Accelerating Open Access.
MDPI is a pioneer in scholarly open access publishing
and has supported academic communities since 1996.
Open AccessArticle
PD-1-Associated Gene Expression Signature of Neoadjuvant Trastuzumab-Treated Tumors Correlates with Patient Survival in HER2-Positive Breast Cancer
Cancers 2019, 11(10), 1566; https://doi.org/10.3390/cancers11101566 (registering DOI) - 15 Oct 2019
Abstract
The therapeutic HER2-targeting antibody trastuzumab has been shown to elicit tumor immune response in a subset of HER2-positive (HER2+) breast cancer. We performed genomic and immunohistochemical profiling of tumors from eight patients who have completed multiple rounds of neoadjuvant trastuzumabb to identify predictive [...] Read more.
The therapeutic HER2-targeting antibody trastuzumab has been shown to elicit tumor immune response in a subset of HER2-positive (HER2+) breast cancer. We performed genomic and immunohistochemical profiling of tumors from eight patients who have completed multiple rounds of neoadjuvant trastuzumabb to identify predictive biomarkers for trastuzumab-elicited tumor immune responses. Immunohistochemistry showed that all tumors had an activated tumor immune microenvironment positive for nuclear NF-κB/p65RelA, CD4, and CD8 T cell markers, but only four out of eight tumors were positive for the PD-1 immune checkpoint molecule, which is indicative of an exhausted immune environment. Exome sequencing showed no specific driver mutations correlating with PD-1 positivity. Hierarchical clustering of the RNA sequencing data revealed two distinct groups, of which Group 2 represented the PD-1 positive tumors. A gene expression signature that was derived from this clustering composed of 89 genes stratified HER2+ breast cancer patients in the TCGA dataset and it was named PD-1-Associated Gene Expression Signature in HER2+ Breast Cancer (PAGES-HBC). Patients with the Group 2 PAGES-HBC composition had significantly more favorable survival outcomes with mortality reduced by 83% (hazard ratio 0.17; 95% CI, 0.05 to 0.60; p = 0.011). Analysis of three longitudinal samples from a single patient showed that PAGES-HBC might be transiently induced by trastuzumab, independent of clonal tumor expansion over time. We conclude that PAGES-HBC could be further developed as a prognostic predictor of trastuzumab response in HER2+ breast cancer patients and be potentially used as an alternative biomarker for anti-PD-1 therapy trials. Full article
(This article belongs to the collection Cancer Biomarkers)
Open AccessReview
Molecular Insights into Potential Contributions of Natural Polyphenols to Lung Cancer Treatment
Cancers 2019, 11(10), 1565; https://doi.org/10.3390/cancers11101565 (registering DOI) - 15 Oct 2019
Abstract
Naturally occurring polyphenols are believed to have beneficial effects in the prevention and treatment of a myriad of disorders due to their anti-inflammatory, antioxidant, antineoplastic, cytotoxic, and immunomodulatory activities documented in a large body of literature. In the era of molecular medicine and [...] Read more.
Naturally occurring polyphenols are believed to have beneficial effects in the prevention and treatment of a myriad of disorders due to their anti-inflammatory, antioxidant, antineoplastic, cytotoxic, and immunomodulatory activities documented in a large body of literature. In the era of molecular medicine and targeted therapy, there is a growing interest in characterizing the molecular mechanisms by which polyphenol compounds interact with multiple protein targets and signaling pathways that regulate key cellular processes under both normal and pathological conditions. Numerous studies suggest that natural polyphenols have chemopreventive and/or chemotherapeutic properties against different types of cancer by acting through different molecular mechanisms. The present review summarizes recent preclinical studies on the applications of bioactive polyphenols in lung cancer therapy, with an emphasis on the molecular mechanisms that underlie the therapeutic effects of major polyphenols on lung cancer. We also discuss the potential of the polyphenol-based combination therapy as an attractive therapeutic strategy against lung cancer. Full article
(This article belongs to the Special Issue Role of Natural Bioactive Compounds in the Rise and Fall of Cancers)
Open AccessReview
Platelets and Hepatocellular Cancer: Bridging the Bench to the Clinics
Cancers 2019, 11(10), 1568; https://doi.org/10.3390/cancers11101568 (registering DOI) - 15 Oct 2019
Abstract
Growing interest is recently being focused on the role played by the platelets in favoring hepatocellular cancer (HCC) growth and dissemination. The present review reports in detail both the experimental and clinical evidence published on this topic. Several growth factors and angiogenic molecules [...] Read more.
Growing interest is recently being focused on the role played by the platelets in favoring hepatocellular cancer (HCC) growth and dissemination. The present review reports in detail both the experimental and clinical evidence published on this topic. Several growth factors and angiogenic molecules specifically secreted by platelets are directly connected with tumor progression and neo-angiogenesis. Among them, we can list the platelet-derived growth factor, the vascular endothelial growth factor, the endothelial growth factor, and serotonin. Platelets are also involved in tumor spread, favoring endothelium permeabilization and tumor cells’ extravasation and survival in the bloodstream. From the bench to the clinics, all of these aspects were also investigated in clinical series, showing an evident correlation between platelet count and size of HCC, tumor biological behavior, metastatic spread, and overall survival rates. Moreover, a better understanding of the mechanisms involved in the platelet–tumor axis represents a paramount aspect for optimizing both current tumor treatment and development of new therapeutic strategies against HCC. Full article
(This article belongs to the Special Issue Platelets and Cancer)
Open AccessReview
Microsatellite Instability: Diagnosis, Heterogeneity, Discordance, and Clinical Impact in Colorectal Cancer
Cancers 2019, 11(10), 1567; https://doi.org/10.3390/cancers11101567 (registering DOI) - 15 Oct 2019
Abstract
Tumor DNA mismatch repair (MMR) deficiency testing is important to the identification of Lynch syndrome and decision making regarding adjuvant chemotherapy in stage II colorectal cancer (CRC) and has become an indispensable test in metastatic tumors due to the high efficacy of immune [...] Read more.
Tumor DNA mismatch repair (MMR) deficiency testing is important to the identification of Lynch syndrome and decision making regarding adjuvant chemotherapy in stage II colorectal cancer (CRC) and has become an indispensable test in metastatic tumors due to the high efficacy of immune checkpoint inhibitor (ICI) in deficient MMR (dMMR) tumors. CRCs greatly benefit from this testing as approximately 15% of them are dMMR but only 3% to 5% are at a metastatic stage. MMR status can be determined by two different methods, microsatellite instability (MSI) testing on tumor DNA, and immunohistochemistry of the MMR proteins on tumor tissue. Recent studies have reported a rate of 3% to 10% of discordance between these two tests. Moreover, some reports suggest possible intra- and inter-tumoral heterogeneity of MMR and MSI status. These issues are important to know and to clarify in order to define therapeutic strategy in CRC. This review aims to detail the standard techniques used for the determination of MMR and MSI status, along with their advantages and limits. We review the discordances that may arise between these two tests, tumor heterogeneity of MMR and MSI status, and possible explanations. We also discuss the strategies designed to distinguish sporadic versus germline dMMR/MSI CRC. Finally, we present new and accurate methods aimed at determining MMR/MSI status. Full article
(This article belongs to the Special Issue Metastatic Progression and Tumour Heterogeneity)
Open AccessArticle
A Pan-Cancer Approach to Predict Responsiveness to Immune Checkpoint Inhibitors by Machine Learning
Cancers 2019, 11(10), 1562; https://doi.org/10.3390/cancers11101562 (registering DOI) - 15 Oct 2019
Abstract
Immunotherapy by using immune checkpoint inhibitors (ICI) has dramatically improved the treatment options in various cancers, increasing survival rates for treated patients. Nevertheless, there are heterogeneous response rates to ICI among different cancer types, and even in the context of patients affected by [...] Read more.
Immunotherapy by using immune checkpoint inhibitors (ICI) has dramatically improved the treatment options in various cancers, increasing survival rates for treated patients. Nevertheless, there are heterogeneous response rates to ICI among different cancer types, and even in the context of patients affected by a specific cancer. Thus, it becomes crucial to identify factors that predict the response to immunotherapeutic approaches. A comprehensive investigation of the mutational and immunological aspects of the tumor can be useful to obtain a robust prediction. By performing a pan-cancer analysis on gene expression data from the Cancer Genome Atlas (TCGA, 8055 cases and 29 cancer types), we set up and validated a machine learning approach to predict the potential for positive response to ICI. Support vector machines (SVM) and extreme gradient boosting (XGboost) models were developed with a 10×5-fold cross-validation schema on 80% of TCGA cases to predict ICI responsiveness defined by a score combining tumor mutational burden and TGF- β signaling. On the remaining 20% validation subset, our SVM model scored 0.88 accuracy and 0.27 Matthews Correlation Coefficient. The proposed machine learning approach could be useful to predict the putative response to ICI treatment by expression data of primary tumors. Full article
(This article belongs to the Special Issue Application of Next-Generation Sequencing in Cancers)
Show Figures

Figure 1

Open AccessFeature PaperReview
Biologically-Inspired Computational Neural Mechanism for Human Action/activity Recognition: A Review
Electronics 2019, 8(10), 1169; https://doi.org/10.3390/electronics8101169 (registering DOI) - 15 Oct 2019
Abstract
Theoretical neuroscience investigation shows valuable information on the mechanism for recognizing the biological movements in the mammalian visual system. This involves many different fields of researches such as psychological, neurophysiology, neuro-psychological, computer vision, and artificial intelligence (AI). The research on these areas provided [...] Read more.
Theoretical neuroscience investigation shows valuable information on the mechanism for recognizing the biological movements in the mammalian visual system. This involves many different fields of researches such as psychological, neurophysiology, neuro-psychological, computer vision, and artificial intelligence (AI). The research on these areas provided massive information and plausible computational models. Here, a review on this subject is presented. This paper describes different perspective to look at this task including action perception, computational and knowledge based modeling, psychological, and neuroscience approaches. Full article
Open AccessArticle
Tuning Structure and Dynamics of Blue Copper Azurin Junctions via Single Amino-Acid Mutations
Biomolecules 2019, 9(10), 611; https://doi.org/10.3390/biom9100611 (registering DOI) - 15 Oct 2019
Abstract
In the growing field of biomolecular electronics, blue-copper Azurin stands out as one of the most widely studied protein in single-molecule contacts. Interestingly, despite the paramount importance of the structure/dynamics of molecular contacts in their transport properties, these factors remain largely unexplored from [...] Read more.
In the growing field of biomolecular electronics, blue-copper Azurin stands out as one of the most widely studied protein in single-molecule contacts. Interestingly, despite the paramount importance of the structure/dynamics of molecular contacts in their transport properties, these factors remain largely unexplored from the theoretical point of view in the context of single Azurin junctions. Here we address this issue using all-atom Molecular Dynamics (MD) of Pseudomonas Aeruginosa Azurin adsorbed to a Au(111) substrate. In particular, we focus on the structure and dynamics of the free/adsorbed protein and how these properties are altered upon single-point mutations. The results revealed that wild-type Azurin adsorbs on Au(111) along two well defined configurations: one tethered via cysteine groups and the other via the hydrophobic pocket surrounding the Cu 2 + . Surprisingly, our simulations revealed that single amino-acid mutations gave rise to a quenching of protein vibrations ultimately resulting in its overall stiffening. Given the role of amino-acid vibrations and reorientation in the dehydration process at the protein-water-substrate interface, we suggest that this might have an effect on the adsorption process of the mutant, giving rise to new adsorption configurations. Full article
(This article belongs to the Special Issue Biomolecular Electronics)
Open AccessArticle
Explanation for the Multi-Component Scintillation of Cerium Fluoride Through the Equilibrium and Photophysical Investigation of Cerium(III)-Fluoro Complexes
Nanomaterials 2019, 9(10), 1462; https://doi.org/10.3390/nano9101462 (registering DOI) - 15 Oct 2019
Abstract
CeF3 displays favorable scintillation properties, which have been utilized for decades in various solid-state systems. Its emission undergoes multi-component decays, which were interpreted by lattice defects and so-called intrinsic features herein. This study of the complex equilibria in connection with photophysical behavior [...] Read more.
CeF3 displays favorable scintillation properties, which have been utilized for decades in various solid-state systems. Its emission undergoes multi-component decays, which were interpreted by lattice defects and so-called intrinsic features herein. This study of the complex equilibria in connection with photophysical behavior of the cerium(III)-fluoride system in solution gave us the possibility to reveal the individual contribution of the [CeIIIFx(H2O)9−x]3−x species to the photoluminescence. Spectrophotometry and spectrofluorometry (also in time-resolved mode) were used, and combined with sophisticated evaluation methods regarding both the complex equilibria and the kinetics of the photoinduced processes. The individual photophysical parameters of the [CeIIIFx(H2O)9−x]3−x complexes were determined. For the kinetic evaluation, three methods of various simplifications were applied and compared. The results indicated that the rates of some excited-state equilibrium processes were comparable to those of the emission decay steps. Our results also contribute to the explanation of the multi-component emission decays in the CeF3-containing scintillators, due to the various coordination environments of Ce3+, which can be affected by the excitation leading to the dissociation of the metal-ligand bonds. Full article
(This article belongs to the Special Issue Luminescent Rare-Earth Based Nanomaterials)
Show Figures

Graphical abstract

Open AccessReview
Breast Cancer Stem Cells as Drivers of Tumor Chemoresistance, Dormancy and Relapse: New Challenges and Therapeutic Opportunities
Cancers 2019, 11(10), 1569; https://doi.org/10.3390/cancers11101569 (registering DOI) - 15 Oct 2019
Abstract
Breast cancer is the most frequent cancer among women worldwide. Therapeutic strategies to prevent or treat metastatic disease are still inadequate although great progress has been made in treating early‐stage breast cancer. Cancer stem-like cells (CSCs) that are endowed with high plasticity and [...] Read more.
Breast cancer is the most frequent cancer among women worldwide. Therapeutic strategies to prevent or treat metastatic disease are still inadequate although great progress has been made in treating early‐stage breast cancer. Cancer stem-like cells (CSCs) that are endowed with high plasticity and self-renewal properties have been shown to play a key role in breast cancer development, progression, and metastasis. A subpopulation of CSCs that combines tumor-initiating capacity and a dormant/quiescent/slow cycling status is present throughout the clinical history of breast cancer patients. Dormant/quiescent/slow cycling CSCs are a key component of tumor heterogeneity and they are responsible for chemoresistance, tumor migration, and metastatic dormancy, defined as the ability of CSCs to survive in target organs and generate metastasis up to two decades after diagnosis. Understanding the strategies that are used by CSCs to resist conventional and targeted therapies, to interact with their niche, to escape immune surveillance, and finally to awaken from dormancy is of key importance to prevent and treat metastatic cancer. This review summarizes the current understanding of mechanisms involved in CSCs chemoresistance, dissemination, and metastasis in breast cancer, with a particular focus on dormant cells. Finally, we discuss how advancements in the detection, molecular understanding, and targeting of dormant CSCs will likely open new therapeutic avenues for breast cancer treatment. Full article
Open AccessArticle
The Role of the Embodiment Disturbance in the Anorexia Nervosa Psychopathology: A Network Analysis Study
Brain Sci. 2019, 9(10), 276; https://doi.org/10.3390/brainsci9100276 (registering DOI) - 15 Oct 2019
Abstract
Anorexia Nervosa (AN) is characterized by body image distortion. From a phenomenological perspective, body image disturbance has been associated with a more profound disturbance encompassing disorders of the way persons experience their own body. The aim of this study was to disentangle the [...] Read more.
Anorexia Nervosa (AN) is characterized by body image distortion. From a phenomenological perspective, body image disturbance has been associated with a more profound disturbance encompassing disorders of the way persons experience their own body. The aim of this study was to disentangle the complex dynamics that connect the experience of one’s own body and self-identity to the psychopathological features of AN by applying a network analysis. Fifty-seven patients with AN restrictive subtype and 27 with AN binge–purging subtype participated in the study. Eating Disorders Inventory-2 and Identity and Eating Disorders subscores, measuring the embodiment dimensions, were included in the network. Two of the main dimensions of embodiment—feeling extraneous from one’s own body and feeling oneself through objective measures—were the nodes with the highest strength together with interoceptive awareness (IA). IA was a node included in several pathways connecting embodiment dimensions with most of the AN psychopathological dimensions. The centrality of the embodiment disorder suggests the importance of considering the body image disturbance in people with AN as resulting from their difficulty in experiencing inner states and as a tool to build its own self. This assumption may orient therapeutic interventions. Full article
(This article belongs to the Special Issue Psychotherapeutic Treatment for Anorexia Nervosa)
Open AccessArticle
Size and Shape Evolution of GaAsSb-Capped InAs/GaAs Quantum Dots: Dependence on the Sb Content
Crystals 2019, 9(10), 530; https://doi.org/10.3390/cryst9100530 (registering DOI) - 15 Oct 2019
Abstract
Capping InAs/GaAs quantum dots (QDs) with a thin GaAsSb layer alters the QDs structural properties, leading to considerable changes in their optical properties. The increase of the Sb content induces a redshift of the emission energies, indicating a change in the buried QDs [...] Read more.
Capping InAs/GaAs quantum dots (QDs) with a thin GaAsSb layer alters the QDs structural properties, leading to considerable changes in their optical properties. The increase of the Sb content induces a redshift of the emission energies, indicating a change in the buried QDs shape and size. The presence of well-defined ground- and excited-state emission bands in all the photoluminescence spectra allow an accurate estimation of the buried QDs size and shape by numerical evaluation and tuning of the theoretical emission energies. For an Sb content below 14%, the QDs are found to have a type I band alignment with a truncated height pyramidal form. However, for higher Sb content (22%), the QDs are present in a full pyramidal shape. The observed behavior is interpreted in terms of increasing prevention of InAs QDs decomposition with increasing the Sb content in the cap layer. Full article
(This article belongs to the Special Issue Nanowires and Quantum Dots for IoT Applications)
Show Figures

Figure 1

Open AccessReview
MicroRNAs as a Potential Quality Measurement Tool of Platelet Concentrate Stored in Blood Banks—A Review
Cells 2019, 8(10), 1256; https://doi.org/10.3390/cells8101256 (registering DOI) - 15 Oct 2019
Abstract
Background: Platelet concentrate (PC) is one of the main products used in a therapeutic transfusion. This blood component requires special storage at blood banks, however, even under good storage conditions, modifications or degradations may occur and are known as platelet storage lesions. Methods: [...] Read more.
Background: Platelet concentrate (PC) is one of the main products used in a therapeutic transfusion. This blood component requires special storage at blood banks, however, even under good storage conditions, modifications or degradations may occur and are known as platelet storage lesions. Methods: This research was performed on scientific citation databases PubMed/Medline, ScienceDirect, and Web of Science, for publications containing platelet storage lesions. The results obtained mainly reveal the clinical applicability of miRNAs as biomarkers of storage injury and as useful tools for a problem affecting public and private health, the lack of PC bags in countries with few blood donors. The major studies listed in this review identified miRNAs associated with important platelet functions that are relevant in clinical practice as quality biomarkers of PC, such as miR-223, miR-126, miR-10a, miR-150, miR-16, miR-21, miR-326, miR-495, let-7b, let-7c, let-7e, miR-107, miR-10b, miR-145, miR-155, miR-17, miR-191, miR-197, miR-200b, miR-24, miR-331, miR-376. These miRNAs can be used in blood banks to identify platelet injury in PC bags. Conclusion: The studies described in this review relate the functions of miRNAs with molecular mechanisms that result in functional platelet differences, such as apoptosis. Thus, miRNA profiles can be used to measure the quality of storage PC for more than 5 days, identify bags with platelet injury, and distinguish those with functional platelets. Full article
(This article belongs to the Special Issue Regulatory Functions of microRNAs)
Show Figures

Figure 1

Open AccessReview
Potential Therapeutic Application of Estrogen in Gender Disparity of Nonalcoholic Fatty Liver Disease/Nonalcoholic Steatohepatitis
Cells 2019, 8(10), 1259; https://doi.org/10.3390/cells8101259 (registering DOI) - 15 Oct 2019
Abstract
Nonalcoholic fatty liver disease (NAFLD) caused by fat accumulation in the liver is globally the most common cause of chronic liver disease. Simple steatosis can progress to nonalcoholic steatohepatitis (NASH), a more severe form of NAFLD. The most potent driver for NASH is [...] Read more.
Nonalcoholic fatty liver disease (NAFLD) caused by fat accumulation in the liver is globally the most common cause of chronic liver disease. Simple steatosis can progress to nonalcoholic steatohepatitis (NASH), a more severe form of NAFLD. The most potent driver for NASH is hepatocyte death induced by lipotoxicity, which triggers inflammation and fibrosis, leading to cirrhosis and/or liver cancer. Despite the significant burden of NAFLD, there is no therapy for NAFLD/NASH. Accumulating evidence indicates gender-related NAFLD progression. A higher incidence of NAFLD is found in men and postmenopausal women than premenopausal women, and the experimental results, showing protective actions of estradiol in liver diseases, suggest that estrogen, as the main female hormone, is associated with the progression of NAFLD/NASH. However, the mechanism explaining the functions of estrogen in NAFLD remains unclear because of the lack of reliable animal models for NASH, the imbalance between the sexes in animal experiments, and subsequent insufficient results. Herein, we reviewed the pathogenesis of NAFLD/NASH focused on gender and proposed a feasible association of estradiol with NAFLD/NASH based on the findings reported thus far. This review would help to expand our knowledge of the gender differences in NAFLD and for developing gender-based treatment strategies for NAFLD/NASH. Full article
Open AccessArticle
Determination of Directional Residual Stresses by the Contour Method
Metals 2019, 9(10), 1104; https://doi.org/10.3390/met9101104 (registering DOI) - 15 Oct 2019
Abstract
This study evaluated residual stresses in heat-treated specimens made of 316L stainless steel using FE analysis and compared them with stresses determined by the contour method. Contour method is usually used just for evaluation of residual stresses that are normal to the cut [...] Read more.
This study evaluated residual stresses in heat-treated specimens made of 316L stainless steel using FE analysis and compared them with stresses determined by the contour method. Contour method is usually used just for evaluation of residual stresses that are normal to the cut plan. In the current study this approach is extended and both normal and tangential stresses are determined. The specimens were cut using wire electrical discharge machine and the contours of the cut were measured using a coordinate measuring machine. The prior treatment of the specimens was simulated using the finite-element method. An appropriate boundary condition and temperature-dependent material model were employed. The finite-element model was validated against neutron-diffraction measurement data. The results showed a good agreement in normal and tangential directions of stress. Full article
Show Figures

Figure 1

Open AccessFeature PaperArticle
Optimal Control of a PDE Model of an Invasive Species in a River
Mathematics 2019, 7(10), 975; https://doi.org/10.3390/math7100975 (registering DOI) - 15 Oct 2019
Abstract
Managing invasive species in rivers can be assisted by appropriate adjustment of flow rates. Using a partial differential equation (PDE) model representing an invasive population in a river, we investigate controlling the water discharge rate as a management strategy. Our goal is to [...] Read more.
Managing invasive species in rivers can be assisted by appropriate adjustment of flow rates. Using a partial differential equation (PDE) model representing an invasive population in a river, we investigate controlling the water discharge rate as a management strategy. Our goal is to see how controlling the water discharge rate will affect the invasive population, and more specifically how water discharges may force the invasive population downstream. We complete the analysis of a flow control problem, which seeks to minimize the invasive population upstream while minimizing the cost of this management. Using an optimality system, consisting of our population PDE, an adjoint PDE, and corresponding optimal control characterization, we illustrate some numerical simulations in which parameters are varied to determine how far upstream the invasive population reaches. We also change the river’s cross-sectional area to investigate its impact on the optimal control. Full article
(This article belongs to the Special Issue Partial Differential Equations in Ecology: 80 Years and Counting)
Show Figures

Figure 1

Open Access Journals

Browse by Indexing Browse by Subject Selected Journals
Back to TopTop