bluuebunny/crossref_metadata_2025 huggingface dataset:
The Influence of In Vitro Gastrointestinal Digestion on the Anticancer Activity of Manuka Honey
Authors: Cianciosi Danila , Forbes-Hernández Tamara Yuliett , Afrin Sadia , Gasparrini Massimiliano , Quiles José L. , Gil Emilio , Bompadre Stefano , Simal-Gandara Jesus , Battino Maurizio , Giampieri Francesca
Published: January 2020

Manuka honey (MH) is a natural food with many beneficial properties to human health, thanks to its high variety of bioactive compounds; however, little is known about its bioaccessibility. The aim of this study was to evaluate and compare the polyphenol compounds, the antioxidant capacity and the anticancer activity of MH subjected to an in vitro gastrointestinal digestion in human HCT-116 colon cancer cells. Raw MH and digested MH (DMH) were assessed for total polyphenols and flavonoids by spectrophotometric and HPLC-ESI-MS/MS analysis, and total antioxidant capacity (TAC) using different methods. Cell viability, intracellular ROS production, apoptosis, cell cycle and colony formation capacity were tested after treatment with MH or DMH. Results showed that total polyphenols, total flavonoids and TAC were significantly (p < 0.05) reduced after in vitro digestion. In addition, MH and DMH at 8, 16 and 24 mg/mL had similar effects in inducing intracellular ROS production and in inhibiting the colon formation ability; MH induced a more marked apoptosis compared to DMH, while cell cycle was blocked in S phase by MH and in Sub G1 phase by DMH. Our results increase knowledge of the effect of gastrointestinal digestion on the biological effect of honey against colorectal cancer.
Washing Batch Test of Contaminated Sediment: The Case of Augusta Bay (SR, Italy)
Authors: Lumia Lucia , Giustra Maria Gabriella , Viviani Gaspare , Di Bella Gaetano
Published: January 2020

Two experimental campaigns were conducted to optimize the applicability of the Sediment Washing treatment on the marine sediments of Augusta Bay contaminated with heavy metals and total petroleum hydrocarbons (TPH). In the first campaign were used EDTA, citric acid, and acetic acid to removal only heavy metals (Ni, Cu, Zn, Cr, and Hg) from the sediments, while in the second campaign EDTA, citric acid, and EDDS were used to removal heavy metals (Ni, Cu, Cr, and Pb) and TPH. The tests were conducted at different pH values and contact times with 1:10 solid:liquid weight ratio. In the first experimental, at pH values 4, contact time 3 h, and citric acid, high removal efficiencies (78–82%) have been obtained for Ni, Cu, Zn, and Cr metals, while, in the second experimental campaign, at pH value 4, contact time 0.5 h, and citric acid, high removal efficiencies have been achieved especially for Pb and TPH. Finally, on the basis of the results obtained, a conceptual sediment washing treatment layout was proposed and the related costs estimated.
PRIPRO: A Comparison of Classification Algorithms for Managing Receiving Notifications in Smart Environments
Authors: Martins João Antônio , Ochôa Iago Sestrem , Silva Luis Augusto , Mendes André Sales , González Gabriel Villarrubia , De Paz Santana Juan , Leithardt Valderi Reis Quietinho
Published: January 2020

With the evolution of technology over the years, it has become possible to develop intelligent environments based on the concept of the Internet of Things, distributed systems, and machine learning. Such environments are infused with various solutions to solve user demands from services. One of these solutions is the Ubiquitous Privacy (UBIPRI) middleware, whose central concept is to maintain privacy in smart environments and to receive notifications as one of its services. However, this service is freely performed, disregarding the privacy that the environment employs. Another consideration is that, based on the researched related work, it was possible to identify that the authors do not use statistical hypothesis tests in their solutions developed in the presented context. This work proposes an architecture for notification management in smart environments, composed by a notification manager named Privacy Notification Manager (PRINM) to assign it to UBIPRI and to aim to perform experiments between classification algorithms to delimit which one is most feasible to implement in the PRINM decision-making mechanism. The experiments showed that the J48 algorithm obtained the best results compared to the other algorithms tested and compared.
Tampered and Computer-Generated Face Images Identification Based on Deep Learning
Authors: Dang L. Minh , Min Kyungbok , Lee Sujin , Han Dongil , Moon Hyeonjoon
Published: January 2020

Image forgery is an active topic in digital image tampering that is performed by moving a region from one image into another image, combining two images to form one image, or retouching an image. Moreover, recent developments of generative adversarial networks (GANs) that are used to generate human facial images have made it more challenging for even humans to detect the tampered one. The spread of those images on the internet can cause severe ethical, moral, and legal issues if the manipulated images are misused. As a result, much research has been conducted to detect facial image manipulation based on applying machine learning algorithms on tampered face datasets in the last few years. This paper introduces a deep learning-based framework that can identify manipulated facial images and GAN-generated images. It is comprised of multiple convolutional layers, which can efficiently extract features using multi-level abstraction from tampered regions. In addition, a data-based approach, cost-sensitive learning-based approach (class weight), and ensemble-based approach (eXtreme Gradient Boosting) is applied to the proposed model to deal with the imbalanced data problem (IDP). The superiority of the proposed model that deals with an IDP is verified using a tampered face dataset and a GAN-generated face dataset under various scenarios. Experimental results proved that the proposed framework outperformed existing expert systems, which has been used for identifying manipulated facial images and GAN-generated images in terms of computational complexity, area under the curve (AUC), and robustness. As a result, the proposed framework inspires the development of research on image forgery identification and enables the potential to integrate these models into practical applications, which require tampered facial image detection.
Modified Structures for Hybrid Active Sound Quality Control System Disturbed by Gaussian Random Noise
Authors: Li Shanjun , Jin Guoyong , Li Xiaobo , Ye Tiangui
Published: January 2020

A hybrid active sound quality control system, in which a hybrid feedforward and feedback structure is applied, can not only be used in cases where the line-spectrum noise is obtained easily with reference sensors, but it can also improve the comfortability of noise and eliminate unexpected Gaussian random noise. However, the traditional structure for a hybrid active sound quality control system, whereby a reference signal in the feedback control structure is synthesized by the output signals of the feedforward control filter, feedback control filter, and line-spectrum noise cancellation control filter, introduces couplings of the three control filters. To remove the coupling interactions of the feedforward and feedback control structures and to reduce the complexity of the control system, two modified structures with less computational complexity or a smaller increase in computation are investigated in this paper. The first one involves a simplified structure in which the reference signal in the feedback control structure is replaced by the summation of the residual error signal and the output signal of the line-spectrum noise cancellation control filter, and the second one is a modified structure which integrates the output signals of the feedback control filter and the line-spectrum noise cancellation control filter for the reference signal in the feedback control structure. Numerical simulations are carried out to show the performance of the modified structures. The results illustrate that the two modified structures have the ability to cancel Gaussian random noise and to reduce or enhance the amplitude of line-spectrum noise to promote sound quality. Moreover, a simplified structure with a new leaky filtered-x least mean square (FxLMS) algorithm is proposed to upgrade the noise reduction performance and elevate stability in the feedback control structure. The effectiveness of the proposed algorithm also is proven by the simulation results.
AISAC: An Artificial Immune System for Associative Classification Applied to Breast Cancer Detection
Authors: González-Patiño David , Villuendas-Rey Yenny , Argüelles-Cruz Amadeo José , Camacho-Nieto Oscar , Yáñez-Márquez Cornelio
Published: January 2020

Early breast cancer diagnosis is crucial, as it can prevent further complications and save the life of the patient by treating the disease at its most curable stage. In this paper, we propose a new artificial immune system model for associative classification with competitive performance for breast cancer detection. The proposed model has its foundations in the biological immune system; it mimics the detection skills of the immune system to provide correct identification of antigens. The Wilcoxon test was used to identify the statistically significant differences between our proposal and other classification algorithms based on the same bio-inspired model. These statistical tests evidenced the enhanced performance shown by the proposed model by outperforming other immune-based algorithms. The proposed model proved to be competitive with respect to other well-known classification models. In addition, the model benefits from a low computational cost. The success of this model for classification tasks shows that swarm intelligence is useful for this kind of problem, and that it is not limited to optimization tasks.
Evaluation of Non-Conventional Biological and Molecular Parameters as Potential Indicators of Quality and Functionality of Urban Biosolids Used as Organic Amendments of Agricultural Soils
Authors: Medina-Herrera Miriam del Rocío , Negrete-Rodríguez María de la Luz Xochilt , Álvarez-Trejo José Luis , Samaniego-Hernández Midory , González-Cruz Leopoldo , Bernardino-Nicanor Aurea , Conde-Barajas Eloy
Published: January 2020

Biosolids are waste from wastewater treatment and have a high content of organic matter and nutrients. In this study, not conventional physicochemical and biological properties of biosolids produced during different seasons of the year were evaluated. These properties are not considered in environmental regulations; however, they are of agronomic interest as indicators of quality and functionality in soils. Also, molecular analysis by Fourier-transform infrared (FTIR) was conducted, enzymatic analysis using the APIZYM® system was performed and two indices of functional and microbial diversity were established. The results showed that the biosolids had a high content of total organic carbon, total nitrogen, P, and K. FTIR analyses showed that chemical composition of biosolids was similar during all year. The C and N of microbial biomass demonstrated presence of active microorganisms, as well as a uniformity in its richness and abundance of species that could present a positive synergy with soil microorganisms. The enzymatic activities showed that the biosolids contained an enzymatic machinery available to promote the mineralisation of the organic matter of biosolids and could even transcend into the soil. Finally, biological properties can be used as indicators of quality and functionality of biosolids before being used as an organic amendment, especially in agricultural soils.
VES: A Mixed-Reality System to Assist Multisensory Spatial Perception and Cognition for Blind and Visually Impaired People
Authors: Real Santiago , Araujo Alvaro
Published: January 2020

In this paper, the Virtually Enhanced Senses (VES) System is described. It is an ARCore-based, mixed-reality system meant to assist blind and visually impaired people’s navigation. VES operates in indoor and outdoor environments without any previous in-situ installation. It provides users with specific, runtime-configurable stimuli according to their pose, i.e., position and orientation, and the information of the environment recorded in a virtual replica. It implements three output data modalities: Wall-tracking assistance, acoustic compass, and a novel sensory substitution algorithm, Geometry-based Virtual Acoustic Space (GbVAS). The multimodal output of this algorithm takes advantage of natural human perception encoding of spatial data. Preliminary experiments of GbVAS have been conducted with sixteen subjects in three different scenarios, demonstrating basic orientation and mobility skills after six minutes training.
Coupled Thermo-Hydro-Mechanical Analysis of Valley Narrowing Deformation of High Arch Dam: A Case Study of the Xiluodu Project in China
Authors: Yin Tao , Li Qingbin , Hu Yu , Yu Sanda , Liang Guohe
Published: January 2020

General studies examining reservoir bank deformation during its impoundment primarily consider the coupling effect between the seepage field and the stress field, but thermal field variation in the bedrock and its effect are rarely considered. In this paper, a case study concerning a 285.5 m high arch dam project, where a valley narrowing deformation occurs after the initial impoundment, is implemented. An analysis of in situ measurement is given to interpret the causes of the unique hydro-thermal phenomenon of the project. Possible reasons for the valley narrowing deformation pattern are discussed. A numerical model based on the thermo-hydro-mechanical (THM) coupling theory of porous medium is used to calculate the evolution processes of the thermal, seepage, and stress fields of the area after impoundment of the reservoir. The simulated deformation trend and pattern of the river valley are consistent with the monitoring data. The results demonstrate that water infiltration after impounding cools the bedrock and the temperature decrease makes the bedrock contract, which induces the narrowing deformation of the valley. Factor analysis of the hydrothermal field shows that temperature variation is the main cause of long-term deformation. Thus, it shall be considered as a key factor in terms of structural safety assessment. Furthermore, sensitivity analysis of the hydraulic conductivities of rock strata suggests that future development of the deformation can be eased off if the anti-seepage method is adopted on the bedrock.
Precise Measurement of Hyperfine Structure of Cesium 7S1/2 Excited State
Authors: He Yunhui , Fan Jiabei , Hao Liping , Jiao Yuechun , Zhao Jianming
Published: January 2020

We present a precise measurement of the hyperfine structure of cesium 7 S 1 / 2 excited state by employing electromagnetically induced spectroscopy (EIS) with a cesium three-level cascade ( 6 S 1 / 2 − 6 P 3 / 2 − 7 S 1 / 2 ) atom in a room temperature vapor cell. A probe laser, λ p = 852 nm, was coupled to a transition | 6 S 1 / 2 ⟩ → | 6 P 3 / 2 ⟩ , related frequency locked to the resonance hyperfine transition of | 6 S 1 / 2 ⟩ → | 6 P 3 / 2 ⟩ with a Fabry–Perot (FP) cavity and an electro-optic modulator (EOM). A coupling laser, λ c = 1470 nm, drove the | 6 P 3 / 2 ⟩ → | 7 S 1 / 2 ⟩ transition with the frequency scanned over the | 6 P 3 / 2 ⟩ → | 7 S 1 / 2 ⟩ transition line. The hyperfine level interval was extracted to be 2183.61 ± 0.50 MHz by analyzing EIS spectroscopy. The optical–optical double-resonance (OODR) spectroscopy is also presented for comparison, with the corresponding value of the hyperfine level interval being 2183.48 MHz ± 0.04 MHz, and the measured hyperfine splitting of excited 7 S 1 / 2 state is shown to be in excellent agreement with the previous work.
Maribor Synagogue: Between Facts and Reinterpretation
Authors: Premk Janez
Published: January 2020

Maribor Synagogue is one of the few preserved medieval synagogues in Central Europe. The renovation of the building between 1992 and 1999, undertaken by the Institute for the Protection of Cultural Heritage of Slovenia, proved to be much more demanding than originally foreseen. Its architectural shell and architectural elements have served as a reference point for the (visual) reconstruction of related monuments in the wider region. However, the renovation itself has left numerous unanswered questions, especially in regard to the building phases during the Jewish and later Christian use of the building. The present article is the first scientific publication to thoroughly examine the medieval building phases, based on the findings of archaeological research and investigation of the documented and preserved architectural elements. Ground plans are attached for the initial two building phases, related to the archeological charts. The last phase corresponds to the reconstructed version of the synagogue, but convincing evidence relating to its appearance is missing. Although it is practically impossible to provide an entirely accurate building history based on the archival, oral and material evidence so far available, a significant step toward its general comprehension is made.
Characterization of Urban New Particle Formation in Amman—Jordan
Authors: Hussein Tareq , Atashi Nahid , Sogacheva Larisa , Hakala Simo , Dada Lubna , Petäjä Tuukka , Kulmala Markku
Published: January 2020

We characterized new particle formation (NPF) events in the urban background of Amman during August 2016–July 2017. The monthly mean of submicron particle number concentration was 1.2 × 104–3.7 × 104 cm−3 (exhibited seasonal, weekly, and diurnal variation). Nucleation mode (10–15 nm) concentration was 0.7 × 103–1.1 × 103 cm−3 during daytime with a sharp peak (1.1 × 103–1.8 × 103 cm−3) around noon. We identified 110 NPF events (≈34% of all days) of which 55 showed a decreasing mode diameter after growth. The NPF event occurrence was higher in summer than in winter, and events were accompanied with air mass back trajectories crossing over the Eastern Mediterranean. The mean nucleation rate (J10) was 1.9 ± 1.1 cm−3 s−1 (monthly mean 1.6–2.7 cm−3 s−1) and the mean growth rate was 6.8 ± 3.1 nm/h (4.1–8.8 nm/h). The formation rate did not have a seasonal pattern, but the growth rate had a seasonal variation (maximum around August and minimum in winter). The mean condensable vapor source rate was 4.1 ± 2.2 × 105 molecules/cm3 s (2.6–6.9 × 105 molecules/cm3 s) with a seasonal pattern (maximum around August). The mean condensation sink was 8.9 ± 3.3 × 10−3 s−1 (6.4–14.8 × 10−3 s−1) with a seasonal pattern (minimum around June and maximum in winter).
Study of Chemical and Optical Properties of Biomass Burning Aerosols during Long-Range Transport Events toward the Arctic in Summer 2017
Authors: Zielinski Tymon , Bolzacchini Ezio , Cataldi Marco , Ferrero Luca , Graßl Sandra , Hansen Georg , Mateos David , Mazzola Mauro , Neuber Roland , Pakszys Paulina , Posyniak Michal , Ritter Christoph , Severi Mirko , Sobolewski Piotr , Traversi Rita , Velasco-Merino Christian
Published: January 2020

Biomass burning related aerosol episodes are becoming a serious threat to the radiative balance of the Arctic region. Since early July 2017 intense wildfires were recorded between August and September in Canada and Greenland, covering an area up to 4674 km2 in size. This paper describes the impact of these biomass burning (BB) events measured over Svalbard, using an ensemble of ground-based, columnar, and vertically-resolved techniques. BB influenced the aerosol chemistry via nitrates and oxalates, which exhibited an increase in their concentrations in all of size fractions, indicating the BB origin of particles. The absorption coefficient data (530 nm) at ground reached values up to 0.6 Mm–1, highlighting the impact of these BB events when compared to average Arctic background values, which do not exceed 0.05 Mm–1. The absorption behavior is fundamental as implies a subsequent atmospheric heating. At the same time, the AERONET Aerosol Optical Depth (AOD) data showed high values at stations located close to or in Canada (AOD over 2.0). Similarly, increased values of AODs were then observed in Svalbard, e.g., in Hornsund (daily average AODs exceeded 0.14 and reached hourly values up to 0.5). Elevated values of AODs were then registered in Sodankylä and Andenes (daily average AODs exceeding 0.150) a few days after the Svalbard observation of the event highlighting the BB columnar magnitude, which is crucial for the radiative impact. All the reported data suggest to rank the summer 2017 plume of aerosols as one of the biggest atmosphere related environmental problems over Svalbard region in last 10 years.
Numerical Study of the Interaction between Oasis and Urban Areas within an Arid Mountains-Desert System in Xinjiang, China
Authors: Cai Peng , Hamdi Rafiq , He Huili , Luo Geping , Wang Jin , Zhang Miao , Li Chaofan , Termonia Piet , De Maeyer Philippe
Published: January 2020

The rapid oasis expansion and urbanization that occurred in Xinjiang province (China) in the last decades have greatly modified the land surface energy balance and influenced the local circulation under the arid mountains-plain background system. In this study, we first evaluated the ALARO regional climate model coupled to the land surface scheme SURFEX at 4 km resolution using 53 national climatological stations and 5 automatic weather stations. We found that the model correctly simulates daily and hourly variation of 2 m temperature and relative humidity. A 4-day clear sky period has been chosen to study both local atmospheric circulations and their mutual interaction. Observations and simulations both show that a low-level divergence over oasis appears between 19:00 and 21:00 Beijing Time when the background mountain-plain wind system is weak. The model simulates a synergistic interaction between the oasis-desert breeze and urban-rural breeze from 16:00 until 22:00 with a maximum effect at 20:00 when the downdraft over oasis (updraft over urban) areas increases by 0.8 (0.4) Pa/s. The results show that the oasis expansion decreases the nocturnal urban heat island in the city of Urumqi by 0.8 °C, while the impact of urban expansion on the oasis cold island is negligible.
Meta-Analysis of Hypoxic Transcriptomes from Public Databases
Authors: Bono Hidemasa , Hirota Kiichi
Published: January 2020

Hypoxia is the insufficiency of oxygen in the cell, and hypoxia-inducible factors (HIFs) are central regulators of oxygen homeostasis. In order to obtain functional insights into the hypoxic response in a data-driven way, we attempted a meta-analysis of the RNA-seq data from the hypoxic transcriptomes archived in public databases. In view of methodological variability of archived data in the databases, we first manually curated RNA-seq data from appropriate pairs of transcriptomes before and after hypoxic stress. These included 128 human and 52 murine transcriptome pairs. We classified the results of experiments for each gene into three categories: upregulated, downregulated, and unchanged. Hypoxic transcriptomes were then compared between humans and mice to identify common hypoxia-responsive genes. In addition, meta-analyzed hypoxic transcriptome data were integrated with public ChIP-seq data on the known human HIFs, HIF-1 and HIF-2, to provide insights into hypoxia-responsive pathways involving direct transcription factor binding. This study provides a useful resource for hypoxia research. It also demonstrates the potential of a meta-analysis approach to public gene expression databases for selecting candidate genes from gene expression profiles generated under various experimental conditions.
Stage IV Gastric Cancer: The Surgical Perspective of the Italian Research Group on Gastric Cancer
Authors: Ministrini Silvia , Bencivenga Maria , Solaini Leonardo , Cipollari Chiara , Sofia Silvia , Marino Elisabetta , d’Ignazio Alessia , Molteni Beatrice , Mura Gianni , Marrelli Daniele , Degiuli Maurizio , Donini Annibale , Roviello Franco , de Manzoni Giovanni , Morgagni Paolo , Tiberio Guido A. M.
Published: January 2020

Background/Aim: This work explored the prognostic role of curative versus non-curative surgery, the prognostic value of the various localizations of metastatic disease, and the possibility of identifying patients to be submitted to aggressive therapies. Patients and Methods: Retrospective chart review of stage IV patients operated on in our institutions. Results: Two hundred and eighty-two patients were considered; 73.4% had a single metastatic presentation. In 117 cases, a curative (R0) resection of primary and metastases was possible; 75 received a R1 resection and 90 a palliative R2 gastrectomy. Surgery was integrated with chemotherapy in multiple forms: conversion therapy, HIPEC, neo-adjuvant and adjuvant treatment. Median overall survival (OS) of the entire cohort was 10.9 months, with 14 months for the R0 subgroup. There was no correlation between metastasis site and survival. At multivariate analysis, several variables associated with the lymphatic sphere showed prognostic value, as well as tumor histology and the curativity of the surgical procedure, with a worse prognosis associated with a low number of resected nodes, D1 lymphectomy, pN3, non-intestinal histology, and R+ surgery. Considering the subgroup of R0 patients, the variables pT, pN and D displayed an independent prognostic role with a cumulative effect, showing that patients with no more than 1 risk factor can reach a median survival of 33 months. Conclusions: Our data show that the possibility of effective care also exists for Western patients with stage IV gastric cancer.
Circulating Tumor Cells as a Marker of Disseminated Disease in Patients with Newly Diagnosed High-Risk Prostate Cancer
Authors: Cieślikowski Wojciech A. , Budna-Tukan Joanna , Świerczewska Monika , Ida Agnieszka , Hrab Michał , Jankowiak Agnieszka , Mazel Martine , Nowicki Michał , Milecki Piotr , Pantel Klaus , Alix-Panabières Catherine , Zabel Maciej , Antczak Andrzej
Published: January 2020

The aim of this study was to investigate whether the enumeration of circulating tumor cells (CTCs) in blood can differentiate between true localized and metastatic prostate cancer. A cross-sectional study of 104 prostate cancer patients with newly diagnosed high-risk prostate cancer was conducted. In total, 19 patients presented metastatic disease and 85 were diagnosed with localized disease. Analyses included intergroup comparison of CTC counts, determined using the CellSearch® system, EPISPOT assay and GILUPI CellCollector®, and ROC analysis verifying the accuracy of CTC count as a maker of disseminated prostate cancer. The vast majority (94.7%) of patients with advanced-stage cancer tested positively for CTCs in at least one of the assays. However, significantly higher CTC counts were determined with the CellSearch® system compared to EPISPOT assay and GILUPI CellCollector®. Identification of ≥4 CTCs with the CellSearch® system was the most accurate predictor of metastatic disease (sensitivity 0.500; specificity 0.900; AUC (95% CI) 0.760 (0.613–0.908). Furthermore, we tried to create a model to enhance the specificity and sensitivity of metastatic prediction with CTC counts by incorporating patient’s clinical data, including PSA serum levels, Gleason score and clinical stage. The composite biomarker panel achieved the following performance: sensitivity, 0.611; specificity, 0.971; AUC (95% CI), 0.901 (0.810–0.993). Thus, although the sensitivity of CTC detection needs to be further increased, our findings suggest that high CTC counts might contribute to the identification of high-risk prostate cancer patients with occult metastases at the time of diagnosis.
Krebs Cycle Intermediate-Modified Carbonate Apatite Nanoparticles Drastically Reduce Mouse Tumor Burden and Toxicity by Restricting Broad Tissue Distribution of Anticancer Drugs
Authors: Hossain Sultana Mehbuba , Zainal Abidin Syafiq Asnawi , Chowdhury Ezharul Hoque
Published: January 2020

The morphology, size, and surface area of nanoparticles (NPs), with the existence of functional groups on their surface, contribute to the drug binding affinity, distribution of the payload in different organs, and targeting of a particular tumor for exerting effective antitumor activity in vivo. However, the inherent chemical structure of NPs causing unpredictable biodistribution with a toxic outcome still poses a serious challenge in clinical chemotherapy. In this study, carbonate apatite (CA), citrate-modified CA (CMCA) NPs, and α-ketoglutaric acid-modified CA (α-KAMCA) NPs were employed as carriers of anticancer drugs for antitumor, pharmacokinetic, and toxicological analysis in a murine breast cancer model. The results demonstrated almost five-fold enhanced tumor regression in the cyclophosphamide (CYP)-loaded α-KAMCA NP-treated group compared to the group treated with CYP only. Also, NPs promoted much higher drug accumulation in blood and tumor in comparison with the drug injected without a carrier. In addition, doxorubicin (DOX)-loaded NPs exhibited less accumulation in the heart, indicating less potential myocardial toxicity in mice compared to free DOX. Our findings, thus, conclude that CA, CMCA, and α-KAMCA NPs extended the circulation half-life and enhanced the anticancer effect with reduced toxicity of conventional chemotherapeutics in healthy organs, signifying that they are promising drug delivery devices in breast cancer treatment.
Improvement in the Anti-Tumor Efficacy of Doxorubicin Nanosponges in In Vitro and in Mice Bearing Breast Tumor Models
Authors: Argenziano Monica , Gigliotti Casimiro Luca , Clemente Nausicaa , Boggio Elena , Ferrara Benedetta , Trotta Francesco , Pizzimenti Stefania , Barrera Giuseppina , Boldorini Renzo , Bessone Federica , Dianzani Umberto , Cavalli Roberta , Dianzani Chiara
Published: January 2020

Doxorubicin (DOX) is an anthracycline widely used in cancer therapy and in particular in breast cancer treatment. The treatment with DOX appears successful, but it is limited by a severe cardiotoxicity. This work evaluated the in vitro and in vivo anticancer effect of a new formulation of β-cyclodextrin nanosponges containing DOX (BNS-DOX). The BNS-DOX effectiveness was evaluated in human and mouse breast cancer cell lines in vitro in terms of effect on cell growth, cell cycle distribution, and apoptosis induction; and in vivo in BALB-neuT mice developing spontaneous breast cancer in terms of biodistribution, cancer growth inhibition, and heart toxicity. BNS-DOX significantly inhibited cancer cell proliferation, through the induction of apoptosis, with higher efficiency than free DOX. The breast cancer growth in BALB-neuT mice was inhibited by 60% by a BNS-DOX dose five times lower than the DOX therapeutic dose, with substantial reduction of tumor neoangiogenesis and lymphangiogenesis. Biodistribution after BNS-DOX treatment revealed a high accumulation of DOX in the tumor site and a low accumulation in the hearts of mice. Results indicated that use of BNS may be an efficient strategy to deliver DOX in the treatment of breast cancer, since it improves the anti-cancer effectiveness and reduces cardiotoxicity.
Ferroptosis in Cancer Cell Biology
Authors: Bebber Christina M. , Müller Fabienne , Prieto Clemente Laura , Weber Josephine , von Karstedt Silvia
Published: January 2020

A major hallmark of cancer is successful evasion of regulated forms of cell death. Ferroptosis is a recently discovered type of regulated necrosis which, unlike apoptosis or necroptosis, is independent of caspase activity and receptor-interacting protein 1 (RIPK1) kinase activity. Instead, ferroptotic cells die following iron-dependent lipid peroxidation, a process which is antagonised by glutathione peroxidase 4 (GPX4) and ferroptosis suppressor protein 1 (FSP1). Importantly, tumour cells escaping other forms of cell death have been suggested to maintain or acquire sensitivity to ferroptosis. Therefore, therapeutic exploitation of ferroptosis in cancer has received increasing attention. Here, we systematically review current literature on ferroptosis signalling, cross-signalling to cellular metabolism in cancer and a potential role for ferroptosis in tumour suppression and tumour immunology. By summarising current findings on cell biology relevant to ferroptosis in cancer, we aim to point out new conceptual avenues for utilising ferroptosis in systemic treatment approaches for cancer.
Photochemical Internalization: Light Paves Way for New Cancer Chemotherapies and Vaccines
Authors: Šošić Lara , Selbo Pål Kristian , Kotkowska Zuzanna K. , Kündig Thomas M. , Høgset Anders , Johansen Pål
Published: January 2020

Photochemical internalization (PCI) is a further development of photodynamic therapy (PDT). In this report, we describe PCI as a potential tool for cellular internalization of chemotherapeutic agents or antigens and systematically review the ongoing research. Eighteen published papers described the pre-clinical and clinical developments of PCI-mediated delivery of chemotherapeutic agents or antigens. The studies were screened against pre-defined eligibility criteria. Pre-clinical studies suggest that PCI can be effectively used to deliver chemotherapeutic agents to the cytosol of tumor cells and, thereby, improve treatment efficacy. One Phase-I clinical trial has been conducted, and it demonstrated that PCI-mediated bleomycin treatment was safe and identified tolerable doses of the photosensitizer disulfonated tetraphenyl chlorin (TPCS2a). Likewise, PCI was pre-clinically shown to mediate major histocompatibility complex (MHC) class I antigen presentation and generation of tumor-specific cytotoxic CD8+ T-lymphocytes (CTL) and cancer remission. A first clinical Phase I trial with the photosensitizer TPCS2a combined with human papilloma virus antigen (HPV) was recently completed and results are expected in 2020. Hence, photosensitizers and light can be used to mediate cytosolic delivery of endocytosed chemotherapeutics or antigens. While the therapeutic potential in cancer has been clearly demonstrated pre-clinically, further clinical trials are needed to reveal the true translational potential of PCI in humans.
The Crossroads of Precision Medicine and Therapeutic Decision-Making: Use of an Analytical Computational Platform to Predict Response to Cancer Treatments
Authors: Boichard Amélie , Richard Stephane B. , Kurzrock Razelle
Published: January 2020

Metastatic cancer is a medical challenge that has been historically resistant to treatments. One area of leverage in cancer care is the development of molecularly-driven combination therapies, offering the possibility to overcome resistance. The selection of optimized treatments based on the complex molecular features of a patient’s tumor may be rendered easier by using a computer-assisted program. We used the PreciGENE® platform that uses multi-pathway molecular analysis to identify personalized therapeutic options. These options are ranked using a predictive score reflecting the degree to which a therapy or combination of therapies matches the patient’s biomarker profile. We searched PubMed from February 2010 to June 2017 for all patients described as exceptional responders who also had molecular data available. Altogether, 70 patients with cancer who had received 202 different treatment lines and who had responded (stable disease ≥12 months/partial or complete remission) to ≥1 regimen were curated. We demonstrate that an algorithm reflecting the degree to which patients were matched to the drugs administered correctly ranked the response to the regimens with a sensitivity of 84% and a specificity of 77%. The difference in matching score between successful and unsuccessful treatment lines was significant (median, 65% versus 0%, p-value <0.0001).
Differential Depletion of Bone Marrow Resident B-ALL after Systemic Administration of Endosomal TLR Agonists
Authors: Jo Sumin , Fotovati Abbas , Duque-Afonso Jesus , Cleary Michael L. , van den Elzen Peter , Seif Alix E. , Reid Gregor S.D.
Published: January 2020

Acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy. While frontline chemotherapy regimens are generally very effective, the prognosis for patients whose leukemia returns remains poor. The presence of measurable residual disease (MRD) in bone marrow at the completion of induction therapy is the strongest predictor of relapse, suggesting that strategies to eliminate the residual leukemic blasts from this niche could reduce the incidence of recurrence. We have previously reported that toll-like receptor (TLR) agonists achieve durable T cell-mediated protection in transplantable cell line-based models of B cell precursor leukemia (B-ALL). However, the successful application of TLR agonist therapy in an MRD setting would require the induction of anti-leukemic immune activity specifically in the bone marrow, a site of the chemotherapy-resistant leukemic blasts. In this study, we compare the organ-specific depletion of human and mouse primary B-ALL cells after systemic administration of endosomal TLR agonists. Despite comparable splenic responses, only the TLR9 agonist induced strong innate immune responses in the bone marrow and achieved a near-complete elimination of B-ALL cells. This pattern of response was associated with the most significantly prolonged disease-free survival. Overall, our findings identify innate immune activity in the bone marrow that is associated with durable TLR-induced protection against B-ALL outgrowth.
The MicroRNA-23b/27b/24 Cluster Facilitates Colon Cancer Cell Migration by Targeting FOXP2
Authors: Nishida Kensei , Kuwano Yuki , Rokutan Kazuhito
Published: January 2020

Acquisition of cell migration capacity is an early and essential process in cancer development. The aim of this study was to identify microRNA gene expression networks that induced high migration capacity. Using colon cancer HCT116 cells subcloned by transwell-based migrated cell selection, microRNA array analysis was performed to examine the microRNA expression profile. Promoter activity and microRNA targets were assessed with luciferase reporters. Cell migration capacity was assessed by either the transwell or scratch assay. In isolated subpopulations with high migration capacity, the expression levels of the miR-23b/27b/24 cluster increased in accordance with the increased expression of the short C9orf3 transcript, a host gene of the miR-23b/27b/24 cluster. E2F1-binding sequences were involved in the basic transcription activity of the short C9orf3 expression, and E2F1-small-interfering (si)RNA treatment reduced the expression of both the C9orf3 and miR-23b/27b/24 clusters. Overexpression experiments showed that miR-23b and miR-27b promoted cell migration, but the opposite effect was observed with miR-24. Forkhead box P2 (FOXP2) mRNA and protein levels were reduced by both/either miR-23b and miR-27b. Furthermore, FOXP2 siRNA treatment significantly promoted cell migration. Our findings demonstrated a novel role of the miR-23b/27b/24 cluster in cell migration through targeting FOXP2, with potential implications for the development of microRNA-based therapy targeted at inhibiting cancer migration.
Perovskites in the Energy Grid and CO2 Conversion: Current Context and Future Directions
Authors: Tabish Ahmad , Varghese Anish Mathai , Wahab Md A. , Karanikolos Georgios N.
Published: January 2020

CO2 emissions from the consumption of fossil fuels are continuously increasing, thus impacting Earth’s climate. In this context, intensive research efforts are being dedicated to develop materials that can effectively reduce CO2 levels in the atmosphere and convert CO2 into value-added chemicals and fuels, thus contributing to sustainable energy and meeting the increase in energy demand. The development of clean energy by conversion technologies is of high priority to circumvent these challenges. Among the various methods that include photoelectrochemical, high-temperature conversion, electrocatalytic, biocatalytic, and organocatalytic reactions, photocatalytic CO2 reduction has received great attention because of its potential to efficiently reduce the level of CO2 in the atmosphere by converting it into fuels and value-added chemicals. Among the reported CO2 conversion catalysts, perovskite oxides catalyze redox reactions and exhibit high catalytic activity, stability, long charge diffusion lengths, compositional flexibility, and tunable band gap and band edge. This review focuses on recent advances and future prospects in the design and performance of perovskites for CO2 conversion, particularly emphasizing on the structure of the catalysts, defect engineering and interface tuning at the nanoscale, and conversion technologies and rational approaches for enhancing CO2 transformation to value-added chemicals and chemical feedstocks.
Pathogens MenTORing Macrophages and Dendritic Cells: Manipulation of mTOR and Cellular Metabolism to Promote Immune Escape
Authors: Nouwen Lonneke V. , Everts Bart
Published: January 2020

Myeloid cells, including macrophages and dendritic cells, represent an important first line of defense against infections. Upon recognition of pathogens, these cells undergo a metabolic reprogramming that supports their activation and ability to respond to the invading pathogens. An important metabolic regulator of these cells is mammalian target of rapamycin (mTOR). During infection, pathogens use host metabolic pathways to scavenge host nutrients, as well as target metabolic pathways for subversion of the host immune response that together facilitate pathogen survival. Given the pivotal role of mTOR in controlling metabolism and DC and macrophage function, pathogens have evolved strategies to target this pathway to manipulate these cells. This review seeks to discuss the most recent insights into how pathogens target DC and macrophage metabolism to subvert potential deleterious immune responses against them, by focusing on the metabolic pathways that are known to regulate and to be regulated by mTOR signaling including amino acid, lipid and carbohydrate metabolism, and autophagy.
In Silico Analysis of the Age-Dependent Evolution of the Transcriptome of Mouse Skin Stem Cells
Authors: Lorenzo-Martín L. Francisco , Bustelo Xosé R.
Published: January 2020

The stem cells located in the hair follicle bulge area are critical for skin regeneration and repair. To date, little is known about the evolution of the transcriptome of these cells across time. Here, we have combined genome-wide expression analyses and a variety of in silico tools to determine the age-dependent evolution of the transcriptome of those cells. Our results reveal that the transcriptome of skin stem cells fluctuates extensively along the lifespan of mice. The use of both unbiased and pathway-centered in silico approaches has also enabled the identification of biological programs specifically regulated at those specific time-points. It has also unveiled hubs of highly transcriptionally interconnected genes and transcriptional factors potentially located at the core of those age-specific changes.
RK-33 Is a Broad-Spectrum Antiviral Agent That Targets DEAD-Box RNA Helicase DDX3X
Authors: Yang Sundy N. Y. , Atkinson Sarah C. , Audsley Michelle D. , Heaton Steven M. , Jans David A. , Borg Natalie A.
Published: January 2020

Viral disease is one of the greatest burdens for human health worldwide, with an urgent need for efficacious antiviral strategies. While antiviral drugs are available, in many cases, they are prone to the development of drug resistance. A way to overcome drug resistance associated with common antiviral therapies is to develop antivirals targeting host cellular co-factors critical to viral replication, such as DEAD-box helicase 3 X-linked (DDX3X), which plays key roles in RNA metabolism and the antiviral response. Here, we use biochemical/biophysical approaches and infectious assays to show for the first time that the small molecule RK-33 has broad-spectrum antiviral action by inhibiting the enzymatic activities of DDX3X. Importantly, we show that RK-33 is efficacious at low micromolar concentrations in limiting infection by human parainfluenza virus type 3 (hPIV-3), respiratory syncytial virus (RSV), dengue virus (DENV), Zika virus (ZIKV) or West Nile virus (WNV)—for all of which, no Food and Drug Administration (FDA)-approved therapeutic is widely available. These findings establish for the first time that RK-33 is a broad-spectrum antiviral agent that blocks DDX3X’s catalytic activities in vitro and limits viral replication in cells.
Transcriptional Coactivator TAZ Negatively Regulates Tumor Suppressor p53 Activity and Cellular Senescence
Authors: Miyajima Chiharu , Kawarada Yuki , Inoue Yasumichi , Suzuki Chiaki , Mitamura Kana , Morishita Daisuke , Ohoka Nobumichi , Imamura Takeshi , Hayashi Hidetoshi
Published: January 2020

Transcriptional coactivator with a PDZ-binding motif (TAZ) is one of the mammalian orthologs of Drosophila Yorkie, a transcriptional coactivator of the Hippo pathway. TAZ has been suggested to function as a regulator that modulates the expression of cell proliferation and anti-apoptotic genes in order to stimulate cell proliferation. TAZ has also been associated with a poor prognosis in several cancers, including breast cancer. However, the physiological role of TAZ in tumorigenesis remains unclear. We herein demonstrated that TAZ negatively regulated the activity of the tumor suppressor p53. The overexpression of TAZ down-regulated p53 transcriptional activity and its downstream gene expression. In contrast, TAZ knockdown up-regulated p21 expression induced by p53 activation. Regarding the underlying mechanism, TAZ inhibited the interaction between p53 and p300 and suppressed the p300-mediated acetylation of p53. Furthermore, TAZ knockdown induced cellular senescence in a p53-dependent manner. These results suggest that TAZ negatively regulates the tumor suppressor functions of p53 and attenuates p53-mediated cellular senescence.
Discovery and Preliminary Characterization of Translational Modulators that Impair the Binding of eIF6 to 60S Ribosomal Subunits
Authors: Pesce Elisa , Miluzio Annarita , Turcano Lorenzo , Minici Claudia , Cirino Delia , Calamita Piera , Manfrini Nicola , Oliveto Stefania , Ricciardi Sara , Grifantini Renata , Degano Massimo , Bresciani Alberto , Biffo Stefano
Published: January 2020

Eukaryotic initiation factor 6 (eIF6) is necessary for the nucleolar biogenesis of 60S ribosomes. However, most of eIF6 resides in the cytoplasm, where it acts as an initiation factor. eIF6 is necessary for maximal protein synthesis downstream of growth factor stimulation. eIF6 is an antiassociation factor that binds 60S subunits, in turn preventing premature 40S joining and thus the formation of inactive 80S subunits. It is widely thought that eIF6 antiassociation activity is critical for its function. Here, we exploited and improved our assay for eIF6 binding to ribosomes (iRIA) in order to screen for modulators of eIF6 binding to the 60S. Three compounds, eIFsixty-1 (clofazimine), eIFsixty-4, and eIFsixty-6 were identified and characterized. All three inhibit the binding of eIF6 to the 60S in the micromolar range. eIFsixty-4 robustly inhibits cell growth, whereas eIFsixty-1 and eIFsixty-6 might have dose- and cell-specific effects. Puromycin labeling shows that eIF6ixty-4 is a strong global translational inhibitor, whereas the other two are mild modulators. Polysome profiling and RT-qPCR show that all three inhibitors reduce the specific translation of well-known eIF6 targets. In contrast, none of them affect the nucleolar localization of eIF6. These data provide proof of principle that the generation of eIF6 translational modulators is feasible.