bluuebunny/crossref_metadata_2025 huggingface dataset:
Model of Early Stage Intermediate in Respect to Its Final Structure
Authors: Fabian Piotr , Stapor Katarzyna , Roterman Irena
Published: December 2019

The model, describing a method of determining the structure of an early intermediate in the process of protein folding to analyze nonredundant PDB protein bases, allows determining the relationship between the sequence of tetrapeptides and their structural forms expressed by structural codes. The contingency table expressing such a relationship can be used to predict the structure of polypeptides by proposing a structural form with a precision limited to the structural code. However, by analyzing structural forms in native forms of proteins based on the fuzzy oil drop model, one can also determine the status of polypeptide chain fragments with respect to the assumptions of this model. Whether the probability distributions for both compliant and noncompliant forms were similar or whether the tetrapeptide sequences showed some differences at a level of a set of structural codes was investigated. The analysis presented here indicated that some sequences in both forms revealed differences in probability distributions expressed as a negative statistically significant correlation coefficient. This meant that the identified sections (tetrapeptides) took different forms against the fuzzy oil drop model. It may suggest that the information of the final status with respect to hydrophobic core formation is already carried by the structure of the early-stage intermediate.
Lagerstroemia Speciosa (L.) Pers Leaf Extract Attenuates Lung Tumorigenesis via Alleviating Oxidative Stress, Inflammation and Apoptosis
Authors: Mousa Amria M. , El-Sammad Nermin M. , Abdel-Halim Abeer H. , Anwar Nayera , Khalil Wagdy K. B. , Nawwar Mahmoud , Hashim Amani N. , Elsayed Elsayed A. , Hassan Sherien K.
Published: December 2019

One of the major etiological factors that account for lung cancer is tobacco use. Benzo(a)pyrene [B(a)P], one of the main constituents of tobacco smoke, has a key role in lung carcinogenesis. The present study was conducted to investigate the cytotoxicity of an aqueous ethanolic extract of Lagerstroemia speciosa (L.) Pers leaves (LLE) on human lung adenocarcinoma cells (A549), as well as its in vivo antitumor effect on a lung tumorigenesis mice model. Our results revealed that LLE possesses cytotoxic activity against the A549 cell line. Mice orally administered B(a)P (50 mg/kg body weight) showed an increase in relative lung weight with subsequent decrease in final body weight. Serum levels of tumor marker enzymes AHH, ADA and LDH and the inflammatory mediator NF-κB increased, while total antioxidant capacity (TAC) decreased. In addition, we observed the increased activity of metalloproteinases (MMP-2 and MMP-12) and levels of the tumor angiogenesis marker VEFG and the lipid peroxidation marker MDA, as well as decreased levels of the non-enzymatic antioxidant GSH and enzymatic antioxidants CAT and GSH-Px in lung tissues. Moreover, B(a)P administration up-regulated the expression of the COX-2 gene, pro-inflammatory cytokines TNF-α and IL-6, and an anti-apoptotic gene Bcl-2, and at the same time down-regulated expression of pro-apoptotic genes BAX and caspase-3 and the p53 gene. Pre- and post-treatment with LLE (250 mg/kg body weight) attenuated all these abnormalities. Histopathological observations verified the protective effect of LLE. Overall, the present data positively confirm the potent antitumor effect of L. speciosa leaves against lung tumorigenesis.
RSM–GA Based Optimization of Bacterial PHA Production and In Silico Modulation of Citrate Synthase for Enhancing PHA Production
Authors: Rao Apoorva , Haque Shafiul , El-Enshasy Hesham A. , Singh Vineeta , Mishra Bhartendu Nath
Published: December 2019

The inexhaustible nature and biodegradability of bioplastics like polyhydroxyalkanoates (PHAs) make them suitable assets to replace synthetic plastics. The eventual fate of these eco-friendly and non-toxic bioplastics relies upon the endeavors towards satisfying cost and, in addition, execution necessity. In this study, we utilized and statistically optimized different food (kitchen-/agro-) waste as a sole carbon/nitrogen source for the production of PHA at a reduced cost, indicating a proficient waste administration procedure. Seven different types of kitchen-/agro-waste were used as unique carbon source and four different types of nitrogen source were used to study their impact on PHA production by Bacillus subtilis MTCC 144. Among four different studied production media, mineral salt medium (MSM) (biomass: 37.7 g/L; cell dry weight: 1.8 g/L; and PHA: 1.54 g/L) was found most suitable for PHA production. Further, carbon and nitrogen components of MSM were optimized using one-factor-at-a-time experiments, and found that watermelon rind (PHA = 12.97 g/L) and pulse peel (PHA = 13.5 g/L) were the most suitable carbon and nitrogen sources, respectively, in terms of PHA (78.60%) recovery. The concentrations of these factors (sources) were statistically optimized using response surface methodology coupled with the genetic algorithm approach. Additionally, in order to enhance microbial PHA production, the interaction of citrate synthase, a key enzyme in the TCA cycle, with different known inhibitors was studied using in silico molecular docking approach. The inhibition of citrate synthase induces the blockage of the tricarboxylic cycle (TCA), thereby increasing the concentration of acetyl-CoA that helps in enhanced PHA production. Molecular docking of citrate synthase with different inhibitors of PubChem database revealed that hesperidin (PubChem compound CID ID 10621), generally present in citrus fruits, is the most efficient inhibitor of the TCA cycle with the binding score of –11.4 and warrants experimental validation. Overall, this study provides an efficient food waste management approach by reducing the production cost and enhancing the production of PHA, thereby lessening our reliance on petroleum-based plastics.
Protective Effects of Scolopendra Water Extract on Trimethyltin-Induced Hippocampal Neurodegeneration and Seizures in Mice
Authors: Seo Yun-Soo , Ang Mary Jasmin , Moon Byeong Cheol , Kim Hyo Seon , Choi Goya , Lim Hye-Sun , Kang Sohi , Jeon Mijin , Kim Sung-Ho , Moon Changjong , Kim Joong Sun
Published: December 2019

Trimethyltin (TMT) is an organotin compound with potent neurotoxic action characterized by neuronal degeneration in the hippocampus. This study evaluated the protective effects of a Scolopendra water extract (SWE) against TMT intoxication in hippocampal neurons, using both in vitro and in vivo model systems. Specifically, we examined the actions of SWE on TMT- (5 mM) induced cytotoxicity in primary cultures of mouse hippocampal neurons (7 days in vitro) and the effects of SWE on hippocampal degeneration in adult TMT- (2.6 mg/kg, intraperitoneal) treated C57BL/6 mice. We found that SWE pretreatment (0–100 μg/mL) significantly reduced TMT-induced cytotoxicity in cultured hippocampal neurons in a dose-dependent manner, as determined by lactate dehydrogenase and 3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyltetrazolium bromide assays. Additionally, this study showed that perioral administration of SWE (5 mg/kg), from −6 to 0 days before TMT injection, significantly attenuated hippocampal cell degeneration and seizures in adult mice. Furthermore, quantitative analysis of Iba-1 (Allograft inflammatory factor 1)- and GFAP (Glial fibrillary acidic protein)-immunostained cells revealed a significant reduction in the levels of Iba-1- and GFAP-positive cell bodies in the dentate gyrus (DG) of mice treated with SWE prior to TMT injection. These data indicated that SWE pretreatment significantly protected the hippocampus against the massive activation of microglia and astrocytes elicited by TMT. In addition, our data showed that the SWE-induced reduction of immune cell activation was linked to a significant reduction in cell death and a significant improvement in TMT-induced seizure behavior. Thus, we conclude that SWE ameliorated the detrimental effects of TMT toxicity on hippocampal neurons, both in vivo and in vitro. Altogether, our findings hint at a promising pharmacotherapeutic use of SWE in hippocampal degeneration and dysfunction.
Profession Loss Crisis at an Old Age: Specific Features, Factors, and Mechanisms of Coping
Authors: Symanyuk Elvira , Borisov Georgy , Berdnikova Daria , Tomberg Olga , Ryabukhina Alexandra
Published: December 2019

This article discusses the specific characteristics of profession loss crisis at an old age. Profession loss crisis is the last normative crisis of personal professional development that is caused by the completion of one’s professional biography after reaching a certain age. The research employs a psychobiographic method and a critical events method. These methods are based on the use of a formalized biographical questionnaire worked out by Norakidze V.G. and reconstructed by Zeer E.F. The authors have identified and provided a detailed description of the main factors that cause profession loss crisis: random events, adverse circumstances while implementing professional plans, etc. The article outlines the main strategies for coping with this crisis: changing jobs, re-training, the assistance of colleagues and administration, etc. The authors suggest technologies to minimize the effects of these factors and overcome profession loss crisis effectively.
A Ferrocement Patent for Emergency Housing: The Technological Hut
Authors: Roa-Fernández Jorge , Galán-Marín Carmen , Rivera-Gómez Carlos
Published: December 2019

This article focuses on the comparison between the Spanish architects de La Hoz (Madrid, 1924) and José María García de Paredes (Seville, 1924) projects for ‘ultra-cheap’ housing in Cordoba, how it evolved from a British patent named Ctesiphon, and the study of some of existing buildings erected following this construction system. The aim of this article is to stablish the evolution of the system from the original patent into a new possibility for low-income social housing. This system was used to erect new developments in the 1950s that would relocate people living in huts during the dictatorship era in Spain, thus new “technological huts” were proposed and erected. The research process includes an analysis of the documents and literature available of the patent and the projects themselves, and in situ tests (infrared thermography and samples extraction) will allow to establish the relation between its original inventor, the dissemination of his works in publications from that era, and the Spanish company that subsequently, as a concession of the original patent, introduced that system in Spanish architecture. Analysis of the original patent document allows to study the primitive system as it was invented and for what uses it was conceived. Thus, such a methodology supports an establishment of the technical innovations achieved in order to adapt the system to the Andalusian environment at that time and its use for housing.
Recovering Industrial Heritage: Restoration of the Wine Cellar Cooperative in Falset (Catalonia, Spain)
Authors: Cuerva Eva , Urbano Judith , Cornadó Còssima
Published: December 2019

Awareness regarding conservation of industrial heritage is recent. Several policies have been adopted to start protecting these buildings because of their historic, artistic and scientific values. Wine cellars are an important example of industrial heritage in Catalonia due to the tradition of this product in the territory and the influence of Art Nouveau and Catalan ‘Noucentisme’ in their construction and style. The wine cellar in Falset, built by Cèsar Martinell in 1919, has recently been restored and still maintains its original function. This article analyses its history, its architectonic and construction characteristics, as well as the restoration process carried out in 2009, which consisted of recovering its original appearance and allowed to emphasize the architectural value of the building. This restoration is a prototypical example whose experience can be applied in other cases of restoration of wine cellars both for the characteristics of the building and for its good restoration practices. This restoration enabled the wine cellar to continue carrying out its original industrial function, providing suitable conditions to add a new cultural use as well.
Exploiting Current Understanding of Hypoxia Mediated Tumour Progression for Nanotherapeutic Development
Authors: Feng Jie , Byrne Niall M. , Al Jamal Wafa , Coulter Jonathan A.
Published: December 2019

Hypoxia is one of the most common phenotypes of malignant tumours. Hypoxia leads to the increased activity of hypoxia-inducible factors (HIFs), which regulate the expression of genes controlling a raft of pro-tumour phenotypes. These include maintenance of the cancer stem cell compartment, epithelial-mesenchymal transition (EMT), angiogenesis, immunosuppression, and metabolic reprogramming. Hypoxia can also contribute to the tumour progression in a HIF-independent manner via the activation of a complex signalling network pathway, including JAK-STAT, RhoA/ROCK, NF-κB and PI3/AKT. Recent studies suggest that nanotherapeutics offer a unique opportunity to target the hypoxic microenvironment, enhancing the therapeutic window of conventional therapeutics. In this review, we summarise recent advances in understanding the impact of hypoxia on tumour progression, while outlining possible nanotherapeutic approaches for overcoming hypoxia-mediated resistance.
Transcriptomic Analyses Revealed Systemic Alterations in Gene Expression in Circulation and Tumor Microenvironment of Colorectal Cancer Patients
Authors: Shaath Hibah , Toor Salman , Nair Varun Sasidharan , Elkord Eyad , Alajez Nehad M.
Published: December 2019

Colorectal cancer (CRC) is among the leading causes of cancer-related deaths worldwide, underscoring a need for better understanding of the disease and development of novel diagnostic biomarkers and therapeutic interventions. Herein, we performed transcriptome analyses on peripheral blood mononuclear cells (PBMCs), CRC tumor tissue and adjacent normal tissue from 10 CRC patients and PBMCs from 15 healthy controls. Up regulated transcripts from CRC PBMCs were associated with functions related to immune cell trafficking and cellular movement, while downregulated transcripts were enriched in cellular processes related to cell death. Most affected signaling networks were those involved in tumor necrosis factor (TNF) and interleukin signaling. The expression of selected immune-related genes from the RNA-Seq data were further validated using qRT-PCR. Transcriptome analysis of CRC tumors and ingenuity pathway analysis revealed enrichment in several functional categories related to cellular movement, cell growth and proliferation, DNA replication, recombination and repair, while functional categories related to cell death were suppressed. Upstream regulator analysis revealed activation of ERBB2 and FOXM1 networks. Interestingly, there were 18 common upregulated and 36 common downregulated genes when comparing PBMCs and tumor tissue, suggesting transcriptomic changes in the tumor microenvironment could be reflected, in part, in the periphery with potential utilization as disease biomarkers.
Analysis of PMEPA1 Isoforms (a and b) as Selective Inhibitors of Androgen and TGF-β Signaling Reveals Distinct Biological and Prognostic Features in Prostate Cancer
Authors: Sharad Shashwat , Sztupinszki Zsófia M. , Chen Yongmei , Kuo Claire , Ravindranath Lakshmi , Szallasi Zoltan , Petrovics Gyorgy , Sreenath Taduru L. , Dobi Albert , Rosner Inger L. , Srinivasan Alagarsamy , Srivastava Shiv , Cullen Jennifer , Li Hua
Published: December 2019

Dysfunctions of androgen/TGF-β signaling play important roles in prostate tumorigenesis. Prostate Transmembrane Protein Androgen Induced 1 (PMEPA1) inhibits androgen and TGF-β signaling via a negative feedback loop. The loss of PMEPA1 confers resistance to androgen signaling inhibitors and promotes bone metastasis. Conflicting reports on the expression and biological functions of PMEPA1 in prostate and other cancers propelled us to investigate isoform specific functions in prostate cancer (PCa). One hundred and twenty laser capture micro-dissection matched normal prostate and prostate tumor tissues were analyzed for correlations between quantitative expression of PMEPA1 isoforms and clinical outcomes with Q-RT-PCR, and further validated with a The Cancer Genome Atlas (TCGA) RNA-Seq dataset of 499 PCa. Cell proliferation was assessed with cell counting, plating efficiency and soft agar assay in androgen responsive LNCaP and TGF-β responsive PC3 cells. TGF-β signaling was measured by SMAD dual-luciferase reporter assay. Higher PMEPA1-a mRNA levels indicated biochemical recurrence (p = 0.0183) and lower PMEPA1-b expression associated with metastasis (p = 0.0173). Further, lower PMEPA1-b and a higher ratio of PMEPA1-a vs. -b were correlated to higher Gleason scores and lower progression free survival rate (p < 0.01). TGF-β-responsive PMEPA1-a promoted PCa cell growth, and androgen-responsive PMEPA1-b inhibited cancer cell proliferation. PMEPA1 isoforms -a and -b were shown to be promising candidate biomarkers indicating PCa aggressiveness including earlier biochemical relapse and lower disease specific life expectancy via interrupting androgen/TGF-β signaling.
5-Fluorouracil as a Tumor-Treating Field-Sensitizer in Colon Cancer Therapy
Authors: Lee Yeon-Joo , Cho Jae-Min , Sai Sei , Oh Ju Yeon , Park Ji-Ae , Oh Se Jong , Park Misun , Kwon Junhye , Shin Ui Sup , Baek Jeong-Hwa , Lim Sun Ha , Song Jie-Young , Hwang Sang-Gu , Kim Eun Ho
Published: December 2019

Colorectal cancer (CRC) is a major cause of mortality that can be treated effectively with chemotherapy and radiotherapy, although resistance to these therapeutic modalities often occurs. Tumor-treating fields (TTFields) can block tumor growth by selectively impairing tumor cell division. In this study, we investigated the mechanism by which 5-fluorouracil (5-FU) sensitizes tumor cells to TTFields. Human HCT116 and SW480 CRC cells were treated with 5-FU and/or TTFields, and characterized in vitro in terms of cell viability, apoptosis through reactive oxygen species production, autophagy, and metastatic potentials. The biological effects of 5-FU and/or TTFields were studied via positron emission tomography and computed tomography on xenograft tumor growth and were confirmed with organoid models of patients. Our results revealed that combination treatment with 5-FU and TTFields increased the efficiency of TTFields therapy in colon cancer cells by downregulating signaling pathways associated with cell proliferation, survival, cell invasion, and migration while upregulating pathways mediating apoptosis and autophagic cell death. The novel mechanistic insights gleaned in this study suggest that combination therapy with TTFields and 5-FU may be effective in treating CRC, although safety and efficacy testing in patients with CRC will need to be performed before this strategy can be implemented clinically for TTF-sensitization.
The Genetic Architecture of Gliomagenesis–Genetic Risk Variants Linked to Specific Molecular Subtypes
Authors: Wu Wendy Yi-Ying , Johansson Gunnar , Wibom Carl , Brännström Thomas , Malmström Annika , Henriksson Roger , Golovleva Irina , Bondy Melissa L. , Andersson Ulrika , Dahlin Anna M. , Melin Beatrice
Published: December 2019

Genome-wide association studies have identified 25 germline genetic loci that increase the risk of glioma. The somatic tumor molecular alterations, including IDH-mutation status and 1p/19q co-deletion, have been included into the WHO 2016 classification system for glioma. To investigate how the germline genetic risk variants correlate with the somatic molecular subtypes put forward by WHO, we performed a meta-analysis that combined findings from 330 Swedish cases and 876 controls with two other recent studies. In total, 5,103 cases and 10,915 controls were included. Three categories of associations were found. First, variants in TERT and TP53 were associated with increased risk of all glioma subtypes. Second, variants in CDKN2B-AS1, EGFR, and RTEL1 were associated with IDH-wildtype glioma. Third, variants in CCDC26 (the 8q24 locus), C2orf80 (close to IDH), LRIG1, PHLDB1, ETFA, MAML2 and ZBTB16 were associated with IDH-mutant glioma. We therefore propose three etiopathological pathways in gliomagenesis based on germline variants for future guidance of diagnosis and potential functional targets for therapies. Future prospective clinical trials of patients with suspicion of glioma diagnoses, using the genetic variants as biomarkers, are necessary to disentangle how strongly they can predict glioma diagnosis.
JAK-STAT Signaling: A Double-Edged Sword of Immune Regulation and Cancer Progression
Authors: Owen Katie L. , Brockwell Natasha K. , Parker Belinda S.
Published: December 2019

Janus kinase-signal transducer and activator of transcription (JAK-STAT) signaling mediates almost all immune regulatory processes, including those that are involved in tumor cell recognition and tumor-driven immune escape. Antitumor immune responses are largely driven by STAT1 and STAT2 induction of type I and II interferons (IFNs) and the downstream programs IFNs potentiate. Conversely, STAT3 has been widely linked to cancer cell survival, immunosuppression, and sustained inflammation in the tumor microenvironment. The discovery of JAK-STAT cross-regulatory mechanisms, post-translational control, and non-canonical signal transduction has added a new level of complexity to JAK-STAT governance over tumor initiation and progression. Endeavors to better understand the vast effects of JAK-STAT signaling on antitumor immunity have unearthed a wide range of targets, including oncogenes, miRNAs, and other co-regulatory factors, which direct specific phenotypical outcomes subsequent to JAK-STAT stimulation. Yet, the rapidly expanding field of therapeutic developments aimed to resolve JAK-STAT aberrations commonly reported in a multitude of cancers has been marred by off-target effects. Here, we discuss JAK-STAT biology in the context of immunity and cancer, the consequences of pathway perturbations and current therapeutic interventions, to provide insight and consideration for future targeting innovations.
Adjuvant Therapy for High-Risk Stage II or III Colon Adenocarcinoma: A Propensity Score-Matched, Nationwide, Population-Based Cohort Study
Authors: Chang Chia-Lun , Yuan Kevin Sheng-Po , Wu Alexander T.H. , Wu Szu-Yuan
Published: December 2019

Purpose: To determine the optimal adjuvant chemotherapy regimen for patients with high-risk stage II or III colon adenocarcinoma, we conducted this propensity score-matched, nationwide, population-based cohort study to estimate the effects of adjuvant treatments in high-risk stage II or III colon adenocarcinoma. Patients and Methods: Using propensity score matching, we minimized the confounding effects of sex, age, pathologic stage, tumor location, total chemotherapy cycles, and Charlson comorbidity index scores on adjuvant treatment outcomes in patients with high-risk stage II or III resectable colon adenocarcinoma. We selected the patients from the Taiwan Cancer Registry database and divided them into four groups: Group 1, comprising patients who received surgery alone; group 2, comprising those who received adjuvant fluoropyrimidine alone; group 3, comprising those who received adjuvant oxaliplatin-fluoropyrimidine-leucovorin (FOLFOX); and group 4, comprising those who received adjuvant folinic acid-fluorouracil-irinotecan (FOLFIRI). Results: In both univariate and multivariate Cox regression analyses, the adjusted hazard ratios (aHRs, as well as the 95% confidence intervals (Cis)) for mortality observed for groups 1, 2, and 4 relative to group 3 were 1.55 (1.32 to 1.82), 1.22 (1.05 to 1.43), and 2.97 (2.43 to 3.63), respectively. After a stratified subgroup analysis for high-risk stage II colon adenocarcinoma, we noted that the aHR (95% CI) for mortality for group 2 relative to group 3 was 0.52 (0.30 to 0.89). Conclusions: Adjuvant fluoropyrimidine alone is the most optimal regimen for patients with high-risk stage II colon adenocarcinoma compared with the other adjuvant chemotherapy regimens. Adjuvant FOLFOX can serve as an optimal regimen for patients with pathologic stage III colon adenocarcinoma, regardless of age, sex, or tumor location.
Implementing Patient-Derived Xenografts to Assess the Effectiveness of Cyclin-Dependent Kinase Inhibitors in Glioblastoma
Authors: Noonan Janis J. , Jarzabek Monika , Lincoln Frank A. , Cavanagh Brenton L. , Pariag Arhona R. , Juric Viktorija , Young Leonie S. , Ligon Keith L. , Jahns Hanne , Zheleva Daniella , Prehn Jochen H. M. , Rehm Markus , Byrne Annette T. , Murphy Brona M.
Published: December 2019

Glioblastoma (GBM) is the most common primary brain tumor with no available cure. As previously described, seliciclib, a first-generation cyclin-dependent kinase (CDK) inhibitor, down-regulates the anti-apoptotic protein, Mcl-1, in GBM, thereby sensitizing GBM cells to the apoptosis-inducing effects of the death receptor ligand, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Here, we have assessed the efficacy of seliciclib when delivered in combination with the antibody against human death receptor 5, drozitumab, in clinically relevant patient-derived xenograft (PDX) models of GBM. A reduction in viability and significant levels of apoptosis were observed in vitro in human GBM neurospheres following treatment with seliciclib plus drozitumab. While the co-treatment strategy induced a similar effect in PDX models, the dosing regimen required to observe seliciclib-targeted responses in the brain, resulted in lethal toxicity in 45% of animals. Additional studies showed that the second-generation CDK inhibitor, CYC065, with improved potency in comparison to seliciclib, induced a significant decrease in the size of human GBM neurospheres in vitro and was well tolerated in vivo, upon administration at clinically relevant doses. This study highlights the continued need for robust pre-clinical assessment of promising treatment approaches using clinically relevant models.
Prediction of Colon Cancer Stages and Survival Period with Machine Learning Approach
Authors: Gupta Pushpanjali , Chiang Sum-Fu , Sahoo Prasan Kumar , Mohapatra Suvendu Kumar , You Jeng-Fu , Onthoni Djeane Debora , Hung Hsin-Yuan , Chiang Jy-Ming , Huang Yenlin , Tsai Wen-Sy
Published: December 2019

The prediction of tumor in the TNM staging (tumor, node, and metastasis) stage of colon cancer using the most influential histopathology parameters and to predict the five years disease-free survival (DFS) period using machine learning (ML) in clinical research have been studied here. From the colorectal cancer (CRC) registry of Chang Gung Memorial Hospital, Linkou, Taiwan, 4021 patients were selected for the analysis. Various ML algorithms were applied for the tumor stage prediction of the colon cancer by considering the Tumor Aggression Score (TAS) as a prognostic factor. Performances of different ML algorithms were evaluated using five-fold cross-validation, which is an effective way of the model validation. The accuracy achieved by the algorithms taking both cases of standard TNM staging and TNM staging with the Tumor Aggression Score was determined. It was observed that the Random Forest model achieved an F-measure of 0.89, when the Tumor Aggression Score was considered as an attribute along with the standard attributes normally used for the TNM stage prediction. We also found that the Random Forest algorithm outperformed all other algorithms, with an accuracy of approximately 84% and an area under the curve (AUC) of 0.82 ± 0.10 for predicting the five years DFS.
Progress and Trend on the Regulation Methods for Nanozyme Activity and Its Application
Authors: Hou Li , Jiang Gaoyan , Sun Ying , Zhang Xuanhan , Huang Juanjuan , Liu Shendong , Lin Tianran , Ye Fanggui , Zhao Shulin
Published: December 2019

Natural enzymes, such as biocatalysts, are widely used in biosensors, medicine and health, the environmental field, and other fields. However, it is easy for natural enzymes to lose catalytic activity due to their intrinsic shortcomings including a high purification cost, insufficient stability, and difficulties of recycling, which limit their practical applications. The unexpected discovery of the Fe3O4 nanozyme in 2007 has given rise to tremendous efforts for developing natural enzyme substitutes. Nanozymes, which are nanomaterials with enzyme-mimetic catalytic activity, can serve as ideal candidates for artificial mimic enzymes. Nanozymes possess superiorities due to their low cost, high stability, and easy preparation. Although great progress has been made in the development of nanozymes, the catalytic efficiency of existing nanozymes is relatively low compared with natural enzymes. It is still a challenging task to develop nanozymes with a precise regulation of catalytic activity. This review summarizes the classification and various strategies for modulating the activity as well as research progress in the different application fields of nanozymes. Typical examples of the recent research process of nanozymes will be presented and critically discussed.
Electrochemical Synthesis of Zirconium Pre-Catalysts for Homogeneous Ethylene Oligomerization
Authors: Bekmukhamedov Giyjaz E. , Sukhov Aleksandr V. , Kuchkaev Aidar M. , Khayarov Khasan R. , Gerasimov Alexander V. , Vasilenko Irina V. , Kostjuk Sergei V. , Yakhvarov Dmitry G.
Published: December 2019

The catalytic activity of electrochemically synthesized zirconium carboxylates was studied in the process of ethylene oligomerization. Zirconium carboxylates were electrochemically synthesized directly from metallic zirconium and corresponding carboxylic acids (acetic, octanoic and lauric). A comprehensive study (element analysis, nuclear magnetic resonance (NMR) and infrared (IR) spectroscopy, powder X-ray diffraction (PXRD)) of the synthesized zirconium carboxylates showed that these species contain bidentate carboxylate moieties. It was shown that obtained zirconium carboxylates, in combination with Et3Al2Cl3 (Al/Zr = 20), have a moderate activity of (7.6–9.9) × 103 molC2H4⋅molZr−1⋅h−1 in terms of ethylene oligomerization (at T = 80 °C, p = 20 bar), leading to even-numbered C4–C10 linear alpha-olefins.
Mesenchymal Stem Cell-Derived Exosomes and Other Extracellular Vesicles as New Remedies in the Therapy of Inflammatory Diseases
Authors: Harrell Carl Randall , Jovicic Nemanja , Djonov Valentin , Arsenijevic Nebojsa , Volarevic Vladislav
Published: December 2019

There is growing evidence that mesenchymal stem cell (MSC)-based immunosuppression was mainly attributed to the effects of MSC-derived extracellular vesicles (MSC-EVs). MSC-EVs are enriched with MSC-sourced bioactive molecules (messenger RNA (mRNA), microRNAs (miRNAs), cytokines, chemokines, immunomodulatory factors) that regulate phenotype, function and homing of immune cells. In this review article we emphasized current knowledge regarding molecular mechanisms responsible for the therapeutic effects of MSC-EVs in attenuation of autoimmune and inflammatory diseases. We described the disease-specific cellular targets of MSC-EVs and defined MSC-sourced molecules, which were responsible for MSC-EV-based immunosuppression. Results obtained in a large number of experimental studies revealed that both local and systemic administration of MSC-EVs efficiently suppressed detrimental immune response in inflamed tissues and promoted survival and regeneration of injured parenchymal cells. MSC-EVs-based anti-inflammatory effects were relied on the delivery of immunoregulatory miRNAs and immunomodulatory proteins in inflammatory immune cells (M1 macrophages, dendritic cells (DCs), CD4+Th1 and Th17 cells), enabling their phenotypic conversion into immunosuppressive M2 macrophages, tolerogenic DCs and T regulatory cells. Additionally, through the delivery of mRNAs and miRNAs, MSC-EVs activated autophagy and/or inhibited apoptosis, necrosis and oxidative stress in injured hepatocytes, neurons, retinal cells, lung, gut and renal epithelial cells, promoting their survival and regeneration.
Multi-Omics Integration Reveals Short and Long-Term Effects of Gestational Hypoxia on the Heart Development
Authors: Gao Yu , Dasgupta Chiranjib , Huang Lei , Song Rui , Zhang Ziwei , Zhang Lubo
Published: December 2019

Antenatal hypoxia caused epigenetic reprogramming of methylome and transcriptome in the developing heart and increased the risk of heart disease later in life. Herein, we investigated the impact of gestational hypoxia in proteome and metabolome in the hearts of fetus and adult offspring. Pregnant rats were treated with normoxia or hypoxia (10.5% O2) from day 15 to 21 of gestation. Hearts were isolated from near-term fetuses and 5 month-old offspring, and proteomics and metabolomics profiling was determined. The data demonstrated that antenatal hypoxia altered proteomics and metabolomics profiling in the heart, impacting energy metabolism, lipid metabolism, oxidative stress, and inflammation-related pathways in a developmental and sex dependent manner. Of importance, integrating multi-omics data of transcriptomics, proteomics, and metabolomics profiling revealed reprogramming of the mitochondrion, especially in two clusters: (a) the cluster associated with “mitochondrial translation”/“aminoacyl t-RNA biosynthesis”/“one-carbon pool of folate”/“DNA methylation”; and (b) the cluster with “mitochondrion”/“TCA cycle and respiratory electron transfer”/“acyl-CoA dehydrogenase”/“oxidative phosphorylation”/“complex I”/“troponin myosin cardiac complex”. Our study provides a powerful means of multi-omics data integration and reveals new insights into phenotypic reprogramming of the mitochondrion in the developing heart by fetal hypoxia, contributing to an increase in the heart vulnerability to disease later in life.
Effect of Ethylene on Cell Wall and Lipid Metabolism during Alleviation of Postharvest Chilling Injury in Peach
Authors: Zhu Yongchao , Wang Ke , Wu Chunxia , Zhao Yun , Yin Xueren , Zhang Bo , Grierson Don , Chen Kunsong , Xu Changjie
Published: December 2019

Peach is prone to postharvest chilling injury (CI). Here it was found that exogenous ethylene alleviated CI, accompanied by an increased endogenous ethylene production. Ethylene treatment resulted in a moderately more rapid flesh softening as a result of stronger expression of genes encoding expansin and cell wall hydrolases, especially xylosidase and galactosidase. Ethylene treatment alleviated internal browning, accompanied by changes in expression of polyphenol oxidase, peroxidase and lipoxygenases. An enhanced content of phospholipids and glycerolipids and a reduced content of ceramide were observed in ethylene-treated fruit, and these were associated with up-regulation of lipid phosphate phosphatase, fatty acid alpha-hydroxylase, and golgi-localized nucleotide sugar transporter, as well as down-regulation of aminoalcohol phosphotransferases. Expression of two ethylene response factors (ERFs), ESE3 and ABR1, was highly correlated with that of genes involved in cell wall metabolism and lipid metabolism, respectively. Furthermore, the expression of these two ERFs was strongly regulated by ethylene treatment and the temperature changes during transfer of fruit into or out of cold storage. It is proposed that ERFs fulfill roles as crucial integrators between cell wall modifications and lipid metabolism involved in CI processes ameliorated by exogenous ethylene.
The Relationship Between the miRNA Sequence and Disease May be Revealed by Focusing on Hydrogen Bonding Sites in RNA–RNA Interactions
Authors: Osone Tatsunori , Yoshida Naohiro
Published: December 2019

MicroRNAs are important genes in biological processes. Although the function of microRNAs has been elucidated, the relationship between the sequence and the disease is not sufficiently clear. It is important to clarify the relationship between the sequence and the disease because it is possible to clarify the meaning of the microRNA genetic code consisting of four nucleobases. Since seed theory is based on sequences, its development can be expected to reveal the meaning of microRNA sequences. However, this method has many false positives and false negatives. On the other hand, disease-related microRNA searches using network analysis are not based on sequences, so it is difficult to clarify the relationship between sequences and diseases. Therefore, RNA–RNA interactions which are caused by hydrogen bonding were focused on. As a result, it was clarified that sequences and diseases were highly correlated by calculating the electric field in microRNA which is considered as the torus. It was also suggested that four diseases with different major classifications can be distinguished. Conventionally, RNA was interpreted as a one-dimensional array of four nucleobases, but a new approach to RNA from this study can be expected to provide a new perspective on RNA-RNA interactions.
Molecular and Cellular Mechanisms of Melatonin in Osteosarcoma
Authors: Lu Ko-Hsiu , Lin Renn-Chia , Yang Jia-Sin , Yang Wei-En , Reiter Russel J. , Yang Shun-Fa
Published: December 2019

Osteosarcoma, the most common primary bone malignancy, occurs most frequently in adolescents with a peak of incidence at 11–15 years. Melatonin, an indole amine hormone, shows a wide range of anticancer activities. The decrease in melatonin levels simultaneously concurs with the increase in bone growth and the peak age distribution of osteosarcoma during puberty, so melatonin has been utilized as an adjunct to chemotherapy to improve the quality of life and clinical outcomes. While a large amount of research has been conducted to understand the complex pleiotropic functions and the molecular and cellular actions elicited by melatonin in various types of cancers, a few review reports have focused on osteosarcoma. Herein, we summarized the anti-osteosarcoma effects of melatonin and its underlying molecular mechanisms to illustrate the known significance of melatonin in osteosarcoma and to address cellular signaling pathways of melatonin in vitro and in animal models. Even in the same kind of osteosarcoma, melatonin has been sparingly investigated to counteract tumor growth, apoptosis, and metastasis through different mechanisms, depending on different cell lines. We highlighted the underlying mechanism of anti-osteosarcoma properties evoked by melatonin, including antioxidant activity, anti-proliferation, induction of apoptosis, and the inhibition of invasion and metastasis. Moreover, we discussed the drug synergy effects of the role of melatonin involved and the method to fortify the anti-cancer effects on osteosarcoma. As a potential therapeutic agent, melatonin is safe for children and adolescents and is a promising candidate for an adjuvant by reinforcing the therapeutic effects and abolishing the unwanted consequences of chemotherapies.
TGF-β and microRNA Interplay in Genitourinary Cancers
Authors: Boguslawska Joanna , Kryst Piotr , Poletajew Slawomir , Piekielko-Witkowska Agnieszka
Published: December 2019

Genitourinary cancers (GCs) include a large group of different types of tumors localizing to the kidney, bladder, prostate, testis, and penis. Despite highly divergent molecular patterns, most GCs share commonly disturbed signaling pathways that involve the activity of TGF-β (transforming growth factor beta). TGF-β is a pleiotropic cytokine that regulates key cancer-related molecular and cellular processes, including proliferation, migration, invasion, apoptosis, and chemoresistance. The understanding of the mechanisms of TGF-β actions in cancer is hindered by the “TGF-β paradox” in which early stages of cancerogenic process are suppressed by TGF-β while advanced stages are stimulated by its activity. A growing body of evidence suggests that these paradoxical TGF-β actions could result from the interplay with microRNAs: Short, non-coding RNAs that regulate gene expression by binding to target transcripts and inducing mRNA degradation or inhibition of translation. Here, we discuss the current knowledge of TGF-β signaling in GCs. Importantly, TGF-β signaling and microRNA-mediated regulation of gene expression often act in complicated feedback circuits that involve other crucial regulators of cancer progression (e.g., androgen receptor). Furthermore, recently published in vitro and in vivo studies clearly indicate that the interplay between microRNAs and the TGF-β signaling pathway offers new potential treatment options for GC patients.
SWR1 Chromatin Remodeling Complex: A Key Transcriptional Regulator in Plants
Authors: Aslam Mohammad , Fakher Beenish , Jakada Bello Hassan , Cao Shijiang , Qin Yuan
Published: December 2019

The nucleosome is the structural and fundamental unit of eukaryotic chromatin. The chromatin remodeling complexes change nucleosome composition, packaging and positioning to regulate DNA accessibility for cellular machinery. SWI2/SNF2-Related 1 Chromatin Remodeling Complex (SWR1-C) belongs to the INO80 chromatin remodeling family and mainly catalyzes the exchange of H2A-H2B with the H2A.Z-H2B dimer. The replacement of H2A.Z into nucleosomes affects nucleosome stability and chromatin structure. Incorporation of H2A.Z into the chromatin and its physiochemical properties play a key role in transcriptional regulation during developmental and environmental responses. In Arabidopsis, various studies have uncovered several pivotal roles of SWR1-C. Recently, notable progress has been achieved in understanding the role of SWR1-C in plant developmental and physiological processes such as DNA damage repair, stress tolerance, and flowering time. The present article introduces the SWR1-C and comprehensively reviews recent discoveries made in understanding the function of the SWR1 complex in plants.
Identification of TRIM25 as a Negative Regulator of Caspase-2 Expression Reveals a Novel Target for Sensitizing Colon Carcinoma Cells to Intrinsic Apoptosis
Authors: Nasrullah Usman , Haeussler Kristina , Biyanee Abhiruchi , Wittig Ilka , Pfeilschifter Josef , Eberhardt Wolfgang
Published: December 2019

Colorectal cancer (CRC) is one of the most common cancers that is characterized by a high mortality due to the strong metastatic potential of the primary tumor and the high rate of therapy resistance. Hereby, evasion of apoptosis is the primary underlying cause of reduced sensitivity of tumor cells to chemo- and radiotherapy. Using RNA affinity chromatography, we identified the tripartite motif-containing protein 25 (TRIM25) as a bona fide caspase-2 mRNA-binding protein in colon carcinoma cells. Loss-of-function and gain-of-function approaches revealed that TRIM25 attenuates the protein levels of caspase-2 without significantly affecting caspase-2 mRNA levels. In addition, experiments with cycloheximide revealed that TRIM25 does not affect the protein stability of caspase-2. Furthermore, silencing of TRIM25 induced a significant redistribution of caspase-2 transcripts from RNP particles to translational active polysomes, indicating that TRIM25 negatively interferes with caspase-2 translation. Functionally, the elevation in caspase-2 upon TRIM25 depletion significantly increased the sensitivity of colorectal cells to drug-induced intrinsic apoptosis as implicated by increased caspase-3 cleavage and cytochrome c release. Importantly, the apoptosis-sensitizing effects by transient TRIM25 knockdown were rescued by concomitant silencing of caspase-2, demonstrating a critical role of caspase-2. Inhibition of caspase-2 by TRIM25 implies a survival mechanism that critically contributes to chemotherapeutic drug resistance in CRC.
Vascular PPARβ/δ Promotes Tumor Angiogenesis and Progression
Authors: Wagner Kay-Dietrich , Du Siyue , Martin Luc , Leccia Nathalie , Michiels Jean-François , Wagner Nicole
Published: December 2019

Peroxisome proliferator-activated receptors (PPARs) are nuclear receptors, which function as transcription factors. Among them, PPARβ/δ is highly expressed in endothelial cells. Pharmacological activation with PPARβ/δ agonists had been shown to increase their angiogenic properties. PPARβ/δ has been suggested to be involved in the regulation of the angiogenic switch in tumor progression. However, until now, it is not clear to what extent the expression of PPARβ/δ in tumor endothelium influences tumor progression and metastasis formation. We addressed this question using transgenic mice with an inducible conditional vascular-specific overexpression of PPARβ/δ. Following specific over-expression of PPARβ/δ in endothelial cells, we induced syngenic tumors. We observed an enhanced tumor growth, a higher vessel density, and enhanced metastasis formation in the tumors of animals with vessel-specific overexpression of PPARβ/δ. In order to identify molecular downstream targets of PPARβ/δ in the tumor endothelium, we sorted endothelial cells from the tumors and performed RNA sequencing. We identified platelet-derived growth factor receptor beta (Pdgfrb), platelet-derived growth factor subunit B (Pdgfb), and the tyrosinkinase KIT (c-Kit) as new PPARβ/δ -dependent molecules. We show here that PPARβ/δ activation, regardless of its action on different cancer cell types, leads to a higher tumor vascularization which favors tumor growth and metastasis formation.
Battling Glioblastoma: A Novel Tyrosine Kinase Inhibitor with Multi-Dimensional Anti-Tumor Effect
Authors: Viswanathan Anisha , Musa Aliyu , Murugesan Akshaya , Vale João , Afonso Carlos , Konda Mani Saravanan , Yli-Harja Olli , Candeias Nuno , Kandhavelu Meenakshisundaram
Published: December 2019

Glioblastoma (GB), a grade IV glioma, with high heterogeneity and chemoresistance, obligates a multidimensional antagonist to debilitate its competence. Considering the previous reports on thioesters as antitumor compounds, this paper investigates on use of this densely functionalized sulphur rich molecule as a potent anti-GB agent. Bio-evaluation of 12 novel compounds, containing α-thioether ketone and orthothioester functionalities, identified that five analogs exhibited better cytotoxic profile compared to standard drug cisplatin. Detailed toxicity studies of top compound were evaluated in two cell lines, using cell viability test, apoptotic activity, oxidative stress and caspase activation and RNA-sequencing analysis, to obtain a comprehensive molecular profile of drug activity. The most effective molecule presented half maximal inhibitory concentration (IC50) values of 27 μM and 23 μM against U87 and LN229 GB cells, respectively. Same compound effectively weakened various angiogenic pathways, mainly MAPK and JAK-STAT pathways, downregulating VEGF. Transcriptome analysis identified significant promotion of apoptotic genes, and genes involved in cell cycle arrest, with concurrent inhibition of various tyrosine kinase cascades and stress response genes. Docking and immunoblotting studies suggest EGFR as a strong target of the orthothioester identified. Therefore, orthothioesters can potentially serve as a multi-dimensional chemotherapeutic possessing strong cytotoxic, anti-angiogenic and chemo-sensitization activity, challenging glioblastoma pathogenesis.