The androgen receptor and signal-transduction pathways in hormone-refractory prostate cancer. Part 1: modifications to the androgen receptor

Prostate cancer is the second most common male malignancy in the western world an increasing incidence in an ageing population. Treatment of advanced prostate cancer relies on androgen deprivation. Although the majority of patients initially respond favourably to androgen deprivation therapy, the mean time to relapse is 12-18 months. Currently there are few treatments available for men who have developed resistance to hormone therapy, due to the lack of understanding of the molecular mechanisms underlying development of this disease. Recently, however, major advances have been made in understanding both androgen receptor (AR) dependent and independent pathways which promote development of hormone resistant prostate cancer. This review will focus on modifications to the AR and associated pathways. Molecular modifications to the androgen receptor itself, e.g. mutations and/or amplification, although involved in the development of hormone resistance cannot explain all cases. Phosphorylation of AR, via either Ras/MAP kinase or PI3K/Akt signal transduction pathways, have been shown to activate AR in both a ligand (androgen) dependent and independent fashion. During this review we will discuss the clinical evidence to support AR dependent pathways as mediators of hormone resistance

Antibodies to Enteroviruses in Cerebrospinal Fluid of Patients with Acute Flaccid Myelitis.

Acute flaccid myelitis (AFM) has caused motor paralysis in >560 children in the United States since 2014. The temporal association of enterovirus (EV) outbreaks with increases in AFM cases and reports of fever, respiratory, or gastrointestinal illness prior to AFM in >90% of cases suggest a role for infectious agents. Cerebrospinal fluid (CSF) from 14 AFM and 5 non-AFM patients with central nervous system (CNS) diseases in 2018 were investigated by viral-capture high-throughput sequencing (VirCapSeq-VERT system). These CSF and serum samples, as well as multiple controls, were tested for antibodies to human EVs using peptide microarrays. EV RNA was confirmed in CSF from only 1 adult AFM case and 1 non-AFM case. In contrast, antibodies to EV peptides were present in CSF of 11 of 14 AFM patients (79%), significantly higher than controls, including non-AFM patients (1/5 [20%]), children with Kawasaki disease (0/10), and adults with non-AFM CNS diseases (2/11 [18%]) (P = 0.023, 0.0001, and 0.0028, respectively). Six of 14 CSF samples (43%) and 8 of 11 sera (73%) from AFM patients were immunoreactive to an EV-D68-specific peptide, whereas the three control groups were not immunoreactive in either CSF (0/5, 0/10, and 0/11; P = 0.008, 0.0003, and 0.035, respectively) or sera (0/2, 0/8, and 0/5; P = 0.139, 0.002, and 0.009, respectively).IMPORTANCE The presence in cerebrospinal fluid of antibodies to EV peptides at higher levels than non-AFM controls supports the plausibility of a link between EV infection and AFM that warrants further investigation and has the potential to lead to strategies for diagnosis and prevention of disease

On the evaluation of some three-body variational integrals

Stable recursive relations are presented for the numerical computation of the integrals $$\int d{\bf r}_1 d{\bf r}_2 r_1^{l-1} r_2^{m-1} r_{12}^{n-1} \exp{\{-\alpha r_1 -\beta r_2 -\gamma r_{12}\}}$$ ($l$, $m$ and $n$ integer, $\alpha$, $\beta$ and $\gamma$ real) when the indices $l$, $m$ or $n$ are negative. Useful formulas are given for particular values of the parameters $\alpha$, $\beta$ and $\gamma$.Comment: 12 pages, 1 figure (PS) and 3 tables. Old figures 2 and 3 replaced by Tables I and III. A further table added. Paper enlarged giving some tips on the convergence of quadrature

Pseudospectral Calculation of the Wavefunction of Helium and the Negative Hydrogen Ion

We study the numerical solution of the non-relativistic Schr\"{o}dinger equation for two-electron atoms in ground and excited S-states using pseudospectral (PS) methods of calculation. The calculation achieves convergence rates for the energy, Cauchy error in the wavefunction, and variance in local energy that are exponentially fast for all practical purposes. The method requires three separate subdomains to handle the wavefunction's cusp-like behavior near the two-particle coalescences. The use of three subdomains is essential to maintaining exponential convergence. A comparison of several different treatments of the cusps and the semi-infinite domain suggest that the simplest prescription is sufficient. For many purposes it proves unnecessary to handle the logarithmic behavior near the three-particle coalescence in a special way. The PS method has many virtues: no explicit assumptions need be made about the asymptotic behavior of the wavefunction near cusps or at large distances, the local energy is exactly equal to the calculated global energy at all collocation points, local errors go down everywhere with increasing resolution, the effective basis using Chebyshev polynomials is complete and simple, and the method is easily extensible to other bound states. This study serves as a proof-of-principle of the method for more general two- and possibly three-electron applications.Comment: 23 pages, 20 figures, 2 tables, Final refereed version - Some references added, some stylistic changes, added paragraph to matrix methods section, added last sentence to abstract