Seriniquinones as Therapeutic Leads for Treatment of BRAF and NRAS Mutant Melanomas

Isolated from the marine bacteria Serinicoccus sp., seriniquinone (SQ1) has been characterized by its selective activity in melanoma cell lines marked by its modulation of human dermcidin and induction of autophagy and apoptosis. While an active lead, the lack of solubility of SQ1 in both organic and aqueous media has complicated its preclinical evaluation. In response, our team turned its effort to explore analogues with the goal of returning synthetically accessible materials with comparable selectivity and activity. The analogue SQ2 showed improved solubility and reached a 30–40-fold greater selectivity for melanoma cells. Here, we report a detailed comparison of the activity of SQ1 and SQ2 in SK-MEL-28 and SK-MEL-147 cell lines, carrying the top melanoma-associated mutations, BRAFV600E and NRASQ61R, respectively. These studies provide a definitive report on the activity, viability, clonogenicity, dermcidin expression, autophagy, and apoptosis induction following exposure to SQ1 or SQ2. Overall, these studies showed that SQ1 and SQ2 demonstrated comparable activity and modulation of dermcidin expression. These studies are further supported through the evaluation of a panel of basal expression of key-genes related to autophagy and apoptosis, providing further insight into the role of these mutations. To explore this rather as a survival or death mechanism, autophagy inhibition sensibilized BRAF mutants to SQ1 and SQ2, whereas the opposite happened to NRAS mutants. These data suggest that the seriniquinones remain active, independently of the melanoma mutation, and suggest the future combination of their application with inhibitors of autophagy to treat BRAF-mutated tumors.

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Antisense Inhibition of c-fes Proto-oncogene Blocks PMA-Induced Macrophage Differentiation in HL60 and in FDC-P1/MAC-11 Cells

Blood ◽

10.1182/blood.v89.1.135.135_135_145 ◽

1997 ◽

Vol 89 (1) ◽

pp. 135-145 ◽

Cited By ~ 1

Author(s):

Rossella Manfredini ◽

Raffaella Balestri ◽

Enrico Tagliafico ◽

Francesca Trevisan ◽

Michela Pizzanelli ◽

...

Keyword(s):

Cell Lines ◽

Phorbol Esters ◽

Myeloid Cell ◽

Macrophage Differentiation ◽

Primary Transcript ◽

Experimental Conditions ◽

Fibronectin Receptor ◽

Splice Junctions ◽

Insight Into

To gain some insight into the role of c-fes in macrophage differentiation, we have analyzed the ability of HL60 leukemic promyelocytic cells and FDC-P1/MAC-11 murine myeloid precursor cells to differentiate in response to phorbol esters after inhibition of c-fes function. Fes inactivation has been obtained by using oligodeoxynucleotides (ODN) complementary to the 5′ region of c-fes mRNA and to 5′ splice junctions of c-fes primary transcript. After 5 days (d) in culture, in several separate experiments performed with different ODN preparations, a complete inhibition of c-fes expression was observed in HL60 and in FDC-P1/MAC-11 cells. No perturbation of cell growth was evident in our experimental conditions in both cell lines after c-fes inhibition. Furthermore, in HL60 cells lacking c-fes product, an almost complete downregulation of the α4β1 fibronectin receptor occurred. However, in both cell lines, the induction of macrophage differentiation by phorbol esters resulted in an almost complete maturation arrest as evaluated by morphological, cytochemical, immunological criteria, and by the cytofluorimetric cell cycle analysis. A loss of the adhesion capacity of both myeloid cell lines, when compared to terminally differentated macrophages, was also observed. These results suggest that HL60 and FDC-P1/MAC-11 cells, when treated with phorbol 12-myristate 13-acetate, require c-fes protein expression to activate the genetic program underlying macrophage differentiation.

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The role of autophagy inhibition in the enhanced cytotoxicity of temozolomide on melanoma cell lines

Advances in molecular oncology ◽

10.17650/2313-805x-2017-4-3-75-82 ◽

2017 ◽

Vol 4 (3) ◽

pp. 75-82

Author(s):

O. O. Ryabaya ◽

A. N. Inshakov ◽

A. A. Malysheva ◽

I. S. Abramov ◽

N. V. Sholina ◽

...

Keyword(s):

Cell Lines ◽

Melanoma Cell ◽

Autophagy Inhibition ◽

Melanoma Cell Lines

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miR-27b Targets HOXB8 to Inhibit Malignant Behaviors of Osteosarcoma

Technology in Cancer Research & Treatment ◽

10.1177/1533033819870791 ◽

2019 ◽

Vol 18 ◽

pp. 153303381987079

Author(s):

Yingyong Wu ◽

Jinyun Peng

Keyword(s):

Cell Proliferation ◽

Western Blot ◽

Cell Lines ◽

Colony Formation ◽

Cell Counting ◽

Osteosarcoma Cell ◽

Polymerase Chain ◽

And Migration ◽

Insight Into

MicroRNAs function as either tumor suppressor or oncogene in human cancers. This study aimed to explore the role of miR-27b in osteosarcoma. Expression of miR-27b or homeobox B8 in osteosarcoma cell lines was analyzed by quantitative real-time polymerase chain reaction and Western blot, respectively. Luciferase activity reporter assay and Western blot were conducted to explore the association between miR-27b and homeobox B8. Cell Counting Kit-8, colony formation assay, and wound-healing assay were performed to investigate the role of miR-27b or homeobox B8 on cell proliferation, colony formation, and cell migration. Expression of miR-27b was significantly reduced, while homeobox B8 was increased in osteosarcoma cell lines. In addition, homeobox B8 was validated as a direct target of homeobox B8. Moreover, miR-27b regulates osteosarcoma cell proliferation, colony formation, and migration through targeting homeobox B8. Taken together, our study provides novel insight into the progression of osteosarcoma, and the miR-27b–homeobox B8 axis identified may be developed as therapeutic targets against hepatocellular carcinoma in the future.

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Antisense Inhibition of c-fes Proto-oncogene Blocks PMA-Induced Macrophage Differentiation in HL60 and in FDC-P1/MAC-11 Cells

Blood ◽

10.1182/blood.v89.1.135 ◽

1997 ◽

Vol 89 (1) ◽

pp. 135-145 ◽

Cited By ~ 26

Author(s):

Rossella Manfredini ◽

Raffaella Balestri ◽

Enrico Tagliafico ◽

Francesca Trevisan ◽

Michela Pizzanelli ◽

...

Keyword(s):

Cell Lines ◽

Phorbol Esters ◽

Myeloid Cell ◽

Macrophage Differentiation ◽

Primary Transcript ◽

Experimental Conditions ◽

Fibronectin Receptor ◽

Splice Junctions ◽

Insight Into

Abstract To gain some insight into the role of c-fes in macrophage differentiation, we have analyzed the ability of HL60 leukemic promyelocytic cells and FDC-P1/MAC-11 murine myeloid precursor cells to differentiate in response to phorbol esters after inhibition of c-fes function. Fes inactivation has been obtained by using oligodeoxynucleotides (ODN) complementary to the 5′ region of c-fes mRNA and to 5′ splice junctions of c-fes primary transcript. After 5 days (d) in culture, in several separate experiments performed with different ODN preparations, a complete inhibition of c-fes expression was observed in HL60 and in FDC-P1/MAC-11 cells. No perturbation of cell growth was evident in our experimental conditions in both cell lines after c-fes inhibition. Furthermore, in HL60 cells lacking c-fes product, an almost complete downregulation of the α4β1 fibronectin receptor occurred. However, in both cell lines, the induction of macrophage differentiation by phorbol esters resulted in an almost complete maturation arrest as evaluated by morphological, cytochemical, immunological criteria, and by the cytofluorimetric cell cycle analysis. A loss of the adhesion capacity of both myeloid cell lines, when compared to terminally differentated macrophages, was also observed. These results suggest that HL60 and FDC-P1/MAC-11 cells, when treated with phorbol 12-myristate 13-acetate, require c-fes protein expression to activate the genetic program underlying macrophage differentiation.

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Possible Role of Hydrogen Peroxide in Apoptosis Induction by Ascorbic Acid in Human Myelogenous Leukemic Cell Lines

The Showa University Journal of Medical Sciences ◽

10.15369/sujms1989.6.135 ◽

1994 ◽

Vol 6 (2) ◽

pp. 135-144 ◽

Cited By ~ 14

Author(s):

Satoru FUJINAGA ◽

Hiroshi SAKAGAMI ◽

Nobuyuki KURIBAYASHI ◽

Hideo TAKAHASHI ◽

Yasuyuki AMANO ◽

...

Keyword(s):

Hydrogen Peroxide ◽

Ascorbic Acid ◽

Cell Lines ◽

Leukemic Cell ◽

Apoptosis Induction ◽

Leukemic Cell Lines

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Plasminogen Activation In Vivo upon Intravenous Infusion of DDAVP

Thrombosis and Haemostasis ◽

10.1055/s-0038-1648390 ◽

1992 ◽

Vol 67 (01) ◽

pp. 111-116 ◽

Cited By ~ 64

Author(s):

Marcel Levi ◽

Jan Paul de Boer ◽

Dorina Roem ◽

Jan Wouter ten Cate ◽

C Erik Hack

Keyword(s):

Monoclonal Antibodies ◽

Plasminogen Activator ◽

Plasma Levels ◽

Fold Increase ◽

Fibrinolytic System ◽

Plasminogen Activation ◽

Plasminogen Activator Activity ◽

Insight Into

SummaryInfusion of desamino-d-arginine vasopressin (DDAVP) results in an increase in plasma plasminogen activator activity. Whether this increase results in the generation of plasmin in vivo has never been established.A novel sensitive radioimmunoassay (RIA) for the measurement of the complex between plasmin and its main inhibitor α2 antiplasmin (PAP complex) was developed using monoclonal antibodies preferentially reacting with complexed and inactivated α2-antiplasmin and monoclonal antibodies against plasmin. The assay was validated in healthy volunteers and in patients with an activated fibrinolytic system.Infusion of DDAVP in a randomized placebo controlled crossover study resulted in all volunteers in a 6.6-fold increase in PAP complex, which was maximal between 15 and 30 min after the start of the infusion. Hereafter, plasma levels of PAP complex decreased with an apparent half-life of disappearance of about 120 min. Infusion of DDAVP did not induce generation of thrombin, as measured by plasma levels of prothrombin fragment F1+2 and thrombin-antithrombin III (TAT) complex.We conclude that the increase in plasminogen activator activity upon the infusion of DDAVP results in the in vivo generation of plasmin, in the absence of coagulation activation. Studying the DDAVP induced increase in PAP complex of patients with thromboembolic disease and a defective plasminogen activator response upon DDAVP may provide more insight into the role of the fibrinolytic system in the pathogenesis of thrombosis.

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On Metaphysics and the Political: A Polemics of Reading Baudelaire in the 1930s

Nottingham French Studies ◽

10.3366/nfs.2019.0252 ◽

2019 ◽

Vol 58 (2) ◽

pp. 249-259

Author(s):

Joseph Acquisto

Keyword(s):

Twentieth Century ◽

Political Crisis ◽

The Political ◽

Modern Poetry ◽

Progressive Politics ◽

The World ◽

Relationship Of ◽

The Relationship ◽

Insight Into

This essay examines a polemic between two Baudelaire critics of the 1930s, Jean Cassou and Benjamin Fondane, which centered on the relationship of poetry to progressive politics and metaphysics. I argue that a return to Baudelaire's poetry can yield insight into what seems like an impasse in Cassou and Fondane. Baudelaire provides the possibility of realigning metaphysics and politics so that poetry has the potential to become the space in which we can begin to think the two of them together, as opposed to seeing them in unresolvable tension. Or rather, the tension that Baudelaire animates between the two allows us a new way of thinking about the role of esthetics in moments of political crisis. We can in some ways see Baudelaire as responding, avant la lettre, to two of his early twentieth-century readers who correctly perceived his work as the space that breathes a new urgency into the questions of how modern poetry relates to the world from which it springs and in which it intervenes.

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Glioblastoma invasion and NMDA receptors: A novel prospect

Physiology International ◽

10.1556/2060.106.2019.22 ◽

2019 ◽

Vol 106 (3) ◽

pp. 250-260 ◽

Cited By ~ 3

Author(s):

DN Nandakumar ◽

P Ramaswamy ◽

C Prasad ◽

D Srinivas ◽

K Goswami

Keyword(s):

Glutamate Receptors ◽

Cell Lines ◽

Intracellular Signaling ◽

Transcript Level ◽

Glioblastoma Cells ◽

Invasion And Migration ◽

Matrigel Invasion ◽

Nmdar Activation ◽

And Migration

Purpose Glioblastoma cells create glutamate-rich tumor microenvironment, which initiates activation of ion channels and modulates downstream intracellular signaling. N-methyl-D-aspartate receptors (NMDARs; a type of glutamate receptors) have a high affinity for glutamate. The role of NMDAR activation on invasion of glioblastoma cells and the crosstalk with α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) is yet to be explored. Main methods LN18, U251MG, and patient-derived glioblastoma cells were stimulated with NMDA to activate NMDAR glutamate receptors. The role of NMDAR activation on invasion and migration and its crosstalk with AMPAR were evaluated. Invasion and migration of glioblastoma cells were investigated by in vitro trans-well Matrigel invasion and trans-well migration assays, respectively. Expression of NMDARs and AMPARs at transcript level was evaluated by quantitative real-time polymerase chain reaction. Results We determined that NMDA stimulation leads to enhanced invasion in LN18, U251MG, and patient-derived glioblastoma cells, whereas inhibition of NMDAR using MK-801, a non-competitive antagonist of the NMDAR, significantly decreased the invasive capacity. Concordant with these findings, migration was significantly augmented by NMDAR in both cell lines. Furthermore, NMDA stimulation upregulated the expression of GluN2 and GluA1 subunits at the transcript level. Conclusions This study demonstrated the previously unexplored role of NMDAR in invasion of glioblastoma cells. Furthermore, the expression of the GluN2 subunit of NMDAR and the differential overexpression of the GluA1 subunit of AMPAR in both cell lines provide a plausible rationale of crosstalk between these calcium-permeable subunits in the glutamate-rich microenvironment of glioblastoma.

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Dažu vācu muzikālo tradīciju pārnese latviešu kultūrtelpā 18. gadsimta II pusē

Letonica ◽

10.35539/ltnc.2020.0041.m.g.0003 ◽

2020 ◽

Author(s):

Māra Grudule

Keyword(s):

18Th Century ◽

Musical Instrument ◽

German Society ◽

Original Form ◽

Musical Life ◽

Popular Songs ◽

Death Of Jesus ◽

Musical Traditions ◽

Insight Into

The article gives insight into a specific component of the work of Baltic enlightener Gotthard Friedrich Stender (1714–1796) that has heretofore been almost unexplored — the transfer of German musical traditions to the Latvian cultural space. Even though there are no sources that claim that Stender was a composer himself, and none of his books contain musical notation, the texts that had been translated by Stender and published in the collections “Jaunas ziņģes” (New popular songs, 1774) and “Ziņģu lustes” (The Joy of singing, 1785, 1789) were meant for singing and, possibly, also for solo-singing with the accompaniment of some musical instrument. This is suggested, first, by how the form of the translation corresponds to the original’s form; second, by the directions, oftentimes attached to the text, that indicate the melody; and third, by the genres of the German originals cantata and song. Stender translated several compositions into Latvian including the text of the religious cantata “Der Tod Jesu” (The Death of Jesus, 1755) by composer Karl Heinrich Graun (1754–1759); songs by various composers that were widely known in German society; as well as a collection of songs by the composer Johann Gottlieb Naumann (1741–1801) that, in its original form, was published together with notation and was intended for solo-singing (female vocals) with the accompaniment of a piano. This article reveals the context of German musical life in the second half of the 18th century and explains the role of music as an instrument of education in Baltic-German and Latvian societies.

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The Role of Industry-Academia Collaborative Research in Mineral Exploration

The Canadian Mineralogist ◽

10.3749/canmin.1900086 ◽

2020 ◽

Author(s):

James Marlatt

Keyword(s):

Collaborative Research ◽

New Technologies ◽

Mineral Exploration ◽

Board Members ◽

Technological Innovations ◽

Development Programs ◽

The University ◽

Insight Into ◽

Economic Mineral

ABSTRACT Many people may not be aware of the extent of Kurt Kyser's collaboration with mineral exploration companies through applied research and the development of innovative exploration technologies, starting at the University of Saskatchewan and continuing through the Queen's Facility for Isotope Research. Applied collaborative, geoscientific, industry-academia research and development programs can yield technological innovations that can improve the mineral exploration discovery rates of economic mineral deposits. Alliances between exploration geoscientists and geoscientific researchers can benefit both parties, contributing to the pure and applied geoscientific knowledge base and the development of innovations in mineral exploration technology. Through a collaboration that spanned over three decades, we gained insight into the potential for economic uranium deposits around the world in Canada, Australia, USA, Finland, Russia, Gabon, Namibia, Botswana, South Africa, and Guyana. Kurt, his research team, postdoctoral fellows, and students developed technological innovations related to holistic basin analysis for economic mineral potential, isotopes in mineral exploration, and biogeochemical exploration, among others. In this paper, the business of mineral exploration is briefly described, and some examples of industry-academic collaboration innovations brought forward through Kurt's research are identified. Kurt was a masterful and capable knowledge broker, which is a key criterion for bringing new technologies to application—a grand, curious, credible, patient, and attentive communicator—whether talking about science, business, or life and with first ministers, senior technocrats, peers, board members, first nation peoples, exploration geologists, investors, students, citizens, or friends.

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