring in young adult men and the incidence of these tumours is increasing. Current research priorities in this field include improving overall survival for patients classified as being 'poor-risk' and reducing late effects of treatment for patients classified as 'good-risk'. Testicular GCTs are broadly classified into seminomas and nonseminomatous GCTs (NSGCTs). The conventional serum protein tumour markers α-fetoprotein (AFP), human chorionic gonadotrophin (hCG) and lactate dehydrogenase (LDH) show some utility in the management of testicular malignant GCT. However, AFP and hCG display limited sensitivity and specificity, being indicative of yolk sac tumour (AFP) and choriocarcinoma or syncytiotrophoblast (hCG) subtypes. Furthermore, LDH is a very nonspecific biomarker. Consequently, seminomas and NSGCTs comprising a pure embryonal carcinoma subtype are generally negative for these conventional markers. As a result, novel universal biomarkers for testicular malignant GCTs are required. MicroRNAs are short, non-protein-coding RNAs that show much general promise as biomarkers. MicroRNAs from two 'clusters', miR-371–373 and miR-302–367, are overexpressed in all malignant GCTs, regardless of age (adult or paediatric), site (gonadal or extragonadal) and subtype (seminomas, yolk sac tumours or embryonal carcinomas). A panel of four circulating microRNAs from these two clusters (miR-371a-3p, miR-372-3p, miR-373-3p and miR-367-3p) is highly sensitive and specific for the diagnosis of malignant GCT, including seminoma and embryonal carcinoma. In the future, circulating microRNAs might be useful in diagnosis, disease monitoring and prognostication of malignant testicular GCTs, which might also reduce reliance on serial CT scanning. For translation into clinical practice, important practical considerations now need addressing.The authors would like to acknowledge grant funding from CwCUK/GOSHCC (M.J.M. N.C. grant W1058), SPARKS (M.J.M. N.C. grant 11CAM01), CRUK (N.C. grant A13080) MRC (M.J.M. grant MC_EX_G0800464) and National Health Service funding to the Royal Marsden/Institute of Cancer Research National Institute for Health Research Biomedical Research Centre for Cancer (R.A.H.). The authors also thank the Max Williamson Fund, the Josh Carrick Foundation and The Perse Preparatory School, Cambridge for support.This is the author accepted manuscript. The final version is available fromNature Publishing Group via https://doi.org/10.1038/nrurol.2016.17

G_2^1 Affine Toda Field Theory: A Numerical Test of Exact S-Matrix results

We present the results of a Monte--Carlo simulation of the $G_2^{(1)}$ Affine Toda field theory action in two dimensions. We measured the ratio of the masses of the two fundamental particles as a function of the coupling constant. Our results strongly support the conjectured duality with the $D_4^{(3)}$ theory, and are consistent with the mass formula of Delius et al.Comment: 5 pages, LaTeX, DTP-9223, DAMTP-92-4

Theory for nucleation at an interface and magnetization reversal of a two-layer nanowire

Nucleation at the interface between two adjoining regions with dissimilar physical properties is investigated using a model for magnetization reversal of a two-layer ferromagnetic nanowire. Each layer of the nanowire is considered to have a different degree of magnetic anisotropy, representing a hard magnetic layer exchange-coupled to a softer layer. A magnetic field applied along the easy axis causes the softer layer to reverse, forming a domain wall close to the interface. For small applied fields this state is metastable and complete reversal of the nanowire takes place via activation over a barrier. A reversal mechanism involving nucleation at an interface is proposed, whereby a domain wall changes in width as it passes from the soft layer to the hard layer during activation. Langer’s statistical theory for the decay of a metastable state is used to derive rates of magnetization reversal, and simple formulas are found in limiting cases for the activation energy, rate of reversal, and critical field at which the metastable state becomes unstable. These formulas depend on the anisotropy difference between each layer, and the behavior of the reversal rate prefactor is interpreted in terms of activation entropy and domain-wall dynamics

Magnetic Resonance Imaging of Optic Nerve Traction During Adduction in Primary Open-Angle Glaucoma With Normal Intraocular Pressure.

PurposeWe used magnetic resonance imaging (MRI) to ascertain effects of optic nerve (ON) traction in adduction, a phenomenon proposed as neuropathic in primary open-angle glaucoma (POAG).MethodsSeventeen patients with POAG and maximal IOP ≤ 20 mm Hg, and 31 controls underwent MRI in central gaze and 20° to 30° abduction and adduction. Optic nerve and sheath area centroids permitted computation of midorbital lengths versus minimum paths.ResultsAverage mean deviation (±SEM) was -8.2 ± 1.2 dB in the 15 patients with POAG having interpretable perimetry. In central gaze, ON path length in POAG was significantly more redundant (104.5 ± 0.4% of geometric minimum) than in controls (102.9 ± 0.4%, P = 2.96 × 10-4). In both groups the ON became significantly straighter in adduction (28.6 ± 0.8° in POAG, 26.8 ± 1.1° in controls) than central gaze and abduction. In adduction, the ON in POAG straightened to 102.0% ± 0.2% of minimum path length versus 104.5% ± 0.4% in central gaze (P = 5.7 × 10-7), compared with controls who straightened to 101.6% ± 0.1% from 102.9% ± 0.3% in central gaze (P = 8.7 × 10-6); and globes retracted 0.73 ± 0.09 mm in POAG, but only 0.07 ± 0.08 mm in controls (P = 8.8 × 10-7). Both effects were confirmed in age-matched controls, and remained significant after correction for significant effects of age and axial globe length (P = 0.005).ConclusionsAlthough tethering and elongation of ON and sheath are normal in adduction, adduction is associated with abnormally great globe retraction in POAG without elevated IOP. Traction in adduction may cause mechanical overloading of the ON head and peripapillary sclera, thus contributing to or resulting from the optic neuropathy of glaucoma independent of IOP

Comparison of Outcomes between Endoscopic and Transcleral Cyclophotocoagulation.

Importance: Traditionally cyclophotocoagulation has been reserved as a treatment of last resort for eyes with advanced stage glaucoma, but increasingly it is offered to eyes with less severe disease. Endoscopic approaches in particular are utilized in increasing numbers of patients despite only a small number of publications on its results. Objective: The purpose of this study was to compare the efficacy and safety of endoscopic and transcleral cyclophotocoagulation (ECP and TCP) procedures in eyes with refractory glaucomas. Design, Setting, and Participants: A chart review was performed on consecutive patients who underwent ECP and TCP at a tertiary ophthalmology care center between January 2000 and December 2010. Cases with fewer than 3 months of follow-up or that had concurrent pressure reducing procedures were excluded. The main outcome measures examined were intraocular pressure (IOP), number of glaucoma medications, best corrected visual acuity (BCVA), additional glaucoma procedure required, and complications. Main Outcomes and Measures: Forty-two eyes (42 patients) that underwent ECP and forty-four eyes (44 patients) that underwent TCP were identified. The TCP group had a statistically higher mean age (71.2 ± 16.7 vs. 58.1 ± 22.9 years, respectively), larger proportion of neovascular glaucoma (40.9% vs. 16.7%), worse initial BCVA (logMAR 2.86 vs. 1.81), and higher preoperative IOP (45.3 vs. 26.6 mmHg) than the ECP group. At 12 months follow-up, the mean IOP difference between groups was not statistically significant, although the change in IOP from baseline to 12 months was greater for the TCP group (p = 0.006). The rates of progression to no light perception (NLP) and phthisis bulbi were significantly higher amongst TCP eyes than ECP eyes (27.2% vs. 4.8%, p = 0.017, and 20.5% vs. 0%, p = 0.003, respectively). Of these eyes that progressed, a majority had neovascular glaucoma (NVG). Corneal decompensation was the most frequent complication following ECP (11.9%). Conclusions and Relevance: In patients with preoperative BCVA of 20/400 or better, overall complication rates (cystoid macular edema, exudative retinal detachment, inflammation, cornea decompensation) were higher after ECP than with TCP. In refractory glaucomas in a real world setting (not a trial), TCP was more frequently used in ischemic eyes. TCP was associated with a higher rate of progression to phthisis bulbi and loss of light perception than ECP. However, ECP was associated with a clinically significant rate of corneal decompensation. These outcomes likely were related to the severity of underlying ocular diseases found in these eyes

Leveling the Playing Field: Epitomizing Devolution through Faith-Based Organizations

The original New-Federalism agenda that emerged with the Reagan administration weakened federal programs and transferred power to states and localities. While Ronald Reagan and George Herbert Walker Bush\u27s years were characterized by block grants and dismantling public assistance, the Clinton years will be remembered for the dismantling of AFDC. Recruiting faith-based organizations to provide social services epitomized the second Bush presidency. In this article, we demonstrate how the seeds for recruiting faith-based groups were planted before and during the Reagan years, and how two waves of devolution chipped away at our national commitment to welfare. These first two waves provided both the ideological and practical means for faith-based social service delivery, which epitomizes the third wave of devolution. We also briefly review the incorporation of religion in social services as part of the neo-federalist trend of the Reagan legacy

Recent Decisions

Comments on recent decisions by Joseph N. Low, Robert A. Stewart, William M. Dickson, Edward G. Coleman, James F. O\u27Rieley, James J. Haranzo, Robert C. Enburg, E. Milton Farley III, Jerome A. Kolenda, Bernard James McGraw, Joseph C. Spalding, R. Emmett Fitzgerald, Joseph T. Helling, John F. Laughlin, Andrew V. Giorgi, and Jack Fena