scholarly journals Pharmacogenomics characterization of the MDM2 inhibitor MI-773 reveals candidate tumours and predictive biomarkers

2021 ◽  
Vol 5 (1) ◽  
Author(s):  
Vincent Vuaroqueaux ◽  
Hans R. Hendriks ◽  
Hoor Al-Hasani ◽  
Anne-Lise Peille ◽  
Samayita Das ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Predictive Biomarkers ◽  
Wild Type ◽  
Mutation Status ◽  
Anti Tumour Activity ◽  
Molecule Inhibitor ◽  
Tumour Activity ◽  
Selection Of

AbstractMI-773 is a recently developed small-molecule inhibitor of the mouse double minute 2 (MDM2) proto-oncogene. Preclinical data on the anti-tumour activity of MI-773 are limited and indicate that tumour cell lines (CLs) with mutated TP53 are more resistant to MI-773 than wild type TP53. Here, we explored the compound’s therapeutic potential in vitro using a panel of 274 annotated CLs derived from a diversity of tumours. MI-773 exhibited a pronounced selectivity and moderate potency, with anti-tumour activity in the sub-micromolar range in about 15% of the CLs. The most sensitive tumour types were melanoma, sarcoma, renal and gastric cancers, leukaemia, and lymphoma. A COMPARE analysis showed that the profile of MI-773 was similar to that of Nutlin-3a, the first potent inhibitor of p53–MDM2 interactions, and, in addition, had a superior potency. In contrast, it poorly correlates with profiles of compounds targeting the p53 pathway with another mechanism of action. OMICS analyses confirmed that MI-773 was primarily active in CLs with wild type TP53. In silico biomarker investigations revealed that the TP53 mutation status plus the aggregated expression levels of 11 genes involved in the p53 signalling pathway predicted sensitivity or resistance of CLs to inhibitors of p53–MDM2 interactions reliably. The results obtained for MI-773 could help to refine the selection of cancer patients for therapy.

CRYSTALLOGRAPHIC CHARACTERIZATION OF {Ph2SnCl2[(Me2pz)2CH2]}. IN VITRO ANTI-TUMOUR ACTIVITY

1995 ◽  
Vol 18 (2) ◽  
Author(s):  
Micheal J. Cox ◽  
Silvina Rainone ◽  
George Siasios ◽  
Edward R.T. Tiekink ◽  
Lorraine K. Webster
Keyword(s):  
Anti Tumour Activity ◽  
Tumour Activity

scholarly journals Preclinical Testing of Radiopharmaceuticals for the Detection and Characterization of Osteomyelitis: Experiences from a Porcine Model

Molecules ◽  
2021 ◽  
Vol 26 (14) ◽  
pp. 4221
Author(s):  
Aage Kristian Olsen Alstrup ◽  
Svend Borup Jensen ◽  
Ole Lerberg Nielsen ◽  
Lars Jødal ◽  
Pia Afzelius
Keyword(s):  
Animal Model ◽  
Animal Models ◽  
Porcine Model ◽  
Animal Experiments ◽  
Radioactive Tracers ◽  
The Individual ◽  
Selection Of

The development of new and better radioactive tracers capable of detecting and characterizing osteomyelitis is an ongoing process, mainly because available tracers lack selectivity towards osteomyelitis. An integrated part of developing new tracers is the performance of in vivo tests using appropriate animal models. The available animal models for osteomyelitis are also far from ideal. Therefore, developing improved animal osteomyelitis models is as important as developing new radioactive tracers. We recently published a review on radioactive tracers. In this review, we only present and discuss osteomyelitis models. Three ethical aspects (3R) are essential when exposing experimental animals to infections. Thus, we should perform experiments in vitro rather than in vivo (Replacement), use as few animals as possible (Reduction), and impose as little pain on the animal as possible (Refinement). The gain for humans should by far exceed the disadvantages for the individual experimental animal. To this end, the translational value of animal experiments is crucial. We therefore need a robust and well-characterized animal model to evaluate new osteomyelitis tracers to be sure that unpredicted variation in the animal model does not lead to a misinterpretation of the tracer behavior. In this review, we focus on how the development of radioactive tracers relies heavily on the selection of a reliable animal model, and we base the discussions on our own experience with a porcine model.

Biochemical and genetic characterization of a yeast TFIID mutant that alters transcription in vivo and DNA binding in vitro

1992 ◽  
Vol 12 (5) ◽  
pp. 2372-2382
Author(s):  
K M Arndt ◽  
S L Ricupero ◽  
D M Eisenmann ◽  
F Winston
Keyword(s):  
Amino Acid ◽  
Dna Binding ◽  
Direct Repeat ◽  
Single Amino Acid ◽  
Wild Type ◽  
Dna Binding Specificity ◽  
Selection For

A mutation in the gene that encodes Saccharomyces cerevisiae TFIID (SPT15), which was isolated in a selection for mutations that alter transcription in vivo, changes a single amino acid in a highly conserved region of the second direct repeat in TFIID. Among eight independent spt15 mutations, seven cause this same amino acid change, Leu-205 to Phe. The mutant TFIID protein (L205F) binds with greater affinity than that of wild-type TFIID to at least two nonconsensus TATA sites in vitro, showing that the mutant protein has altered DNA binding specificity. Site-directed mutations that change Leu-205 to five different amino acids cause five different phenotypes, demonstrating the importance of this amino acid in vivo. Virtually identical phenotypes were observed when the same amino acid changes were made at the analogous position, Leu-114, in the first repeat of TFIID. Analysis of these mutations and additional mutations in the most conserved regions of the repeats, in conjunction with our DNA binding results, suggests that these regions of the repeats play equivalent roles in TFIID function, possibly in TATA box recognition.

scholarly journals Rhizosphere-enriched microbes as a pool to design synthetic communities for reproducible beneficial outputs

2018 ◽  
Author(s):  
Maria-Dimitra Tsolakidou ◽  
Ioannis A. Stringlis ◽  
Natalia Fanega-Sleziak ◽  
Stella Papageorgiou ◽  
Antria Tsalakou ◽  
...  
Keyword(s):  
Antifungal Activity ◽  
Fungal Pathogens ◽  
Growth Parameters ◽  
Tomato Plants ◽  
Beneficial Effects ◽  
Negative Effect ◽  
Tomato Growth ◽  
Selection Of

AbstractComposts represent a sustainable way to suppress diseases and improve plant growth. Identification of compost-derived microbial communities enriched in the rhizosphere of plants and characterization of their traits, could facilitate the design of microbial synthetic communities (SynComs) that upon soil inoculation could yield consistent beneficial effects towards plants. Here, we characterized a collection of compost-derived bacteria, previously isolated from tomato rhizosphere, forin vitroantifungal activity against soil-borne fungal pathogens and for their potential to change growth parameters inArabidopsis. We further assessed root-competitive traits in the dominant rhizospheric genusBacillus. Certain isolated rhizobacteria displayed antifungal activity against the tested pathogens and affected growth ofArabidopsis, and Bacilli members possessed several enzymatic activities. Subsequently, we designed two SynComs with different composition and tested their effect onArabidopsisand tomato growth and health. SynCom1, consisting of different bacterial genera, displayed negative effect onArabidopsis in vitro, but promoted tomato growth in pots. SynCom2, consisting of Bacilli, didn’t affectArabidopsisgrowth, enhanced tomato growth and suppressed Fusarium wilt symptoms. Overall, we found selection of compost-derived microbes with beneficial properties in the rhizosphere of tomato plants, and observed that application of SynComs on poor substrates can yield reproducible plant phenotypes.

Effect of temperature on transition and transversion mutagenesis: characterization of wild type and a mutator T4 DNA polymerase mutant

1984 ◽  
Vol 26 (3) ◽  
pp. 386-389 ◽  
Author(s):  
Linda J. Reha-Krantz ◽  
Sükran Parmaksizoglu
Keyword(s):  
Dna Polymerase ◽  
Low Temperatures ◽  
Bacteriophage T4 ◽  
Effect Of Temperature ◽  
In Vitro Mutagenesis ◽  
Wild Type ◽  
Mutational Site

The effect of temperature on genetically well-defined mutational pathways was examined in the bacteriophage T4. The mutational site was a T4 rII ochre mutant which could revert to rII+ via a transversion or to the amber convertant via a transition. Temperature did not strongly affect any of the pathways examined in a wild-type background; however, increased temperature reduced the mutational activity of a mutator DNA polymerase mutant. Possible models to explain the role of temperature in mutagenesis are discussed as well as the significance of low temperatures for in vitro mutagenesis reactions.Key words: bacteriophage T4, mutator, transition, transversion, temperature effects.

scholarly journals Trichomes Morphology and Essential Oils Characterization of Field-Growing and In Vitro Propagated Plants of Lavandula pedunculata

2008 ◽  
Vol 14 (S3) ◽  
pp. 148-149 ◽  
Author(s):  
M. Zuzarte ◽  
A.M. Dinis ◽  
C. Cavaleiro ◽  
J. Canhoto ◽  
L. Salgueiro
Keyword(s):  
Chemical Composition ◽  
Antifungal Activity ◽  
Essential Oils ◽  
Vegetative Propagation ◽  
Leaf Trichomes ◽  
Economic Exploitation ◽  
Selection Of

The selection of native Lavandula species and their economic exploitation have increased in the last few years. Micropropagation techniques have been used as an alternative for vegetative propagation allowing the multiplication of selected genotypes and chemotypes. Our previous studies showed that the essential oils of Lavandula pedunculata have an important antifungal activity against dermatophyte strains. Therefore, a new line of investigation concerning the in vitro culture of this species is justified. In the present study we compare the morphology of the leaf trichomes and the chemical composition of their essential oils in both field-growing and in vitro propagated plants.

scholarly journals Functional characterization of the rod visual pigment of the echidna (Tachyglossus aculeatus), a basal mammal

2012 ◽  
Vol 29 (4-5) ◽  
pp. 211-217 ◽  
Author(s):  
CONSTANZE BICKELMANN ◽  
JAMES M. MORROW ◽  
JOHANNES MÜLLER ◽  
BELINDA S.W. CHANG
Keyword(s):  
Half Life ◽  
Functional Characterization ◽  
Egg Laying ◽  
Sensory Transduction ◽  
Wild Type ◽  
Functional Variation ◽  
Bovine Rhodopsin ◽  
Tachyglossus Aculeatus

AbstractMonotremes are the most basal egg-laying mammals comprised of two extant genera, which are largely nocturnal. Visual pigments, the first step in the sensory transduction cascade in photoreceptors of the eye, have been examined in a variety of vertebrates, but little work has been done to study the rhodopsin of monotremes. We isolated the rhodopsin gene of the nocturnal short-beaked echidna (Tachyglossus aculeatus) and expressed and functionally characterized the protein in vitro. Three mutants were also expressed and characterized: N83D, an important site for spectral tuning and metarhodopsin kinetics, and two sites with amino acids unique to the echidna (T158A and F169A). The λmax of echidna rhodopsin (497.9 ± 1.1 nm) did not vary significantly in either T158A (498.0 ± 1.3 nm) or F169A (499.4 ± 0.1 nm) but was redshifted in N83D (503.8 ± 1.5 nm). Unlike other mammalian rhodopsins, echidna rhodopsin did react when exposed to hydroxylamine, although not as fast as cone opsins. The retinal release rate of light-activated echidna rhodopsin, as measured by fluorescence spectroscopy, had a half-life of 9.5 ± 2.6 min−1, which is significantly shorter than that of bovine rhodopsin. The half-life of the N83D mutant was 5.1 ± 0.1 min−1, even shorter than wild type. Our results show that with respect to hydroxylamine sensitivity and retinal release, the wild-type echidna rhodopsin displays major differences to all previously characterized mammalian rhodopsins and appears more similar to other nonmammalian vertebrate rhodopsins such as chicken and anole. However, our N83D mutagenesis results suggest that this site may mediate adaptation in the echidna to dim light environments, possibly via increased stability of light-activated intermediates. This study is the first characterization of a rhodopsin from a most basal mammal and indicates that there might be more functional variation in mammalian rhodopsins than previously assumed.

scholarly journals Prion replication without host adaptation during interspecies transmissions

2017 ◽  
Vol 114 (5) ◽  
pp. 1141-1146 ◽  
Author(s):  
Jifeng Bian ◽  
Vadim Khaychuk ◽  
Rachel C. Angers ◽  
Natalia Fernández-Borges ◽  
Enric Vidal ◽  
...  
Keyword(s):  
Disease Transmission ◽  
Protein Misfolding ◽  
Guanidine Hydrochloride ◽  
Host Adaptation ◽  
Wild Type ◽  
Epidemiological Features ◽  
Significant Barrier ◽  
Prion Transmission ◽  
Selection Of

Adaptation of prions to new species is thought to reflect the capacity of the host-encoded cellular form of the prion protein (PrPC) to selectively propagate optimized prion conformations from larger ensembles generated in the species of origin. Here we describe an alternate replicative process, termed nonadaptive prion amplification (NAPA), in which dominant conformers bypass this requirement during particular interspecies transmissions. To model susceptibility of horses to prions, we produced transgenic (Tg) mice expressing cognate PrPC. Although disease transmission to only a subset of infected TgEq indicated a significant barrier to EqPrPCconversion, the resulting horse prions unexpectedly failed to cause disease upon further passage to TgEq. TgD expressing deer PrPCwas similarly refractory to deer prions from diseased TgD infected with mink prions. In both cases, the resulting prions transmitted to mice expressing PrPCfrom the species of prion origin, demonstrating that transmission barrier eradication of the originating prions was ephemeral and adaptation superficial in TgEq and TgD. Horse prions produced in vitro by protein misfolding cyclic amplification of mouse prions using horse PrPCalso failed to infect TgEq but retained tropism for wild-type mice. Concordant patterns of neuropathology and prion deposition in susceptible mice infected with NAPA prions and the corresponding prion of origin confirmed preservation of strain properties. The comparable responses of both prion types to guanidine hydrochloride denaturation indicated this occurs because NAPA precludes selection of novel prion conformations. Our findings provide insights into mechanisms regulating interspecies prion transmission and a framework to reconcile puzzling epidemiological features of certain prion disorders.

scholarly journals Characterization of New Virulence Factors Involved in the Intracellular Growth and Survival of Burkholderia pseudomallei

2015 ◽  
Vol 84 (3) ◽  
pp. 701-710 ◽  
Author(s):  
Madeleine G. Moule ◽  
Natasha Spink ◽  
Sam Willcocks ◽  
Jiali Lim ◽  
José Afonso Guerra-Assunção ◽  
...  
Keyword(s):  
Burkholderia Pseudomallei ◽  
Insertion Site ◽  
Wild Type ◽  
Content Type ◽  
Growth And Survival ◽  
New Genes ◽  
Insertion Sites

Burkholderia pseudomallei, the causative agent of melioidosis, has complex and poorly understood extracellular and intracellular lifestyles. We used transposon-directed insertion site sequencing (TraDIS) to retrospectively analyze a transposon library that had previously been screened through a BALB/c mouse model to identify genes important for growth and survivalin vivo. This allowed us to identify the insertion sites and phenotypes of negatively selected mutants that were previously overlooked due to technical constraints. All 23 unique genes identified in the original screen were confirmed by TraDIS, and an additional 105 mutants with various degrees of attenuationin vivowere identified. Five of the newly identified genes were chosen for further characterization, and clean, unmarkedbpsl2248,tex,rpiR,bpsl1728, andbpss1528deletion mutants were constructed from the wild-type strain K96243. Each of these mutants was testedin vitroandin vivoto confirm their attenuated phenotypes and investigate the nature of the attenuation. Our results confirm that we have identified new genes important toin vivovirulence with roles in different stages ofB. pseudomalleipathogenesis, including extracellular and intracellular survival. Of particular interest, deletion of the transcription accessory protein Tex was shown to be highly attenuating, and thetexmutant was capable of providing protective immunity against challenge with wild-typeB. pseudomallei, suggesting that the genes identified in our TraDIS screen have the potential to be investigated as live vaccine candidates.

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