bluuebunny/crossref_metadata_2025 huggingface dataset:
Mitochondrial Dysfunction in Parkinson’s Disease—Cause or Consequence?
Authors: Chen Chun , Turnbull Doug M. , Reeve Amy K.
Published: May 2019

James Parkinson first described the motor symptoms of the disease that took his name over 200 years ago. While our knowledge of many of the changes that occur in this condition has increased, it is still unknown what causes this neurodegeneration and why it only affects some individuals with advancing age. Here we review current literature to discuss whether the mitochondrial dysfunction we have detected in Parkinson’s disease is a pathogenic cause of neuronal loss or whether it is itself a consequence of dysfunction in other pathways. We examine research data from cases of idiopathic Parkinson’s with that from model systems and individuals with familial forms of the disease. Furthermore, we include data from healthy aged individuals to highlight that many of the changes described are also present with advancing age, though not normally in the presence of severe neurodegeneration. While a definitive answer to this question may still be just out of reach, it is clear that mitochondrial dysfunction sits prominently at the centre of the disease pathway that leads to catastrophic neuronal loss in those affected by this disease.
Peptosome Coadministration Improves Nanoparticle Delivery to Tumors through NRP1-Mediated Co-Endocytosis
Authors: Xiang Zhichu , Jiang Gexuan , Yang Xiaoliang , Fan Di , Nan Xiaohui , Li Dan , Hu Zhiyuan , Fang Qiaojun
Published: May 2019

Improving the efficacy of nanoparticles (NPs) delivery to tumors is critical for cancer diagnosis and therapy. In our previous work, amphiphilic peptide APPA self-assembled nanocarriers were designed and constructed for cargo delivery to tumors with high efficiency. In this study, we explore the use of APPA self-assembled peptosomes as a nanoparticle adjuvant to enhance the delivery of nanoparticles and antibodies to integrin αvβ3 and neuropilin-1 (NRP1) positive tumors. The enhanced tumor delivery of coadministered NPs was confirmed by better magnetosome (Mag)-based T2-weighted magnetic resonance imaging (MRI), liposome-based fluorescence imaging, as well as the improved anti-tumor efficacy of monoclonal antibodies (trastuzumab in this case) and doxorubicin (DOX)-containing liposomes. Interestingly, the improvement is most significant for the delivering of compounds that have active or passive tumor targeting ability, such as antibodies or NPs that have enhanced permeability and retention (EPR) effect. However, for non-targeting small molecules, the effect is not significant. In vitro and in vivo studies suggest that both peptosomes and the coadministered compounds might be internalized into cells through a NRP1 mediated co-endocytosis (CoE) pathway. The improved delivery of coadministered NPs and antibodies to tumors suggests that the coadministration with APPA self-assembled peptosomes could be a valuable approach for advancing αvβ3 and NRP1 positive tumors diagnosis and therapy.
Fisetin and Quercetin: Promising Flavonoids with Chemopreventive Potential
Authors: Kashyap Dharambir , Garg Vivek Kumar , Tuli Hardeep Singh , Yerer Mukerrem Betul , Sak Katrin , Sharma Anil Kumar , Kumar Manoj , Aggarwal Vaishali , Sandhu Sardul Singh
Published: May 2019

Despite advancements in healthcare facilities for diagnosis and treatment, cancer remains the leading cause of death worldwide. As prevention is always better than cure, efficient strategies are needed in order to deal with the menace of cancer. The use of phytochemicals as adjuvant chemotherapeutic agents in heterogeneous human carcinomas like breast, colon, lung, ovary, and prostate cancers has shown an upward trend during the last decade or so. Flavonoids are well-known products of plant derivatives that are reportedly documented to be therapeutically active phytochemicals against many diseases encompassing malignancies, inflammatory disorders (cardiovascular disease, neurodegenerative disorder), and oxidative stress. The current review focuses on two key flavonols, fisetin and quercetin, known for their potential pharmacological relevance. Also, efforts have been made to bring together most of the concrete studies pertaining to the bioactive potential of fisetin and quercetin, especially in the modulation of a range of cancer signaling pathways. Further emphasis has also been made to highlight the molecular action of quercetin and fisetin so that one could explore cancer initiation pathways and progression, which could be helpful in designing effective treatment strategies.
Electrochemical Sensor for Rapid and Sensitive Detection of Tryptophan by a Cu2O Nanoparticles-Coated Reduced Graphene Oxide Nanocomposite
Authors: He Quanguo , Tian Yaling , Wu Yiyong , Liu Jun , Li Guangli , Deng Peihong , Chen Dongchu
Published: May 2019

In this paper, a nanocomposite of cuprous oxide and electrochemically reduced graphene oxide (Cu2O–ERGO) was prepared by a simple and low-cost method; hereby, a new method for the electrochemical determination of tryptophan (Trp) by this composite modified glassy carbon electrode (GCE) is proposed. The prepared materials and modified electrodes were characterized by scanning electron microscopy (SEM), X-ray diffraction (XRD), and cyclic voltammetry (CV). The results showed that Cu2O–ERGO/GCE had good electrocatalytic activity for Trp. The effects of supporting electrolyte, scanning rate, accumulation potential, and accumulation time on the determination of Trp were studied. Under the optimum experimental conditions, Trp was quantitatively analyzed by square-wave voltammetry (SWV). The oxidation peak current of Trp had a good linear relationship with its concentration in the range of 0.02–20 μM, and the detection limit was 0.01 μM (S/N = 3). In addition, the modified electrode has high sensitivity, good repeatability, and long-term stability. Finally, the proposed method has been successfully applied in the determination of Trp concentration in practical samples.
Assessment of DNA Topoisomerase I Unwinding Activity, Radical Scavenging Capacity, and Inhibition of Breast Cancer Cell Viability of N-alkyl-acridones and N,N′-dialkyl-9,9′-biacridylidenes
Authors: Krokidis Marios G. , Molphy Zara , Efthimiadou Eleni K. , Kokoli Marianna , Argyri Smaragda-Maria , Dousi Irini , Masi Annalisa , Papadopoulos Kyriakos , Kellett Andrew , Chatgilialoglu Chryssostomos
Published: May 2019

The anticancer activity of acridone derivatives has attracted increasing interest, therefore, a variety of substituted analogs belonging to this family have been developed and evaluated for their anti-cancer properties. A series of N-alkyl-acridones 1–6 and N,N′-dialkyl-9,9′-biacridylidenes 7–12 with variable alkyl chains were examined for their topoisomerase I activity at neutral and acidic conditions as well as for their binding capacity to calf thymus and possible radical trapping antioxidant activity. It was found that at a neutral pH, topoisomerase I activity of both classes of compounds was similar, while under acidic conditions, enhanced intercalation was observed. N-alkyl-acridone derivatives 1–6 exhibited stronger, dose-dependent, cytotoxic activity against MCF-7 human breast epithelial cancer cells than N,N′-dialkyl-9,9′-biacridylidenes 7–12, revealing that conjugation of the heteroaromatic system plays a significant role on the effective distribution of the compound in the intracellular environment. Cellular investigation of long alkyl derivatives against cell migration exhibited 40–50% wound healing effects and cytoplasm diffusion, while compounds with shorter alkyl chains were accumulated both in the nucleus and cytoplasm. All N,N′-dialkyl-9,9′-biacridylidenes showed unexpected high scavenging activity towards DPPH or ABTS radicals which may be explained by higher stabilization of radical cations by the extended conjugation of heteroaromatic ring system.
Identification of miRNAs and Their Response to Cold Stress in Astragalus Membranaceus
Authors: Abla Merhaba , Sun Huigai , Li Zhuyun , Wei Chunxiang , Gao Fei , Zhou Yijun , Feng Jinchao
Published: May 2019

Astragalus membranaceus is an important medicinal plant widely cultivated in East Asia. MicroRNAs (miRNAs) are endogenous regulatory molecules that play essential roles in plant growth, development, and the response to environmental stresses. Cold is one of the key environmental factors affecting the yield and quality of A. membranaceus, and miRNAs may mediate the gene regulation network under cold stress in A. membranaceus. To identify miRNAs and reveal their functions in cold stress response in A. membranaceus, small RNA sequencing was conducted followed by bioinformatics analysis, and quantitative real time PCR (qRT-PCR) analysis was performed to profile the expression of miRNAs under cold stress. A total of 168 conserved miRNAs belonging to 34 families and 14 putative non-conserved miRNAs were identified. Many miRNA targets were predicted and these targets were involved in diversified regulatory and metabolic pathways. By using qRT-PCR, 27 miRNAs were found to be responsive to cold stress, including 4 cold stress-induced and 17 cold-repressed conserved miRNAs, and 6 cold-induced non-conserved miRNAs. These cold-responsive miRNAs probably mediate the response to cold stress by regulating development, hormone signaling, defense, redox homeostasis, and secondary metabolism in A. membranaceus. These cold-corresponsive miRNAs may be used as the candidate genes in further molecular breeding for improving cold tolerance of A. membranaceus.
Histone Deacetylase Inhibitors Dose-Dependently Switch Neutrophil Death from NETosis to Apoptosis
Authors: Hamam Hussein J. , Palaniyar Nades
Published: May 2019

Acetylation is an important post translational modification of histone that plays a role in regulation of physiological and pathological process in the body. We have recently shown that the inhibition of histone deacetylases (HDAC) by low concentrations of HDAC inhibitors (HDACis), belinostat (up to 0.25 µM) and panobinostat (up to 0.04 µM) promote histone acetylation (e.g., AcH4) and neutrophil extracellular trap formation (NETosis). Clinical use of belinostat and panobinostat often leads to neutropenia and the in vivo concentrations vary with time and tissue locations. However, the effects of different concentrations of these HDACis on neutrophil death are not fully understood. We considered that increasing concentrations of belinostat and panobinostat could alter the type of neutrophil death. To test this hypothesis, we treated human neutrophils with belinostat and panobinostat in the presence or absence of agonists that promote NOX-dependent NETosis (phorbol myristate acetate or lipopolysaccharide from Escherichia coli 0128) and NOX-independent NETosis (calcium ionophores A23187 or ionomycin from Streptomyces conglobatus). Increasing concentrations of HDACis induced histone acetylation in a dose-dependent manner. ROS analyses showed that increasing concentrations of HDACis, increased the degree of NOX-derived ROS production. Higher levels (>1 µM belinostat and >0.2 µM panobinostat) of AcH4 resulted in a significant inhibition of spontaneous as well as the NOX-dependent and -independent NETosis. By contrast, the degree of neutrophil apoptosis significantly increased, particularly in non-activated cells. Collectively, this study establishes that increasing concentrations of belinostat and panobinostat initially increases NETosis but subsequently reduces NETosis or switches the form of cell death to apoptosis. This new information indicates that belinostat and panobinostat can induce different types of neutrophil death and may induce neutropenia and regulate inflammation at different concentrations.
A Highly Stretchable, Tough, Fast Self-Healing Hydrogel Based on Peptide–Metal Ion Coordination
Authors: Zeng Liang , Song Mingming , Gu Jie , Xu Zhengyu , Xue Bin , Li Ying , Cao Yi
Published: May 2019

Metal coordination bonds are widely used as the dynamic cross-linkers to construct self-healing hydrogels. However, it remains challenging to independently improve the toughness of metal coordinated hydrogels without affecting the stretchability and self-healing properties, as all these features are directly correlated with the dynamic properties of the same metal coordination bonds. In this work, using histidine–Zn2+ binding as an example, we show that the coordination number (the number of binding sites in each cross-linking ligand) is an important parameter for the mechanical strength of the hydrogels. By increasing the coordination number of the binding site, the mechanical strength of the hydrogels can be greatly improved without sacrificing the stretchability and self-healing properties. By adjusting the peptide and Zn2+ concentrations, the hydrogels can achieve a set of demanding mechanical features, including the Young’s modulus of 7–123 kPa, fracture strain of 434–781%, toughness of 630–1350 kJ m−3, and self-healing time of ~1 h. We anticipate the engineered hydrogels can find broad applications in a variety of biomedical fields. Moreover, the concept of improving the mechanical strength of metal coordinated hydrogels by tuning the coordination number may inspire the design of other dynamically cross-linked hydrogels with further improved mechanical performance.
Stimulation of the Angular Gyrus Improves the Level of Consciousness
Authors: Legostaeva Liudmila , Poydasheva Alexandra , Iazeva Elizaveta , Sinitsyn Dmitry , Sergeev Dmitry , Bakulin Ilya , Lagoda Dmitry , Kremneva Elena , Morozova Sofya , Ryabinkina Yulia , Suponeva Natalia , Piradov Michael
Published: May 2019

Background: Navigated repetitive transcranial magnetic stimulation (rTMS) is a promising tool for neuromodulation. In previous studies it has been shown that the activity of the default mode network (DMN) areas, particularly of its key region—the angular gyrus—is positively correlated with the level of consciousness. Our study aimed to explore the effect of rTMS of the angular gyrus as a new approach for disorders of consciousness (DOC) treatment; Methods: A 10-session 2-week high-frequency rTMS protocol was delivered over the left angular gyrus in 38 DOC patients with repeated neurobehavioral assessments obtained at baseline and in 2 days after the stimulation course was complete; Results: 20 Hz-rTMS over left angular gyrus improved the coma recovery scale revised (CRS-R) total score in minimally conscious state (MCS) patients. We observed no effects in vegetative state (VS) patients; and Conclusions: The left angular gyrus is likely to be effective target for rTMS in patients with present signs of consciousness.
Can Evaluative Conditioning Change Well-Established Attitudes Towards Popular Brands? Your Brain Says Yes Even Though Your Mouth Says No
Authors: Bosshard Shannon , Koller Monika , Walla Peter
Published: May 2019

In the present study, using both implicit and explicit measures, we addressed the issue of whether strongly developed relationships towards brands could be modified through the use of evaluative conditioning. Using an online survey, individual participant brand lists were created, and formed the basis of this experiment. Participants were then exposed to conditioning during a longitudinal study. Throughout the experiment, a combination of explicit and implicit measures was used to assess changes in attitude. Specifically, participants were asked to rate the brand names on a Likert-type scale. Simultaneously, changes in the brains electrical activity in response to the brands were recorded via electroencephalography (EEG). Upon completion of this task, participants underwent two Implicit Association Tests (IAT; one for liked brands and one for disliked brands). There were two main findings of this study. Firstly, no significant changes in attitude were observed via the use of explicit measures, and those that were found relating to the IAT were regarded as questionable. Secondly, EEG presented consistent results which showed that conditioning elicited changes in cortical activity towards both liked and disliked brands, which suggest it may be a useful tool in measuring the impact of evaluative conditioning that is not reflected in verbal responses.
BIM-based and AR Application Combined with Location-Based Management System for the Improvement of the Construction Performance
Authors: Ratajczak Julia , Riedl Michael , Matt Dominik
Published: May 2019

The information and communication technologies (ICTs) utilization ratio in the construction industry is relatively low. This industry is characterized by low productivity, time and cost overruns in projectsdue to inefficient management processes, poor communication and low process automation. To improve construction performance, a BIM-based (BIM - (Building Information Modelling) and augmented reality (AR) application (referred to as the AR4C: Augmented Reality for Construction) is proposed, which integrates a location-based management system (LBMS). The application provides context-specific information on construction projects and tasks, as well as key performance indicators on the progress and performance of construction tasks. The construction projects are superimposed onto the real world, while a site manager is walking through the construction site. This paper describes the most important methods and technologies, which are needed to develop the AR4C application. In particular, the data exchange between BIM software and the Unity environment is discussed, as well as the integration of LBMS into BIM software and the AR4C application. Finally, the implemented and planned functionalities are argued. The AR4C application prototype was tested in a laboratory environment and produced positive feedback. Since the application addresses construction sites, a validation in semi-real scenarios with end users is recommended.
Genomic Profiling of the Steroidogenic Acute Regulatory Protein in Breast Cancer: In Silico Assessments and a Mechanistic Perspective
Authors: Manna Pulak R. , Ahmed Ahsen U. , Yang Shengping , Narasimhan Madhusudhanan , Cohen-Tannoudji Joëlle , Slominski Andrzej T. , Pruitt Kevin
Published: May 2019

Cancer is a multifactorial condition with aberrant growth of cells. A substantial number of cancers, breast in particular, are hormone sensitive and evolve due to malfunction in the steroidogenic machinery. Breast cancer, one of the most prevalent form of cancers in women, is primarily stimulated by estrogens. Steroid hormones are made from cholesterol, and regulation of steroid/estrogen biosynthesis is essentially influenced by the steroidogenic acute regulatory (StAR) protein. Although the impact of StAR in breast cancer remains a mystery, we recently reported that StAR protein is abundantly expressed in hormone sensitive breast cancer, but not in its non-cancerous counterpart. Herein, we analyzed genomic profiles, hormone receptor expression, mutation, and survival for StAR and steroidogenic enzyme genes in a variety of hormone sensitive cancers. These profiles were specifically assessed in breast cancer, exploiting The Cancer Genome Atlas (TCGA) datasets. Whereas StAR and key steroidogenic enzyme genes evaluated (CYP11A1, HSD3B, CYP17A1, CYP19A1, and HSD17B) were altered to varying levels in these hormone responsive cancers, amplification of the StAR gene was correlated with poor overall survival of patients afflicted with breast cancer. Amplification of the StAR gene and its correlation to survival was also verified in a number of breast cancer studies. Additionally, TCGA breast cancer tumors associated with aberrant high expression of StAR mRNA were found to be an unfavorable risk factor for survival of patients with breast cancer. Further analyses of tumors, nodal status, and metastases of breast cancer tumors expressing StAR mRNA displayed cancer deaths in stage specific manners. The majority of these tumors were found to express estrogen and progesterone receptors, signifying a link between StAR and luminal subtype breast cancer. Collectively, analyses of genomic and molecular profiles of key steroidogenic factors provide novel insights that StAR plays an important role in the biologic behavior and/or pathogenesis of hormone sensitive breast cancer.
Immune Checkpoint Ligand Reverse Signaling: Looking Back to Go Forward in Cancer Therapy
Authors: Lecis Daniele , Sangaletti Sabina , Colombo Mario P. , Chiodoni Claudia
Published: May 2019

The so-called immune checkpoints are pathways that regulate the timing and intensity of the immune response to avoid an excessive reaction and to protect the host from autoimmunity. Immune checkpoint inhibitors (ICIs) are designed to target the negative regulatory pathways of T cells, and they have been shown to restore anti-tumor immune functions and achieve considerable clinical results. Indeed, several clinical trials have reported durable clinical response in different tumor types, such as melanoma, renal cell carcinoma (RCC) and non-small cell lung cancer (NSCLC). Nonetheless, after the initial enthusiasm, it is now evident that the majority of patients do not benefit from ICIs, due to innate or acquired tumor resistance. It is therefore mandatory to find ways to identify those patients who will respond and to find ways to induce response in those who at present do not benefit from ICIs. In this regard, the expression of programmed death ligand 1 (PD-L1) on neoplastic cells was the first, and most obvious, biomarker exploited to predict the activity of anti-programmed death 1 (PD-1) and/or anti-PD-L1 antibodies. As expected, a correlation was confirmed between the levels of PD-L1 and the efficacy of anti-PD-1 therapy in melanoma, NSCLC and RCC. However, further results from clinical trials showed that some patients display a clinical response regardless of tumor cell PD-L1 expression levels, while others do not benefit from ICI treatment despite the expression of PD-L1 on neoplastic elements. These findings strongly support the notion that other factors may be relevant for the efficacy of ICI-based treatment regimens. Furthermore, although the current dogma indicates that the PD-1/PD-L1 axis exerts its regulatory effects via the signal transduced in PD-1-expressing T cells, recent evidence suggests that a reverse signaling may also exist downstream of PD-L1 in both tumor and immune cells. The reverse signaling of PD-L1, but also of other immune checkpoints, might contribute to the pro-tumoral/immune suppressive environment associated with tumor development and progression. Clarifying this aspect could facilitate the prediction of patients’ clinical outcomes, which are so far unpredictable and result in response, resistance or even hyper-progressive disease in some cases.
Beyond PD-1/PD-L1 Inhibition: What the Future Holds for Breast Cancer Immunotherapy
Authors: Chrétien Sebastian , Zerdes Ioannis , Bergh Jonas , Matikas Alexios , Foukakis Theodoros
Published: May 2019

Cancer immunotherapy has altered the management of human malignancies, improving outcomes in an expanding list of diseases. Breast cancer - presumably due to its perceived low immunogenicity - is a late addition to this list. Furthermore, most of the focus has been on the triple negative subtype because of its higher tumor mutational load and lymphocyte-enriched stroma, although emerging data show promise on the other breast cancer subtypes as well. To this point the clinical use of immunotherapy is limited to the inhibition of two immune checkpoints, Programmed Cell Death Protein 1 (PD-1) and Cytotoxic T-lymphocyte-associated Protein 4 (CTLA-4). Consistent with the complexity of the regulation of the tumor – host interactions and their lack of reliance on a single regulatory pathway, combinatory approaches have shown improved efficacy albeit at the cost of increased toxicity. Beyond those two checkpoints though, a large number of co-stimulatory or co-inhibitory molecules play major roles on tumor evasion from immunosurveillance. These molecules likely represent future targets of immunotherapy provided that the promise shown in early data is translated into improved patient survival in randomized trials. The biological role, prognostic and predictive implications regarding breast cancer and early clinical efforts on exploiting these immune-related therapeutic targets are herein reviewed.
Tumour-Derived Laminin α5 (LAMA5) Promotes Colorectal Liver Metastasis Growth, Branching Angiogenesis and Notch Pathway Inhibition
Authors: Gordon-Weeks Alex , Lim Su Yin , Yuzhalin Arseniy , Lucotti Serena , Vermeer Jenny Adriana Francisca , Jones Keaton , Chen Jianzhou , Muschel Ruth J.
Published: May 2019

Hepatic metastatic growth is dependent upon stromal factors including the matrisomal proteins that make up the extracellular matrix (ECM). Laminins are ECM glycoproteins with several functions relevant to tumour progression including angiogenesis. We investigated whether metastatic colon cancer cells produce the laminins required for vascular basement membrane assembly as a mechanism for the promotion of angiogenesis and liver metastasis growth. qPCR was performed using human-specific primers to laminin chains on RNA from orthotopic human colorectal liver metastases. Laminin α5 (LAMA5) expression was inhibited in colon cancer cells using shRNA. Notch pathway gene expression was determined in endothelia from hepatic metastases. Orthotopic hepatic metastases expressed human laminin chains α5, β1 and γ1 (laminin 511), all of which are required for vascular basement membrane assembly. The expression of Laminin 511 was associated with reduced survival in several independent colorectal cancer cohorts and angiogenesis signatures or vessel density significantly correlated with LAMA5 expression. Colorectal cancer cells in culture made little LAMA5, but its levels were increased by culture in a medium conditioned by tumour-derived CD11b+ myeloid cells through TNFα/NFκB pathway signalling. Down-regulation of LAMA5 in cancer cells impaired liver metastatic growth and resulted in reduced intra-tumoural vessel branching and increased the expression of Notch pathway genes in metastasis-derived endothelia. This data demonstrates a mechanism whereby tumour inflammation induces LAMA5 expression in colorectal cancer cells. LAMA5 is required for the successful growth of hepatic metastases where it promotes branching angiogenesis and modulates Notch signalling.
Perturbing Enhancer Activity in Cancer Therapy
Authors: Hamdan Feda H. , Johnsen Steven A.
Published: May 2019

Tight regulation of gene transcription is essential for normal development, tissue homeostasis, and disease-free survival. Enhancers are distal regulatory elements in the genome that provide specificity to gene expression programs and are frequently misregulated in cancer. Recent studies examined various enhancer-driven malignant dependencies and identified different approaches to specifically target these programs. In this review, we describe numerous features that make enhancers good transcriptional targets in cancer therapy and discuss different approaches to overcome enhancer perturbation. Interestingly, a number of approved therapeutic agents, such as cyclosporine, steroid hormones, and thiazolidinediones, actually function by affecting enhancer landscapes by directly targeting very specific transcription factor programs. More recently, a broader approach to targeting deregulated enhancer programs has been achieved via Bromodomain and Extraterminal (BET) inhibition or perturbation of transcription-related cyclin-dependent kinases (CDK). One challenge to enhancer-targeted therapy is proper patient stratification. We suggest that monitoring of enhancer RNA (eRNA) expression may serve as a unique biomarker of enhancer activity that can help to predict and monitor responsiveness to enhancer-targeted therapies. A more thorough investigation of cancer-specific enhancers and the underlying mechanisms of deregulation will pave the road for an effective utilization of enhancer modulators in a precision oncology approach to cancer treatment.
F-Box/WD Repeat Domain-Containing 7 Induces Chemotherapy Resistance in Colorectal Cancer Stem Cells
Authors: Honma Shusaku , Hisamori Shigeo , Nishiuchi Aya , Itatani Yoshiro , Obama Kazutaka , Shimono Yohei , Sakai Yoshiharu
Published: May 2019

Although the cancer stem cell (CSC) concept has provided a reasonable explanation for cancer recurrence following chemotherapy, the relationship between CSCs and chemotherapy resistance has not been thoroughly investigated, especially in solid tumors. We aimed to identify the mechanism underlying colorectal cancer (CRC) chemoresistance focusing on the cell cycle mediator F-Box/WD repeat domain-containing 7 (FBXW7). From 55 consecutive CRC cases who underwent neoadjuvant chemotherapy (NAC) or neoadjuvant chemoradiotherapy (NACRT) at Kyoto University Hospital, pre-treatment endoscopic biopsy specimens were collected and divided into two groups upon immunohistochemical (IHC) analysis: 21 cases of FBXW7 high expression (FBXW7-high group) and 34 cases of low expression (FBXW7-low group). High FBXW7 expression in pre-treatment biopsy specimen was significantly associated with poor pathological therapeutic effect (p = 0.019). The proportion of FBXW7-positive cells in surgically resected CRC specimens from patients who underwent NAC or NACRT was significantly higher than that in the pre-treatment biopsy specimens (p < 0.001). The expression of FBXW7 was inversely correlated with that of Ki67 in both pre-treatment biopsy specimens and surgically resected specimens. FBXW7 expression in the EpCAMhigh/CD44high subpopulation isolated by flow cytometry from CRC samples was significantly higher than that in the EpCAMhigh/CD44low subpopulation. Cell-cycle analysis in CRC cell lines revealed that, upon FBXW7 silencing, the proportion of G0/G1 cells was significantly lower than that in control cells. Moreover, knockdown of FBXW7 in CRC cell lines increased the sensitivity to anti-cancer drugs in vitro and in vivo. A subset of CRC stem cells possesses chemoresistance through FBXW7 expression. Cell cycle arrest induced by FBXW7 expression should be considered as a potential therapeutic target to overcome chemoresistance in CRC stem cell subsets.
Acute Tumor Transition Angle on Computed Tomography Predicts Chromosomal Instability Status of Primary Gastric Cancer: Radiogenomics Analysis from TCGA and Independent Validation
Authors: Lai Ying-Chieh , Yeh Ta-Sen , Wu Ren-Chin , Tsai Cheng-Kun , Yang Lan-Yan , Lin Gigin , Kuo Michael D.
Published: May 2019

Chromosomal instability (CIN) of gastric cancer is correlated with distinct outcomes. This study aimed to investigate the role of computed tomography (CT) imaging traits in predicting the CIN status of gastric cancer. We screened 443 patients in the Cancer Genome Atlas gastric cancer cohort to filter 40 patients with complete CT imaging and genomic data as the training cohort. CT imaging traits were subjected to logistic regression to select independent predictors for the CIN status. For the validation cohort, we prospectively enrolled 18 gastric cancer patients for CT and tumor genomic analysis. The imaging predictors were tested in the validation cohort using receiver operating characteristic curve (ROC) analysis. Thirty patients (75%) in the training cohort and 9 patients (50%) in the validation cohort had CIN subtype gastric cancers. Smaller tumor diameter (p = 0.017) and acute tumor transition angle (p = 0.045) independently predict CIN status in the training cohort. In the validation cohort, acute tumor transition angle demonstrated the highest accuracy, sensitivity, and specificity of 88.9%, 88.9%, and 88.9%, respectively, and areas under ROC curve of 0.89. In conclusion, this pilot study showed acute tumor transition angle on CT images may predict the CIN status of gastric cancer.
Mechanical Durotactic Environment Enhances Specific Glioblastoma Cell Responses
Authors: Palamà Ilaria Elena , D’Amone Stefania , Ratano Patrizia , Donatelli Amato , Liscio Andrea , Antonacci Giuseppe , Testini Mariangela , Di Angelantonio Silvia , Ragozzino Davide , Cortese Barbara
Published: May 2019

Background: A hallmark of glioblastoma is represented by their ability to widely disperse throughout the brain parenchyma. The importance of developing new anti-migratory targets is critical to reduce recurrence and improve therapeutic efficacy. Methods: Polydimethylsiloxane substrates, either mechanically uniform or presenting durotactic cues, were fabricated to assess GBM cell morphological and dynamical response with and without pharmacological inhibition of NNMII contractility, of its upstream regulator ROCK and actin polymerization. Results: Glioma cells mechanotactic efficiency varied depending on the rigidity compliance of substrates. Morphologically, glioma cells on highly rigid and soft bulk substrates displayed bigger and elongated aggregates whereas on durotactic substrates the same cells were homogeneously dispersed with a less elongated morphology. The durotactic cues also induced a motility change, cell phenotype dependent, and with cells being more invasive on stiffer substrates. Pharmacological inhibition of myosin or ROCK revealed a rigidity-insensitivity, unlike inhibition of microfilament contraction and polymerization of F-actin, suggesting that alternative signalling is used to respond to durotactic cues. Conclusions: The presence of a distinct mechanical cue is an important factor in cell migration. Together, our results provide support for a durotactic role of glioma cells that acts through actomyosin contractility to regulate the aggressive properties of GBM cells.
Erratum: Stella, G.M. et al. Brain Metastases from Lung Cancer: Is MET an Actionable Target? Cancers 2019, 11, 271
Authors: Stella Giulia M. , Corino Alessandra , Berzero Giulia , Kolling Stefan , Filippi Andrea R. , Benvenuti Silvia
Published: May 2019

The authors wish to make the following corrections to this paper [...]
Histone Deacetylase Inhibitors Sensitize TRAIL-Induced Apoptosis in Colon Cancer Cells
Authors: Zhang Baojie , Liu Bin , Chen Deng , Setroikromo Rita , Haisma Hidde J. , Quax Wim J.
Published: May 2019

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is considered as a promising anti-cancer therapeutic. However, many cancers have been found to be or to become inherently resistant to TRAIL. A combination of epigenetic modifiers, such as histone deacetylase inhibitors (HDACi’s), with TRAIL was effective to overcome TRAIL resistance in some cancers. Broad spectrum HDACi’s, however, show considerable toxicity constraining clinical use. Since overexpression of class I histone deacetylase (HDAC) has been found in colon tumors relative to normal mucosa, we have focused on small spectrum HDACi’s. We have now tested agonistic receptor-specific TRAIL variants rhTRAIL 4C7 and DHER in combination with several class I specific HDACi’s on TRAIL-resistant colon cancer cells DLD-1 and WiDr. Our data show that TRAIL-mediated apoptosis is largely improved in WiDr cells by pre-incubation with Entinostat-a HDAC1, 2, and 3 inhibitor- and in DLD-1 cells by RGFP966-a HDAC3-specific inhibitor- or PCI34051-a HDAC8-specific inhibitor. We are the first to report that using RGFP966 or PCI34051 in combination with rhTRAIL 4C7 or DHER represents an effective cancer therapy. The intricate relation of HDACs and TRAIL-induced apoptosis was confirmed in cells by knockdown of HDAC1, 2, or 3 gene expression, which showed more early apoptotic cells upon adding rhTRAIL 4C7 or DHER. We observed that RGFP966 and PCI34051 increased DR4 expression after incubation on DLD-1 cells, while RGFP966 induced more DR5 expression on WiDr cells, indicating a different role for DR4 or DR5 in these combinations. At last, we show that combined treatment of RGFP966 with TRAIL variants (rhTRAIL 4C7/DHER) increases apoptosis on 3D tumor spheroid models.
Polymorphism in Toll-Like Receptors and Helicobacter Pylori Motility in Autoimmune Atrophic Gastritis and Gastric Cancer
Authors: De Re Valli , Repetto Ombretta , De Zorzi Mariangela , Casarotto Mariateresa , Tedeschi Massimo , Giuffrida Paolo , Lenti Marco Vincenzo , Magris Raffaella , Miolo Gianmaria , Mazzon Cinzia , Zanette Giorgio , Alessandrini Lara , Canzonieri Vincenzo , Caggiari Laura , Zanussi Stefania , Steffan Agostino , Di Sabatino Antonio , Cannizzaro Renato
Published: May 2019

Autoimmune atrophic gastritis (AAG) is associated with an increased risk of certain types of gastric cancer (GC). Helicobacter pylori (H. pylori) infection may have a role in the induction and/or maintenance of AAG and GC. Toll-like receptors (TLR) are essential for H. pylori recognition and subsequent innate and adaptive immunity responses. This study therefore aimed to characterize TLR polymorphisms, and features of bacterial flagellin A in samples from patients with AAG (n = 67), GC (n = 114) and healthy donors (HD; n = 97). TLR5 rs5744174 C/C genotype was associated with GC, lower IgG anti H. pylori response and a higher H. pylori flagellin A abundance and motility. In a subset of patients with AAG, H. pylori strains showed a reduction of the flagellin A abundance and a moderate motility compared with strains from GC patients, a prerequisite for active colonization of the deeper layers of the mucosa, host immune response and inflammation. TLR9 rs5743836 T allele showed an association with serum gastrin G17. In conclusion, our study suggests that alterations of flaA protein, moderate motility in H. pylori and two polymorphisms in TLR5 and TLR9 may favor the onset of AAG and GC, at least in a subset of patients. These findings corroborate the function of pathogen–host cell interactions and responses, likely influencing the pathogenetic process.
Interleukin-17F Has Anti-Tumor Effects in Oral Tongue Cancer
Authors: Almahmoudi Rabeia , Salem Abdelhakim , Murshid Sakhr , Dourado Mauricio Rocha , Apu Ehsanul Hoque , Salo Tuula , Al-Samadi Ahmed
Published: May 2019

We recently showed that extracellular interleukin-17F (IL-17F) correlates with better disease-specific survival in oral tongue squamous cell carcinoma (OTSCC) patients. However, the underlying mechanisms of such effect remain obscure. Here, we used qRT-PCR to assess the expression of IL-17F and its receptors (IL-17RA and IL-17RC) in two OTSCC cell lines (HSC-3 and SCC-25) and in normal human oral keratinocytes (HOKs). IL-17F effects on cancer cell proliferation, migration, and invasion were studied using a live-imaging IncuCyte system, and a Caspase-3/7 reagent was used for testing apoptosis. 3D tumor spheroids were utilized to assess the impact of IL-17F on invasion with or without cancer-associated fibroblasts (CAFs). Tube-formation assays were used to examine the effects of IL-17F on angiogenesis using human umbilical vein endothelial cells (HUVEC). OTSCC cells express low levels of IL-17F, IL-17RA, and IL-17RC mRNA compared with HOKs. IL-17F inhibited cell proliferation and random migration of highly invasive HSC-3 cells. CAFs promoted OTSCC invasion in tumor spheroids, whereas IL-17F eliminated such effect. IL-17F suppressed HUVEC tube formation in a dose-dependent manner. Collectively, we suggest that IL-17F counteracts the pro-tumorigenic activity in OTSCC. Due to its downregulation in tumor cells and inhibitory activity in in vitro cancer models, targeting IL-17F or its regulatory pathways could lead to promising immunotherapeutic strategies against OTSCC.
Prospect of Plasmacytoid Dendritic Cells in Enhancing Anti-Tumor Immunity of Oncolytic Herpes Viruses
Authors: Schuster Philipp , Lindner Georg , Thomann Sabrina , Haferkamp Sebastian , Schmidt Barbara
Published: May 2019

The major type I interferon-producing plasmacytoid dendritic cells (pDC) surround and infiltrate certain tumors like malignant melanoma, head and neck cancer, and ovarian and breast cancer. The presence of pDC in these tumors is associated with an unfavorable prognosis for the patients as long as these cells are unstimulated. Upon activation by synthetic Toll-like receptor agonists or viruses, however, pDC develop cytotoxic activities. Viruses have the additional advantage to augment cytotoxic activities of pDC via lytic replication in malignant lesions. These effects turn cold tumors into hotspots, recruiting further immune cells to the site of inflammation. Activated pDC contribute to cross-presentation of tumor-associated antigens by classical dendritic cells, which induce cytotoxic T-cells in particular in the presence of checkpoint inhibitors. The modification of oncolytic herpes viruses via genetic engineering favorably affects this process through the enhanced production of pro-inflammatory cytokines, curbing of tumor blood supply, and removal of extracellular barriers for efficient viral spread. Importantly, viral vectors may contribute to stimulation of memory-type adaptive immune responses through presentation of tumor-related neo- and/or self-antigens. Eventually, both replication-competent and replication-deficient herpes simplex virus 1 (HSV-1) may serve as vaccine vectors, which contribute to tumor regression by the stimulation of pDC and other dendritic cells in adjuvant and neo-adjuvant situations.
Histone H3 Mutations: An Updated View of Their Role in Chromatin Deregulation and Cancer
Authors: Lowe Brandon R. , Maxham Lily A. , Hamey Joshua J. , Wilkins Marc R. , Partridge Janet F.
Published: May 2019

In this review, we describe the attributes of histone H3 mutants identified in cancer. H3 mutants were first identified in genes encoding H3.3, in pediatric high-grade glioma, and subsequently in chondrosarcomas and giant cell tumors of bone (GCTB) in adolescents. The most heavily studied are the lysine to methionine mutants K27M and K36M, which perturb the target site for specific lysine methyltransferases and dominantly perturb methylation of corresponding lysines in other histone H3 proteins. We discuss recent progress in defining the consequences of these mutations on chromatin, including a newly emerging view of the central importance of the disruption of H3K36 modification in many distinct K to M histone mutant cancers. We also review new work exploring the role of H3.3 G34 mutants identified in pediatric glioma and GCTB. G34 is not itself post-translationally modified, but G34 mutation impinges on the modification of H3K36. Here, we ask if G34R mutation generates a new site for methylation on the histone tail. Finally, we consider evidence indicating that histone mutations might be more widespread in cancer than previously thought, and if the perceived bias towards mutation of H3.3 is real or reflects the biology of tumors in which the histone mutants were first identified.
Synthesis and Structure of Copper Complexes of a N6O4 Macrocyclic Ligand and Catalytic Application in Alcohol Oxidation
Authors: Ma Zhen , Wang Qijun , C. B. A. Alegria Elisabete , C. Guedes da Silva M. Fátima , M. D. R. S. Martins Luísa , Telo João P. , Correia Isabel , J. L. Pombeiro Armando
Published: May 2019

Reactions between N6O4 macrocyclic 1,4,19,22,25,40-hexaaza-10,13,31,34-tetraoxa-6,14,27,35(1,4)-tetrabenzenacyclopentacontane (L) and several copper salts (viz. trifuoromethane and toluene sulfonates, nitrate, perchlorate, benzoate, and acetate) led to the formation of dinuclear compounds [Cu2(OSO2CF3)2(DMF)2L](SO3CF3)2 (1), [Cu2(p-OSO2C6H4Me)2L(DMF)2](SO3C6H4Me)2 (2), [Cu2(ONO2)2L(DMF)2](NO3)2 (3), [Cu2(OClO3)2(DMF)2L](ClO4)2 (4), [Cu2(OOCPh)2L(H2O)2](O2CPh)2 (5), and [Cu2(OOCMe)4L] (6), which were characterized by IR, elemental analysis and TG-DTA (thermogravimetric-differential thermal analysis), as well as by single-crystal X-ray diffraction, EPR (electron paramagnetic resonance) spectroscopy, and electrochemical techniques (cyclic voltammetry and controlled potential electrolysis). The molecular structures of compounds 1–6 reveal a considerable conformational flexibility of the ligand L, which allowed its readjustment for the formation of the metal compounds and confirmed the presence of dinuclear endo macrocyclic species. In every case, the L ligand coordinates to each copper cation via three nitrogen atoms, with the remaining coordination positions of the metal square pyramid environment being accomplished by neutral or anionic ligands. The macrocyclic cavities appear to be adequate for the enclosure of a neutral species as proved by compound 6 with 1,4-dioxane. The compounds, in combination with the TEMPO (2,2,6,6-tetramethyl-piperidinyloxyl) radical and in alkaline aqueous solution, act as efficient catalysts in the aerobic oxidation of different alcohols to the corresponding aldehydes (yields up to 99% and TON up 232) after 20 h at 70 °C. In addition, the microwave-assisted solvent-free peroxidative oxidation (by tert-butylhydroperoxide, TBHP) of 1-phenylethanol led to acetophenone yields up to 99% and TOF of 1.1 × 103 after 0.5 h, without any additive.
Enhanced (−)-α-Bisabolol Productivity by Efficient Conversion of Mevalonate in Escherichia coli
Authors: Kim Soo-Jung , Kim Seong Keun , Seong Wonjae , Woo Seung-Gyun , Lee Hyewon , Yeom Soo-Jin , Kim Haseong , Lee Dae-Hee , Lee Seung-Goo
Published: May 2019

(−)-α-Bisabolol, a naturally occurring sesquiterpene alcohol, has been used in pharmaceuticals and cosmetics owing to its beneficial effects on inflammation and skin healing. Previously, we reported the high production of (−)-α-bisabolol by fed-batch fermentation using engineered Escherichia coli (E. coli) expressing the exogenous mevalonate (MVA) pathway genes. The productivity of (−)-α-bisabolol must be improved before industrial application. Here, we report enhancement of initial (−)-α-bisabolol productivity to 3-fold higher than that observed in our previous study. We first harnessed a farnesyl pyrophosphate (FPP)-resistant mevalonate kinase 1 (MvaK1) from an archaeon Methanosarcina mazei (M. mazei) to create a more efficient heterologous MVA pathway that produces (−)-α-bisabolol in the engineered E. coli. The resulting strain produced 1.7-fold higher (−)-α-bisabolol relative to the strain expressing a feedback-inhibitory MvaK1 from Staphylococcus aureus (S. aureus). Next, to efficiently convert accumulated MVA to (−)-α-bisabolol, we additionally overexpressed genes involved in the lower MVA mevalonate pathway in E. coli containing the entire MVA pathway genes. (−)-α-Bisabolol production increased by 1.8-fold with reduction of MVA accumulation, relative to the control strain. Finally, we optimized the fermentation conditions including inducer concentration, aeration and enzymatic cofactor. The strain was able to produce 8.5 g/L of (−)-α-bisabolol with an initial productivity of 0.12 g/L h in the optimal fed-batch fermentation. Thus, the microbial production of (−)-α-bisabolol would be an economically viable bioprocess for its industrial application.
Immobilized Whole-Cell Transaminase Biocatalysts for Continuous-Flow Kinetic Resolution of Amines
Authors: Molnár Zsófia , Farkas Emese , Lakó Ágnes , Erdélyi Balázs , Kroutil Wolfgang , Vértessy Beáta G. , Paizs Csaba , Poppe László
Published: May 2019

Immobilization of transaminases creates promising biocatalysts for production of chiral amines in batch or continuous-flow mode reactions. E. coli cells containing overexpressed transaminases of various selectivities and hollow silica microspheres as supporting agent were immobilized by an improved sol-gel process to produce immobilized transaminase biocatalysts with suitable stability and mechanical properties for continuous-flow applications. The immobilized cell-based transaminase biocatalyst proved to be durable and easy-to-use in kinetic resolution of four racemic amines 1a–d. The batch and continuous-flow mode kinetic resolutions with transaminase biocatalyst of opposite stereopreference provided access to both enantiomers of the corresponding amines. By using the most suitable immobilized transaminase biocatalysts, this study describes the first transaminase-based approach for the production of both pure enantiomers of 1-(3,4-dimethoxyphenyl)ethan-1-amine 1d.