Targeted multidimensional gas chromatography using a heart-cutting device and cryogenic focusing for the determination of benzophenone derivatives in foodstuffs

Photoinitiators are used to promote the polymerization process during the curing of varnishes or inks on cartonboard packaging. Depending on storage conditions and shelf life, these substances are able to migrate through the packaging layer into the foodstuff. This type of contamination phenomenon is therefore becoming a critical issue in terms of food safety. In order to tackle this problem, a fast and selective method was developed for the determination of benzophenone and three methylbenzophenone isomers in cereal-based foodstuffs and their cardboard packaging. Food samples or packages were efficiently extracted by pressurized liquid extraction using acetonitrile, and the extracts were directly injected onto the analytical system. The analysis was performed by multidimensional gas chromatography-mass spectrometry using a heart-cutting approach to reduce the background noise from complex matrices. The strategy employed two distinct cuts each containing its proper deuterated internal standard leading to accurate quantification. By integrating a cryofocusing effect, an enhancement in signal/noise ratio was achieved by a factor >10, which markedly decreased the sensitivity threshold. Moreover, baseline separation of the critical isomers allowed their unequivocal determination. The method was fully validated on cereal-based foodstuffs based upon an analysis of variance, and excellent performances were obtained at the decision limit making this method well suited for official food control

Building of the Amsterdam-Saint Paul plateau: A 10 Myr history of a ridge-hot spot interaction and variations in the strength of the hot spot source

International audienceThe Amsterdam-Saint Paul plateau results from a 10 Myr interaction between the South East Indian Ridge and the Amsterdam-Saint Paul hot spot. During this period of time, the structure of the plateau changed as a consequence of changes in both the ridge-hot spot relative distance and in the strength of the hot spot source. The joint analysis of gravity-derived crust thickness and bathymetry reveals that the plateau started to form at ~10 Ma by an increase of the crustal production at the ridge axis, due to the nearby hot spot. This phase, which lasted 3-4 Myr, corresponds to a period of a strong hot spot source, maybe due to a high temperature or material flux, and decreasing ridge-hot spot distance. A second phase, between ~6 and ~3 Ma, corresponds to a decrease in the ridge crustal production. During this period, the hot spot center was close to the ridge axis and this reduced magmatic activity suggests a weak hot spot source. At ~3 Ma, the ridge was located approximately above the hot spot center. An increase in the hot spot source strength then resulted in the building of the shallower part of the plateau. The variations of the melt production at the ridge axis through time resulted in variations in crustal thickness but also in changes in the ridge morphology. The two periods of increased melt production correspond to smooth ridge morphology, characterized by axial highs, while the intermediate period corresponds to a rougher, rift-valley morphology. These variations reveal changes in axial thermal structure due to higher melting production rates and temperatures

Aberrant Splicing Is the Pathogenicity Mechanism of the p.Glu314Lys Variant in CYP11A1 Gene

Context: The cholesterol side chain cleavage enzyme (CYP11A1) catalyzes the conversion of cholesterol to pregnenolone, the first rate-limiting step of steroidogenesis. CYP11A1 mutations are associated with primary adrenal insufficiency (PAI) as well as disorders of sex development (DSD) in 46,XY patients.Objective: To define the pathogenicity mechanism for the p.Glu314Lys variant, previously reported, and found in four additional patients with CYP11A1 deficiency.Subjects and Methods: DNA of four patients presenting with delayed PAI and/or 46,XY DSD were studied by Sanger or Massively Parallel sequencing. Three CYP11A1 mutations were characterized in vitro and in silico, and one by mRNA analysis on testicular tissue.Results: All patients were compound heterozygous for the previously described p.Glu314Lys variant. In silico studies predicted this mutation as benign with no effect on splicing but mRNA analysis found that it led to incomplete exon 5 skipping. This mechanism was confirmed by minigene experiment. The protein carrying this mutation without exon skipping should conserve almost normal activity, according to in vitro studies. Two other mutations found in trans, the p.Arg120Gln and p.Arg465Trp, had similar activity compared to negative control, consistent with the in silico studies.Conclusions: We provide biological proof that the p. Glu314Lys variant is pathogenic due to its impact on splicing and seems responsible for the moderate phenotype of the four patients reported herein. The present study highlights the importance of considering the potential effect of a missense variant on splicing when it is not predicted to be disease causing

A novel facility for reduced-gravity testing: A setup for studying low-velocity collisions into granular surfaces

This work presents an experimental design for studying low-velocity collisions into granular surfaces in low-gravity. In the experiment apparatus, reduced-gravity is simulated by releasing a free-falling projectile into a surface container with a downward acceleration less than that of Earth’s gravity. The acceleration of the surface is controlled through the use of an Atwood machine, or a system of pulleys and counterweights. The starting height of the surface container and the initial separation distance between the projectile and surface are variable and chosen to accommodate collision velocities up to 20 cm/s and effective accelerations of ∼0.1 to 1.0 m/s2. Accelerometers, placed on the surface container and inside the projectile, provide acceleration data, while high-speed cameras capture the collision and act as secondary data sources. The experiment is built into an existing 5.5 m drop tower frame and requires the custom design of all components, including the projectile, surface sample container, release mechanism, and deceleration system. Data from calibration tests verify the efficiency of the experiment’s deceleration system and provide a quantitative understanding of the performance of the Atwood system

Exquisite Sensitivity of TP53 Mutant and Basal Breast Cancers to a Dose-Dense Epirubicin−Cyclophosphamide Regimen

BACKGROUND: In breast cancers, only a minority of patients fully benefit from the different chemotherapy regimens currently in use. Identification of markers that could predict the response to a particular regimen would thus be critically important for patient care. In cell lines or animal models, tumor protein p53 (TP53) plays a critical role in modulating the response to genotoxic drugs. TP53 is activated in response to DNA damage and triggers either apoptosis or cell-cycle arrest, which have opposite effects on cell fate. Yet, studies linking TP53 status and chemotherapy response have so far failed to unambiguously establish this paradigm in patients. Breast cancers with a TP53 mutation were repeatedly shown to have a poor outcome, but whether this reflects poor response to treatment or greater intrinsic aggressiveness of the tumor is unknown. METHODS AND FINDINGS: In this study we analyzed 80 noninflammatory breast cancers treated by frontline (neoadjuvant) chemotherapy. Tumor diagnoses were performed on pretreatment biopsies, and the patients then received six cycles of a dose-dense regimen of 75 mg/m(2) epirubicin and 1,200 mg/m(2) cyclophosphamide, given every 14 days. After completion of chemotherapy, all patients underwent mastectomies, thus allowing for a reliable assessment of chemotherapy response. The pretreatment biopsy samples were used to determine the TP53 status through a highly efficient yeast functional assay and to perform RNA profiling. All 15 complete responses occurred among the 28 TP53-mutant tumors. Furthermore, among the TP53-mutant tumors, nine out of ten of the highly aggressive basal subtypes (defined by basal cytokeratin [KRT] immunohistochemical staining) experienced complete pathological responses, and only TP53 status and basal subtype were independent predictors of a complete response. Expression analysis identified many mutant TP53-associated genes, including CDC20, TTK, CDKN2A, and the stem cell gene PROM1, but failed to identify a transcriptional profile associated with complete responses among TP53 mutant tumors. In patients with unresponsive tumors, mutant TP53 status predicted significantly shorter overall survival. The 15 patients with responsive TP53-mutant tumors, however, had a favorable outcome, suggesting that this chemotherapy regimen can overcome the poor prognosis generally associated with mutant TP53 status. CONCLUSIONS: This study demonstrates that, in noninflammatory breast cancers, TP53 status is a key predictive factor for response to this dose-dense epirubicin–cyclophosphamide regimen and further suggests that the basal subtype is exquisitely sensitive to this association. Given the well-established predictive value of complete responses for long-term survival and the poor prognosis of basal and TP53-mutant tumors treated with other regimens, this chemotherapy could be particularly suited for breast cancer patients with a mutant TP53, particularly those with basal features

Analogues et dérivés inédits des benzo[c]phénanthridines antitumorales. Synthèse et étude biologique

The work presented deals with the preparation of some analogs of the antitumor benzo[c]phenanthridine alcaloids such as nitidine and fagaronine and bearing a dimethylaminoalkylamino side-chain on the carbon 6 of this tetracyclic ring system. The detailed synthetic work described in this report includes: - The discovery of a new synthetic means to prepare alkoxylated-1-aminonaphtalenes from their corresponding 1-tetralones. From these amines, the generalization of a synthetic path to the 7,8,9,10-tetrahydrobenzo[c]phenanthridin-6(5H)-ones enabled us to prepare 16 benzo[c]phenanthridine derivatives mono or bis functionnalized. - A study of Robinson's access to the benzo[c]phenanthridine was performed in order to prepare tetraoxygenated analogs. In the course of this study, we found conditions to prepare the previously unreported 2-aryl-1-naphthylamines from 2-aryl-1-tetraloneoximes using the Semmler-Wolff reaction. From these amines through the corresponding urethane, thermal cyclization gave benzo[c]phenanthridin-6(5H)-ones, readily transformed into the 6-chlorinated derivatives. Not only substitution gave the tetraoxygenated analogs, but this synthesis is actually a new access to this type of alcaloïd. - Also, the condensation between 6-methoxy-1-tetralone, methylpropiolate and ammonia which yielded 8-methoxy-5,6-dihydrobenzo[h]quinolin-2(1H)-one enabled us to prepare four benzo[h]quinoline derivatives substituted with the above-mentionned amino side chain on carbon 2. The results of cytotoxicity tests of all the compounds and antitumoral activity of some are given.Le travail présenté concerne la préparation d'analogues des alcaloïdes antitumoraux de la famille des benzo[c]phénanthridines, tels la nitidine et la fagaronine, porteurs d'une chaîne diméthylaminoalkylamino en position 6 de ce système tétracyclique. Le travail de synthèse organique, décrit en détail dans le manuscrit, comporte notamment les points suivants : - La découverte d'une nouvelle méthode de synthèse des alcoxy-1-aminonaphthalènes à partir des 1-tétralones correspondantes. A partir de ces amines, la généralisation d'une voie d'accès aux 7,8,9,10-tétrahydro benzo[c]phénanthridin-6(5H)-ones nous a permis de synthétiser 16 dérivés des benzo[c]phénanthridines mono ou bifonctionnalisées. - Une étude de la voie d'accès aux benzo[c]phénanthridines selon Robinson a été réalisée pour préparer les analogues tétraoxygénés. A ce sujet, nous avons trouvé des conditions de préparation de 2-aryl-1-aminonaphthalènes, jamais décrites auparavant, à partir de 2-aryl-1-tétralone oximes utilisant la réaction de Semmler-Wolff. Au départ de ces amines nous avons pu préparer les uréthanes correspondants, dont la cyclisation thermique engendre les benzo[c]phénanthridin-6(5H)-ones, facilement transformées en dérivés 6-chlorés. Tandis que la substitution de ces derniers par les amines conduit aux analogues tétraoxygénés, cette synthèse correspond aussi, formellement, à une nouvelle voie d'accès aux alcaloïdes de cette famille. - Par ailleurs, la condensation entre la 6-méthoxy-1-tétralone, le propiolate de méthyle et l'ammoniac qui conduit à la 8-méthoxy-5,6-dihydrobenzo[h]quinoléin-2(1H)-one a permis de préparer quatre dérivés du noyau benzo[h]quinoléine substitués en position 2 par les mêmes chaînes aminées que ci-dessus. Les résultats des tests de cytotoxicité effectués pour l'ensemble des dérivés aminés, de même que l'activité antitumorale de certains d'entre eux, sont décrits

Thieno(2,3-c)pyrazoles substitués, procédé de préparation, compositions les contenant et utilisation

Barbalat Damour, D.; Barberis, C.; Bigot, A.; Carry, J.C.; Clerc, F.; Doerflinger, G.; Genevois Borella, A.; Janin, Y.L.; Minoux, H.; Ronan, B

Preparations of 4-subtituted 3-carboxypyrazoles

International audienceThe scopes of three synthetic methods reported for the preparation of an array of 3-pyrazolecarboxylates featuring substituents on position 4 were investigated. The first one is based on the potassium permanganate oxidation of methylpyrazoles. The second starts with the condensation between DMF dimethylacetal and ethyl pyruvate and is followed by the addition of hydrazine hydrochloride. The last one makes use of the cycloaddition of diazomethane on acrylate esters followed by a bromine-based oxidative rearrangement into 4-substituted 3-pyrazole ester

On drug discovery against infectious diseases and academic medicinal chemistry contributions

International audienceThis perspective is an attempt to document the problems that medicinal chemists are facing in drug discovery. It is also trying to identify relevant/possible, research areas in which academics can have an impact and should thus be the subject of grant calls. Accordingly, it describes how hit discovery happens, how compounds to be screened are selected from available chemicals and the possible reasons for the recurrent paucity of useful/exploitable results reported. This is followed by the successful hit to lead stories leading to recent and original antibacterials which are, or about to be, used in human medicine. Then, illustrated considerations and suggestions are made on the possible inputs of academic medicinal chemists. This starts with the observation that discovering a “good” hit in the course of a screening campaign still rely on a lot of luck – which is within the reach of academics –, that the hit to lead process requires a lot of chemistry and that if public–private partnerships can be important throughout these stages, they are absolute requirements for clinical trials. Concerning suggestions to improve the current hit success rate, one academic input in organic chemistry would be to identify new and pertinent chemical space, design synthetic accesses to reach these and prepare the corresponding chemical libraries. Concerning hit to lead programs on a given target, if no new hits are available, previously reported leads along with new structural data can be pertinent starting points to design, prepare and assay original analogues. In conclusion, this text is an actual plea illustrating that, in many countries, academic research in medicinal chemistry should be more funded, especially in the therapeutic area neglected by the industry. At the least, such funds would provide the intensive to secure series of hopefully relevant chemical entities which appears to often lack when considering the results of academic as well as industrial screening campaigns