Involvement of the JAK-STAT pathway in the molecular landscape of tyrosine kinase fusion-negative hypereosinophilic syndromes: A nationwide CEREO study.

We investigated using a custom NGS panel of 149 genes the mutational landscape of 64 consecutive adult patients with tyrosine kinase fusion-negative hypereosinophilia (HE)/hypereosinophilic syndrome (HES) harboring features suggestive of myeloid neoplasm. At least one mutation was reported in 50/64 (78%) patients (compared to 8/44 (18%) patients with idiopathic HE/HES/HEUS used as controls; p < .001). Thirty-five patients (54%) had at least one mutation involving the JAK-STAT pathway, including STAT5B (n = 18, among which the hotspot N642H, n = 13), JAK1 (indels in exon 13, n = 5; V658F/L, n = 2), and JAK2 (V617F, n = 6; indels in exon 13, n = 2). Other previously undescribed somatic mutations were also found in JAK2, JAK1, STAT5B, and STAT5A, including three patients who shared the same STAT5A V707fs mutation and features consistent with primary polycythemia. Nearly all JAK-STAT mutations were preceded by (or associated with) myelodysplasia-related gene mutations, especially in RNA-splicing genes or chromatin modifiers. In multivariate analysis, neurologic involvement (hazard ratio [HR] 4.95 [1.87-13.13]; p = .001), anemia (HR 5.50 [2.24-13.49]; p < .001), and the presence of a high-risk mutation (as per the molecular international prognosis scoring system: HR 6.87 [2.39-19.72]; p < .001) were independently associated with impaired overall survival. While corticosteroids were ineffective in all treated JAK-STAT-mutated patients, ruxolitinib showed positive hematological responses including in STAT5A-mutated patients. These findings emphasize the usefulness of NGS for the workup of tyrosine kinase fusion-negative HE/HES patients and support the use of JAK inhibitors in this setting. Updated classifications could consider patients with JAK-STAT mutations and eosinophilia as a new "gene mutated-entity" that could be differentiated from CEL, NOS, and idiopathic HES.

Real-world study of the efficacy and safety of belantamab mafodotin (GSK2857916) in relapsed or refractory multiple myeloma based on data from the nominative ATU in France: the IFM 2020-04 study.

Belantamab mafodotin (BM) is an anti-BCMA antibody-drug conjugate (GSK2857916) that represents an alternative option in multiple myeloma. We sought to assess the efficacy and safety of BM in a real-world setting in patients who benefited from an early access program. We conducted an observational, retrospective, multicenter study. Eligibility criteria were treatment of relapsed or refractory multiple myeloma (RRMM) in monotherapy in adult patients who have received at least three lines of therapy previously, including at least one immunomodulatory agent (IMiD), a proteasome inhibitor (PI) and an anti-CD38 monoclonal antibody, and whose disease progressed during the last treatment period. The primary endpoint of the study is to assess the overall survival (OS). Between November 2019 and December 2020, 106 patients were treated with BM; 97 were eligible for the efficacy evaluation and 104 for safety. The median age was 66 (range, 37-82) years. High-risk cytogenetics were identified in 40.9% of patients. Fifty-five (56.7%) patients were triple-class refractory and 11 (11.3%) were penta-class refractory. The median number of prior lines of treatment was five (range, 3-12). The median number of BM cycles administered was three (range, 1-22). The overall response rate at best response was 38.1% (37/97). The median OS was 9.3 months (95% confidence interval [CI]: 5.9-15.3), and median progression-free survival was 3.5 months (95% CI: 1.9-4.7). The median duration of response was 9 months (range, 4.65-10.4). Treatment was delayed for 55 (52.9%) patients including 36.5% for treatment-related toxicity. Ophthalmic adverse events, mainly grade ≤2, were the most common toxicity (48%). The occurrence of keratopathy was 37.5%. Overall, our data are concordant with the results from DREAMM-2 in terms of efficacy and safety on a non-biased population.

Development of a decision tree for the pharmacy-led consultation of elderly patients with haematological malignancies.

INTRODUCTION: Elderly patients with haematological malignancies are a population at risk of iatrogenic for whom these activities could optimize therapeutic management. However, the limitation of human resources requires optimization of the process in order to improve the efficiency of pharmaceutical activities. The objective was to build a decision tree to optimize the pharmaceutical consultation in these population within a multidisciplinary team in haematology. METHOD: Pharmaceutical consultations were proposed to elderly subjects with haematological malignancies followed up in a haematology day hospitalization at the University Hospital of Limoges. Risk factors for prescribing risky drugs in this population were determined by logistic regression models. A decision tree was constructed based on these results and by agreement between pharmacist, geriatrician and hematologist. RESULTS: Female gender (aOR[CI95%] = 1.71 [1.14-2.57]), polypharmacy (aOR[CI95%] = 1.89 [1.14-3.13]), hyper-polypharmacy (aOR[CI95%] = 5.73 [3.03-10.84]) and moderate cholinergic load (aOR[CI95%] = 2.15 [1.04-4.45]) were risk factors for the prescription of inappropriate medicine. Female gender (aOR[CI95%] = 1.55 [1.02-2.35]) and hyper-polypharmacy (aOR[CI95%] = 6.19 [1-1.28]) were risk factors for prescribing anticholinergic drugs or anticoagulants; in contrast, frailty status was a protective factor for prescribing anticholinergics (aOR[CI95%] = 0.51 [0.33-0.81]). Prioritization of pharmaceutical consultations is based on frailty status, prescription of a target drug and polypharmacy. DISCUSSION: Pharmaceutical consultations during the day hospitalization of elderly subjects with hematological diseases allow to propose therapeutic optimizations. The prioritization proposed in our study would increase the efficiency of pharmaceutical activities in order to improve quality and safety throughout the care pathway of these patients.

Design, synthesis, and antiproliferative effect of 2,9-bis[4-(pyridinylalkylaminomethyl)phenyl]-1,10-phenanthroline derivatives on human leukemic cells by targeting G-quadruplex.

Current multiagent chemotherapy regimens have improved the cure rate in acute leukemia patients, but they are highly toxic and poorly efficient in relapsed patients. To improve the treatment approaches, new specific molecules are needed. The G-quadruplexes (G4s), which are noncanonical nucleic acid structures found in specific guanine-rich DNA or RNA, are involved in many cellular events, including control of gene expression. G4s are considered as targets for the development of anticancer agents. Heterocyclic molecules are well known to target and stabilize G4 structures. Thus, a new series of 2,9-bis[(substituted-aminomethyl)phenyl]-1,10-phenanthroline derivatives (1a-i) was designed, synthesized, and evaluated against five human myeloid leukemia cell lines (K562, KU812, MV4-11, HL60, and U937). Their ability to stabilize various oncogene promoter G4 structures (c-MYC, BCL-2, and K-RAS) as well as the telomeric G4 was also determined through the fluorescence resonance energy transfer melting assay and native mass spectrometry. In addition, the more bioactive ligands 1g-i were tested for telomerase activity in HuT78 and MV4-11 protein extracts.

Design, synthesis, and antiprotozoal evaluation of new 2,4-bis[(substituted-aminomethyl)phenyl]quinoline, 1,3-bis[(substituted-aminomethyl)phenyl]isoquinoline and 2,4-bis[(substituted-aminomethyl)phenyl]quinazoline derivatives.

A series of new 2,4-bis[(substituted-aminomethyl)phenyl]quinoline, 1,3-bis[(substituted-aminomethyl)phenyl]isoquinoline, and 2,4-bis[(substituted-aminomethyl)phenyl]quinazoline derivatives was designed, synthesised, and evaluated in vitro against three protozoan parasites (Plasmodium falciparum, Leishmania donovani, and Trypanosoma brucei brucei). Biological results showed antiprotozoal activity with IC50 values in the µM range. In addition, the in vitro cytotoxicity of these original molecules was assessed with human HepG2 cells. The quinoline 1c was identified as the most potent antimalarial candidate with a ratio of cytotoxic to antiparasitic activities of 97 against the P. falciparum CQ-sensitive strain 3D7. The quinazoline 3h was also identified as the most potent trypanosomal candidate with a selectivity index (SI) of 43 on T. brucei brucei strain. Moreover, as the telomeres of the parasites P. falciparum and Trypanosoma are possible targets of this kind of nitrogen heterocyclic compounds, we have also investigated stabilisation of the Plasmodium and Trypanosoma telomeric G-quadruplexes by our best compounds through FRET melting assays.

Physician uncertainty aversion impacts medical decision making for older patients with acute myeloid leukemia: results of a national survey.

Elderly patients with acute myeloid leukemia can be treated with intensive chemotherapy, low-intensity therapy such as low-dose aracytine or hypomethylating agents, or best supportive care. The choice between these treatments is a function of many patient-related and disease-related factors. We investigated how physicians' behavioral characteristics affect medical decision-making between intensive and non-intensive therapy in this setting. A nationwide cross-sectional online survey of hematologists collected data on medical decision-making for 6 clinical vignettes involving older acute myeloid leukemia patients that were representative of routine practice. Questionnaires elicited physicians' demographic and occupational characteristics along with their individual behavioral characteristics according to a decision theory framework. From the pattern of responses to the vignettes, a K-means clustering algorithm was used to distinguish those who were likely to prescribe more intensive therapy and those who were likely to prescribe less intensive or no therapy. Multivariate analyses were used to identify physician's characteristics predictive of medical decision-making. We obtained 230 assessable answers, which represented an adjusted response rate of 45.4%. A multivariate model (n=210) revealed that physicians averse to uncertainty recommend significantly more intensive chemotherapy: Odds Ratio (OR) [95% Confidence Interval (CI)]: 1.15 [1.01;1.30]; P=0.039. Male physicians who do not conform to the expected utility model (assumed as economically irrational) recommend more intensive chemotherapy [OR (95% CI) = 3.45 (1.34; 8.85); P=0.01]. Patient volume per physician also correlated with therapy intensity [OR (95% CI)=0.98 (0.96; 0.99); P=0.032]. The physicians' medical decision-making was not affected by their age, years of experience, or hospital facility. The significant association between medical decision and individual behavioral characteristics of the physician identifies a novel non-biological factor that may affect acute myeloid leukemia patients' outcomes and explain variations in clinical practice. It should also encourage the use of validated predictive models and the description of novel bio-markers to best select patients for intensive chemotherapy or low-intensity therapy.

Fully automated sample preparation procedure to measure drugs of abuse in plasma by liquid chromatography tandem mass spectrometry.

For the analysis of drugs and pharmaceutical compounds in biological matrices, extraction procedures are typically used for LC-MS/MS analysis often requiring manual steps in sample preparation. In this study, we report a fully automated extraction method carried out by a programable liquid handler directly coupled to an LC-MS/MS system for the determination of 42 components (illicit drugs and/or metabolites) (plus 20 deuterated internal standards). The acquisition was performed in positive ionization mode with up to 15 MRM transitions per compound, each with optimized collision energy (MRM spectrum mode) to enable qualitative library searching in addition to quantitation. After placing the sample tube into the system, no further intervention was necessary: automated preparation used 50 µL of blood or plasma with 3 µL of extracted sample injected for analysis. The method was validated according to the requirements of ISO 15189. The limit of detection and quantification was 1-5 ng/mL depending on the compound. Stability experiments found that historic calibration curve data files could accurately quantify for up to 1 month with less than 20% uncertainty. Comparison to a QuEChERS method was made using patient samples providing a regression correlation R2 = 0.98 between the two methods. This approach was successfully designed to support parallel sample preparation and analysis therefore significantly increasing sample throughput and reduced cycle times. Graphical abstract ᅟ.

Fast and accurate analytical modeling of broadband noise for a low-speed fan.

The broadband noise sources are investigated on an isolated low-speed fan typical of engine cooling systems. Reynolds-averaged Navier-Stokes (RANS) simulations have been performed on a single blade passage for several flow rates at the same rotational speed. The flow structures responsible for the different noise contributions are identified by a systematic analysis of the simulation results. The aeroacoustic noise predictions are based on Amiet's model for rotating sources in free-field. The contribution of the turbulence-interaction noise and the trailing-edge noise are considered by the appropriate isolated blade response and statistical model of the turbulent sources. The flow parameters of the aeroacoustic response and the turbulent models are extracted from the RANS simulations. The radial evolution of the flow parameters for the different flow rates is analyzed and related to the three-dimensional flows in the machine. The acoustic predictions are validated with experimental spectra measured upstream of the fan in a reverberant room. The two considered mechanisms evolve differently with the flow rate. The leading-edge sources are dominant at low flow rate up to the design point and the self-noise becomes dominant at high flow rate for which the secondary flow structures are limited.

Design, synthesis and antimalarial activity of novel bis{N-[(pyrrolo[1,2-a]quinoxalin-4-yl)benzyl]-3-aminopropyl}amine derivatives.

Novel series of bis- and tris-pyrrolo[1,2-a]quinoxaline derivatives 1 were synthesized and tested for in vitro activity upon the intraerythrocytic stage of W2 and 3D7 Plasmodium falciparum strains. Biological results showed good antimalarial activity with IC50 in the µM range. In attempting to investigate the large broad-spectrum antiprotozoal activities of these new derivatives, their properties toward Leishmania donovani were also investigated and revealed their selective antiplasmodial profile. In parallel, the in vitro cytotoxicity of these molecules was assessed on the human HepG2 cell line. Structure-activity relationships of these new synthetic compounds are discussed here. The bis-pyrrolo[1,2-a]quinoxalines 1n and 1p were identified as the most potent antimalarial candidates with selectivity index (SI) of 40.6 on W2 strain, and 39.25 on 3D7 strain, respectively. As the telomeres of the parasite could constitute an attractive target, we investigated the possibility of targeting Plasmodium telomeres by stabilizing the Plasmodium telomeric G-quadruplexes through a FRET melting assay by our new compounds.

Interior sound field control using generalized singular value decomposition in the frequency domain.

The problem of controlling a sound field inside a region surrounded by acoustic control sources is considered. Inspired by the Kirchhoff-Helmholtz integral, the use of double-layer source arrays allows such a control and avoids the modification of the external sound field by the control sources by the approximation of the sources as monopole and radial dipole transducers. However, the practical implementation of the Kirchhoff-Helmholtz integral in physical space leads to large numbers of control sources and error sensors along with excessive controller complexity in three dimensions. The present study investigates the potential of the Generalized Singular Value Decomposition (GSVD) to reduce the controller complexity and separate the effect of control sources on the interior and exterior sound fields, respectively. A proper truncation of the singular basis provided by the GSVD factorization is shown to lead to effective cancellation of the interior sound field at frequencies below the spatial Nyquist frequency of the control sources array while leaving the exterior sound field almost unchanged. Proofs of concept are provided through simulations achieved for interior problems by simulations in a free field scenario with circular arrays and in a reflective environment with square arrays.

Direct Imaging of the Onset of Electrical Conduction in Silver Nanowire Networks by Infrared Thermography: Evidence of Geometrical Quantized Percolation.

Advancement in the science and technology of random metallic nanowire (MNW) networks is crucial for their appropriate integration in many applications including transparent electrodes for optoelectronics and transparent film heaters. We have recently highlighted the discontinuous activation of efficient percolating pathways (EPPs) for networks having densities slightly above the percolation threshold. Such networks exhibit abrupt drops of electrical resistance when thermal or electrical annealing is performed, which gives rise to a "geometrically quantized percolation". In this Letter, lock-in thermography (LiT) is used to provide visual evidence of geometrical quantized percolation: when low voltage is applied to the network, individual "illuminated pathways" can be detected, and new branches get highlighted as the voltage is incrementally increased. This experimental approach has allowed us to validate our original model and map the electrical and thermal distributions in silver nanowire (AgNW) networks. We also study the effects of electrode morphology and wire dimensions on quantized percolation. Furthermore, we demonstrate that the network failure at high temperature can also be governed by a quantized increase of the electrical resistance, which corresponds to the discontinuous destruction of individual pathways (antipercolation). More generally, we demonstrate that LiT is a promising tool for the detection of conductive subclusters as well as hot spots in AgNW networks.

Cost savings of home bortezomib injection in patients with multiple myeloma treated by a combination care in Outpatient Hospital and Hospital care at Home.

At home injectable chemotherapy for patients receiving treatment for hematological diseases is still in debate. Given the expense of new innovative medicines, at home treatment has been proposed as a suitable option for improving patient quality of life and decreasing treatment costs. We decided to assess the cost of bortezomib administration in France among multiple myeloma patients from an economic standpoint. Patients in this study were treated within a regional hematological network combining outpatient hospital care and Hospital care at Home administration. To make the cost comparison, our team simulated outpatient hospital care expenses. Fifty-four consecutive multiple myeloma patients who received at least one injection of bortezomib in Hospital care at Home from January 2009 to December 2011 were included in the study. The median number of injections was 12 (range 1-44) at home and 6 (range 0-30) in the outpatient care unit. When compared with the cost simulation of outpatient hospital care alone, bortezomib administration with combined care was significantly less expensive for the National Health Insurance (NHI) budget. The mean total cost per patient and per injection was 954.20 € for combined outpatient and Hospital care at Home vs 1143.42 € for outpatient hospital care alone. This resulted in an estimated 16.5 % cost saving (Wilcoxon signed-rank test, p < 0.0001). The greatest savings were observed in administration costs (37.5 % less) and transportation costs (68.1 % less). This study reflects results for a regionally implemented program for multiple myeloma patients treated with bortezomib in routine practice in a large rural area.

Sub-harmonic broadband humps and tip noise in low-speed ring fans.

A joint experimental and numerical study has been achieved on a low-speed axial ring fan in clean inflow. Experimental evidence shows large periodic broadband humps at lower frequencies than the blade passing frequencies and harmonics even at design conditions. These sub-harmonic humps are also found to be sensitive to the fan process and consequently to its tip geometry. Softer fans yield more intense humps more shifted to lower frequencies with respect to the fan harmonics. Unsteady turbulent flow simulations of this ring fan mounted on a test plenum have been achieved by four different methods that have been validated by comparing with overall performances and detailed hot-wire velocity measurements in the wake. Noise predictions are either obtained directly or are obtained through Ffowcs Williams and Hawkings' analogy, and compared with narrowband and third-octave power spectra. All unsteady simulations correctly capture the low flow rates, the coherent vortex dynamics in the tip clearance and consequently the noise radiation dominated by the tip noise in the low- to mid-frequency range. Yet, only the scale-adaptive simulation and the lattice Boltzmann method simulations which can describe most of the turbulent structures accurately provide the proper spectral shape and levels, and consequently the overall sound power level.

Direct noise simulation of a canonical high lift device and comparison with an analytical model.

The noise of a canonical main-element/flap high-lift device (HLD) is computed directly using compressible wall-resolved Large Eddy Simulation. An experimental database for the chosen configuration allows us to successfully validate the chosen numerical approach. Both the noise sources and the far-field acoustic pressure are shown to be well predicted. Although the two elements trailing-edge noise can be observed in the near field, the flap remains as the dominant source in the far-field. The simplicity of the studied configuration enables the comparison of the validated numerical results with a recently developed analytical model that takes into account the diffraction of the flap noise by the main-element. A two-dimensional (2D) (with and without Kutta condition) and a three-dimensional (without Kutta correction) analytical formulations are compared with the numerical results. All formulations compare favorably with the numerical reference in terms of noise levels and directivities. However, the 2D formulation with a Kutta correction provides the best quantitative agreement as expected from the narrow span of the numerical domain. The recently developed analytical model is therefore a good predictive tool for HLD, showing that it can properly account for the diffraction effect of the main element on the flap main noise source.

Tonal noise of a controlled-diffusion airfoil at low angle of attack and Reynolds number.

The acoustic signature of a controlled-diffusion airfoil immersed in a flow is experimentally characterized. Acoustic measurements have been carried out in an anechoic open-jet-wind-tunnel for low Reynolds numbers (from 5 × 10(4) to 4.3 × 10(5)) and several angles of attack. As with the NACA0012, the acoustic spectrum is dominated by discrete tones. These tonal behaviors are divided into three different regimes. The first one is characterized by a dominant primary tone which is steady over time, surrounded by secondary peaks. The second consists of two unsteady primary tones associated with secondary peaks and the third consists of a hump dominated by several small peaks. A wavelet study allows one to identify an amplitude modulation of the acoustic signal mainly for the unsteady tonal regime. This amplitude modulation is equal to the frequency interval between two successive tones. Finally, a bispectral analysis explains the presence of tones at higher frequencies.

Subharmonic tonal noise from backflow vortices radiated by a low-speed ring fan in uniform inlet flow.

In order to highlight the mechanisms responsible for subharmonic tonal noise, a complete aeroacoustic study of a ring fan in presence of a uniform inlet flow is conducted. Unsteady RANS simulations with a compressible flow solver are used to compute the flow field and identify the acoustic sources on the rotor. The tip clearance recirculation shows upstream vortices that impinge the rotor blades and create the main source of unsteadiness on the fan. Since these vortices rotate at a lower speed than the rotor, the frequency of the impact is lower than the blade passing frequency. The acoustic signature is computed by propagating the noise sources located on the rotor surfaces using two methods: A Ffowcs-Williams and Hawkings analogy in the time-domain and an analytical model in the frequency-domain based on the compact rotating dipole formulation. A comparison with experimental results confirms that the aeroacoustic phenomena responsible for the subharmonic tonal noise are well captured and properly propagated by the acoustic codes.

Factors associated with the designation of a health care proxy and writing advance directives for patients suffering from haematological malignancies.

BACKGROUND: During the last few decades, patients' rights have been reinforced in many countries by acts of law. Measures now include health care proxies to uphold the doctor-patient relationship and advance directives for end-of-life patients. These could be relevant tools as early as the initial diagnosis of haematological malignancies because of the uncertain disease course. The aim of this research was to assess the factors associated with the designation of a proxy and writing advance directives by patients in a haematology department in France. METHODS: After a specific programme to encourage discussions about end-of-life preferences, we conducted a mixed-methods study comprising retrospective analysis of a random sample of 200 patients' medical records, crossed with a qualitative analysis of the content of advance directives. Statistical analysis was performed by the RKward V 0.6.1 software with 0.05 denoting significance. The study was performed and presented in accordance with the STROBE guidelines. A thematic analysis of the advance directives was performed by two researchers. RESULTS: A total of 197 medical records were evaluable. The mean age of the patients was 66 years (range: 18-91). Nearly 2/3 of them (64.5%) designated a proxy, 6.1% wrote advance directives, and 8.1% and 4.6% expressed a wish to meet a religious representative or a volunteer, respectively. The 2-year survival rate was 78.4% [95%CI: 68.2-90.2]. Patients who wrote advance directives were statistically older (p <0.00025). Patients who wrote an advance directive were more likely to have expressed a wish to meet a religious representative (p <0.001) or a volunteer (p = 0.003). Marital status was a significant factor in appointing a proxy (p = 0.04). CONCLUSIONS: To the best of our knowledge, this is the first paper to identify influencing factors for proxies and advance directives in a homogenous population of patients with haematological malignancies. Most patients chose a proxy. However, despite several training programmes for the carers and a care planning programme, few patients wrote advance directives. Our findings suggest that influencing factors are advanced age and a wish to see a religious representative. This study highlights the importance of oral communication about end-of-life issues between carers, patients and their relatives.

Experimental vibroacoustic testing of plane panels using synthesized random pressure fields.

The experimental reproduction of random pressure fields on a plane panel and corresponding induced vibrations is studied. An open-loop reproduction strategy is proposed that uses the synthetic array concept, for which a small array element is moved to create a large array by post-processing. Three possible approaches are suggested to define the complex amplitudes to be imposed to the reproduction sources distributed on a virtual plane facing the panel to be tested. Using a single acoustic monopole, a scanning laser vibrometer and a baffled simply supported aluminum panel, experimental vibroacoustic indicators such as the Transmission Loss for Diffuse Acoustic Field, high-speed subsonic and supersonic Turbulent Boundary Layer excitations are obtained. Comparisons with simulation results obtained using a commercial software show that the Transmission Loss estimation is possible under both excitations. Moreover and as a complement to frequency domain indicators, the vibroacoustic behavior of the panel can be studied in the wave number domain.

Reproduction of random pressure fields based on planar nearfield acoustic holography.

This article discusses an open-loop approach based on planar nearfield acoustic holography (P-NAH) for the reproduction of random pressure fields, mainly intended for the measurement of vibroacoustic properties of plane panels. The main application is the simulation of turbulent boundary layer excitation in a laboratory environment, as an alternative to in-flight or wind tunnel experiments. The problem under study is the synthesis of random pressure distributions on a plane reproduction surface using acoustic monopoles distributed on a plane source surface facing the reproduction surface. The problem of reproducing a pressure distribution on a plane surface is addressed using the theoretical framework of P-NAH, which is extended to random pressure fields with corresponding imposed cross-spectral density functions. Results of numerical simulations are presented for the reproduction of a diffuse acoustic field, and a subsonic and supersonic turbulent boundary layer. The influence on the reproduction accuracy of the respective sizes of the two planes, their separation and the reproduction source separation are studied. The reproduction approach shows to be effective for the reproduction of diffuse acoustic field and turbulent boundary layer, but with different requirements in terms of plane separation and reproduction sources separation. In the specific case of subsonic turbulent boundary layer and associated sub-wavelength correlation scales reproduction, possible improvements of the method are suggested.

New 2,4-bis[(substituted-aminomethyl)phenyl]phenylquinazoline and 2,4-bis[(substituted-aminomethyl)phenyl]phenylquinoline Derivatives: Synthesis and Biological Evaluation as Novel Anticancer Agents by Targeting G-Quadruplex.

The syntheses of novel 2,4-bis[(substituted-aminomethyl)phenyl]phenylquinazolines 12 and 2,4-bis[(substituted-aminomethyl)phenyl]phenylquinolines 13 are reported here in six steps starting from various halogeno-quinazoline-2,4-(1H,3H)-diones or substituted anilines. The antiproliferative activities of the products were determined in vitro against a panel of breast (MCF-7 and MDA-MB-231), human adherent cervical (HeLa and SiHa), and ovarian (A2780) cell lines. Disubstituted 6- and 7-phenyl-bis(3-dimethylaminopropyl)aminomethylphenyl-quinazolines 12b, 12f, and 12i displayed the most interesting antiproliferative activities against six human cancer cell lines. In the series of quinoline derivatives, 6-phenyl-bis(3-dimethylaminopropyl)aminomethylphenylquinoline 13a proved to be the most active. G-quadruplexes (G4) stacked non-canonical nucleic acid structures found in specific G-rich DNA, or RNA sequences in the human genome are considered as potential targets for the development of anticancer agents. Then, as small aza-organic heterocyclic derivatives are well known to target and stabilize G4 structures, their ability to bind G4 structures have been determined through FRET melting, circular dichroism, and native mass spectrometry assays. Finally, telomerase inhibition ability has been also assessed using the MCF-7 cell line.