Methotrexate area under the curve is an important outcome predictor in patients with primary CNS lymphoma: A pharmacokinetic–pharmacodynamic analysis from the IELSG no. 20 trial

This analysis was initiated to define the predictive value of the area under the curve of high-dose methotrexate (AUC(HD-MTX)) in patients with primary central nervous system lymphoma (PCNSL).; We included 55 patients with PCNSL and available pharmacokinetic (PK) data from the International Extranodal Lymphoma Study Group (IELSG) no. 20 trial, randomised to HD-MTX (n=30) or HD-MTX and high-dose cytarabine (HD-AraC) (n=25). Individual AUC(HD-MTX) from population PK analysis was tested on drug toxicity and clinical outcome using multivariate logistic regression analysis and Cox hazards modelling.; AUC(HD-MTX), the IELSG score and treatment group were significant predictors for treatment response (complete or partial) in the adjusted model. The AUC(HD-MTX) did not predict toxicity, with the exception of liver toxicity and neutropaenia. A high AUC(HD-MTX) was associated with better event-free survival (EFS) (P=0.01) and overall survival (OAS) (P=0.02). Both the AUC(HD-MTX) and the IELSG score were significant predictors of EFS and OAS in the adjusted model, with a hazard ratio of 0.82 and 0.73, respectively, per 100 micromol l(-1) h(-1) increase in AUC(HD-MTX).; Individualised dosing of HD-MTX might have the potential to improve clinical outcome in patients with PCNSL, even when administered concurrently with HD-AraC. In the future, this could be carried out by using first-cycle PK modelling with determination of potential dose adaptations for later cycles using Bayesian analysis

Ensemble-Based Computational Approach Discriminates Functional Activity of p53 Cancer and Rescue Mutants

The tumor suppressor protein p53 can lose its function upon single-point missense mutations in the core DNA-binding domain (“cancer mutants”). Activity can be restored by second-site suppressor mutations (“rescue mutants”). This paper relates the functional activity of p53 cancer and rescue mutants to their overall molecular dynamics (MD), without focusing on local structural details. A novel global measure of protein flexibility for the p53 core DNA-binding domain, the number of clusters at a certain RMSD cutoff, was computed by clustering over 0.7 µs of explicitly solvated all-atom MD simulations. For wild-type p53 and a sample of p53 cancer or rescue mutants, the number of clusters was a good predictor of in vivo p53 functional activity in cell-based assays. This number-of-clusters (NOC) metric was strongly correlated (r2 = 0.77) with reported values of experimentally measured ΔΔG protein thermodynamic stability. Interpreting the number of clusters as a measure of protein flexibility: (i) p53 cancer mutants were more flexible than wild-type protein, (ii) second-site rescue mutations decreased the flexibility of cancer mutants, and (iii) negative controls of non-rescue second-site mutants did not. This new method reflects the overall stability of the p53 core domain and can discriminate which second-site mutations restore activity to p53 cancer mutants

First-in human, phase 1, dose-escalation pharmacokinetic and pharmacodynamic study of the oral dual PI3K and mTORC1/2 inhibitor PQR309 in patients with advanced solid tumors (SAKK 67/13)

BACKGROUND: PQR309 is an orally bioavailable, balanced pan-phosphatidylinositol-3-kinase (PI3K), mammalian target of rapamycin (mTOR) C1 and mTORC2 inhibitor. PATIENTS AND METHODS: This is an accelerated titration, 3 + 3 dose-escalation, open-label phase I trial of continuous once-daily (OD) PQR309 administration to evaluate the safety, pharmacokinetics (PK) and pharmacodynamics in patients with advanced solid tumours. Primary objectives were to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D). RESULTS: Twenty-eight patients were included in six dosing cohorts and treated at a daily PQR309 dose ranging from 10 to 150 mg. Common adverse events (AEs; ≥30% patients) included fatigue, hyperglycaemia, nausea, diarrhoea, constipation, rash, anorexia and vomiting. Grade (G) 3 or 4 drug-related AEs were seen in 13 (46%) and three (11%) patients, respectively. Dose-limiting toxicity (DLT) was observed in two patients at 100 mg OD (>14-d interruption in PQR309 due to G3 rash, G2 hyperbilirubinaemia, G4 suicide attempt; dose reduction due to G3 fatigue, G2 diarrhoea, G4 transaminitis) and one patient at 80 mg (G3 hyperglycaemia >7 d). PK shows fast absorption (Tmax 1-2 h) and dose proportionality for Cmax and area under the curve. A partial response in a patient with metastatic thymus cancer, 24% disease volume reduction in a patient with sinonasal cancer and stable disease for more than 16 weeks in a patient with clear cell Bartholin's gland cancer were observed. CONCLUSION: The MTD and RP2D of PQR309 is 80 mg of orally OD. PK is dose-proportional. PD shows PI3K pathway phosphoprotein downregulation in paired tumour biopsies. Clinical activity was observed in patients with and without PI3K pathway dysregulation. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov # NCT01940133

14-3-3 activation of DNA binding of p53 by enhancing its association into tetramers

Activation of the tumour suppressor p53 on DNA damage involves post-translational modification by phosphorylation and acetylation. Phosphorylation of certain residues is critical for p53 stabilization and plays an important role in DNA-binding activity. The 14-3-3 family of proteins activates the DNA-binding affinity of p53 upon stress by binding to a site in its intrinsically disordered C-terminal domain containing a phosphorylated serine at 378. We have screened various p53 C-terminal phosphorylated peptides for binding to two different isoforms of 14-3-3, ɛ and γ. We found that phosphorylation at either S366 or T387 caused even tighter binding to 14-3-3. We made by semi-synthesis a tetrameric construct comprised of the tetramerization plus C-terminal domains of p53 that was phosphorylated on S366, S378 and T387. It bound 10 times tighter than did the monomeric counterpart to dimeric 14-3-3. We showed indirectly from binding curves and directly from fluorescence-detection analytical ultracentrifugation that 14-3-3 enhanced the binding of sequence-specific DNA to p53 by causing p53 dimers to form tetramers at lower concentrations. If the in vitro data extrapolate to in vivo, then it is an attractive hypothesis that p53 activity may be subject to control by accessory proteins lowering its tetramer–dimer dissociation constant from its normal value of 120–150 nM

Composite structural motifs of binding sites for delineating biological functions of proteins

Most biological processes are described as a series of interactions between proteins and other molecules, and interactions are in turn described in terms of atomic structures. To annotate protein functions as sets of interaction states at atomic resolution, and thereby to better understand the relation between protein interactions and biological functions, we conducted exhaustive all-against-all atomic structure comparisons of all known binding sites for ligands including small molecules, proteins and nucleic acids, and identified recurring elementary motifs. By integrating the elementary motifs associated with each subunit, we defined composite motifs which represent context-dependent combinations of elementary motifs. It is demonstrated that function similarity can be better inferred from composite motif similarity compared to the similarity of protein sequences or of individual binding sites. By integrating the composite motifs associated with each protein function, we define meta-composite motifs each of which is regarded as a time-independent diagrammatic representation of a biological process. It is shown that meta-composite motifs provide richer annotations of biological processes than sequence clusters. The present results serve as a basis for bridging atomic structures to higher-order biological phenomena by classification and integration of binding site structures.Comment: 34 pages, 7 figure

Developing a Nationwide Infrastructure for Therapeutic Drug Monitoring of Targeted Oral Anticancer Drugs: The ON-TARGET Study Protocol

Exposure-efficacy and/or exposure-toxicity relationships have been identified for up to 80% of oral anticancer drugs (OADs). Usually, OADs are administered at fixed doses despite their high interindividual pharmacokinetic variability resulting in large differences in drug exposure. Consequently, a substantial proportion of patients receive a suboptimal dose. Therapeutic Drug Monitoring (TDM), i.e., dosing based on measured drug concentrations, may be used to improve treatment outcomes. The prospective, multicenter, non-interventional ON-TARGET study (DRKS00025325) aims to investigate the potential of routine TDM to reduce adverse drug reactions in renal cell carcinoma patients receiving axitinib or cabozantinib. Furthermore, the feasibility of using volumetric absorptive microsampling (VAMS), a minimally invasive and easy to handle blood sampling technique, for sample collection is examined. During routine visits, blood samples are collected and sent to bioanalytical laboratories. Venous and VAMS blood samples are collected in the first study phase to facilitate home-based capillary blood sampling in the second study phase. Within one week, the drug plasma concentrations are measured, interpreted, and reported back to the physician. Patients report their drug intake and toxicity using PRO-CTCAE-based questionnaires in dedicated diaries. Ultimately, the ON-TARGET study aims to develop a nationwide infrastructure for TDM for oral anticancer drugs

Obesity Alters Endoxifen Plasma Levels in Young Breast Cancer Patients: A Pharmacometric Simulation Approach

Endoxifen is the most important metabolite of the prodrug tamoxifen. High interindividual variability in endoxifen steady-state concentrations (CSS,min ENDX) is observed under tamoxifen standard dosing breast cancer patients that do not reach endoxifen concentrations above a proposed therapeutic threshold of 5.97 ng/mL may be at higher recurrence risk. In this investigation, 10 clinical tamoxifen studies were pooled (nPatients=1388) to investigate influential factors on CSS,min ENDX using nonlinear mixed-effects modelling. Age and body weight were found to significantly impact CSS,min ENDX in addition to CYP2D6 phenotype. Compared to post-menopausal patients, pre-menopausal patients had a 30% higher risk for subtarget CSS,min ENDX at tamoxifen 20 mg per day. In treatment simulations for distinct patient subpopulations, young overweight patients had a 3.1-13.8-fold higher risk for subtarget CSS,min ENDX compared to elderly low-weight patients. Considering ever-rising obesity rates and the clinical importance of tamoxifen for pre-menopausal patients, this subpopulation may benefit most from individualised tamoxifen dosing

Histoire des syndicats de fonctionnaires et du mouvement social en Seine Maritime de 1944 à 1981

In 1944, the National Council of Resistance decides to rebuild a welfare state, in continuation of the Popular Front, that the second World War stops it. The trade unions reunified, in CGT (except CFTC) decide to sustain this program. The trade unions of civil servants from Seine-Maritime organize themselves to take part in this rebuild that they waited for it. What are their demands ? On What do they lean themselves to put them before ? What are their values for which they fight? Do they wait all from the state ? What is their idea of this welfare state ? At least, what means do they use to fight for it and bring it to progress ? Getting the recognition of their freedom union laws, which includes right striking, they agree civil servant status which turn out very protective against their adminstration and its hierarchy. They get too the management of Health Security by their mutual insurances which lead them, in Seine-Maritme, to build a powerful departemental mutual insurance. However, the division of world in two blocks, one liberal and one communist, goes through these trade unions and leads to the break away of 1947 That does not prevent the participation to strikes of 1953 wich they are be able to save their retirement. If they sustain general De Gaulle in his decolonization policy and against seditious generals, they clash him on his institutional, économic and social policy. The strike of 1968 is the culmination of it, throuhgout adjournements. But in order to restore the welfare state that they hope, they must sustain lefts’ candidate, François Mitterrand, in their electoral compaigns of 1974 and 1981, who wins in this last year, in spite of their differences and thanks to the Will of unity of their activists.En 1944, le Conseil national de la Résistance décide de reconstruire un Etat social dans la continuité du Front populaire, avant que le second conflit ne l’interrompe. Les syndicats ouvriers réunifiés dans la CGT (sauf la CFTC) décident de soutenir ce programme. Les syndicats de fonctionnaires de Seine-Maritime s’organisent pour participer à cette reconstruction qu’ils attendaient. Quels sont leurs revendications ? Sur quoi s’appuient-ils pour les mettre en avant ? Quels sont les valeurs qu’ils défendent ? Attendent-ils tout de l’Etat social ? Quelle est leur conception de cet Etat social ? Enfin, quels moyens utilisent-ils pour le défendre et le faire progresser ? Obtenant la reconnaissance de leur liberté syndicale qui comprend le droit de grève, ils acceptent un statut qui se révèle fort protecteur vis-à-vis de l’administration et de sa hiérarchie. Ils obtiennent aussi la gestion de la Sécurité sociale par leurs mutuelles qui les entraînent, en Seine-Maritime, à construire une mutualité départementale unifiée et puissante. Toutefois, la division du monde en deux blocs, un libéral et un communiste, traverse ces syndicats et aboutit à la scission de 1947. Cela n’empêche pas la participation aux grèves de 1953 qui leur permet de sauver leur retraite. S’ils soutiennent le général de Gaulle (1890-1970) dans sa politique de décolonisation et contre les généraux factieux, ils l’affrontent sur sa politique institutionnelle, économique et sociale. La grève de 1968 en est l’aboutissement, par-delà les remises en cause. Mais pour rétablir l’Etat social qu’ils souhaitent, il leur faut soutenir les campagnes électorales de 1974 et 1981 du candidat de la gauche, François Mitterrand (1916-1996), qui l’emporte en 1981, en dépit de leurs divergences et grâce à la volonté unitaire de leurs militants