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

Percutaneous pulmonary valve implantation alters electrophysiologic substrate

BACKGROUND: Percutaneous pulmonary valve implantation (PPVI) is first‐line therapy for some congenital heart disease patients with right ventricular outflow tract dysfunction. The hemodynamics improvements after PPVI are well documented, but little is known about its effects on the electrophysiologic substrate. The objective of this study is to assess the short‐ and medium‐term electrophysiologic substrate changes and elucidate postprocedure arrhythmias. METHODS AND RESULTS: A retrospective chart review of patients undergoing PPVI from May 2010 to April 2015 was performed. A total of 106 patients underwent PPVI; most commonly these patients had tetralogy of Fallot (n=59, 55%) and pulmonary insufficiency (n=60, 57%). The median follow‐up time was 28 months (7‐63 months). Pre‐PPVI, 25 patients (24%) had documented arrhythmias: nonsustained ventricular tachycardia (NSVT) (n=9, 8%), frequent premature ventricular contractions (PVCs) (n=6, 6%), and atrial fibrillation/flutter (AF/AFL) (n=10, 9%). Post‐PPVI, arrhythmias resolved in 4 patients who had NSVT (44%) and 5 patients who had PVCs (83%). New arrhythmias were seen in 16 patients (15%): 7 NSVT, 8 PVCs, and 1 AF/AFL. There was resolution at medium‐term follow‐up in 6 (86%) patients with new‐onset NSVT and 7 (88%) patients with new‐onset PVCs. There was no difference in QRS duration pre‐PPVI, post‐PPVI, and at medium‐term follow‐up (P=0.6). The median corrected QT lengthened immediately post‐PPVI but shortened significantly at midterm follow‐up (P<0.01). CONCLUSIONS: PPVI reduced the prevalence of NSVT. The majority of postimplant arrhythmias resolve by 6 months of follow‐up

MicroRNAs can regulate human APP levels

A number of studies have shown that increased APP levels, resulting from either a genomic locus duplication or alteration in APP regulatory sequences, can lead to development of early-onset dementias, including Alzheimer's disease (AD). Therefore, understanding how APP levels are regulated could provide valuable insight into the genetic basis of AD and illuminate novel therapeutic avenues for AD. Here we test the hypothesis that APP protein levels can be regulated by miRNAs, evolutionarily conserved small noncoding RNA molecules that play an important role in regulating gene expression. Utilizing human cell lines, we demonstrate that miRNAs hsa-mir-106a and hsa-mir-520c bind to their predicted target sequences in the APP 3'UTR and negatively regulate reporter gene expression. Over-expression of these miRNAs, but not control miRNAs, results in translational repression of APP mRNA and significantly reduces APP protein levels. These results are the first to demonstrate that levels of human APP can be regulated by miRNAs

Retinal Alpha-Synuclein Accumulation Correlates with Retinal Dysfunction and Structural Thinning in the A53T Mouse Model of Parkinson’s Disease

Abnormal alpha-synuclein (α-SYN) protein deposition has long been recognized as one of the pathological hallmarks of Parkinson\u27s disease\u27s (PD). This study considers the potential utility of PD retinal biomarkers by investigating retinal changes in a well characterized PD model of α-SYN overexpression and how these correspond to the presence of retinal α-SYN. Transgenic A53T homozygous (HOM) mice overexpressing human α-SYN and wildtype (WT) control littermates were assessed at 4, 6, and 14  months of age (male and female

Laminin-6 and Laminin-5 Are Recognized by Autoantibodies in a Subset of Cicatricial Pemphigoid

We characterized basement membrane zone (BMZ) autoantigens targeted by autoantibodies (AAb) from patients with cicatricial pemphigoid. Serum from a patient with severe oral cicatricial pemphigoid contained IgG anti-BMZ AAb. The AAb labeled a lower BMZ component on salt-split skin and localized to the lower lamina lucida/lamina densa by direct and indirect immunoelectron microscopy (HEM) but did not label blood vessels. The AAb did not react with EHS laminin-1 and type IV collagen, pepsinized human type IV collagen, recombinant entactin, or NC1 domain of type VII collagen by dot blotting and western blotting. We focused our studies on the laminin family, as laminin-5 was identified as an autoantigen in cicatricial pemphigoid. Culture-conditioned media from normal keratinocytes (containing laminin-6 and laminin-5) and JEB keratinocytes (containing laminin-6 but not laminin-5) were studied by western blotting. Under nonreducing conditions, the patient's AAb recognized a 600-kDa protein (laminin-6) intensely and a 400-kDa protein (laminin-5) weakly in normal keratinocyte medium even though abundant laminin-5 was present. In JEB keratinocyte medium, however, the 600-kDa protein (laminin-6) alone was recognized by the patient's AAb. The AAb also immunolabeled BMZ of JEB skin that lacked laminin-5. The AAb from this patient and two other patients with anti-laminin-5 cicatricial pemphigoid immunoprecipitated both laminin-6 an4 laminin-5. Taken together, the results of IEM, non-reducing western blotting, immunoprecipitation, and JEB skin BMZ immunolabeling indicate that laminin-6, as well as laminin-5, is identified by the AAb from a subset of cicatricial pemphigoid patients. We propose the name “anti-laminin cicatricial pemphigoid” for this subset

Pharmacologic suppression of JAK1/2 by JAK1/2 inhibitor AZD1480 potently inhibits IL-6-induced experimental prostate cancer metastases formation.

Metastatic prostate cancer is lethal and lacks effective strategies for prevention or treatment, requiring novel therapeutic approaches. Interleukin-6 (IL-6) is a cytokine that has been linked with prostate cancer pathogenesis by multiple studies. However, the direct functional roles of IL-6 in prostate cancer growth and progression have been unclear. In the present study, we show that IL-6 is produced in distant metastases of clinical prostate cancers. IL-6-activated signaling pathways in prostate cancer cells induced a robust 7-fold increase in metastases formation in nude mice. We further show that IL-6 promoted migratory prostate cancer cell phenotype, including increased prostate cancer cell migration, microtubule reorganization, and heterotypic adhesion of prostate cancer cells to endothelial cells. IL-6-driven metastasis was predominantly mediated by Stat3 and to lesser extent by ERK1/2. Most importantly, pharmacologic inhibition of Jak1/2 by AZD1480 suppressed IL-6-induced signaling, migratory prostate cancer cell phenotypes, and metastatic dissemination of prostate cancer in vivo in nude mice. In conclusion, we demonstrate that the cytokine IL-6 directly promotes prostate cancer metastasis in vitro and in vivo via Jak-Stat3 signaling pathway, and that IL-6-driven metastasis can be effectively suppressed by pharmacologic targeting of Jak1/2 using Jak1/2 inhibitor AZD1480. Our results therefore provide a strong rationale for further development of Jak1/2 inhibitors as therapy for metastatic prostate cancer

Operator Product Expansion and Quark-Hadron Duality: Facts and Riddles

We review the status of the practical operator product expansion (OPE), when applied to two-point correlators of QCD currents which interpolate to mesonic resonances, in view of the violations of local quark-hadron duality. Covered topics are: a mini-review of mesonic QCD sum rules in vacuum, at finite temperature, or at finite baryon density, a comparison of model calculations of current-current correlation functions in 2D and 4D with the OPE expression, a discussion of meson distribution amplitudes in the light of nonperturbatively nonlocal modifications of the OPE, and a reorganization of the OPE which (partially) resums powers of covariant derivatives.Comment: now 68 pages, 29 figures (1 figure added), habilitation thesis, mild restructuring, typos corrected, about 30 references and corresponding text added, version to be published in Prog. Part. Nucl. Phy

The origin of dust polarization in the Orion Bar

The linear polarization of thermal dust emission provides a powerful tool to probe interstellar and circumstellar magnetic fields, because aspherical grains tend to align themselves with magnetic field lines. While the Radiative Alignment Torque (RAT) mechanism provides a theoretical framework to this phenomenon, some aspects of this alignment mechanism still need to be quantitatively tested. One such aspect is the possibility that the reference alignment direction changes from the magnetic field ("B-RAT") to the radiation field k-vector ("k-RAT") in areas of strong radiation fields. We investigate this transition toward the Orion Bar PDR, using multi-wavelength SOFIA HAWC+ dust polarization observations. The polarization angle maps show that the radiation field direction is on average not the preferred grain alignment axis. We constrain the grain sizes for which the transition from B-RAT to k-RAT occur in the Orion Bar (grains > 0.1 {\mu}m toward the most irradiated locations), and explore the radiatively driven rotational disruption that may take place in the high-radiation environment of the Bar for large grains. While the grains susceptible to rotational disruption should be in supra-thermal rotation and aligned with the magnetic field, k-RAT aligned grains would rotate at thermal velocities. We find that the grain size at which the alignment shifts from B-RAT to k-RAT corresponds to grains too large to survive the rotational disruption. Therefore, we expect a large fraction of grains to be aligned at supra-thermal rotation with the magnetic field, and potentially be subject to rotational disruption depending on their tensile strength

Early-Life Farm Exposures and Eczema Among Adults in the Agricultural Lung Health Study

Background Several studies conducted in Europe have suggested a protective association between early-life farming exposure and childhood eczema or atopic dermatitis; however, few studies have examined associations in adults. Objectives We investigated associations between early-life exposures and eczema among 3217 adult farmers and farm spouses (mean age, 62.8 years) in a case–control study nested within an US agricultural cohort. Methods We used sampling-weighted logistic regression to estimate odds ratios and 95% confidence intervals for associations between early-life exposures and self-reported doctor-diagnosed eczema (273 cases) and polytomous logistic regression to estimate odds ratios (95% confidence intervals) for a 4-level outcome combining information on eczema and atopy (specific IgE ≥ 0.35). Additionally, we explored genetic and gene–environment associations with eczema. Results Although early-life farming exposures were not associated with eczema overall, several early-life exposures were associated with a reduced risk of having both eczema and atopy. Notably, results suggest stronger protective associations among individuals with both eczema and atopy than among those with either alone. For example, odds ratios (95% confidence intervals) for having a mother who did farm work while pregnant were 1.01 (0.60, 1.69) for eczema alone and 0.80 (0.65, 0.99) for atopy alone, but 0.54 (0.33, 0.80) for having both. A genetic risk score based on previously identified atopic dermatitis variants was strongly positively associated with eczema, and interaction testing suggested protective effects of several early-life farming exposures only in individuals at lower genetic risk. Conclusions In utero and childhood farming exposures are associated with decreased odds of having eczema with atopy in adults