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Suhong Xiao, Ying-Sheng Tang, Praveen Kusumanchi, Sally P Stabler, Ying Zhang, Asok C Antony
Background: Epidemiologic and in vitro studies suggest independent linkages between poor folate and/or vitamin B-12 nutrition, genomic human papillomavirus (HPV) type 16 viral integration, and cancer. However, there is no direct evidence in vivo to support the causative role of poor folate nutrition in HPV16 integration into the cellular genome. Objective: We tested the hypothesis that folate deficiency enables the integration of HPV16 into the genome of HPV16-harboring keratinocytes, and could thereby influence earlier transformation of these cells to cancer in an animal model...
March 1, 2018: Journal of Nutrition
Sen Xu, Zong-Yuan Yang, Ping Jin, Xin Yang, Xiaoting Li, Xiao Wei, Ya Wang, Sixiang Long, Taoran Zhang, Gang Chen, Chaoyang Sun, Ding Ma, Qinglei Gao
Ovarian cancer (OC) is a devastating disease due to its high incidence of relapse and chemoresistance. The tumor microenvironment, especially the tumor stroma compartment, was proven to contribute tremendously to the unsatisfactory chemotherapeutic efficacy in OC. Cytotoxic agents not only effect tumor cells, but also modulate the phenotype and characteristics of the vast stromal cell population, which can in turn alter the tumor cell response to chemointervention. In this study, we focused on the tumor stroma response to cytotoxic agents and the subsequent effect on the OC tumor cells...
March 15, 2018: Molecular Cancer Therapeutics
Heather L Lehman, Michal Kidacki, Joshua I Warrick, Douglas B Stairs
Four out of five patients diagnosed with esophageal squamous cell carcinoma (ESCC) will die within five years. This is primarily a result of the aggressive invasive potential of the disease. Our research is focused on the interplay between tumor suppressors and oncogenes in the invasive process. Specifically, EGFR and p120-catenin (p120ctn) are commonly dysregulated genes that are indicative of poor prognosis in ESCC. In a previous study we demonstrated that in our 3D organotypic culture model, only when EGFR overexpression is combined with p120ctn inactivation do the cells transform and invade - as opposed to either event alone...
February 16, 2018: Oncotarget
F de Michele, J Poels, M G Giudice, F De Smedt, J Ambroise, M Vermeulen, D Gruson, C Wyns
STUDY QUESTION: How does the formation of the blood-testis barrier (BTB), as reflected by the expression of connexin 43 and claudin 11 proteins during the pubertal transition period, take place in vitro compared to samples from a large cohort of pre/peripubertal boys? SUMMARY ANSWER: The BTB connexin 43 and claudin 11 expression patterns appeared to be partially achieved in organotypic culture when compared to that in samples from 71 pre/peripubertal patients. WHAT IS KNOWN ALREADY: Although alterations in the protein expression patterns of the BTB, whose main components are connexin 43 and claudin 11, are known to be associated with impaired spermatogenesis in mice and adult men, there is a lack of knowledge on its formation in pre-peripubertal human tissue both in vitro and in vivo...
March 12, 2018: Molecular Human Reproduction
Marie C Matrka, Katherine A Cimperman, Sarah R Haas, Geraldine Guasch, Lisa A Ehrman, Ronald R Waclaw, Kakajan Komurov, Adam Lane, Kathryn A Wikenheiser-Brokamp, Susanne I Wells
Esophageal cancer occurs as either squamous cell carcinoma (ESCC) or adenocarcinoma. ESCCs comprise almost 90% of cases worldwide, and recur with a less than 15% five-year survival rate despite available treatments. The identification of new ESCC drivers and therapeutic targets is critical for improving outcomes. Here we report that expression of the human DEK oncogene is strongly upregulated in esophageal SCC based on data in the cancer genome atlas (TCGA). DEK is a chromatin-associated protein with important roles in several nuclear processes including gene transcription, epigenetics, and DNA repair...
March 14, 2018: PLoS Genetics
Christine L Monteleon, Tanvir Agnihotri, Ankit Dahal, Mingen Liu, Vito W Rebecca, Gregory L Beatty, Ravi K Amavaradi, Todd W Ridky
Keratinocytes undergo significant structural remodeling during epidermal differentiation, including a broad transformation of the proteome coupled with a reduction in total cellular biomass. This suggests that intracellular digestion of proteins and organelles is necessary for keratinocyte differentiation. Here, we use both genetic and pharmacologic approaches to demonstrate that autophagy and lysosomal functions are required for keratinocyte differentiation in organotypic human skin. Lysosomal activity was required for mTOR signaling and mitochondrial oxidative metabolism...
March 8, 2018: Journal of Investigative Dermatology
Ryota Kurogi, Akira Nakamizo, Satoshi O Suzuki, Masahiro Mizoguchi, Koji Yoshimoto, Toshiyuki Amano, Takeo Amemiya, So Takagishi, Koji Iihara
OBJECTIVE Human bone marrow-derived mesenchymal stem cells (hMSCs) show tropism for brain tumors and may be a useful vehicle for drug or gene delivery to malignant gliomas. Recently, some microRNAs (miRNAs) have been shown to suppress the invasiveness of malignant gliomas. METHODS To test their potential to become vehicles for the delivery of miRNA to malignant gliomas, hMSCs were engineered so that hMSC secretion of miRNAs that inhibit glioma cell invasion was enabled without altering the hMSC tropism for glioma cells...
March 9, 2018: Journal of Neurosurgery
Aditi Jain, Jafar Hasan, Perumal Arumugam Desingu, Nagalingam R Sundaresan, Kaushik Chatterjee
Neonatal cardiomyocytes cultured on flat surfaces are commonly used as a model to study cardiac failure of diverse origin. A major drawback of such a system is that the cardiomyocytes do not exhibit alignment, organization and calcium transients, similar to the native heart. Therefore, there is a need to develop in vitro platforms that recapitulate the cellular microenvironment of the murine heart as organotypic models to study cardiovascular diseases. In this study, we report an engineered platform that mimics cardiac cell organization and function of the heart...
February 27, 2018: Colloids and Surfaces. B, Biointerfaces
Marta Machado-Pereira, Tiago Santos, Lino Ferreira, Liliana Bernardino, Raquel Ferreira
Perinatal stroke is often difficult to diagnose and an established treatment has not yet been validated, except for symptomatic measures. Herein, we propose to test the neuroprotective potential of the intravenous injection of retinoic acid-loaded nanoparticles (RA-NP) upon ischemic injury to the immature brain. The role of RA-NP on endothelial cells and organotypic slice cultures exposed to oxygen and glucose deprivation was assessed by evaluating markers pertaining to survival, proliferation, oxidative stress (NO, ROS), neuronal damage (enolase), vascular oxidation (p47phox) and microglia activation (CD68)...
March 5, 2018: Neuroscience Letters
Filippo Zanetti, Alain Sewer, Elena Scotti, Bjoern Titz, Walter K Schlage, Patrice Leroy, Athanasios Kondylis, Gregory Vuillaume, Anita R Iskandar, Emmanuel Guedj, Keyur Trivedi, Thomas Schneider, Ashraf Elamin, Florian Martin, Nikolai V Ivanov, Stefan Frentzel, Manuel C Peitsch, Julia Hoeng
Cigarette smoke (CS) is affecting considerably the oral mucosa. Heating, instead of burning, tobacco reduces consistently the amount of toxic compounds and may exert a lower impact on oral health than combusted cigarettes. The carbon-heated tobacco product 1.2 (CHTP1.2) is a potential modified risk tobacco product (MRTP) based on heat-not-burn technology. Using a systems toxicology assessment framework, we compared the effects of exposure to CHTP1.2 aerosol with those of CS from a reference cigarette (3R4F)...
March 2, 2018: Food and Chemical Toxicology
E M André, N Daviaud, L Sindji, J Cayon, R Perrot, C N Montero-Menei
Organotypic brain slice cultures have been recently used to study neurodegenerative disorders such as Parkinson's disease and Huntington's disease (HD). They preserve brain three-dimensional architecture, synaptic connectivity and brain cells microenvironment. Here, we developed an innovative model of Huntington's disease from coronal rat brain slices, that include all the areas involved in the pathology. HD-like neurodegeneration was obtained in only one week, in a single step, during organotypic slice preparation, without the use of neurotoxins...
2018: PloS One
Malgorzata Bienkowska-Haba, Wioleta Luszczek, Julia E Myers, Timothy R Keiffer, Stephen DiGiuseppe, Paula Polk, Jason M Bodily, Rona S Scott, Martin Sapp
Herein, we describe a novel infection model that achieves highly efficient infection of primary keratinocytes with human papillomavirus type 16 (HPV16). This cell culture model does not depend on immortalization and is amenable to extensive genetic analyses. In monolayer cell culture, the early but not late promoter was active and yielded a spliced viral transcript pattern similar to HPV16-immortalized keratinocytes. However, relative levels of the E8^E2 transcript increased over time post infection suggesting the expression of this viral repressor is regulated independently of other early proteins and that it may be important for the shift from the establishment to the maintenance phase of the viral life cycle...
March 2018: PLoS Pathogens
Katyayani Singh, Desirée Loreth, Bruno Pöttker, Kyra Hefti, Jürgen Innos, Kathrin Schwald, Heidi Hengstler, Lutz Menzel, Clemens J Sommer, Konstantin Radyushkin, Oliver Kretz, Mari-Anne Philips, Carola A Haas, Katrin Frauenknecht, Kersti Lilleväli, Bernd Heimrich, Eero Vasar, Michael K E Schäfer
Neuronal growth regulator 1 (NEGR1), a member of the immunoglobulin superfamily cell adhesion molecule subgroup IgLON, has been implicated in neuronal growth and connectivity. In addition, genetic variants in or near the NEGR1 locus have been associated with obesity and more recently with learning difficulties, intellectual disability and psychiatric disorders. However, experimental evidence is lacking to support a possible link between NEGR1, neuronal growth and behavioral abnormalities. Initial expression analysis of NEGR1 mRNA in C57Bl/6 wildtype (WT) mice by in situ hybridization demonstrated marked expression in the entorhinal cortex (EC) and dentate granule cells...
2018: Frontiers in Molecular Neuroscience
Seyoum Ayehunie, Tim Landry, Zachary Stevens, Alex Armento, Patrick Hayden, Mitchell Klausner
PURPOSE: The study evaluates the use of new in vitro primary human cell-based organotypic small intestinal (SMI) microtissues for predicting intestinal drug absorption and drug-drug interaction. METHODS: The SMI microtissues were reconstructed using human intestinal fibroblasts and enterocytes cultured on a permeable support. To evaluate the suitability of the intestinal microtissues to model drug absorption, the permeability coefficients across the microtissues were determined for a panel of 11 benchmark drugs with known human absorption and Caco-2 permeability data...
February 23, 2018: Pharmaceutical Research
Sooah Jang, Hyunjeong Kim, Hye-Jin Kim, Su Kyoung Lee, Eun Woo Kim, Kee Namkoong, Eosu Kim
OBJECTIVE: Conventional methods for organotypic hippocampal tissue slice culture (OHSC) have shown several disadvantages or limitations regarding age of animals used, duration of culture and difficulty using neurodegenerative models. Therefore, we tried to establish OHSC from old 3xTg-Alzheimer's disease (AD) mice for longer period (over 4 weeks) and to validate utility of this system as a valid platform for translational neuroscience of AD. METHODS: OHSC was performed with old 3xTg-AD mice (12-14 months), old wild type mice (12-14 months) and young 3xTg-AD mice (2-4 months) using serum-free medium for 4 weeks...
February 2018: Psychiatry Investigation
Jan Tønnesen, V V G Krishna Inavalli, U Valentin Nägerl
The extracellular space (ECS) of the brain has an extremely complex spatial organization, which has defied conventional light microscopy. Consequently, despite a marked interest in the physiological roles of brain ECS, its structure and dynamics remain largely inaccessible for experimenters. We combined 3D-STED microscopy and fluorescent labeling of the extracellular fluid to develop super-resolution shadow imaging (SUSHI) of brain ECS in living organotypic brain slices. SUSHI enables quantitative analysis of ECS structure and reveals dynamics on multiple scales in response to a variety of physiological stimuli...
February 22, 2018: Cell
Yi-Je Chen, Hai M Nguyen, Izumi Maezawa, Lee-Way Jin, Heike Wulff
Objective: Inhibitors of the voltage-gated K+ channel Kv1.3 are currently in development as immunomodulators for the treatment of autoimmune diseases. As Kv1.3 is also expressed on microglia and has been shown to be specifically up-regulated on "M1-like" microglia, we here tested the therapeutic hypothesis that the brain-penetrant small-molecule Kv1.3-inhibitor PAP-1 reduces secondary inflammatory damage after ischemia/reperfusion. Methods: We studied microglial Kv1...
February 2018: Annals of Clinical and Translational Neurology
Seon-Ah Chong, Silvia Balosso, Catherine Vandenplas, Gregory Szczesny, Etienne Hanon, Kasper Claes, Xavier Van Damme, Bénédicte Danis, Jonathan Van Eyll, Christian Wolff, Annamaria Vezzani, Rafal M Kaminski, Isabelle Niespodziany
Understanding the mechanisms of epileptogenesis is essential to develop novel drugs that could prevent or modify the disease. Neuroinflammation has been proposed as a promising target for therapeutic interventions to inhibit the epileptogenic process that evolves from traumatic brain injury. However, it remains unclear whether cytokine-related pathways, particularly TNFα signaling, have a critical role in the development of epilepsy. In this study, we investigated the role of innate inflammation in an in vitro model of post-traumatic epileptogenesis...
February 20, 2018: Neurotherapeutics: the Journal of the American Society for Experimental NeuroTherapeutics
Wiktor S Phillips, Christopher A Del Negro, Jens C Rekling
The brainstem preBötzinger complex (preBötC) generates the inspiratory rhythm for breathing. The onset of neural activity that precipitates the inspiratory phase of the respiratory cycle may depend on the activity of type-1 preBötC neurons, which exhibit a transient outward K+ current, IA Inspiratory rhythm generation can be studied ex vivo since the preBötC remains rhythmically active in vitro , both in acute brainstem slices and organotypic cultures. Advantageous optical conditions in organotypic slice cultures from newborn mice of either sex allowed us to investigate how IA impacts Ca2+ transients occurring in the dendrites of rhythmically active type-1 preBötC neurons...
February 19, 2018: Journal of Neuroscience: the Official Journal of the Society for Neuroscience
Jakub Zimoch, Joan Simó Padial, Agnes S Klar, Queralt Vallmajo-Martin, Martin Meuli, Thomas Biedermann, Christopher J Wilson, Alan Rowan, Ernst Reichmann
Molecular and mechanical interactions with the 3D extracellular matrix are essential for cell functions such as survival, proliferation, migration, and differentiation. Thermo-responsive biomimetic polyisocyanopeptide (PIC) hydrogels are promising new candidates for 3D cell, tissue, and organ cultures. This is a synthetic, thermo-responsive and stress-stiffening material synthesized via polymerization of the corresponding monomers using a nickel perchlorate as a catalyst. It can be tailored to meet various demands of cells by modulating its stiffness and through the decoration of the polymer with short GRGDS peptides using copper free click chemistry...
February 14, 2018: Acta Biomaterialia
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