bluuebunny/crossref_metadata_2025 huggingface dataset:
Radiotherapy of Conjunctival Melanoma: Role and Challenges of Brachytherapy, Photon-Beam and Protontherapy
Authors: Spatola Corrado , Liardo Rocco Luca Emanuele , Milazzotto Roberto , Raffaele Luigi , Salamone Vincenzo , Basile Antonio , Foti Pietro Valerio , Palmucci Stefano , Cirrone Giuseppe Antonio Pablo , Cuttone Giacomo , Russo Andrea , Avitabile Teresio , Reibaldi Michele , Longo Antonio , Broggi Giuseppe , Bonfiglio Vincenza , Caltabiano Rosario , Pergolizzi Stefano , Arena Floriana
Published: December 2020

Conjunctival melanoma is a rare neoplasia, whose therapeutic management is generally of ophthalmological relevance, through radical surgical resection. The high incidence of local relapses after surgery, has made it necessary to combine various types of adjuvant treatments, which in some cases take on the role of radical treatments. Among these non-surgical treatments, those involving the application of ionizing radiation are becoming particularly important. In this review, we discuss the role of episcleral brachytherapy, external photon-beam radiotherapy, also made through stereotactic or radiosurgical modality, and of proton-beam radiotherapy. We try also to take stock of the benefits of the different irradiation modalities and the application difficulties of each.
Indian Gooseberry and Barley Sprout Mixture Inhibits Adipogenesis and Lipogenesis Activity in 3T3-L1 Adipocytes
Authors: Park Soo-Jeung , Kim Dakyung , Kim Jong-Lae , Park Mi-Ryeong , Kim Tae Gi , Kim Ok-Kyung , Nam Da-Eun
Published: December 2020

This study aimed to confirm the synergistic effect of an Indian gooseberry (IG) and barley sprout (BP) mixture in differentiated adipocytes. To this end, 3T3-L1 adipocytes were treated with IG, BP, and IGBP mixtures during the differentiation period. On the last day of differentiation, we measured intracellular cAMP, triglyceride (TG), and fatty acid (FA) levels, as well as performed Oil Red O staining, glycerol release, and Western blot assays. During adipogenesis, IGBP (200 μg/mL) increased the cAMP levels by more than 2-fold and decreased the protein expressions levels of p-CREB (66.3%), C/EBPα (79.4%), C/EBPβ (85.9%), and PPARγ (74.1%) compared to those in the C group. Furthermore, the expression levels of the adipogenesis-related genes and GLUT4 (more than 3-fold) were regulated. During lipogenesis, the IGBP (200 μg/mL) activated AMPK and ACC levels and reduced the protein expression levels of SREBP1c, FAS, and LPL. This reduced the FA and TG contents in the cells by 47.6% and 76.3%, respectively, compared to those in the differentiated control (C) group, resulting in a more than 5-fold increase in glycerol release. In conclusion, we found that IGBP inhibited TG synthesis during adipogenesis and lipogenesis, and thus, displayed potential as a functional health food for preventing obesity.
The Influence of Eggshell on Bone Regeneration in Preclinical In Vivo Studies
Authors: Opris Horia , Dinu Cristian , Baciut Mihaela , Baciut Grigore , Mitre Ileana , Crisan Bogdan , Armencea Gabriel , Prodan Daiana Antoaneta , Bran Simion
Published: December 2020

The aim of this study is to systemically review the available evidence on the in vivo behavior of eggshell as a guided bone regeneration substitute material. Five databases (PubMed, Cochrane, Web of Science, Scopus, EMBASE) were searched up to October 2020. In vivo animal studies with a bone defect model using eggshell as a grafting material were included. Risk of bias was assessed using SYRCLE tool and the quality assessment using the ARRIVE guidelines. Overall, a total of 581 studies were included in the study, 187 after duplicate removal. Using the inclusion and exclusion criteria 167 records were further excluded. The full text of the remaining 20 articles was assessed for eligibility and included in the qualitative and quantitative assessment synthesis. There were different methods of obtaining eggshell grafting materials. Eggshell is a biocompatible grafting material, with osteoconduction proprieties. It forms new bone similar to Bio-Oss and demineralized freeze-dried bone matrix. It can be combined with other materials to enhance its proprieties. Due to the high variability of the procedures, animals, production and assessment methods, no meta-analysis could be performed. Eggshell might be considered a promising biomaterial to be used in bone grafting procedures, though further research is needed.
The Mitochondrial Proteome of Tumor Cells: A SnapShot on Methodological Approaches and New Biomarkers
Authors: Moro Loredana
Published: December 2020

Mitochondria are highly dynamic and regulated organelles implicated in a variety of important functions in the cell, including energy production, fatty acid metabolism, iron homeostasis, programmed cell death, and cell signaling. Changes in mitochondrial metabolism, signaling and dynamics are hallmarks of cancer. Understanding whether these modifications are associated with alterations of the mitochondrial proteome is particularly relevant from a translational point of view because it may contribute to better understanding the molecular bases of cancer development and progression and may provide new potential prognostic and diagnostic biomarkers as well as novel molecular targets for anti-cancer treatment. Making an inventory of the mitochondrial proteins has been particularly challenging given that there is no unique consensus targeting sequence that directs protein import into mitochondria, some proteins are present at very low levels, while other proteins are expressed only in some cell types, in a particular developmental stage or under specific stress conditions. This review aims at providing the state-of-the-art on methodologies used to characterize the mitochondrial proteome in tumors and highlighting the biological relevance of changes in expression and delocalization of proteins in and out the mitochondria in cancer biology.
Nrf2—A Molecular Target for Sepsis Patients in Critical Care
Authors: Gunne Sandra , Heinicke Ulrike , Parnham Michael J. , Laux Volker , Zacharowski Kai , von Knethen Andreas
Published: December 2020

The transcription factor NF-E2 p45-related factor 2 (Nrf2) is an established master regulator of the anti-oxidative and detoxifying cellular response. Thus, a role in inflammatory diseases associated with the generation of large amounts of reactive oxygen species (ROS) seems obvious. In line with this, data obtained in cell culture experiments and preclinical settings have shown that Nrf2 is important in regulating target genes that are necessary to ensure cellular redox balance. Additionally, Nrf2 is involved in the induction of phase II drug metabolizing enzymes, which are important both in degrading and converting drugs into active forms, and into putative carcinogens. Therefore, Nrf2 has also been implicated in tumorigenesis. This must be kept in mind when new therapy approaches are planned for the treatment of sepsis. Therefore, this review highlights the function of Nrf2 in sepsis with a special focus on the translation of rodent-based results into sepsis patients in the intensive care unit (ICU).
Model-Agnostic Method for Thoracic Wall Segmentation in Fetal Ultrasound Videos
Authors: Shozu Kanto , Komatsu Masaaki , Sakai Akira , Komatsu Reina , Dozen Ai , Machino Hidenori , Yasutomi Suguru , Arakaki Tatsuya , Asada Ken , Kaneko Syuzo , Matsuoka Ryu , Nakashima Akitoshi , Sekizawa Akihiko , Hamamoto Ryuji
Published: December 2020

The application of segmentation methods to medical imaging has the potential to create novel diagnostic support models. With respect to fetal ultrasound, the thoracic wall is a key structure on the assessment of the chest region for examiners to recognize the relative orientation and size of structures inside the thorax, which are critical components in neonatal prognosis. In this study, to improve the segmentation performance of the thoracic wall in fetal ultrasound videos, we proposed a novel model-agnostic method using deep learning techniques: the Multi-Frame + Cylinder method (MFCY). The Multi-frame method (MF) uses time-series information of ultrasound videos, and the Cylinder method (CY) utilizes the shape of the thoracic wall. To evaluate the achieved improvement, we performed segmentation using five-fold cross-validation on 538 ultrasound frames in the four-chamber view (4CV) of 256 normal cases using U-net and DeepLabv3+. MFCY increased the mean values of the intersection over union (IoU) of thoracic wall segmentation from 0.448 to 0.493 for U-net and from 0.417 to 0.470 for DeepLabv3+. These results demonstrated that MFCY improved the segmentation performance of the thoracic wall in fetal ultrasound videos without altering the network structure. MFCY is expected to facilitate the development of diagnostic support models in fetal ultrasound by providing further accurate segmentation of the thoracic wall.
High Levels of Receptor Tyrosine Kinases in CCM3-Deficient Cells Increase Their Susceptibility to Tyrosine Kinase Inhibition
Authors: Sartages Miriam , Floridia Ebel , García-Colomer Mar , Iglesias Cristina , Macía Manuel , Peñas Patricia , Couraud Pierre-Olivier , Romero Ignacio A. , Weksler Babette , Pombo Celia M. , Zalvide Juan
Published: December 2020

Cerebral cavernous malformations (CCMs) are vascular malformations that can be the result of the deficiency of one of the CCM genes. Their only present treatment is surgical removal, which is not always possible, and an alternative pharmacological strategy to eliminate them is actively sought. We have studied the effect of the lack of one of the CCM genes, CCM3, in endothelial and non-endothelial cells. By comparing protein expression in control and CCM3-silenced cells, we found that the levels of the Epidermal Growth Factor Receptor (EGFR) are higher in CCM3-deficient cells, which adds to the known upregulation of Vascular Endothelial Growth Factor Receptor 2 (VEGFR2) in these cells. Whereas VEGFR2 is upregulated at the mRNA level, EGFR has a prolonged half-life. Inhibition of EGFR family members in CCM3-deficient cells does not revert the known cellular effects of lack of CCM genes, but it induces significantly more apoptosis in CCM3-deficient cells than in control cells. We propose that the susceptibility to tyrosine kinase inhibitors of CCM3-deficient cells can be harnessed to kill the abnormal cells of these lesions and thus treat CCMs pharmacologically.
Increased Encapsulation Efficiency of Methotrexate in Liposomes for Rheumatoid Arthritis Therapy
Authors: Guimarães Diana , Noro Jennifer , Loureiro Ana , Lager Franck , Renault Gilles , Cavaco-Paulo Artur , Nogueira Eugénia
Published: December 2020

Methotrexate (MTX) is a common drug used to treat rheumatoid arthritis. Due to the excessive side effects, encapsulation of MTX in liposomes is considered an effective delivery system, reducing drug toxicity, while maintaining its efficacy. The ethanol injection method is an interesting technique for liposome production, due to its simplicity, fast implementation, and reproducibility. However, this method occasionally requires the extrusion process, to obtain suitable size distribution, and achieve a low level of MTX encapsulation. Here, we develop a novel pre-concentration method, based on the principles of the ethanol injection, using an initial aqueous volume of 20% and 1:1 ratio of organic:aqueous phase (v/v). The liposomes obtained present small values of size and polydispersity index, without the extrusion process, and a higher MTX encapsulation (efficiency higher than 30%), suitable characteristics for in vivo application. The great potential of MTX to interact at the surface of the lipid bilayer was shown by nuclear magnetic resonance (NMR) studies, revealing mutual interactions between the drug and the main phospholipid via hydrogen bonding. In vivo experiments reveal that liposomes encapsulating MTX significantly increase the biological benefit in arthritic mice. This approach shows a significant advance in MTX therapeutic applications.
Territorial Responses of Nuthatches Sitta europaea—Evaluation of a Robot Model in a Simulated Territorial Intrusion
Authors: Randler Christoph , Randler Erik
Published: December 2020

In birds, aggressive behavior can be elicited in the field with a simulated territory intrusion (STI). Here, we compared four different STI methods in nuthatches in the non-breeding season: playback only, playback combined with an inactive wooden model mounted on a robot device, playback and an active model mounted on a robot device, and playback with the robot device only. In the control treatment, birds were not exposed to STI. Experiments were carried out in 12 territories. Behavioral observations included latency to approach, latency to start calling, time spent in the same tree, number of flyovers, minimum distance, number of individuals, number of flights into the tree, and number of calls. There was no significant influence of stimulus presentation. Nuthatches responded equally to all four experimental manipulations, but order of presentation had a strong influence.
Spatially Filtered Emotional Faces Dominate during Binocular Rivalry
Authors: Turano Maria , Giganti Fiorenza , Gavazzi Gioele , Lamberto Simone , Gronchi Giorgio , Giovannelli Fabio , Peru Andrea , Viggiano Maria
Published: December 2020

The present investigation explores the role of bottom-up and top-down factors in the recognition of emotional facial expressions during binocular rivalry. We manipulated spatial frequencies (SF) and emotive features and asked subjects to indicate whether the emotional or the neutral expression was dominant during binocular rivalry. Controlling the bottom-up saliency with a computational model, physically comparable happy and fearful faces were presented dichoptically with neutral faces. The results showed the dominance of emotional faces over neutral ones. In particular, happy faces were reported more frequently as the first dominant percept even in the presence of coarse information (at a low SF level: 2–6 cycle/degree). Following current theories of emotion processing, the results provide further support for the influence of positive compared to negative meaning on binocular rivalry and, for the first time, showed that individuals perceive the affective quality of happiness even in the absence of details in the visual display. Furthermore, our findings represent an advance in knowledge regarding the association between the high- and low-level mechanisms behind binocular rivalry.
Influence of Static Magnetic Field Stimulation on the Accuracy of Tachystoscopically Presented Line Bisection
Authors: Kirimoto Hikari , Watanabe Tatsunori , Kubo Nami , Date Shota , Sunagawa Toru , Mima Tatsuya , Ogata Katsuya , Nakazono Hisato , Tobimatsu Shozo , Oliviero Antonio
Published: December 2020

Transcranial static magnetic stimulation (tSMS) has been known to reduce human cortical excitability. Here, we investigated whether tSMS would modulate visuo-spatial cognition in healthy humans. Subjects performed a visuo-spatial task requiring judgements about the symmetry of pre-bisected lines. Visual stimuli consisted of symmetrically or asymmetrically transected lines, tachystoscopically presented for 150 ms on a computer monitor. Task performance was examined before, immediately after, and 10 min after tSMS/sham stimulation of 20 min over the posterior parietal cortex (PPC: P4 from the international 10–20 system) or superior temporal gyrus (STG: C6). Nine out of 16 subjects misjudged pre-bisected lines by consistently underestimating the length of the right-side segment (judging lines to be exactly pre-bisected when the transector was located to the left of the midpoint, or judging the left-side segment to be longer when the transector was located at the midpoint). In these subjects showing a leftward bias, tSMS over the right STG reduced the magnitude of the leftward bias. This did not occur with tSMS over the right PPC or sham stimulation. In the remaining right-biased subjects, no intervention effect was observed with any stimulation. Our findings indicate that application of tSMS over the right STG modulates visuo-spatial cognition in healthy adults.
Adequate Knowledge of Stroke Symptoms, Risk Factors, and Necessary Actions in the General Population of Southern Poland
Authors: Krzystanek Ewa , Krzak-Kubica Agnieszka , Świat Maciej , Galus Weronika , Gawryluk Justyna
Published: December 2020

Background and objectives: Stroke is the third most common cause of mortality in developed countries and the primary cause of neurological disability in adults. Recombinant tissue plasminogen activator administered intravenously within 4.5 h from the onset of symptoms constitutes a gold standard in the treatment of acute ischemic stroke. Prompt hospital admission is the prerequisite of effective thrombolysis. Therefore, stroke awareness in the general population is the key factor in timely recognition of the acute stroke victims and determines proper actions. Therefore, the purpose of this study was to determine the awareness of stroke in the general population of the Silesian voivodeship, the most populated region of Poland. We assessed also the “adequate knowledge of stroke”, a combined measure of the optimal level of stroke awareness, as a prerequisite for effective stroke management, and aimed to identify most impacting factor for adequate stoke knowledge, to help shaping education strategies. Materials and Methods: A proprietary anonymous questionnaire consisting of 15 items related to stroke was used in this research. A total of 1134 individuals were surveyed. Additionally to the knowledge of individual aspects of stroke, we assessed “adequate knowledge of stroke”, which was combined measure of risk factors, symptoms, and actions in the case of acute stroke. Results: The accurate definition of stroke was selected by 834 participants (73.5%). The vast majority of them indicated that a stroke is an emergency (92.8%) and medical assistance is required (97.5%). However, 42.4% of respondents did not know any specific symptom of stroke and only 38.6% participants were able to list two or more risk factors, which resulted in only 36.3% of individuals with adequate knowledge of stroke. Education duration, previous occurrence of stroke in relatives or friends, gender and place of residence were identified as independent predictors of adequate knowledge of stroke. Conclusions: 1. Knowledge of stroke in the population of southern Poland is low and may be considered insufficient to address the needs of timely management in the action chain. 2. Previous occurrence of stroke in the relatives or friends is the most impacting factor for adequate knowledge of stroke.
Neurochemical and Behavioral Characterization after Acute and Repeated Exposure to Novel Synthetic Cannabinoid Agonist 5-MDMB-PICA
Authors: Musa Aurora , Simola Nicola , Piras Gessica , Caria Francesca , Onaivi Emmanuel Shan , De Luca Maria Antonietta
Published: December 2020

Since the early 2000s, herbal mixtures containing synthetic cannabinoids (SCs), broadly known as Spice/K2, have been marketed as a legal marijuana surrogate and have become very popular among adolescents. Adolescence is a critical period of development, which is associated with an increased vulnerability to the central effects of drugs. Despite growing concerns about the negative effects of the use of SCs, newly synthetized compounds are increasingly detected in drugs seized by the authorities, posing a serious threat to public health. 5F-MDMB-PICA has been recently detected and classified as a highly potent agonist of CB1 and CB2 cannabinoid receptors. Here, we first investigated the rewarding properties of 5F-MDMB-PICA in C57BL/6 adolescent and adult mice by in vivo brain microdialysis. Data showed that acute administration of a selected dose of 5F-MDMB-PICA (0.01 mg/kg i.p.) stimulates the release of dopamine in the nucleus accumbens shell of adolescent, but not of adult, mice. To further investigate the consequences of repeated exposure to this dose of 5F-MDMB-PICA, a separate group of adolescent mice was treated for 14 consecutive days and evaluated for behavioral abnormalities at adulthood, starting from 7 days after drug discontinuation. Data showed that this group of adult mice displayed an anxiety-like and compulsive-like state as revealed by an altered performance in the marble burying test. Our study suggests an alarming vulnerability of adolescent mice to the effects of 5F-MDMB-PICA. These findings provide a useful basis for understanding and evaluating both early and late detrimental effects that may derive from the use of SCs during adolescence.
Anxiety-Related Attention Bias in Four- to Eight-Year-Olds: An Eye-Tracking Study
Authors: Stuijfzand Suzannah , Stuijfzand Bobby , Reynolds Shirley , Dodd Helen
Published: December 2020

(1) Background: There is evidence of an attention bias–anxiety relationship in children, but lack of appropriate methods has limited the number of studies with children younger than eight years old. This study used eye tracking as a measure of overt attention in young children. The aim of this study was to assess anxiety-related attention bias in children aged four to eight years. Age was considered a moderator, and the influence of effortful control was investigated. (2) Method: A community sample of 104 children was shown pairs of happy–neutral and angry–neutral faces. Growth curve analyses were used to examine patterns of gaze over time. (3) Results: Analyses revealed moderation by age and anxiety, with distinct patterns of anxiety-related biases seen in different age groups in the angry–neutral face trials. Effortful control did not account for age-related effects. (4) Conclusions: The results support a moderation model of the development of anxiety in children.
Tuft and Cancer Stem Cell Marker DCLK1: A New Target to Enhance Anti-Tumor Immunity in the Tumor Microenvironment
Authors: Cao Zhiyun , Weygant Nathaniel , Chandrakesan Parthasarathy , Houchen Courtney W. , Peng Jun , Qu Dongfeng
Published: December 2020

Microtubule-associated doublecortin-like kinase 1 (DCLK1) is an accepted marker of tuft cells (TCs) and several kinds of cancer stem cells (CSCs), and emerging evidence suggests that DCLK1-positive TCs participate in the initiation and formation of inflammation-associated cancer. DCLK1-expressing CSCs regulate multiple biological processes in cancer, promote resistance to therapy, and are associated with metastasis. In solid tumor cancers, tumor epithelia, immune cells, cancer-associated fibroblasts, endothelial cells and blood vessels, extracellular matrix, and hypoxia all support a CSC phenotype characterized by drug resistance, recurrence, and metastasis. Recently, studies have shown that DCLK1-positive CSCs are associated with epithelial-mesenchymal transition, angiogenesis, and immune checkpoint. Emerging data concerning targeting DCLK1 with small molecular inhibitors, monoclonal antibodies, and chimeric antigen receptor T-cells shows promising effects on inhibiting tumor growth and regulating the tumor immune microenvironment. Overall, DCLK1 is reaching maturity as an anti-cancer target and therapies directed against it may have potential against CSCs directly, in remodeling the tumor microenvironment, and as immunotherapies.
LncRNA-mRNA Co-Expression Analysis Identifies AL133346.1/CCN2 as Biomarkers in Pediatric B-Cell Acute Lymphoblastic Leukemia
Authors: Cuadros Marta , García Daniel J. , Andrades Alvaro , Arenas Alberto M. , Coira Isabel F. , Baliñas-Gavira Carlos , Peinado Paola , Rodríguez María I. , Álvarez-Pérez Juan Carlos , Ruiz-Cabello Francisco , Camós Mireia , Jiménez-Velasco Antonio , Medina Pedro P.
Published: December 2020

Pediatric acute B-cell lymphoblastic leukemia (B-ALL) constitutes a heterogeneous and aggressive neoplasia in which new targeted therapies are required. Long non-coding RNAs have recently emerged as promising disease-specific biomarkers for the clinic. Here, we identified pediatric B-ALL-specific lncRNAs and associated mRNAs by comparing the transcriptomic signatures of tumoral and non-tumoral samples. We identified 48 lncRNAs that were differentially expressed between pediatric B-ALL and healthy bone marrow samples. The most relevant lncRNA/mRNA pair was AL133346.1/CCN2 (previously known as RP11-69I8.3/CTGF), whose expression was positively correlated and increased in B-ALL samples. Their differential expression pattern and their strong correlation were validated in external B-ALL datasets (Therapeutically Applicable Research to Generate Effective Treatments, Cancer Cell Line Encyclopedia). Survival curve analysis demonstrated that patients with “high” expression levels of CCN2 had higher overall survival than those with “low” levels (p = 0.042), and this gene might be an independent prognostic biomarker in pediatric B-ALL. These findings provide one of the first detailed descriptions of lncRNA expression profiles in pediatric B-ALL and indicate that these potential biomarkers could help in the classification of leukemia subtypes and that CCN2 expression could predict the survival outcome of pediatric B-cell acute lymphoblastic leukemia patients.
Lung Adenocarcinoma Mouse Models Based on Orthotopic Transplantation of Syngeneic Tumor-Initiating Cells Expressing EpCAM, SCA-1, and Ly6d
Authors: Semba Takashi , Sato Ryo , Kasuga Akiyoshi , Suina Kentaro , Shibata Tatsuhiro , Kohno Takashi , Suzuki Makoto , Saya Hideyuki , Arima Yoshimi
Published: December 2020

Somatic mutations in EGFR and KRAS as well as chromosome rearrangements affecting ALK, ROS1, and RET have been identified in human lung adenocarcinoma (LUAD). We here developed organoid-based orthotopic and syngeneic mouse models for studies of the pathogenesis and treatment of LUAD. We isolated EpCAM-positive epithelial cells from mouse lungs and cultured them as organoids to maintain epithelial stem cell properties. These cells were transformed by KRAS(G12V) or EML4-ALK and then transplanted via the trachea into the lungs of the syngeneic mice, where they formed tumors that expressed the lung lineage marker TTF-1 and which closely recapitulated the pathology of human LUAD. Treatment with crizotinib suppressed the growth of tumors formed by the EML4-ALK–expressing lung epithelial cells in a subcutaneous transplantation model. Organoid culture of normal lung epithelial cells resulted in enrichment of EpCAM+SCA-1(Ly6a)+ cells as well as in that of cells expressing another member of the Ly6 protein family, Ly6d, which was found to be required for the growth of the LUAD-initiating cells expressing KRAS(G12V) or EML4-ALK. We also found that a high expression level of LY6D was associated with poor prognosis in human LUAD. Our results thus suggest that LY6D is a potential lung cancer stem cell marker.
Lactoferrin in the Prevention and Treatment of Intestinal Inflammatory Pathologies Associated with Colorectal Cancer Development
Authors: Cutone Antimo , Ianiro Giusi , Lepanto Maria Stefania , Rosa Luigi , Valenti Piera , Bonaccorsi di Patti Maria Carmela , Musci Giovanni
Published: December 2020

The connection between inflammation and cancer is well-established and supported by genetic, pharmacological and epidemiological data. The inflammatory bowel diseases (IBDs), including Crohn’s disease and ulcerative colitis, have been described as important promoters for colorectal cancer development. Risk factors include environmental and food-borne mutagens, dysbalance of intestinal microbiome composition and chronic intestinal inflammation, with loss of intestinal epithelial barrier and enhanced cell proliferation rate. Therapies aimed at shutting down mucosal inflammatory response represent the foundation for IBDs treatment. However, when applied for long periods, they can alter the immune system and promote microbiome dysbiosis and carcinogenesis. Therefore, it is imperative to find new safe substances acting as both potent anti-inflammatory and anti-pathogen agents. Lactoferrin (Lf), an iron-binding glycoprotein essential in innate immunity, is generally recognized as safe and used as food supplement due to its multifunctionality. Lf possesses a wide range of immunomodulatory and anti-inflammatory properties against different aseptic and septic inflammatory pathologies, including IBDs. Moreover, Lf exerts anti-adhesive, anti-invasive and anti-survival activities against several microbial pathogens that colonize intestinal mucosa of IBDs patients. This review focuses on those activities of Lf potentially useful for the prevention/treatment of intestinal inflammatory pathologies associated with colorectal cancer development.
Cytoskeletal Control and Wnt Signaling—APC’s Dual Contributions in Stem Cell Division and Colorectal Cancer
Authors: Juanes M. Angeles
Published: December 2020

Intestinal epithelium architecture is sustained by stem cell division. In principle, stem cells can divide symmetrically to generate two identical copies of themselves or asymmetrically to sustain tissue renewal in a balanced manner. The choice between the two helps preserve stem cell and progeny pools and is crucial for tissue homeostasis. Control of spindle orientation is a prime contributor to the specification of symmetric versus asymmetric cell division. Competition for space within the niche may be another factor limiting the stem cell pool. An integrative view of the multiple links between intracellular and extracellular signals and molecular determinants at play remains a challenge. One outstanding question is the precise molecular roles of the tumour suppressor Adenomatous polyposis coli (APC) for sustaining gut homeostasis through its respective functions as a cytoskeletal hub and a down regulator in Wnt signalling. Here, we review our current understanding of APC inherent activities and partners in order to explore novel avenues by which APC may act as a gatekeeper in colorectal cancer and as a therapeutic target.
Murine- and Human-Derived Autologous Organoid/Immune Cell Co-Cultures as Pre-Clinical Models of Pancreatic Ductal Adenocarcinoma
Authors: Holokai Loryn , Chakrabarti Jayati , Lundy Joanne , Croagh Daniel , Adhikary Pritha , Richards Scott S. , Woodson Chantal , Steele Nina , Kuester Robert , Scott Aaron , Khreiss Mohammad , Frankel Timothy , Merchant Juanita , Jenkins Brendan J. , Wang Jiang , Shroff Rachna T. , Ahmad Syed A. , Zavros Yana
Published: December 2020

Purpose: Pancreatic ductal adenocarcinoma (PDAC) has the lowest five-year survival rate of all cancers in the United States. Programmed death 1 receptor (PD-1)-programmed death ligand 1 (PD-L1) immune checkpoint inhibition has been unsuccessful in clinical trials. Myeloid-derived suppressor cells (MDSCs) are known to block anti-tumor CD8+ T cell immune responses in various cancers including pancreas. This has led us to our objective that was to develop a clinically relevant in vitro organoid model to specifically target mechanisms that deplete MDSCs as a therapeutic strategy for PDAC. Method: Murine and human pancreatic ductal adenocarcinoma (PDAC) autologous organoid/immune cell co-cultures were used to test whether PDAC can be effectively treated with combinatorial therapy involving PD-1 inhibition and MDSC depletion. Results: Murine in vivo orthotopic and in vitro organoid/immune cell co-culture models demonstrated that polymorphonuclear (PMN)-MDSCs promoted tumor growth and suppressed cytotoxic T lymphocyte (CTL) proliferation, leading to diminished efficacy of checkpoint inhibition. Mouse- and human-derived organoid/immune cell co-cultures revealed that PD-L1-expressing organoids were unresponsive to nivolumab in vitro in the presence of PMN-MDSCs. Depletion of arginase 1-expressing PMN-MDSCs within these co-cultures rendered the organoids susceptible to anti-PD-1/PD-L1-induced cancer cell death. Conclusions: Here we use mouse- and human-derived autologous pancreatic cancer organoid/immune cell co-cultures to demonstrate that elevated infiltration of polymorphonuclear (PMN)-MDSCs within the PDAC tumor microenvironment inhibit T cell effector function, regardless of PD-1/PD-L1 inhibition. We present a pre-clinical model that may predict the efficacy of targeted therapies to improve the outcome of patients with this aggressive and otherwise unpredictable malignancy.
Study of Ni/Al-Fe Catalyst Stability in the Aqueous Phase Hydrogenolysis of Glycerol
Authors: Raso Raquel , García Lucia , Ruiz Joaquín , Oliva Miriam , Arauzo Jesús
Published: December 2020

The present work studied the stability and reusability of Ni/Al-Fe catalyst in the aqueous phase hydrogenolysis of glycerol without external hydrogen addition. The catalyst based on 28 molar % of Ni with 3/1 molar ratio of Al/Fe was prepared through co-precipitation. This catalyst presented the best performance in our last study which compares several Ni/Al-Fe catalysts with different molar ratios of Al/Fe. To see the influence of the pressurized water on the physicochemical characteristics of Ni/Al-Fe catalyst, a test of up to 9 h has been carried out. Fresh and used catalysts were characterized by various techniques: X-ray Diffraction (XRD), N2-physisorption, field emission scanning electron microscopy (FESEM) and STEM. Glycerol conversion and carbon yield to gases and liquids did not vary significantly when compared at 3 h and 9 h. Furthermore, the morphology of the catalyst remains stable after continuous recycling under severe hydrothermal conditions. The nickel rich phase of the catalyst, which was determined by XRD and scanning transmission electron microscopy (STEM) techniques, showed a stable size after 9 h under reaction.
Kindlin-2 Mediates Mechanical Activation of Cardiac Myofibroblasts
Authors: Godbout Elena , Son Dong Ok , Hume Stephanie , Boo Stellar , Sarrazy Vincent , Clément Sophie , Kapus Andras , Wehrle-Haller Bernhard , Bruckner-Tuderman Leena , Has Cristina , Hinz Boris
Published: December 2020

We identify the focal adhesion protein kindlin-2 as player in a novel mechanotransduction pathway that controls profibrotic cardiac fibroblast to myofibroblast activation. Kindlin-2 is co-upregulated with the myofibroblast marker α-smooth muscle actin (α-SMA) in fibrotic rat hearts and in human cardiac fibroblasts exposed to fibrosis-stiff culture substrates and pro-fibrotic TGF-β1. Stressing fibroblasts using ferromagnetic microbeads, stretchable silicone membranes, and cell contraction agonists all result in kindlin-2 translocation to the nucleus. Overexpression of full-length kindlin-2 but not of kindlin-2 missing a putative nuclear localization sequence (∆NLS kindlin-2) results in increased α-SMA promoter activity. Downregulating kindlin-2 with siRNA leads to decreased myofibroblast contraction and reduced α-SMA expression, which is dependent on CC(A/T)-rich GG(CArG) box elements in the α-SMA promoter. Lost myofibroblast features under kindlin-2 knockdown are rescued with wild-type but not ∆NLS kindlin-2, indicating that myofibroblast control by kindlin-2 requires its nuclear translocation. Because kindlin-2 can act as a mechanotransducer regulating the transcription of α-SMA, it is a potential target to interfere with myofibroblast activation in tissue fibrosis.
Mgll Knockout Mouse Resistance to Diet-Induced Dysmetabolism Is Associated with Altered Gut Microbiota
Authors: Dione Niokhor , Lacroix Sébastien , Taschler Ulrike , Deschênes Thomas , Abolghasemi Armita , Leblanc Nadine , Di Marzo Vincenzo , Silvestri Cristoforo
Published: December 2020

Monoglyceride lipase (MGLL) regulates metabolism by catabolizing monoacylglycerols (MAGs), including the endocannabinoid 2-arachidonoyl glycerol (2-AG) and some of its bioactive congeners, to the corresponding free fatty acids. Mgll knockout mice (Mgll−/−) exhibit elevated tissue levels of MAGs in association with resistance to the metabolic and cardiovascular perturbations induced by a high fat diet (HFD). The gut microbiome and its metabolic function are disrupted in obesity in a manner modulated by 2-arachidonoyl glycerol (2-AG’s) main receptors, the cannabinoid CB1 receptors. We therefore hypothesized that Mgll−/− mice have an altered microbiome, that responds differently to diet-induced obesity from that of wild-type (WT) mice. We subjected mice to HFD and assessed changes in the microbiomes after 8 and 22 weeks. As expected, Mgll−/− mice showed decreased adiposity, improved insulin sensitivity, and altered circulating incretin/adipokine levels in response to HFD. Mgll−/− mice on a chow diet exhibited significantly higher levels of Hydrogenoanaerobacterium, Roseburia, and Ruminococcus than WT mice. The relative abundance of the Lactobacillaceae and Coriobacteriaceae and of the Lactobacillus, Enterorhabdus, Clostridium_XlVa, and Falsiporphyromonas genera was significantly altered by HFD in WT but not Mgll−/− mice. Differently abundant families were also associated with changes in circulating adipokine and incretin levels in HFD-fed mice. Some gut microbiota family alterations could be reproduced by supplementing 2-AG or MAGs in culturomics experiments carried out with WT mouse fecal samples. We suggest that the altered microbiome of Mgll−/− mice contributes to their obesity resistant phenotype, and results in part from increased levels of 2-AG and MAGs.
New Insights into X-Chromosome Reactivation during Reprogramming to Pluripotency
Authors: Panda Amitesh , Zylicz Jan J. , Pasque Vincent
Published: December 2020

Dosage compensation between the sexes results in one X chromosome being inactivated during female mammalian development. Chromosome-wide transcriptional silencing from the inactive X chromosome (Xi) in mammalian cells is erased in a process termed X-chromosome reactivation (XCR), which has emerged as a paradigm for studying the reversal of chromatin silencing. XCR is linked with germline development and induction of naive pluripotency in the epiblast, and also takes place upon reprogramming somatic cells to induced pluripotency. XCR depends on silencing of the long non-coding RNA (lncRNA) X inactive specific transcript (Xist) and is linked with the erasure of chromatin silencing. Over the past years, the advent of transcriptomics and epigenomics has provided new insights into the transcriptional and chromatin dynamics with which XCR takes place. However, multiple questions remain unanswered about how chromatin and transcription related processes enable XCR. Here, we review recent work on establishing the transcriptional and chromatin kinetics of XCR, as well as discuss a model by which transcription factors mediate XCR not only via Xist repression, but also by direct targeting of X-linked genes.
Long-Term Cd Exposure Alters the Metabolite Profile in Stem Tissue of Medicago sativa
Authors: Gutsch Annelie , Hendrix Sophie , Guerriero Gea , Renaut Jenny , Lutts Stanley , Alseekh Saleh , Fernie Alisdair R. , Hausman Jean-Francois , Vangronsveld Jaco , Cuypers Ann , Sergeant Kjell
Published: December 2020

As a common pollutant, cadmium (Cd) is one of the most toxic heavy metals accumulating in agricultural soils through anthropogenic activities. The uptake of Cd by plants is the main entry route into the human food chain, whilst in plants it elicits oxidative stress by unbalancing the cellular redox status. Medicago sativa was subjected to chronic Cd stress for five months. Targeted and untargeted metabolic analyses were performed. Long-term Cd exposure altered the amino acid composition with levels of asparagine, histidine and proline decreasing in stems but increasing in leaves. This suggests tissue-specific metabolic stress responses, which are often not considered in environmental studies focused on leaves. In stem tissue, profiles of secondary metabolites were clearly separated between control and Cd-exposed plants. Fifty-one secondary metabolites were identified that changed significantly upon Cd exposure, of which the majority are (iso)flavonoid conjugates. Cadmium exposure stimulated the phenylpropanoid pathway that led to the accumulation of secondary metabolites in stems rather than cell wall lignification. Those metabolites are antioxidants mitigating oxidative stress and preventing cellular damage. By an adequate adjustment of its metabolic composition, M. sativa reaches a new steady state, which enables the plant to acclimate under chronic Cd stress.
Phosphate Groups in the Lipid A Moiety Determine the Effects of LPS on Hepatic Stellate Cells: A Role for LPS-Dephosphorylating Activity in Liver Fibrosis
Authors: Schippers Marlies , Post Eduard , Eichhorn Ilse , Langeland Jitske , Beljaars Leonie , Malo Madhu S. , Hodin Richard A. , Millán José Luis , Popov Yury , Schuppan Detlef , Poelstra Klaas
Published: December 2020

Alkaline phosphatase (AP) activity is highly upregulated in plasma during liver diseases. Previously, we demonstrated that AP is able to detoxify lipopolysaccharide (LPS) by dephosphorylating its lipid A moiety. Because a role of gut-derived LPS in liver fibrogenesis has become evident, we now examined the relevance of phosphate groups in the lipid A moiety in this process. The effects of mono-phosphoryl and di-phosphoryl lipid A (MPLA and DPLA, respectively) were studied in vitro and LPS-dephosphorylating activity was studied in normal and fibrotic mouse and human livers. The effects of intestinal AP were studied in mice with CCL4-induced liver fibrosis. DPLA strongly stimulated fibrogenic and inflammatory activities in primary rat hepatic stellate cells (rHSCs) and RAW264.7 macrophages with similar potency as full length LPS. However, MPLA did not affect any of the parameters. LPS-dephosphorylating activity was found in mouse and human livers and was strongly increased during fibrogenesis. Treatment of fibrotic mice with intravenous intestinal-AP significantly attenuated intrahepatic desmin+− and αSMA+ −HSC and CD68+− macrophage accumulation. In conclusion, the lack of biological activity of MPLA, contrasting with the profound activities of DPLA, shows the relevance of LPS-dephosphorylating activity. The upregulation of LPS-dephosphorylating activity in fibrotic livers and the protective effects of exogenous AP during fibrogenesis indicate an important physiological role of intestinal-derived AP during liver fibrosis.
Regulated Necrotic Cell Death in Alternative Tumor Therapeutic Strategies
Authors: Woo Yunseo , Lee Hyo-Ji , Jung Young Mee , Jung Yu-Jin
Published: December 2020

The treatment of tumors requires the induction of cell death. Radiotherapy, chemotherapy, and immunotherapy are administered to kill cancer cells; however, some cancer cells are resistant to these therapies. Therefore, effective treatments require various strategies for the induction of cell death. Regulated cell death (RCD) is systematically controlled by intracellular signaling proteins. Apoptosis and autophagy are types of RCD that are morphologically different from necrosis, while necroptosis, pyroptosis, and ferroptosis are morphologically similar to necrosis. Unlike necrosis, regulated necrotic cell death (RNCD) is caused by disruption of the plasma membrane under the control of specific proteins and induces tissue inflammation. Various types of RNCD, such as necroptosis, pyroptosis, and ferroptosis, have been used as therapeutic strategies against various tumor types. In this review, the mechanisms of necroptosis, pyroptosis, and ferroptosis are described in detail, and a potential effective treatment strategy to increase the anticancer effects on apoptosis- or autophagy-resistant tumor types through the induction of RNCD is suggested.
Multi-Level Regulatory Interactions between NF-κB and the Pluripotency Factor Lin28
Authors: Mills William T. , Nassar Noor N. , Ravindra Deepa , Li Xinbei , Meffert Mollie K.
Published: December 2020

An appreciation for the complex interactions between the NF-κB transcription factor and the Lin28 RNA binding protein/let-7 microRNA pathways has grown substantially over the past decade. Both the NF-κB and Lin28/let-7 pathways are master regulators impacting cell survival, growth and proliferation, and an understanding of how interfaces between these pathways participate in governing pluripotency, progenitor differentiation, and neuroplastic responses remains an emerging area of research. In this review, we provide a concise summary of the respective pathways and focus on the function of signaling interactions at both the transcriptional and post-transcriptional levels. Regulatory loops capable of providing both reinforcing and extinguishing feedback have been described. We highlight convergent findings in disparate biological systems and indicate future directions for investigation.
Wavelength-Selective Coatings on Glass with High Hardness and Damage Resistance
Authors: Koch Karl W. , Lin Lin , Price James J. , Kim Chang-Gyu , Moon Dong-Gun , Oh Sang-Yoon , Oh Jung-Keun , Oh Jeong-Hong , Paulson Charles A. , Zhang Binwei , Subramanian Ananth , Mayolet Alexandre , Williams Carlo Kosik , Hart Shandon D.
Published: December 2020

Wavelength-selective coatings are broadly applied across diverse industries such as solar energy management, infrared sensing, telecommunications, laser optics, and eye-protective lenses. These coatings have historically not been optimized for hardness or mechanical durability and typically suffer from higher susceptibility to scratch and damage events than uncoated glass. In this work, we describe a family of wavelength-selective coatings with hardness and scratch resistance that are significantly higher than the chemically strengthened glass substrates on which the coatings are fabricated. The coatings are made using industrially scalable reactive sputtering methods. Wavelength-selective coatings are fabricated with nanoindentation hardness as high as 16–20 GPa over indentation depths ranging from 200 to 800 nm, as well as excellent durability in aggressive scratch testing. Tunable visible to near-infrared wavelength selectivity ratios (reflectance of stopband: reflectance of passband) as high as 7:1 are achieved. The feasibility of narrowband hard coating design is also demonstrated, with visible narrowband transmission having a peak FWHM of ~8 nm (~1.6%). A unique “buried layers” hard coating design strategy is shown to deliver particularly excellent hardness profiles. These designs can be tailored for a variety of different wavelengths and selectivity ratios, enabling new uses of wavelength-selective optics in mechanically demanding applications.
Vapor-Stripping and Encapsulating to Construct Particles with Time-Controlled Asymmetry and Anisotropy
Authors: Wu Ting-Ying , Gao Chendi , Huang Man-Chen , Zhang Zhi , Wang Peng-Yuan , Chen Hsun-Yi , Chen Guosong , Chen Hsien-Yeh
Published: December 2020

An innovative chemical vapor sublimation and deposition (CVSD) process was shown to produce nanoscale anisotropic hybrid materials. Taking advantage of controlled thermodynamic properties and the mass transfer of molecules, this process allowed for water vapor sublimation from an iced template/substrate and stagewise vapor deposition of poly-p-xylylene onto the sublimating ice substrate. In this study, the use of sensitive soybean agglutinin (SBA) protein tubes was demonstrated as an example to prepare the anisotropic hybrid material based on the CVSD process. The rationale of a timing parameter, Δt, was controlled to program the sublimation of the SBA-ice templates and the deposition of poly-p-xylylene during the CVSD process. As a result of this control, a stripping stage occurred, during which SBA tubes were exposed on the particle surface, and a subsequent encapsulation stage enabled the transformation of the ice templates into a nanometer-sized anisotropic hybrid material of poly-p-xylylene as the matrix with encapsulated SBA tubes. The timing parameter Δt and the controlled stripping and encapsulating stages during CVSD represent a straightforward and intriguing mechanism stemming from physical chemistry fundamentals for the fabrication of hybrid materials from sensitive molecules and with predetermined sizes and asymmetrical shapes. A simulation analysis showed consistency with the experimental results and controllability of the timing mechanism with predictable particle sizes.