Could the Anti-Chaperone VER155008 Replace Temozolomide for Glioma Treatment

Cancer inducible molecular chaperone HSP90 is of great importance as an anticancer target. Proteomic analysis showed that inhibiting HSP90 by the geldanamycin derivative, 17-AAG elevated the expression of the co-chaperone Hsp70. In this study we used HSP90 selective inhibitor 17-AAG and HSP70/90 dual inhibitor, VER155008 (VER) in U87-MG glioma cells. miRNAs microarray technology was used to evaluate the efficacy of these inhibitory drugs compared with temozolomide (TMZ), used as a standard treatment for glioma. Microarrays data identified 154 differentially expressed miRNAs using stringent or unstringent parameters. 16 miRNAs were overlapped between treatments, 13 upregulated and one downregulated miRNA were overlapped between TMZ and VER. The miRNA target prediction software was used for these overlapped miRNAs and identified 6 of the 13 upregulated miRNAs target methyltransferase genes. The IC50, together with Akt and HSP70 and 90 protein level data favour VER and TMZ to 17-AAG, however due to the selectivity of VER to cancer cells as a potent antichaperon, it may be more favourable to the standard TMZ

Could Upregulated Hsp70 Protein Compensate for the Hsp90-Silence-Induced Cell Death in Glioma Cells?

The molecular chaperone heat shock protein 90 alpha (Hsp90α) has been recognized in various tumours including glioma. This pilot study using a proteomic approach analyses the downstream effects of Hsp90 inhibition using 17-allylamino-17-demethoxygeldanamycin (17AAG) and a short hairpin RNA (shRNA) oligonucleotide targeting hsp90α (shhsp90α) in the U87-MG glioma cell line. Preliminary data coupled with bioinformatic analysis identified several known and unknown Hsp90 client proteins that demonstrated a change in their protein expression after Hsp90 inhibition, signifying an alteration in the canonical pathways of cell cycle progression, apoptosis, cell invasion, angiogenesis, and metastasis. Members of the glycolysis pathway were upregulated, demonstrating increased dependency on glycolysis for energy source by the treated glioma cells. Upregulated proteins also include Hsp70 and members of its family such as Hsp27 and gp96, thereby suggesting the role of Hsp90 co-chaperones in compensating for Hsp90 function after Hsp90 inhibition. Considering Hsp70’s role in antiapoptosis, it was postulated that a combination therapy involving a multitarget approach could be carried out. Consequently inhibition of both Hsp90 and Hsp70 in U87-MG glioma cells resulted in 60% cell death indicating the importance of combination therapy for glioma therapeutics

Could Upregulated Hsp70 Protein Compensate for the Hsp90-Silence-Induced Cell Death in Glioma Cells?

The molecular chaperone heat shock protein 90 alpha (Hsp90α) has been recognized in various tumours including glioma. This pilot study using a proteomic approach analyses the downstream effects of Hsp90 inhibition using 17-allylamino-17-demethoxygeldanamycin (17AAG) and a short hairpin RNA (shRNA) oligonucleotide targeting hsp90α (shhsp90α) in the U87-MG glioma cell line. Preliminary data coupled with bioinformatic analysis identified several known and unknown Hsp90 client proteins that demonstrated a change in their protein expression after Hsp90 inhibition, signifying an alteration in the canonical pathways of cell cycle progression, apoptosis, cell invasion, angiogenesis, and metastasis. Members of the glycolysis pathway were upregulated, demonstrating increased dependency on glycolysis for energy source by the treated glioma cells. Upregulated proteins also include Hsp70 and members of its family such as Hsp27 and gp96, thereby suggesting the role of Hsp90 co-chaperones in compensating for Hsp90 function after Hsp90 inhibition. Considering Hsp70’s role in antiapoptosis, it was postulated that a combination therapy involving a multitarget approach could be carried out. Consequently inhibition of both Hsp90 and Hsp70 in U87-MG glioma cells resulted in 60% cell death indicating the importance of combination therapy for glioma therapeutics

Summary of WG4: 'Lifetime, Mixing and Weak Mixing Phase in Charm and Beauty, Including Direct Determination of V_tx

We present the summary of the Working Group on lifetimes, mixing and weak mixing phases in charm and beauty mesons at the CKM 2010 workshop. In the past year or so good progress was achieved on both experimental and theoretical sides. While this yields improvement in our understanding of neutral meson mixing, further work is necessary to achieve the highest possible precision in order to investigate current hints for deviations between experiment and standard model predictions. With the recent LHC startup we see bright prospects for the near term future for huge improvements

The characterization of operators preserving primitivity for matrix k-tuples

AbstractWe obtain a complete characterization of surjective additive operators acting on the Cartesian product of several matrix spaces over an antinegative semiring without zero divisors, which map primitive matrix k-tuples to primitive matrix k-tuples

γ Heavy Chain Disease in Man: cDNA Sequence Supports Partial Gene Deletion Model

Human gamma heavy chain disease (HCD) is characterized by the presence in serum of a short monoclonal Ig gamma chain unattached to light chains. Although most HCD proteins have internal deletions, in some the defect is NH2-terminal. The OMM gamma 3 HCD serum protein is of the latter type, having undergone an extensive NH2-terminal deletion with a sequence starting within the hinge. A cell line synthesizing the OMM protein has enabled us to study the biogenesis of the abnormal molecule. In vitro translation of isolated mRNA yields a protein containing a hydrophobic NH2-terminal leader sequence. In the intact cell, the precursor molecule is processed normally to yield a protein with an NH2-terminal sequence homologous to the beginning of the variable (V) region. The nucleotide sequence of cDNA prepared from the OMM mRNA encodes a 19-amino acid leader followed by the first 15 residues of the V region. An extensive internal deletion encompasses the remainder of the V and the entire CHl domain. Immediately following the short V region, there is information in the cDNA for the entire normal hinge. The primary synthetic product is thus an internally deleted molecule that undergoes postsynthetic degradation to yield the NH2-terminally deleted serum protein. The structure of the OMM mRNA suggests that the protein abnormality results from a partial gene deletion rather than defective splicing

A novel series of phenolic temozolomide (TMZ) esters with 4 to 5-fold increased potency, compared to TMZ, against glioma cells irrespective of MGMT expression†

The standard of care treatment for patients diagnosed with glioblastoma multiforme (GBM) is temozolomide (TMZ). Tumour resistance to TMZ results in significantly limited clinical effectiveness. There is therefore an inherent need for alternatives to TMZ capable of overcoming resistance associated with MGMT and MMR. In the present study, a series of ester and amide analogues of TMZ, modified at position 8 on the imidazole ring, were prepared and investigated for antiproliferative properties. It was found that phenolic ester analogues of TMZ displayed increased potency, of up to 5-fold, against specified glioblastoma cell lines. The encouraging results displayed by the phenolic TMZ esters prompted further investigations against patient-derived primary glioblastoma cultures. The primary cultures, BTNW914 and BTNW374, were MGMT positive and MGMT negative, respectively. Lead phenolic TMZ esters were found to decrease viability in primary cells at clinically relevant concentrations, irrespective of MGMT expression. Furthermore, TMZ was found to be ineffective against the same primary cells at clinically relevant concentrations. The novel phenyl ester analogues of TMZ, described in this study, could have potential chemotherapeutic properties for the treatment of GBM, overcoming the resistance associated with the expression of MGMT

Major problems encountered in publishing a weekly newspaper in Kansas

Call number: LD2668 .T4 1955 A43Master of Scienc

Les femmes désirables dans le répertoire Disney

Alexander María Leroy, « Les femmes désirables dans le répertoire Disney », RITA [en ligne], N°12 : septembre 2019, mis en ligne le 12 septembre 2019. Disponible en ligne: http://revue-rita.com/dossier-12/les-femmes-desirables-dans-le-repertoire-disney-alexander-maria-leroy.htmlInternational audienceSince cinema is visual and tells a story at the same time, it is a medium that specifically contributes to shared representations, constituting a rich source of study for the sociologist. With its huge number of productions, the diverse films made by Disney are marked by their universal and timeless character, which makes them an important source for the collective imagination. This can equally be applied to sexual fantasy. Indeed the universe created by Disney proposes standards and codes related to desire and more particularly to feminine desirability to a young audience. This article focuses on the Disney studios’ heroines, who, through their appearance and attitudes, define an ideal by establishing references in eroticism, sensuality and moral values. This is an ideal that a qualitative study of the range of Disney’s films leads one to consider as a set of fairly disparate models even if some degree of consistency between them can be observed.Parce qu’il est visuel et narratif à la fois, le cinéma alimente particulièrement les représentations collectives et se présente comme un objet d’étude d’une grande richesse pour le sociologue. Dans la multitude des productions, le répertoire constitué par les films Disney s’impose par son universalité et son intemporalité qui font de lui une source majeure de l’imaginaire commun. Ceci se vérifie aussi en matière de fantasmes sexuels. L’univers disneyen en effet propose, dès l’enfance, des normes et des codes relatifs au désir et, plus particulièrement, relatifs à la désirabilité féminine. Cet article s’intéresse aux héroïnes des studios Disney qui, à travers leurs apparences et leurs attitudes, définissent un idéal fixant des repères en matière d’érotisme, de sensualité et de qualités morales. Un idéal qu’une étude qualitative du répertoire disneyen conduit à plutôt envisager comme un ensemble de modèles relativement hétérogène, quoique des constantes s’observent

Lolita ou le concept de l’adolescente fatale

International audienceLolita’s birth, in the collective imagery in 1955 with the publication of Nabokov novel of the same name, deeply impacted representations related to pedophilia. In modern western societies, pedophilia is criminalized and pathologised both in the desire and in the act. Crime and insanity are not obvious any more, roles change: the teenage girl now becomes a femme fatale responsible for the relationship through a deliberate provocation, changing the pedophile into a prey. Nabokov nymphette approach first gives a justification to behavourial deviance, but also a pretext for this forbidden sexual fantasy. The codes that are proposed face the classic standards and values, and spark controversy. Whether criticism be favourable or unfavourable to this fiction, Lolita becomes a lolita, the archetype of a concept in all minds: a common icon. And now, “lolita” is the common term to designate nymphettes, these young temptresses playing with their ages and bodies liminality. Despite their differing opinions, Kubrick cinematographic adaptations (1962) representing an impossible romance condemned to a tragical end, and Lyne’s one (1997) depicting a sordid and pathetic image of an unhealthy relationship, are putting both special emphasis on a lolita Lolita in Nabokov literary work, which is simultaneously protagonist and concept, is shaking up social representations relative to pedophile fantasy.La naissance de Lolita dans l’imagerie collective en 1955, avec la parution du roman éponyme de Nabokov, a fortement impacté les représentations liées à la pédophilie. Dans les sociétés occidentales contemporaines, celle-ci est criminalisée et pathologisée, tant dans le désir que dans l’acte. Mais le personnage de Lolita s’est imposé comme un véritable concept proposant de porter sur la pédophilie un autre regard. Le crime et la folie ne sont plus évidents, les rôles changent : l’adolescente devient une femme fatale responsable de la relation par une provocation délibérée transformant le pédophile en proie. Donnant une justification à la déviance comportementale, l’approche de la nymphette que réalise Nabokov s’offre aussi comme un prétexte à ce fantasme sexuel interdit. Les codes proposés se heurtent aux normes et valeurs en place et suscitent la controverse. Mais, que la critique soit favorable ou défavorable à cette fiction, Lolita devient une lolita, l’archétype d’un concept dans tous les esprits : une icône commune. Et désormais, « lolita » est le seul terme consacré pour désigner les nymphettes, ces jeunes filles aguicheuses jouant sur la liminalité de leurs âges et corps. Malgré leurs divergences, les adaptations cinématographiques de Kubrick (1962), qui façonne une romance impossible et vouée à une fin tragique, et de Lyne (1997), brossant à l’inverse un portrait sordide et pathétique d’une relation jugée malsaine et maladive, relayent toutes deux l’œuvre de Nabokov dans la mise en avant d’une Lolita lolita, protagoniste-concept bousculant les représentations sociales relatives au fantasme pédophile