Molecular Genetics of Conjunctival Melanoma and Prognostic Value of TERT Promoter Mutation Analysis

The aim of this study was exploration of the genetic background of conjunctival melanoma (CM) and correlation with recurrent and metastatic disease. Twenty-eight CM from the Rotterdam Ocular Melanoma Study group were collected and DNA was isolated from the formalin-fixed paraffin embedded tissue. Targeted next-generation sequencing was performed using a panel covering GNAQ, GNA11, EIF1AX, BAP1, BRAF, NRAS, c-KIT, PTEN, SF3B1, and TERT genes. Recurrences and metastasis were present in eight (29%) and nine (32%) CM cases, respectively. TERT promoter mutations were most common (54%), but BRAF (46%), NRAS (21%), BAP1 (18%), PTEN (14%), c-KIT (7%), and SF3B1 (4%) mutations were also observed. No mutations in GNAQ, GNA11, and EIF1AX were found. None of the mutations was significantly associated with recurrent disease. Presence of a TERT promoter mutation was associated with metastatic disease (p-value = 0.008). Based on our molecular findings, CM comprises a separate entity within melanoma, although there are overlapping molecular features with uveal melanoma, such as the presence of BAP1 and SF3B1 mutations. This warrants careful interpretation of molecular data, in the light of clinical findings. About three quarter of CM contain drug-targetable mutations, and TERT promoter mutations are correlated to metastatic disease in CM.     

Non-Coding RNAs Set a New Phenotypic Frontier in Prostate Cancer Metastasis and Resistance

Prostate cancer (PCa) mortality remains a significant public health problem, as advanced disease has poor survivability due to the development of resistance in response to both standard and novel therapeutic interventions. Therapeutic resistance is a multifaceted problem involving the interplay of a number of biological mechanisms including genetic, signaling, and phenotypic alterations, compounded by the contributions of a tumor microenvironment that supports tumor growth, invasiveness, and metastasis. The androgen receptor (AR) is a primary regulator of prostate cell growth, response and maintenance, and the target of most standard PCa therapies designed to inhibit AR from interacting with androgens, its native ligands. As such, AR remains the main driver of therapeutic response in patients with metastatic castration-resistant prostate cancer (mCRPC). While androgen deprivation therapy (ADT), in combination with microtubule-targeting taxane chemotherapy, offers survival benefits in patients with mCRPC, therapeutic resistance invariably develops, leading to lethal disease. Understanding the mechanisms underlying resistance is critical to improving therapeutic outcomes and also to the development of biomarker signatures of predictive value. The interconversions between epithelial-to-mesenchymal transition (EMT) and mesenchymal-to-epithelial transition (MET) navigate the prostate tumor therapeutic response, and provide a novel targeting platform in overcoming therapeutic resistance. Both microRNA (miRNA)- and long non-coding RNA (lncRNA)-mediated mechanisms have been associated with epigenetic changes in prostate cancer. This review discusses the current evidence-based knowledge of the role of the phenotypic transitions and novel molecular determinants (non-coding RNAs) as contributors to the emergence of therapeutic resistance and metastasis and their integrated predictive value in prostate cancer progression to advanced disease.     

Resolution proof transformation for compression and interpolation

Verification methods based on SAT, SMT, and theorem proving often rely on proofs of unsatisfiability as a powerful tool to extract information in order to reduce the overall effort. For example a proof may be traversed to identify a minimal reason that led to unsatisfiability, for computing abstractions, or for deriving Craig interpolants. In this paper we focus on two important aspects that concern efficient handling of proofs of unsatisfiability: compression and manipulation. First of all, since the proof size can be very large in general (exponential in the size of the input problem), it is indeed beneficial to adopt techniques to compress it for further processing. Secondly, proofs can be manipulated as a flexible preprocessing step in preparation for interpolant computation. Both these techniques are implemented in a framework that makes use of local rewriting rules to transform the proofs. We show that a careful use of the rules, combined with existing algorithms, can result in an effective simplification of the original proofs. We have evaluated several heuristics on a wide range of unsatisfiable problems deriving from SAT and SMT test cases.     

Coprimeness properties of nonlinear fractional system realizations

In this paper, the relationship between the Bezout and the set-theoretic approaches to left coprimeness is studied. It is shown that left coprimeness in the set-theoretic sense implies left coprimeness in the Bezout sense. In addition to these results, we investigate whether some properties for linear left coprime realizations carry over to the nonlinear case, for example we examine the relations between two left coprime realizations of the same system.     

Bisimulations for Temporal Logic

We define bisimulations for temporal logic with Since and Until. This new notion is compared to existing notions of bisimulations, and then used to develop the basic model theory of temporal logic with Since and Until. Our results concern both invariance and definability. We conclude with a brief discussion of the wider applicability of our ideas.     

Magnetically responsive polypyrrole nanotubes using Ce(III)-stabilized maghemite nanoparticles

Nanocomposites (NCs) that are made magnetically responsive in controlled conditions attract continuing interest for their added magnetic properties. In this study, we report on the preparation and full characterization of a multifunctional NC composed of magnetic γ-Fe(2)O(3) nanoparticles (NPs) covalently attached to the surface of polyaminated (polyNH(2)) poly(2,6-di-pyrrol-1-yl-hexanoic acid) (pDPL) nanotubes (NTs). Such a hybrid conducting polymer iron oxide maghemite γ-Fe(2)O(3)@pDPL NC built specifically on covalent bonding has never been reported. The maghemite γ-Fe(2)O(3) NPs were prepared using an innovative ultrasound-assisted Ce(3+) doping process, resulting in polycarboxylation of the NP surface useful for control of aggregation and derivatization of functionality. The second component of the NC, i.e. polyNH(2)-modified pDPL NTs, was prepared from an acid functional pyrrole species followed by amine modification. The resulting innovative γ-Fe(2)O(3)@pDPL NC can be viewed as a multifunctional nanomaterial since it possesses both types of derivatization, i.e. polyCOOH (NPs) and polyNH(2) (NTs) combined with magnetic responsivity.     

The Dynamics of Syntactic Knowledge

The syntactic approach to epistemic logic avoids the logicalomniscience problem by taking knowledge as primary rather thanas defined in terms of possible worlds. In this study, we combinethe syntactic approach with modal logic, using transition systemsto model reasoning. We use two syntactic epistemic modalities:‘knowing at least’ a set of formulae and ‘knowingat most’ a set of formulae. We are particularly interestedin models restricting the set of formulae known by an agentat a point in time to be finite. The resulting systems are investigatedfrom the point of view of axiomatization and complexity. Weshow how these logics can be used to formalise non-omniscientagents who know some inference rules, and study their relationshipto other systems of syntactic epistemic logics, such as Ågotnesand Walicki (2004, Proc. 2nd EUMAS, pp. 1–10), Alechinaet al. (2004, Proc. 3rd AAMAS, pp. 601–613), Duc (1997,J. Logic Comput., 7, 633–648).     

Elevated Circulating and Placental SPINT2 Is Associated with Placental Dysfunction

Biomarkers for placental dysfunction are currently lacking. We recently identified SPINT1 as a novel biomarker; SPINT2 is a functionally related placental protease inhibitor. This study aimed to characterise SPINT2 expression in placental insufficiency. Circulating SPINT2 was assessed in three prospective cohorts, collected at the following: (1) term delivery (n = 227), (2) 36 weeks (n = 364), and (3) 24–34 weeks’ (n = 294) gestation. SPINT2 was also measured in the plasma and placentas of women with established placental disease at preterm (<34 weeks) delivery. Using first-trimester human trophoblast stem cells, SPINT2 expression was assessed in hypoxia/normoxia (1% vs. 8% O2), and following inflammatory cytokine treatment (TNFα, IL-6). Placental SPINT2 mRNA was measured in a rat model of late-gestational foetal growth restriction. At 36 weeks, circulating SPINT2 was elevated in patients who later developed preeclampsia (p = 0.028; median = 2233 pg/mL vs. controls, median = 1644 pg/mL), or delivered a small-for-gestational-age infant (p = 0.002; median = 2109 pg/mL vs. controls, median = 1614 pg/mL). SPINT2 was elevated in the placentas of patients who required delivery for preterm preeclampsia (p = 0.025). Though inflammatory cytokines had no effect, hypoxia increased SPINT2 in cytotrophoblast stem cells, and its expression was elevated in the placental labyrinth of growth-restricted rats. These findings suggest elevated SPINT2 is associated with placental insufficiency.