Decitabine impact on the endocytosis regulator RhoA, the folate carriers RFC1 and FOLR1, and the glucose transporter GLUT4 in human tumors.

BackgroundIn 31 solid tumor patients treated with the demethylating agent decitabine, we performed tumor biopsies before and after the first cycle of decitabine and used immunohistochemistry (IHC) to assess whether decitabine increased expression of various membrane transporters. Resistance to chemotherapy may arise due to promoter methylation/downregulation of expression of transporters required for drug uptake, and decitabine can reverse resistance in vitro. The endocytosis regulator RhoA, the folate carriers FOLR1 and RFC1, and the glucose transporter GLUT4 were assessed.ResultsPre-decitabine RhoA was higher in patients who had received their last therapy >3 months previously than in patients with more recent prior therapy (P = 0.02), and varied inversely with global DNA methylation as assessed by LINE1 methylation (r = -0.58, P = 0.006). Tumor RhoA scores increased with decitabine (P = 0.03), and RFC1 also increased in patients with pre-decitabine scores ≤150 (P = 0.004). Change in LINE1 methylation with decitabine did not correlate significantly with change in IHC scores for any transporter assessed. We also assessed methylation of the RFC1 gene (alias SLC19A1). SLC19A1 methylation correlated with tumor LINE1 methylation (r = 0.45, P = 0.02). There was a small (statistically insignificant) decrease in SLC19A1 methylation with decitabine, and there was a trend towards change in SLC19A1 methylation with decitabine correlating with change in LINE1 methylation (r = 0.47, P <0.15). While SLC19A1 methylation did not correlate with RFC1 scores, there was a trend towards an inverse correlation between change in SLC19A1 methylation and change in RFC1 expression (r = -0.45, P = 0.19).ConclusionsIn conclusion, after decitabine administration, there was increased expression of some (but not other) transporters that may play a role in chemotherapy uptake. Larger patient numbers will be needed to define the extent to which this increased expression is associated with changes in DNA methylation

Multitask Learning on Graph Neural Networks: Learning Multiple Graph Centrality Measures with a Unified Network

The application of deep learning to symbolic domains remains an active research endeavour. Graph neural networks (GNN), consisting of trained neural modules which can be arranged in different topologies at run time, are sound alternatives to tackle relational problems which lend themselves to graph representations. In this paper, we show that GNNs are capable of multitask learning, which can be naturally enforced by training the model to refine a single set of multidimensional embeddings $\in \mathbb{R}^d$ and decode them into multiple outputs by connecting MLPs at the end of the pipeline. We demonstrate the multitask learning capability of the model in the relevant relational problem of estimating network centrality measures, focusing primarily on producing rankings based on these measures, i.e. is vertex $v_1$ more central than vertex $v_2$ given centrality $c$?. We then show that a GNN can be trained to develop a \emph{lingua franca} of vertex embeddings from which all relevant information about any of the trained centrality measures can be decoded. The proposed model achieves $89\%$ accuracy on a test dataset of random instances with up to 128 vertices and is shown to generalise to larger problem sizes. The model is also shown to obtain reasonable accuracy on a dataset of real world instances with up to 4k vertices, vastly surpassing the sizes of the largest instances with which the model was trained ($n=128$). Finally, we believe that our contributions attest to the potential of GNNs in symbolic domains in general and in relational learning in particular.Comment: Published at ICANN2019. 10 pages, 3 Figure

Noncommutative Vortices and Instantons from Generalized Bose Operators

Generalized Bose operators correspond to reducible representations of the harmonic oscillator algebra. We demonstrate their relevance in the construction of topologically non-trivial solutions in noncommutative gauge theories, focusing our attention to flux tubes, vortices, and instantons. Our method provides a simple new relation between the topological charge and the number of times the basic irreducible representation occurs in the reducible representation underlying the generalized Bose operator. When used in conjunction with the noncommutative ADHM construction, we find that these new instantons are in general not unitarily equivalent to the ones currently known in literature.Comment: 25 page

An expression signature of the angiogenic response in gastrointestinal neuroendocrine tumours: correlation with tumour phenotype and survival outcomes.

BACKGROUND: Gastroenteropancreatic neuroendocrine tumours (GEP-NETs) are heterogeneous with respect to biological behaviour and prognosis. As angiogenesis is a renowned pathogenic hallmark as well as a therapeutic target, we aimed to investigate the prognostic and clinico-pathological role of tissue markers of hypoxia and angiogenesis in GEP-NETs. METHODS: Tissue microarray (TMA) blocks were constructed with 86 tumours diagnosed from 1988 to 2010. Tissue microarray sections were immunostained for hypoxia inducible factor 1α (Hif-1α), vascular endothelial growth factor-A (VEGF-A), carbonic anhydrase IX (Ca-IX) and somatostatin receptors (SSTR) 1–5, Ki-67 and CD31. Biomarker expression was correlated with clinico-pathological variables and tested for survival prediction using Kaplan–Meier and Cox regression methods. RESULTS: Eighty-six consecutive cases were included: 51% male, median age 51 (range 16–82), 68% presenting with a pancreatic primary, 95% well differentiated, 51% metastatic. Higher grading (P=0.03), advanced stage (P<0.001), high Hif-1α and low SSTR-2 expression (P=0.03) predicted for shorter overall survival (OS) on univariate analyses. Stage, SSTR-2 and Hif-1α expression were confirmed as multivariate predictors of OS. Median OS for patients with SSTR-2+/Hif-1α-tumours was not reached after median follow up of 8.8 years, whereas SSTR-2-/Hif-1α+ GEP-NETs had a median survival of only 4.2 years (P=0.006). CONCLUSION: We have identified a coherent expression signature by immunohistochemistry that can be used for patient stratification and to optimise treatment decisions in GEP-NETs independently from stage and grading. Tumours with preserved SSTR-2 and low Hif-1α expression have an indolent phenotype and may be offered less aggressive management and less stringent follow up

Balanced electric-magnetic dihole in Kaluza-Klein theory

We present a four-dimensional double-black-hole (or dihole) solution in Kaluza-Klein theory, describing a superposition of an electrically charged and a magnetically charged black hole. This system can be balanced for appropriately chosen parameters, and the resulting space-time is completely regular on and outside the event horizons. This solution was constructed using the inverse-scattering method in five-dimensional vacuum gravity, in which it describes a rotating black ring surrounding a static black hole on a Taub-NUT background space. Various properties of this solution are studied, from both a four- and five-dimensional perspective.Comment: 33 pages, 6 figures; v2: expanded discussion of phase space, published versio

The rise of policy coherence for development: a multi-causal approach

In recent years policy coherence for development (PCD) has become a key principle in international development debates, and it is likely to become even more relevant in the discussions on the post-2015 sustainable development goals. This article addresses the rise of PCD on the Western donors’ aid agenda. While the concept already appeared in the work of Organisation for Economic Co-operation and Development (OECD) in the early 1990s, it took until 2007 before PCD became one of the Organisation’s key priorities. We adopt a complexity-sensitive perspective, involving a process-tracing analysis and a multi-causal explanatory framework. We argue that the rise of PCD is not as contingent as it looks. While actors such as the EU, the DAC and OECD Secretariat were the ‘active causes’ of the rise of PCD, it is equally important to look at the underlying ‘constitutive causes’ which enabled policy coherence to thrive well

On thermodynamics of N=6 superconformal Chern-Simons theory

We study thermodynamics of N=6 superconformal Chern-Simons theory by computing quantum corrections to the free energy. We find that in weakly coupled ABJM theory on R(2) x S(1), the leading correction is non-analytic in the 't Hooft coupling lambda, and is approximately of order lambda^2 log(lambda)^3. The free energy is expressed in terms of the scalar thermal mass m, which is generated by screening effects. We show that this mass vanishes to 1-loop order. We then go on to 2-loop order where we find a finite and positive mass squared m^2. We discuss differences in the calculation between Coulomb and Lorentz gauge. Our results indicate that the free energy is a monotonic function in lambda which interpolates smoothly to the N^(3/2) behaviour at strong coupling.Comment: 29 pages. v2: references added. v3: minor changes, references added, published versio

Phase II study of concurrent chemoradiotherapy with capecitabine and cisplatin in patients with locally advanced squamous cell carcinoma of the head and neck

We aimed to evaluate the efficacy and safety of concurrent chemoradiotherapy with capecitabine and cisplatin in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN). In total, 37 patients with stage III or IV SCCHN were enrolled on the study. The chemotherapy consisted of two cycles of intravenous cisplatin of 80 mg m−2 on day 1 and oral capecitabine 825 mg m−2 twice daily from day 1 to day 14 at 3-week intervals. The radiotherapy (1.8–2.0 Gy 1 fraction day−1 to a total dose of 70–70.2 Gy) was delivered to the primary tumour site and neck. The primary tumour sites were as follows: oral cavity (n=6), oropharynx (n=11), hypopharynx (n=8), larynx (n=3), nasopharynx (n=6), and paranasal sinus (n=3). After the chemoradiotherapy, 29 complete responses (78.4%) and 6 partial responses (16.2%) were confirmed. Grade 3 or 4 neutropenia occurred only in two patients, plus grade 3 febrile neutropenia was observed only in one patient. At a median follow-up duration of 19.8 months, the estimated overall survival and progression-free survival rate at 2-year was 76.8 and 57.9%, respectively. Concurrent chemoradiotherapy with capecitabine and cisplatin was found to be well tolerated and effective in patients with locally advanced SCCHN

W-Curve Alignments for HIV-1 Genomic Comparisons

The W-curve was originally developed as a graphical visualization technique for viewing DNA and RNA sequences. Its ability to render features of DNA also makes it suitable for computational studies. Its main advantage in this area is utilizing a single-pass algorithm for comparing the sequences. Avoiding recursion during sequence alignments offers advantages for speed and in-process resources. The graphical technique also allows for multiple models of comparison to be used depending on the nucleotide patterns embedded in similar whole genomic sequences. The W-curve approach allows us to compare large numbers of samples quickly.We are currently tuning the algorithm to accommodate quirks specific to HIV-1 genomic sequences so that it can be used to aid in diagnostic and vaccine efforts. Tracking the molecular evolution of the virus has been greatly hampered by gap associated problems predominantly embedded within the envelope gene of the virus. Gaps and hypermutation of the virus slow conventional string based alignments of the whole genome. This paper describes the W-curve algorithm itself, and how we have adapted it for comparison of similar HIV-1 genomes. A treebuilding method is developed with the W-curve that utilizes a novel Cylindrical Coordinate distance method and gap analysis method. HIV-1 C2-V5 env sequence regions from a Mother/Infant cohort study are used in the comparison.The output distance matrix and neighbor results produced by the W-curve are functionally equivalent to those from Clustal for C2-V5 sequences in the mother/infant pairs infected with CRF01_AE.Significant potential exists for utilizing this method in place of conventional string based alignment of HIV-1 genomes, such as Clustal X. With W-curve heuristic alignment, it may be possible to obtain clinically useful results in a short time-short enough to affect clinical choices for acute treatment. A description of the W-curve generation process, including a comparison technique of aligning extremes of the curves to effectively phase-shift them past the HIV-1 gap problem, is presented. Besides yielding similar neighbor-joining phenogram topologies, most Mother and Infant C2-V5 sequences in the cohort pairs geometrically map closest to each other, indicating that W-curve heuristics overcame any gap problem