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Konstantina Katsarou, Eleni Mitta, Eirini Bardani, Anastasis Oulas, Elena Dadami, Kriton Kalantidis
RNA silencing is a universal mechanism involved in development, epigenetic modifications and responses against biotic (viruses-viroids) and abiotic stresses. The major components of this mechanism are Dicer-like (DCL), Argonaute (AGO) and RNA-dependent RNA polymerase (RDR) proteins. Understanding the role of each component is of great scientific and agronomic importance. Plants including Nicotiana benthamiana, an important plant model, have usually four DCL proteins, each of which has a specific role namely, being responsible for the production of an exclusive small RNA population...
October 21, 2018: Molecular Plant Pathology
Rodolfo Servín-Blanco, Rosa Mariana Chávaro-Ortiz, Rubén Zamora-Alvarado, Fernando Martínez-Cortes, Goar Gevorkian, Karen Manoutcharian
Although various immune checkpoint inhibitors (ICIs), used for the treatment of advanced cancer, showed remarkably durable tumor regression in a subset of patients, there are important limitations in a large group of non-responders, and the generation of novel immunogens capable of inducing protective cellular immune responses is a priority in cancer immunotherapy field. During the last decades, several types of vaccine immunogens have been used in numerous preclinical studies and clinical trials. However, although immunity to tumor Ags can be elicited by most vaccines tested, their clinical efficacy remains modest...
October 16, 2018: Immunology Letters
Jie Gu, Sha Song, Huiying Han, Hongxia Xu, Gao Fan, Chen'ao Qian, Yingchun Qiu, Wenqi Zhou, Wenzhuo Zhuang, Bingzong Li
Treatment failure remains a main challenge in the management of high-risk multiple myeloma (MM) even with the expanding repertoire of new drugs. Combinatorial therapy is considered an encouraging strategy that can overcome the compensatory mechanisms and undesirable off-target effects that limit the benefits of many prospective agents. Preliminary results of a current phase I trial have indicated that the new BET bromodomain inhibitor OTX015 has favorable activity and tolerability. However, OTX015 is not efficacious enough as a monotherapy...
October 19, 2018: Molecular Pharmaceutics
Chicora F Oliver, Joseph J Palamar, Alberto Salomone, Steven J Simmons, Helene L Philogene-Khalid, Nick Stokes-McCloskey, Scott M Rawls
RATIONALE: Current prevalence estimates of synthetic cathinone ("bath salt") use may be underestimates given that traditional metrics (e.g., surveys, urinalysis) often fail to capture the emergent issue of synthetic cathinone adulteration of more common illegal drugs, such as ecstasy (3,4-methylenedioxymethamphetamine). OBJECTIVES: This review examines the evolution of synthetic cathinones and prevalence of use over the past decade in the United States...
October 18, 2018: Psychopharmacology
Mahmoud Farrag, Nic D Leipzig
A combinatorial approach integrating stem cells and capable of exploiting available cues is likely needed to regenerate lost neural tissues and ultimately restore neurologic functions. This study investigates the effects of the subcutaneous maturation of adult-derived neural stem cell (aNSCs) seeded into biomaterial constructs on aNSC differentiation and ultimate regional neuronal identity as a first step toward a future spinal cord injury treatment. To achieve this, we encapsulated rat aNSCs in chitosan-based hydrogels functionalized with immobilized azide-tagged interferon-γ inside a chitosan conduit...
October 17, 2018: Cells
Y Zhang, S Shi, Q Xu, Q Zhang, R M Shanti, A D Le
Oral cancer has a high annual incidence rate all over the world, and the tongue is the most frequently affected anatomic structure. The current standard care is ablative surgery of malignant neoplasm, followed by tongue reconstruction with free flap. However, such reconstructive modalities with postsurgery radiotherapy or chemotherapy can hardly support the functional recovery of the tongue-particularly, functional taste bud regeneration-in reconstructed areas, thus seriously affecting patients' prognosis and life quality...
October 18, 2018: Journal of Dental Research
Xing-Xing Dai, Jun-Chao Jiang, Qian-Qian Sha, Yu Jiang, Xiang-Hong Ou, Heng-Yu Fan
Meiotic maturation of mammalian oocytes depends on the temporally and spatially regulated cytoplasmic polyadenylation and translational activation of maternal mRNAs. Cytoplasmic polyadenylation is controlled by cis-elements in the 3'-UTRs of mRNAs including the polyadenylation signal (PAS), which is bound by the cleavage and polyadenylation specificity factor (CPSF) and the cytoplasmic polyadenylation element (CPE), which recruits CPE binding proteins. Using the 3'-UTRs of mouse Cpeb1, Btg4 and Cnot6l mRNAs, we deciphered the combinatorial code that controls developmental stage-specific translation during meiotic maturation: (i) translation of a maternal transcript at the germinal vesicle (GV) stage requires one or more PASs that locate far away from CPEs; (ii) PASs distal and proximal to the 3'-end of the transcripts are equally effective in mediating translation at the GV stage, as long as they are not close to the CPEs; (iii) Both translational repression at the GV stage and activation after germinal vesicle breakdown require at least one CPE adjacent to the PAS; (iv) The numbers and positions of CPEs in relation to PASs within the 3'-UTR of a given transcript determines its repression efficiency in GV oocytes...
October 18, 2018: Nucleic Acids Research
André F Moreira, Carolina F Rodrigues, Catarina A Reis, Elisabete C Costa, Paula Ferreira, Ilídio J Correia
AIM: Develop a new poly-2-ethyl-2-oxazoline (PEOZ)-based coating for doxorubicin-loaded gold-core mesoporous silica shell (AuMSS) nanorods application in cancer chemo-photothermal therapy. METHODS: PEOZ functionalized AuMSS nanorods were obtained through the chemical grafting on AuMSS of a PEOZ silane derivative. RESULTS: The PEOZ chemical grafting on the surface of AuMSS nanorods allowed the neutralization of nanodevices' surface charge, from -30 to -15 mV, which improved nanoparticles' biocompatibility, namely by decreasing the blood hemolysis to negligible levels...
October 18, 2018: Nanomedicine
Alexander G Ekström, Jue Theresa Wang, Juraj Bella, Dominic J Campopiano
Dynamic combinatorial chemistry (DCC) is a powerful tool to identify ligands for biological targets. We used 19F NMR as an in situ, non-invasive technique for measuring the composition of a dynamic combinatorial library (DCL) of N-acylhydrazones (NAHs). An NAH DCL, constructed from a fluoro-aromatic aldehyde and a small set of hydrazides, was targetted at ecFabH, an essential enzyme in bacterial fatty acid biosynthesis. Our NMR analysis identified a tert-butyl NAH as the best binder which was confirmed by enzymatic assay...
October 18, 2018: Organic & Biomolecular Chemistry
Xiaoxi Ling, Shaojuan Zhang, Yang Liu, Mingfeng Bai
Cannabinoids are emerging as promising antitumor drugs. However, complete tumor eradication solely by cannabinoid therapy remains challenging. In this study, we developed a far-red light activatable cannabinoid prodrug, which allows for tumor-specific and combinatory cannabinoid and photodynamic therapy. This prodrug consists of a phthalocyanine photosensitizer (PS), reactive oxygen species (ROS)-sensitive linker, and cannabinoid. It targets the type-2 cannabinoid receptor (CB2R) overexpressed in various types of cancers...
October 2018: Journal of Biomedical Optics
Hannah M Pezzi, David J Guckenberger, Jennifer L Schehr, Jacob Rothbauer, Charlotte Stahlfeld, Anupama Singh, Sacha Horn, Zachery D Schultz, Rory M Bade, Jamie M Sperger, Scott M Berry, Joshua M Lang, David J Beebe
Rare cell populations provide a patient-centric tool to monitor disease treatment, response, and resistance. However, understanding rare cells is a complex problem, which requires cell isolation/purification and downstream molecular interrogation - processes challenged by non-target populations, which vary patient-to-patient and change with disease. As such, cell isolation platforms must be amenable to a range of sample types while maintaining high efficiency and purity. The multiplexed technology for automated extraction (mTAE) is a versatile magnetic bead-based isolation platform that facilitates positive, negative, and combinatorial selection with integrated protein staining and nucleic acid isolation...
October 18, 2018: Lab on a Chip
Jeffrey W Tyner, Cristina E Tognon, Daniel Bottomly, Beth Wilmot, Stephen E Kurtz, Samantha L Savage, Nicola Long, Anna Reister Schultz, Elie Traer, Melissa Abel, Anupriya Agarwal, Aurora Blucher, Uma Borate, Jade Bryant, Russell Burke, Amy Carlos, Richie Carpenter, Joseph Carroll, Bill H Chang, Cody Coblentz, Amanda d'Almeida, Rachel Cook, Alexey Danilov, Kim-Hien T Dao, Michie Degnin, Deirdre Devine, James Dibb, David K Edwards, Christopher A Eide, Isabel English, Jason Glover, Rachel Henson, Hibery Ho, Abdusebur Jemal, Kara Johnson, Ryan Johnson, Brian Junio, Andy Kaempf, Jessica Leonard, Chenwei Lin, Selina Qiuying Liu, Pierrette Lo, Marc M Loriaux, Samuel Luty, Tara Macey, Jason MacManiman, Jacqueline Martinez, Motomi Mori, Dylan Nelson, Ceilidh Nichols, Jill Peters, Justin Ramsdill, Angela Rofelty, Robert Schuff, Robert Searles, Erik Segerdell, Rebecca L Smith, Stephen E Spurgeon, Tyler Sweeney, Aashis Thapa, Corinne Visser, Jake Wagner, Kevin Watanabe-Smith, Kristen Werth, Joelle Wolf, Libbey White, Amy Yates, Haijiao Zhang, Christopher R Cogle, Robert H Collins, Denise C Connolly, Michael W Deininger, Leylah Drusbosky, Christopher S Hourigan, Craig T Jordan, Patricia Kropf, Tara L Lin, Micaela E Martinez, Bruno C Medeiros, Rachel R Pallapati, Daniel A Pollyea, Ronan T Swords, Justin M Watts, Scott J Weir, David L Wiest, Ryan M Winters, Shannon K McWeeney, Brian J Druker
The implementation of targeted therapies for acute myeloid leukaemia (AML) has been challenging because of the complex mutational patterns within and across patients as well as a dearth of pharmacologic agents for most mutational events. Here we report initial findings from the Beat AML programme on a cohort of 672 tumour specimens collected from 562 patients. We assessed these specimens using whole-exome sequencing, RNA sequencing and analyses of ex vivo drug sensitivity. Our data reveal mutational events that have not previously been detected in AML...
October 17, 2018: Nature
Erin L Sternburg, Jason A Estep, Daniel K Nguyen, Yahui Li, Fedor V Karginov
Approximately 1500 RNA-binding proteins (RBPs) profoundly impact mammalian cellular function by controlling distinct sets of transcripts, often using sequence-specific binding to 3' untranslated regions (UTRs) to regulate mRNA stability and translation. Aside from their individual effects, higher-order combinatorial interactions between RBPs on specific mRNAs have been proposed to underpin the regulatory network. To assess the extent of such co-regulatory control, we took a global experimental approach followed by targeted validation to examine interactions between two well-characterized and highly conserved RBPs, Argonaute2 (AGO2) and Pumilio (PUM1 and PUM2)...
October 17, 2018: Scientific Reports
Heather L Kinkead, Alexander Hopkins, Eric Lutz, Annie A Wu, Mark Yarchoan, Kayla Cruz, Skylar Woolman, Teena Vithayathil, Laura H Glickman, Chudi O Ndubaku, Sarah M McWhirter, Thomas W Dubensky, Todd D Armstrong, Elizabeth M Jaffee, Neeha Zaidi
Tumor neoantigens arising from somatic mutations in the cancer genome are less likely to be subject to central immune tolerance and are therefore attractive targets for vaccine immunotherapy. We utilized whole-exome sequencing, RNA sequencing (RNASeq), and an in silico immunogenicity prediction algorithm, NetMHC, to generate a neoantigen-targeted vaccine, PancVAX, which was administered together with the STING adjuvant ADU-V16 to mice bearing pancreatic adenocarcinoma (Panc02) cells. PancVAX activated a neoepitope-specific T cell repertoire within the tumor and caused transient tumor regression...
October 18, 2018: JCI Insight
Rajkumar Cheluvappa
The appendix contains copious lymphoid tissue and is constantly exposed to gut flora. Appendicitis followed by appendectomy (AA), when done at a young age, prevents or significantly ameliorates inflammatory bowel diseases (IBDs) in later life. Inflammatory bowel disease comprises Crohn's disease and ulcerative colitis. Our unique murine AA model is the only existing experimental model of AA. Herein, the appendiceal pathology closely resembles the pathological features of human appendicitis. Our AA model protects against experimental colitis in an age-, bacteria- and antigen-dependent manner...
October 16, 2018: Inflammatory Bowel Diseases
Shilpak Chatterjee, Paramita Chakraborty, Anusara Daenthanasanmak, Supinya Iamsawat, Gabriela Andrejeva, Libia A Luevano, Melissa M Wolf, Uday K Baliga, Carsten Krieg, Craig Beeson, Meenal Mehrotra, Elizabeth G Hill, Jeffrey C Rathmell, Xue-Zhong Yu, Andrew S Kraft, Shikhar Mehrotra
PURPOSE: Adoptive T cell therapy (ACT) of cancer, which involves the infusion of ex vivo engineered tumor epitope reactive autologous T cells into the tumor-bearing host, is a potential treatment modality for cancer. However, the durable anti-tumor response following ACT is hampered either by loss of effector function or survival of the anti-tumor T cells. Therefore, strategies to improve the persistence and sustain the effector function of the anti-tumor T cells are of immense importance...
October 16, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Marcos Heredero, Sandra Garrigues, Mónica Gandía, Jose F Marcos, Paloma Manzanares
Antimicrobial peptides (AMPs) have been proposed as candidates to develop new antimicrobial compounds for medicine, agriculture, and food preservation. PAF26 is a synthetic antifungal hexapeptide obtained from combinatorial approaches with potent fungicidal activity against filamentous fungi. Other interesting AMPs are the antifungal proteins (AFPs) of fungal origin, which are basic cysteine-rich and small proteins that can be biotechnologically produced in high amounts. A promising AFP is the AfpB identified in the phytopathogen Penicillium digitatum ...
October 15, 2018: Microorganisms
Laurent Lermusiaux, Alison M Funston
Developments in DNA nanotechnology offer control of the self-assembly of materials into discrete nanostructures. Within this paradigm, pre-assembled DNA origami with hundreds of DNA strands allows for precise and programmable spatial positioning of functionalised nanoparticles. We propose an alternative approach to construct multiple, structurally different, nanoparticle assemblies from just a few complementary nanoparticle-functionalised DNA strands. The approach exploits local minima in the potential energy landscape of hybridised nanoparticle-DNA structures by employing kinetic control of the assembly...
October 16, 2018: Nanoscale
Yuan Liu, Shuangyang Ding, Jianzhong Shen, Kui Zhu
Covering: 2000 to 2018, particularly from 2010 to early 2018The increase in the incidence of antibiotic resistant infections is threatening to overwhelm healthcare practices worldwide. Most antibiotics in clinical use are becoming ineffective, so therefore it is imperative to develop new antibiotics and novel therapeutic strategies. Traditionally, the chemical and mechanistic diversity of nonribosomal antibacterial peptides (NRAPs) as lead compounds have meant that their structures are ideal for antibiotic discovery...
October 16, 2018: Natural Product Reports
Karol Szlachta, Cem Kuscu, Turan Tufan, Sara J Adair, Stephen Shang, Alex D Michaels, Matthew G Mullen, Natasha Lopes Fischer, Jiekun Yang, Limin Liu, Prasad Trivedi, Edward B Stelow, P Todd Stukenberg, J Thomas Parsons, Todd W Bauer, Mazhar Adli
Predicting the response and identifying additional targets that will improve the efficacy of chemotherapy is a major goal in cancer research. Through large-scale in vivo and in vitro CRISPR knockout screens in pancreatic ductal adenocarcinoma cells, we identified genes whose genetic deletion or pharmacologic inhibition synergistically increase the cytotoxicity of MEK signaling inhibitors. Furthermore, we show that CRISPR viability scores combined with basal gene expression levels could model global cellular responses to the drug treatment...
October 15, 2018: Nature Communications
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