Androgen receptor-dependent and -independent mechanisms driving prostate cancer progression: Opportunities for therapeutic targeting from multiple angles.

Despite aggressive treatment for localized cancer, prostate cancer (PC) remains a leading cause of cancer-related death for American men due to a subset of patients progressing to lethal and incurable metastatic castrate-resistant prostate cancer (CRPC). Organ-confined PC is treated by surgery or radiation with or without androgen deprivation therapy (ADT), while options for locally advanced and disseminated PC include radiation combined with ADT, or systemic treatments including chemotherapy. Progression to CRPC results from failure of ADT, which targets the androgen receptor (AR) signaling axis and inhibits AR-driven proliferation and survival pathways. The exact mechanisms underlying the transition from androgen-dependent PC to CRPC remain incompletely understood. Reactivation of AR has been shown to occur in CRPC despite depletion of circulating androgens by ADT. At the same time, the presence of AR-negative cell populations in CRPC has also been identified. While AR signaling has been proposed as the primary driver of CRPC, AR-independent signaling pathways may represent additional mechanisms underlying CRPC progression. Identification of new therapeutic strategies to target both AR-positive and AR-negative PC cell populations and, thereby, AR-driven as well as non-AR-driven PC cell growth and survival mechanisms would provide a two-pronged approach to eliminate CRPC cells with potential for synthetic lethality. In this review, we provide an overview of AR-dependent and AR-independent molecular mechanisms which drive CRPC, with special emphasis on the role of the Jak2-Stat5a/b signaling pathway in promoting castrate-resistant growth of PC through both AR-dependent and AR-independent mechanisms

Siderophile element fractionation in meteor crater impact glasses and metallic spherules

Meteor Crater, Arizona provides an opportunity to study, in detail, elemental fractionation processes occurring during impacts through the study of target rocks, meteorite projectile and several types of impact products. We have performed EMPA and INAA on target rocks, two types of impact glass and metallic spherules from Meteor Crater. Using literature data for the well studied Canyon Diablo iron we can show that different siderophite element fractionations affected the impact glasses than affected the metallic spherules. The impact glasses primarily lost Au, while the metallic spherules lost Fe relative to other siderophile elements

Global standards of Constitutional law : epistemology and methodology

Just as it led the philosophy of science to gravitate around scientific practice, the abandonment of all foundationalist aspirations has already begun making political philosophy into an attentive observer of the new ways in which constitutional law is practiced. Yet paradoxically, lawyers and legal scholars are not those who understand this the most clearly. Beyond analyzing the jurisprudence that has emerged from the expansion of constitutional justice, and taking into account the development of international and regional law, the ongoing globalization of constitutional law requires comparing the constitutional laws of individual nations. Following Waldron, the product of this new legal science can be considered as ius gentium. This legal science is not as well established as one might like to think. But it can be developed on the grounds of the practice that consists in ascertaining standards. As abstract types of best “practices” (and especially norms) of constitutional law from around the world, these are only a source of law in a substantive, not a formal, sense. They thus belong to what I should like to call a “second order legal positivity.” In this article I will undertake, both at a methodological and an epistemological level, the development of a model for ascertaining global standards of constitutional law

Aspects of Axion Phenomenology in a slice of AdS_5

Motivated by multi-throat considerations, we study the phenomenological implications of a bulk axion in a slice of AdS_5 with a large extra dimension: k~0.01 eV, kR > 1. In particular, we compare axion physics with a warped geometry to axions in flat compactifications. As in flat compactification scenarios, we find that the mass of the axion can become independent from the underlying Peccei-Quinn scale. Surprisingly, we find that in warped extra dimensions the axion's invisibility, cosmological viability, and basic phenomenology remain essentially unaltered in comparison to axions in flat compactifications.Comment: 25 pages, 9 figure

Challenging SO(10) SUSY GUTs with family symmetries through FCNC processes

We perform a detailed analysis of the SO(10) SUSY GUT model with D3 family symmetry of Dermisek and Raby (DR). The model is specified in terms of 24 parameters and predicts, as a function of them, the whole MSSM set of parameters at low energy scales. Concerning the SM subset of such parameters, the model is able to give a satisfactory description of the quark and lepton masses, of the PMNS matrix and of the CKM matrix. We perform a global fit to the model, including flavour changing neutral current (FCNC) processes Bs --> mu+ mu-, B --> Xs gamma, B --> Xs l+ l- and the B(d,s) - bar B(d,s) mass differences Delta M(d,s) as well as the flavour changing (FC) process B+ --> tau+ nu. These observables provide at present the most sensitive probe of the SUSY mass spectrum and couplings predicted by the model. Our analysis demonstrates that the simultaneous description of the FC observables in question represents a serious challenge for the DR model, unless the masses of the scalars are moved to regions which are problematic from the point of view of naturalness and probably beyond the reach of the LHC. We emphasize that this problem could be a general feature of SUSY GUT models with third generation Yukawa unification and weak-scale minimal flavour violation.Comment: 1 + 37 pages, 5 figures, 11 tables. v3: minor typos fixed. Matches JHEP published versio

Phenomenology of symmetry breaking from extra dimensions

Motivated by the electroweak hierarchy problem, we consider theories with two extra dimensions in which the four-dimensional scalar fields are components of gauge boson in full space. We explore the Nielsen-Olesen instability for SU(N) on a torus, in the presence of a magnetic background. A field theory approach is developed, computing explicitly the minimum of the complete effective potential, including tri-linear and quartic couplings and determining the symmetries of the stable vacua. We also develop appropriate gauge-fixing terms when both Kaluza-Klein and Landau levels are present and interacting, discussing the interplay between the possible six and four dimensional choices. The equivalence between coordinate dependent and constant Scherk-Schwarz boundary conditions -associated to either continuous or discrete Wilson lines- is analyzed.Comment: 39 pages and 8 eps figures. Few changes in section