Targeting STAT3 in Cancer with Nucleotide Therapeutics.

Signal transducer and activator of transcription 3 (STAT3) plays a critical role in promoting the proliferation and survival of tumor cells. As a ubiquitously-expressed transcription factor, STAT3 has commonly been considered an "undruggable" target for therapy; thus, much research has focused on targeting upstream pathways to reduce the expression or phosphorylation/activation of STAT3 in tumor cells. Recently, however, novel approaches have been developed to directly inhibit STAT3 in human cancers, in the hope of reducing the survival and proliferation of tumor cells. Several of these agents are nucleic acid-based, including the antisense molecule AZD9150, CpG-coupled STAT3 siRNA, G-quartet oligodeoxynucleotides (GQ-ODNs), and STAT3 decoys. While the AZD9150 and CpG-STAT3 siRNA interfere with STAT3 expression, STAT3 decoys and GQ-ODNs target constitutively activated STAT3 and modulate its ability to bind to target genes. Both STAT3 decoy and AZD9150 have advanced to clinical testing in humans. Here we will review the current understanding of the structures, mechanisms, and potential clinical utilities of the nucleic acid-based STAT3 inhibitors

Genomic and Transcriptomic Alterations Associated with STAT3 Activation in Head and Neck Cancer.

BackgroundHyperactivation of STAT3 via constitutive phosphorylation of tyrosine 705 (Y705) is common in most human cancers, including head and neck squamous carcinoma (HNSCC). STAT3 is rarely mutated in cancer and the (epi)genetic alterations that lead to STAT3 activation are incompletely understood. Here we used an unbiased approach to identify genomic and epigenomic changes associated with pSTAT3(Y705) expression using data generated by The Cancer Genome Atlas (TCGA).Methods and findingsMutation, mRNA expression, promoter methylation, and copy number alteration data were extracted from TCGA and examined in the context of pSTAT3(Y705) protein expression. mRNA expression levels of 1279 genes were found to be associated with pSTAT3(705) expression. Association of pSTAT3(Y705) expression with caspase-8 mRNA expression was validated by immunoblot analysis in HNSCC cells. Mutation, promoter hypermethylation, and copy number alteration of any gene were not significantly associated with increased pSTAT3(Y705) protein expression.ConclusionsThese cumulative results suggest that unbiased approaches may be useful in identifying the molecular underpinnings of oncogenic signaling, including STAT3 activation, in HNSCC. Larger datasets will likely be necessary to elucidate signaling consequences of infrequent alterations

Biochemical Properties of a Decoy Oligodeoxynucleotide Inhibitor of STAT3 Transcription Factor.

Cyclic STAT3 decoy (CS3D) is a second-generation, double-stranded oligodeoxynucleotide (ODN) that mimics a genomic response element for signal transducer and activator of transcription 3 (STAT3), an oncogenic transcription factor. CS3D competitively inhibits STAT3 binding to target gene promoters, resulting in decreased expression of proteins that promote cellular proliferation and survival. Previous studies have demonstrated antitumor activity of CS3D in preclinical models of solid tumors. However, prior to entering human clinical trials, the efficiency of generating the CS3D molecule and its stability in biological fluids should be determined. CS3D is synthesized as a single-stranded ODN and must have its free ends ligated to generate the final cyclic form. In this study, we report a ligation efficiency of nearly 95 percent. The ligated CS3D demonstrated a half-life of 7.9 h in human serum, indicating adequate stability for intravenous delivery. These results provide requisite biochemical characterization of CS3D that will inform upcoming clinical trials

Proposal and validation of new indexes to evaluate maize silage fermentative quality in lab-scale ensiling conditions through the use of a receiver operating characteristic analysis

In the context of dairy cow feeding, it is increasingly important to know the quality of the maize silage used in the ration and therefore, it appears to be crucial optimizing the techniques necessary to assess it. The aim of this study was to evaluate whether some reference indexes, like the Flieg-Zimmer's (FZS), the German agricultural society's (DLG) and Vanbelle's scores, could properly estimate the quality of fermentations of maize silage made in a lab-scale ensiling system, and to calculate and validate new quality indexes suitable for lab-scale fermentations. The experimental dataset was obtained by analysing through near-infrared spectroscopy 522 samples of whole maize crop ensiled immediately after the harvest, using the vacuum-packing technique. The six (I1 \u2013 I6) new indexes were calculated on the basis of chemical and physical parameters as: pH, organic acids, ethanol, etc. All the indexes were tested for normality with the Shapiro\u2013Wilk test. In order to define the accuracy with which the new indexes ranked the maize silage on the basis of its fermentation quality, a receiver operating characteristic (ROC) analysis was performed, using the FZS as gold standard test and dichotomizing the FZS in two levels according to a cut-off (FZS 360 g/kg) dry matter (DM). In the lab-scale silages the new indexes were normally distributed, whereas the reference indexes were not. The new indexes showed values of AUC ranging between 0.76 and 0.89, with the I5 index showing the best combination of sensitivity (0.87) and specificity (0.77) in discriminating between good and poor quality silage. The cut-off of the new indexes ranged between 45.0 and 57.4 points. The lab-scale silages were all excellent, no matter the category of DM. However, while FZS and DLG did not differ among the 3 categories, I1 \u2013 I6 were significantly higher in silages with low DM (P < 0.001). Silages with low DM had the highest concentrations of lactic acid (56.4 g/kg DM, P < 0.001), ammonia (61.4 g/kg DM, P < 0.001) and butyric acid (0.62 g/kg DM, P < 0.001) as well. Data confirmed that the new proposed indexes are promising in describing the fermentation quality of maize silage in lab-scale conditions

Frequent mutation of receptor protein tyrosine phosphatases provides a mechanism for STAT3 hyperactivation in head and neck cancer

The underpinnings of STAT3 hyperphosphorylation resulting in enhanced signaling and cancer progression are incompletely understood. Loss-of-function mutations of enzymes that dephosphorylate STAT3, such as receptor protein tyrosine phosphatases, which are encoded by the PTPR gene family, represent a plausible mechanism of STAT3 hyperactivation. We analyzed whole exome sequencing (n = 374) and reverse-phase protein array data (n = 212) from head and neck squamous cell carcinomas (HNSCCs). PTPR mutations are most common and are associated with significantly increased phospho-STAT3 expression in HNSCC tumors. Expression of receptor-like protein tyrosine phosphatase T (PTPRT) mutant proteins induces STAT3 phosphorylation and cell survival, consistent with a “driver” phenotype. Computational modeling reveals functional consequences of PTPRT mutations on phospho-tyrosine–substrate interactions. A high mutation rate (30%) of PTPRs was found in HNSCC and 14 other solid tumors, suggesting that PTPR alterations, in particular PTPRT mutations, may define a subset of patients where STAT3 pathway inhibitors hold particular promise as effective therapeutic agents.Fil: Lui, Vivian Wai Yan. University of Pittsburgh; Estados UnidosFil: Peyser, Noah D.. University of Pittsburgh; Estados UnidosFil: Ng, Patrick Kwok-Shing. University Of Texas Md Anderson Cancer Center;Fil: Hritz, Jozef. University of Pittsburgh at Johnstown; Estados Unidos. University of Pittsburgh; Estados Unidos. Masaryk University; República ChecaFil: Zeng, Yan. University of Pittsburgh at Johnstown; Estados Unidos. University of Pittsburgh; Estados UnidosFil: Lu, Yiling. University Of Texas Md Anderson Cancer Center;Fil: Li, Hua. University of Pittsburgh; Estados Unidos. University of Pittsburgh at Johnstown; Estados UnidosFil: Wang, Lin. University of Pittsburgh; Estados Unidos. University of Pittsburgh at Johnstown; Estados UnidosFil: Gilbert, Breean R.. University of Pittsburgh; Estados Unidos. University of Pittsburgh at Johnstown; Estados UnidosFil: General, Ignacio. University of Pittsburgh; Estados Unidos. University of Pittsburgh at Johnstown; Estados UnidosFil: Bahar, Ivet. University of Pittsburgh at Johnstown; Estados Unidos. University of Pittsburgh; Estados UnidosFil: Ju, Zhenlin. University Of Texas Md Anderson Cancer Center;Fil: Wang, Zhenghe. Case Western Reserve University; Estados UnidosFil: Pendleton, Kelsey P.. University of Pittsburgh; Estados Unidos. University of Pittsburgh at Johnstown; Estados UnidosFil: Xiao, Xiao. University of Pittsburgh at Johnstown; Estados Unidos. University of Pittsburgh; Estados UnidosFil: Du, Yu. University of Pittsburgh at Johnstown; Estados Unidos. University of Pittsburgh; Estados UnidosFil: Vries, John K.. University of Pittsburgh; Estados Unidos. University of Pittsburgh at Johnstown; Estados UnidosFil: Hammerman, Peter S.. Harvard Medical School; Estados UnidosFil: Garraway, Levi A.. Harvard Medical School; Estados UnidosFil: Mills, Gordon B.. University Of Texas Md Anderson Cancer Center;Fil: Johnson, Daniel E.. University of Pittsburgh at Johnstown; Estados Unidos. University of Pittsburgh; Estados UnidosFil: Grandis, Jennifer R.. University of Pittsburgh; Estados Unidos. University of Pittsburgh at Johnstown; Estados Unido

The development of self-regulation in early childhood and its modulating factors

La autorregulación emocional refiere a la capacidad intrínseca de los niños y niñas de modular y modificar respuestas tanto emocionales como cognitivas, por demandas de situaciones específicas (Lewis & Todd, 2007; Vohs & Baumeister, 2004). Sin embargo, su definición no está exenta de ambigüedades (Gross, 2013). La siguiente revisión tiene como objetivo analizar el concepto y desarrollo ontogenético de la autorregulación, y describir los principales factores endógenos y exógenos que modulan esta habilidad cognitiva en los primeros años de vida. Específicamente se trabajará con el período que abarca del momento de nacimiento hasta los 3 años de vida, denominado infancia temprana. Se realizó una revisión narrativa para explicitar el estado de conocimiento hasta el momento, utilizando las bases de datos Scopus, Medline y Web of Science, recuperándose un total de 146 referencias, de las cuáles se seleccionaron 48 que eran acordes a los objetivos establecidos. Los principales factores intrínsecos recabados fueron la maduración de las redes atencionales y el temperamento, mientras que los factores exógenos fueron la sensibilidad materna, los estilos de crianza y los entornos socioeconómicos. Se concluye que esta habilidad debe ser diferenciada conceptualmente de la regulación emocional y las funciones ejecutivas, y que la misma es el resultado de determinantes bio-psico-sociales. En futuros trabajos deberían realizarse más investigaciones empíricas con infantes y en Latinoamérica, para lograr una comprensión más acabada sobre la variable y guiar las políticas públicas para optimizar su desarrollo.Emotional self-regulation refers to the child s intrinsic ability to modulate and modify emotional and cognitive responses, due to the demands of specific situations (Lewis & Todd, 2007; Vohs & Baumeister, 2004). However, its definition is not without ambiguities (Gross, 2013). The following review aims to analyze the ontogenetic concept and development of self-regulation, and describe the main endogenous and exogenous factors that modulate this cognitive ability in the first years of life. Specifically, it will work with the period from the moment of birth to 3 years of life, called early childhood. A narrative review was carried out to explain the state of knowledge, using the Scopus, Medline and Web of Science databases, recovering a total of 146 references, of which 48 were selected according to that were consistent with the established objectives. The main intrinsic factors collected were maturation of the attentional networks and temperament, while the exogenous factors were maternal sensitivity, parenting styles and socio-economic environments. It is concluded that this ability must be conceptually differentiated from emotional regulation and executive functions, and that it is the result of bio-psycho-social determinants. In future work, more empirical research with infants and in Latin America should be carried out to achieve a more complete understanding of the variable and guide public policies to optimize their development.Fil: de Grandis, María Carolina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Universidad Abierta Interamericana. Facultad de Psicología; ArgentinaFil: Gago Galvagno, Lucas Gustavo. Universidad Abierta Interamericana. Facultad de Psicología; Argentina. Universidad de Buenos Aires. Facultad de Psicología. Instituto de Investigaciones; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Clerici, Gonzalo Daniel. Universidad de Buenos Aires. Facultad de Psicología. Instituto de Investigaciones; ArgentinaFil: Elgier, Angel Manuel. Universidad de Buenos Aires. Facultad de Psicología. Instituto de Investigaciones; Argentina. Universidad Abierta Interamericana. Facultad de Psicología; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentin

Genetic and Pharmacological Inhibition of MicroRNA-92a Maintains Podocyte Cell Cycle Quiescence and Limits Crescentic Glomerulonephritis

Crescentic rapidly progressive glomerulonephritis (RPGN) represents the most aggressive form of acquired glomerular disease. While most therapeutic approaches involve potentially toxic immunosuppressive strategies, the pathophysiology remains incompletely understood. Podocytes are glomerular epithelial cells that are normally growth-arrested because of the expression of cyclin-dependent kinase (CDK) inhibitors. An exception is in RPGN where podocytes undergo a deregulation of their differentiated phenotype and proliferate. Here we demonstrate that microRNA-92a (miR-92a) is enriched in podocytes of patients and mice with RPGN. The CDK inhibitor p57Kip2 is a major target of miR-92a that constitutively safeguards podocyte cell cycle quiescence. Podocyte-specific deletion of miR-92a in mice de-repressed the expression of p57Kip2 and prevented glomerular injury in RPGN. Administration of an anti-miR-92a after disease initiation prevented albuminuria and kidney failure, indicating miR-92a inhibition as a potential therapeutic strategy for RPGN. We demonstrate that miRNA induction in epithelial cells can break glomerular tolerance to immune injury

Exploring Cosmic Origins with CORE: Cosmological Parameters

We forecast the main cosmological parameter constraints achievable with theCORE space mission which is dedicated to mapping the polarisation of the CosmicMicrowave Background (CMB). CORE was recently submitted in response to ESA'sfifth call for medium-sized mission proposals (M5). Here we report the resultsfrom our pre-submission study of the impact of various instrumental options, inparticular the telescope size and sensitivity level, and review the great,transformative potential of the mission as proposed. Specifically, we assessthe impact on a broad range of fundamental parameters of our Universe as afunction of the expected CMB characteristics, with other papers in the seriesfocusing on controlling astrophysical and instrumental residual systematics. Inthis paper, we assume that only a few central CORE frequency channels areusable for our purpose, all others being devoted to the cleaning ofastrophysical contaminants. On the theoretical side, we assume LCDM as ourgeneral framework and quantify the improvement provided by CORE over thecurrent constraints from the Planck 2015 release. We also study the jointsensitivity of CORE and of future Baryon Acoustic Oscillation and Large ScaleStructure experiments like DESI and Euclid. Specific constraints on the physicsof inflation are presented in another paper of the series. In addition to thesix parameters of the base LCDM, which describe the matter content of aspatially flat universe with adiabatic and scalar primordial fluctuations frominflation, we derive the precision achievable on parameters like thosedescribing curvature, neutrino physics, extra light relics, primordial heliumabundance, dark matter annihilation, recombination physics, variation offundamental constants, dark energy, modified gravity, reionization and cosmicbirefringence. (ABRIDGED

Interdisciplinary and transdisciplinary research: Finding the common ground of multi-faceted concepts

Inter- and transdisciplinarity are increasingly relevant concepts and practices within academia. While various definitions exist, a clear distinction between inter- and transdisciplinarity remains difficult. Although there is a wide consensus about the need to define and apply these approaches, there is no agreement over definitions. Building on data collected during the first year of the COST Action TD1408 “Interdisciplinarity in research programming and funding cycles” (INTREPID), this paper describes both tensions and common ground about the characteristics and building blocks of interand trans-disciplinarity. Drawing on empirical data from participatory workshops involving INTREPID network members coming from 27 different countries, the paper shows that diverse definitions of inter and trans-disciplinarity coexist within scientific literature and in the mind of researchers and practitioners. The understanding about the involvement of actors outside of academia also differs widely across scientific communities irrespective of disciplinary training or the research subjects. The focus should be on the knowledge that is required to deal with a specific problem, rather than discussing “if” and “how” to integrate actors outside the academia, and collaboration should start with joint problem framing. This diversity is, however, not an absolute obstacle to practice, since the latter is made possible through building blocks such as knowledge domains, problem- and solution- oriented approaches, common goals, as well as target knowledge. In order to move towards more effective inter- and transdisciplinary research, we identify the need for trained interdisciplinarity facilitators and ‘accompanying research’ (derived from the Danish term ‘følgeforskning’). These two roles can be essential to inter- and transdisciplinarity practices including the promotion of reflexivity