HPRA: Hyperedge Prediction using Resource Allocation

Many real-world systems involve higher-order interactions and thus demand complex models such as hypergraphs. For instance, a research article could have multiple collaborating authors, and therefore the co-authorship network is best represented as a hypergraph. In this work, we focus on the problem of hyperedge prediction. This problem has immense applications in multiple domains, such as predicting new collaborations in social networks, discovering new chemical reactions in metabolic networks, etc. Despite having significant importance, the problem of hyperedge prediction hasn't received adequate attention, mainly because of its inherent complexity. In a graph with $n$ nodes the number of potential edges is $\mathcal{O}(n^{2})$, whereas in a hypergraph, the number of potential hyperedges is $\mathcal{O}(2^{n})$. To avoid searching through such a huge space, current methods restrain the original problem in the following two ways. One class of algorithms assume the hypergraphs to be $k$-uniform. However, many real-world systems are not confined only to have interactions involving $k$ components. Thus, these algorithms are not suitable for many real-world applications. The second class of algorithms requires a candidate set of hyperedges from which the potential hyperedges are chosen. In the absence of domain knowledge, the candidate set can have $\mathcal{O}(2^{n})$ possible hyperedges, which makes this problem intractable. We propose HPRA - Hyperedge Prediction using Resource Allocation, the first of its kind algorithm, which overcomes these issues and predicts hyperedges of any cardinality without using any candidate hyperedge set. HPRA is a similarity-based method working on the principles of the resource allocation process. In addition to recovering missing hyperedges, we demonstrate that HPRA can predict future hyperedges in a wide range of hypergraphs.Comment: Accepted at WebSci'2

Crystal-like high frequency phonons in the amorphous phases of solid water

The high frequency dynamics of low- (LDA) and high-density amorphous-ice (HDA) and of cubic ice (I_c) has been measured by inelastic X-ray Scattering (IXS) in the 1-15 nm^{-1} momentum transfer (Q) range. Sharp phonon-like excitations are observed, and the longitudinal acoustic branch is identified up to Q = 8nm^{-1} in LDA and I_c and up to 5nm^{-1} in HDA. The narrow width of these excitations is in sharp contrast with the broad features observed in all amorphous systems studied so far. The "crystal-like" behavior of amorphous ices, therefore, implies a considerable reduction in the number of decay channels available to sound-like excitations which is assimilated to low local disorder.Comment: 4 pages, 3 figure

GLUT1 and LOX inhibitors as perspective anticancer agents tackling glucose avidity and ECM remodeling in tumors

Introduction Most cancers have large hypoxic regions, which display an increase of the glycolytic metabolism leading to the production of lactate, providing cancer cells with adequate amounts of energy and anabolites. To this end, tumor cells generally overexpress glucose transporters (GLUTs), in particular GLUT1, which results in an increased uptake of glucose to support their less efficient energy production (Warburg effect). Therefore, therapeutic interventions aimed at reducing cancer glycolysis may be implemented by several strategies, including the development of inhibitors of glucose transporters. Furthermore, extracellular matrix (ECM) remodeling is one of the key processes preluding metastatic invasion, and it is promoted by several effectors, such as lysyl oxidase (LOX), an enzyme commonly involved in extracellular matrix maturation. LOX is up-regulated by HIF-1 and plays a critical role in the development of metastasis. Therefore, LOX inhibitors may represent an additional and innovative strategy for the treatment and the prevention of metastatic cancer. Methods We have developed various classes of compounds that are able to interfere with GLUTs (Granchi et al. 2015, Tuccinardi et al. 2013) and LOX (Granchi et al. 2009) by molecular design and chemical synthesis. Their effect on cell proliferation, apoptosis, migration and other key determinants of activity were evaluated by sulforhodamine-B and luciferase assays, FACS, wound-healing assay, and Quantitative PCR. The studies were performed in seven PDAC cells, including five primary-cell-cultures and 3D co-cultures with human stellate cells, in normoxic and hypoxic conditions. Results The IC50s of the tested compounds ranged from 13.9 to 32.0 μM after 72-hour exposure. Notably, these compounds were still active in 3D co-cultures of these tumor cells with pancreatic stellate cells, which showed increased resistance to gemcitabine and are more representative of the dense stromal compartment with core hypoxic areas of this tumor type, as detected by immunohistochemical stainings. Remarkably, one compound (PGL-14) showed a synergistic interaction with gemcitabine, increasing apoptosis induction and accumulation of ROS. Furthermore, the combination of these drugs reduced cell migration and enhanced in vitro sensitivity to anoikis, suggesting the ability of these compounds to inhibit metastasis. Discussion GLUT1 inhibitors were more active in hypoxia, but still active also in normoxia. Conversely, we did not detect cytotoxic effects using the LOX-inhibitors in normoxia (at concentration until 50 μM) since they were designed as bioreductively activated prodrugs, which are therefore activated only under hypoxic conditions. However, at O2 tension of 1%, IC50s were below 10 μM. As reported previously, LOX inhibition was associated with reduction of the mRNA levels of fibronectin, suggesting that it might also have impact on the interaction of tumor cells with the stroma that are mediated by integrins and fibronectin, regulating tissue stiffness (Coppola et al. 2017). Conclusion Interventions aimed at blocking the glycolytic activity or the extracellular matrix remodeling of tumors by means of newly designed molecules proved to exert a synergistic effect with clinically approved drugs, such as gemcitabine. These results seem to support the strategy of the simultaneous GLUT/LOX-inhibition in order to further sensitize hypoxic cancer portions to chemotherapy. Bibliography C. Granchi, et al. ChemMedChem 2009, 4, 1590-1594. C. Granchi, et al. ChemMedChem 2015, 10, 1892-1900. T. Tuccinardi, et al. Bioorg. Med. Chem. Lett. 2013, 23, 6923-6927. Coppola S, et al. Drug Resist Updat. 2017, 31, 43-51

Prospective validation of microRNA signatures for detecting pancreatic malignant transformation in endoscopic-ultrasound guided fine-needle aspiration biopsies

Background: Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease. Novel biomarkers are required to aid treatment decisions and improve patient outcomes. MicroRNAs (miRNAs) are potentially ideal diagnostic biomarkers, as they are stable molecules, and tumour and tissue specific.Results: Logistic regression analysis revealed an endoscopic-ultrasound fine-needle aspiration (EUS-FNA) 2-miRNA classifier (miR-21 + miR-155) capable of distinguishing benign from malignant pancreatic lesions with a sensitivity of 81.5% and a specificity of 85.7% (AUC 0.930). Validation FNA cohorts confirmed both miRNAs were overexpressed in malignant disease, while circulating miRNAs performed poorly.Methods: Fifty-five patients with a suspicious pancreatic lesion on cross-sectional imaging were evaluated by EUS-FNA. At echo-endoscopy, the first part of the FNA was sent for cytological assessment and the second part was used for total RNA extraction. Candidate miRNAs were selected after careful review of the literature and expression was quantified by qRT-PCR. Validation was performed on an independent cohort of EUS-FNAs, as well as formalin-fixed paraffin embedded (FFPE) and plasma samples.Conclusions: We provide further evidence for using miRNAs as diagnostic biomarkers for pancreatic malignancy. We demonstrate the feasibility of using fresh EUS-FNAs to establish miRNA-based signatures unique to pancreatic malignant transformation and the potential to enhance risk stratification and selection for surgery

Interfacing polymeric scaffolds with primary pancreatic ductal adenocarcinoma cells to develop 3D cancer models

We analyzed the interactions between human primary cells from pancreatic ductal adenocarcinoma (PDAC) and polymeric scaffolds to develop 3D cancer models useful for mimicking the biology of this tumor. Three scaffold types based on two biocompatible polymeric formulations, such as poly(vinyl alcohol)/gelatin (PVA/G) mixture and poly(ethylene oxide terephthalate)/poly(butylene terephthalate) (PEOT/PBT) copolymer, were obtained via different techniques, namely, emulsion and freeze-drying, compression molding followed by salt leaching, and electrospinning. In this way, primary PDAC cells interfaced with different pore topographies, such as sponge-like pores of different shape and size or nanofiber interspaces. The aim of this study was to investigate the influence played by the scaffold architecture over cancerous cell growth and function. In all scaffolds, primary PDAC cells showed good viability and synthesized tumor-specific metalloproteinases (MMPs) such as MMP-2, and MMP-9. However, only sponge-like pores, obtained via emulsion-based and salt leaching-based techniques allowed for an organized cellular aggregation very similar to the native PDAC morphological structure. Differently, these cell clusters were not observed on PEOT/PBT electrospun scaffolds. MMP-2 and MMP-9, as active enzymes, resulted to be increased in PVA/G and PEOT/PBT sponges, respectively. These findings suggested that spongy scaffolds supported the generation of pancreatic tumor models with enhanced aggressiveness. In conclusion, primary PDAC cells showed diverse behaviors while interacting with different scaffold types that can be potentially exploited to create stage-specific pancreatic cancer models likely to provide new knowledge on the modulation and drug susceptibility of MMPs

Silver Nanoparticle-Coated Polyhydroxyalkanoate Based Electrospun Fibers for Wound Dressing Applications

Wound dressings are high performance and high value products which can improve the regeneration of damaged skin. In these products, bioresorption and biocompatibility play a key role. The aim of this study is to provide progress in this area via nanofabrication and antimicrobial natural materials. Polyhydroxyalkanoates (PHAs) are a bio-based family of polymers that possess high biocompatibility and skin regenerative properties. In this study, a blend of poly(3-hydroxybutyrate) (P(3HB)) and poly(3-hydroxyoctanoate-co-3-hydroxy decanoate) (P(3HO-co-3HD)) was electrospun into P(3HB))/P(3HO-co-3HD) nanofibers to obtain materials with a high surface area and good handling performance. The nanofibers were then modified with silver nanoparticles (AgNPs) via the dip-coating method. The silver-containing nanofiber meshes showed good cytocompatibility and interesting immunomodulatory properties in vitro, together with the capability of stimulating the human beta defensin 2 and cytokeratin expression in human keratinocytes (HaCaT cells), which makes them promising materials for wound dressing applications

The occurrence of prion protein in surgically resected pancreatic adenocarcinoma

Background: Among the several new targets for the comprehension of the biology of pancreatic ductal adenocarcinoma (PDAC), Prion proteins (PrPc) deserve particular mention, since they share a marked neurotropism. Actually, PrPc could have also a role in tumorigenesis, as recently demonstrated. However, only few in vitro studies in cell cultures showed the occurrence of PrPc in PDAC cells. We aim to evaluate the presence of PrPc in vivo in PDAC tissues as a potential new biomarker. Methods: Samples from tumors of 23 patients undergone pancreatic resections from July 2018 to May 2020 at our institution were collected and analyzed. Immunohistochemistry and western blotting of PDAC tissues were compared with control tissues. Immunohistochemistry was used also to evaluate the localization of PrPc and of CD155, a tumoral stem-cell marker. Results: All cases were moderately differentiated PDAC, with perineural invasion (PNI) in 19/23 cases (83%). According to western-blot analysis, PrPc was markedly expressed in PDAC tissues (273.5 ± 44.63 OD) respect to controls (100 ± 28.35 OD, p = 0.0018). Immunohistochemistry confirmed these findings, with higher linear staining of PrPc in PDAC ducts (127.145 ± 7.56 μm vs 75.21 ± 5.01 μm, p < 0.0001). PrPc and CD155 exactly overlapped in ductal tumoral cells, highlighting the possible relationship of PrPc with cancer stemness. Finally, PrPc expression related with cancer stage and there was a potential correspondence with PNI. Conclusions: Our work provides evidence for increased levels of PrPc in PDAC. This might contribute to cancer aggressiveness and provides a potentially new biomarker. Work is in progress to decipher clinical implications

Liquid-Liquid Phase Transitions for Soft-Core Attractive Potentials

Using event driven molecular dynamics simulations, we study a three dimensional one-component system of spherical particles interacting via a discontinuous potential combining a repulsive square soft core and an attractive square well. In the case of a narrow attractive well, it has been shown that this potential has two metastable gas-liquid critical points. Here we systematically investigate how the changes of the parameters of this potential affect the phase diagram of the system. We find a broad range of potential parameters for which the system has both a gas-liquid critical point and a liquid-liquid critical point. For the liquid-gas critical point we find that the derivatives of the critical temperature and pressure, with respect to the parameters of the potential, have the same signs: they are positive for increasing width of the attractive well and negative for increasing width and repulsive energy of the soft core. This result resembles the behavior of the liquid-gas critical point for standard liquids. In contrast, for the liquid-liquid critical point the critical pressure decreases as the critical temperature increases. As a consequence, the liquid-liquid critical point exists at positive pressures only in a finite range of parameters. We present a modified van der Waals equation which qualitatively reproduces the behavior of both critical points within some range of parameters, and give us insight on the mechanisms ruling the dependence of the two critical points on the potential's parameters. The soft core potential studied here resembles model potentials used for colloids, proteins, and potentials that have been related to liquid metals, raising an interesting possibility that a liquid-liquid phase transition may be present in some systems where it has not yet been observed.Comment: 29 pages, 15 figure

3-(6-Phenylimidazo [2,1-b][1,3,4]thiadiazol-2-yl)-1HIndole derivatives as new anticancer agents in the treatment of pancreatic ductal adenocarcinoma

A new series of imidazo[2,1-b][1,3,4]thiadiazole derivatives was efficiently synthesized and screened for their in vitro antiproliferative activity on a panel of pancreatic ductal adenocarcinoma (PDAC) cells, including SUIT-2, Capan-1 and Panc-1. Compounds 9c and 9l, showed relevant in vitro antiproliferative activity on all three pre-clinical models with half maximal inhibitory concentration (IC50) ranging from 5.11 to 10.8 μM, while the compounds 9e and 9n were active in at least one cell line. In addition, compound 9c significantly inhibited the migration rate of SUIT-2 and Capan-1 cells in the scratch wound-healing assay. In conclusion, our results will support further studies to increase the library of imidazo [2,1-b][1,3,4] thiadiazole derivatives for deeper understanding of the relationship between biological activity of the compounds and their structures in the development of new antitumor compounds against pancreatic diseases