Design, synthesis, and structure-activity relationship studies of 6-benzo[]indeno[1,2-]thiophen-6-one derivatives as DYRK1A/CLK1/CLK4/haspin inhibitors.

A series of sulfur-containing tetracycles was designed and evaluated for their ability to inhibit protein kinase DYRK1A, a target known to have several potential therapeutic applications including cancers, Down syndrome or Alzheimer's disease. Our medicinal chemistry strategy relied on the design of new compounds using ring contraction/isosteric replacement and constrained analogy of known DYRK1A inhibitors, thus resulting in their DYRK1A inhibitory activity enhancement. Whereas a good inhibitory effect of targeted DYRK1A protein was observed for 5-hydroxy compounds 4i-k (IC = 35-116 nM) and the 5-methoxy derivative 4e (IC = 52 nM), a fairly good selectivity towards its known DYRK1B off-target was observed for 4k.

Immunomic longitudinal profiling of the NeoPembrOv trial identifies drivers of immunoresistance in high-grade ovarian carcinoma.

PD-1/PD-L1 blockade has so far shown limited survival benefit for high-grade ovarian carcinomas. By using paired samples from the NeoPembrOv randomized phase II trial (NCT03275506), for which primary outcomes are published, and by combining RNA-seq and multiplexed immunofluorescence staining, we explore the impact of NeoAdjuvant ChemoTherapy (NACT) ± Pembrolizumab (P) on the tumor environment, and identify parameters that correlated with response to immunotherapy as a pre-planned exploratory analysis. Indeed, i) combination therapy results in a significant increase in intraepithelial CD8PD-1 T cells, ii) combining endothelial and monocyte gene signatures with the CD8B/FOXP3 expression ratio is predictive of response to NACT + P with an area under the curve of 0.

"Mid-P strategy" versus "internal target volume strategy in locally advanced non small cell lung cancer: Clinical results from the randomized non-comparative phase II study Mid-P.

Background: Locally advanced non-small cell lung cancer (LA-NSCLC) reported poor 5-year survival rates with frequent local or regional recurrences. Personalized RT may contribute to improve control and clinical outcome. We investigated efficacy and tolerance of "Mid-position" (Mid-P) strategy versus the conventional Internal Target Volume (ITV) strategy in LA-NSCLC patients treated by definitive conformal radiotherapy.

Evolution of work conditions for employees driving for work in France based on data from the 2003, 2010 and 2017 SUMER surveys (Surveillance Médicale des expositions aux risques Professionnels).

Introduction: The occupational road-accident risk on public roads and the work conditions for professional driving is still an important issue in occupational health despite lower road-accident rates. This study presents the evolution over time of the work-related constraints for these employees based on the Sumer surveys carried out in 2003, 2010 and 2017.

Method: Data from the 2010 and 2017 surveys were restricted to match the scope of the 2003 survey in order to enable prevalence data to be compared in equivalent populations.

Prompt-gamma track-length estimator with time tagging from proton tracking.

The design of prompt-gamma detectors necessitates numerous Monte Carlo simulations to precisely develop and optimize the detection stages in proton therapy. Alongside the advancement of MC simulations, various variance reduction methods have been explored to speed-up calculations. Among these techniques, track-length estimators are interesting scoring methods for achieving both speed and accuracy in Monte Carlo simulations of rare events.

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 and 2,4-bis[(substituted-aminomethyl)phenyl]phenylquinolines are reported here in six steps starting from various halogeno-quinazoline-2,4-(1,3)-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 , , and displayed the most interesting antiproliferative activities against six human cancer cell lines.

Reduction of cone-beam CT artifacts in a robotic CBCT device using saddle trajectories with integrated infrared tracking.

Background: Cone beam computed tomography (CBCT) is widely used in many medical fields. However, conventional CBCT circular scans suffer from cone beam (CB) artifacts that limit the quality and reliability of the reconstructed images due to incomplete data.

Purpose: Saddle trajectories in theory might be able to improve the CBCT image quality by providing a larger region with complete data.

Stiffness-induced cancer-associated fibroblasts are responsible for immunosuppression in a platelet-derived growth factor ligand-dependent manner.

Pancreatic ductal adenocarcinoma (PDAC) is associated with a vast stromal reaction that arises mainly from cancer-associated fibroblasts (CAFs) and promotes both immune escape and tumor growth. Here, we used a mouse model with deletion of the activin A receptor ALK4 in the context of the mutation, which strongly drives collagen deposition that leads to tissue stiffness. By ligand-receptor analysis of single-cell RNA-sequencing data, we identified that, in stiff conditions, neoplastic ductal cells instructed CAFs through sustained platelet-derived growth factor (PDGF) signaling.

Image quality improvement of a one-step spectral CT reconstruction on a prototype photon-counting scanner.

. X-ray spectral computed tomography (CT) allows for material decomposition (MD). This study compared a one-step material decomposition MD algorithm with a two-step reconstruction MD algorithm using acquisitions of a prototype CT scanner with a photon-counting detector (PCD).

AS1411 aptamer tagged PEGylated liposomes as a smart nanocarrier for tumor-specific delivery of Withaferin A for mitigating pulmonary metastasis.

Metastasis is the most challenging health problem contributing to about 90 % of cancer-related deaths worldwide. Metastatic tumors are highly aggressive and resistant to the most available therapeutic options. Hence, innovative therapeutic approaches are required to target metastatic tumors selectively.

Image reconstruction from truncated fan-beam projections along a circular trajectory using the virtual fan-beam method.

In this paper, we investigate how the virtual fan-beam (VFB) method can be used to perform mathematically correct 2D reconstruction in a region-of-interest (ROI), using truncated fan-beam projections acquired on a circular scan, for truncation that only occurs on one side of the object.We start by choosing a virtual fan-beam trajectory and specifying how to obtain the corresponding virtual projections. Then, three VFB formulas are obtained by applying known super-short-scan (SSS) formulas to this virtual trajectory.

Equal parallel and cone-beam projections: a curious property of D-symmetric object functions.

In tomographic image reconstruction, the object density function is the unknown quantity whose projections are measured by the scanner. In the three-dimensional case, we define the D-reflection of such a density function as the object obtained by a particular weighted reflection about the plane=, and a D-symmetric function as one whose D-reflection is equal to itself. D-symmetric object functions have the curious property that their parallel projection onto the detector plane=is equal to their cone-beam projection onto the same detector with x-ray source location at the origin.

Systematic Review on Learning-based Spectral CT.

Spectral computed tomography (CT) has recently emerged as an advanced version of medical CT and significantly improves conventional (single-energy) CT. Spectral CT has two main forms: dual-energy computed tomography (DECT) and photon-counting computed tomography (PCCT), which offer image improvement, material decomposition, and feature quantification relative to conventional CT. However, the inherent challenges of spectral CT, evidenced by data and image artifacts, remain a bottleneck for clinical applications.

The INFN proton computed tomography system for relative stopping power measurements: calibration and verification.

. This paper describes the procedure to calibrate the three-dimensional (3D) proton stopping power relative to water (SPR) maps measured by the proton computed tomography (pCT) apparatus of the Istituto Nazionale di Fisica Nucleare (INFN, Italy). Measurements performed on water phantoms are used to validate the method.

Characterization of the INFN proton CT scanner for cross-calibration of x-ray CT.

. The goal of this study was to assess the imaging performances of the pCT system developed in the framework of INFN-funded (Italian National Institute of Nuclear Physics) research projects. The spatial resolution, noise power spectrum (NPS) and RSP accuracy has been investigated, as a preliminary step to implement a new cross-calibration method for x-ray CT (xCT).

Reliability and reproducibility of the DICART device to assess capillary refill time: a bench and in-silico study.

Capillary refill time (CRT) is an important indicator of peripheral perfusion with a strong prognostic value, but it is sensitive to environmental factors and numerous measurement methods are reported in the litterature. DiCARTECH has developed a device that assesses CRT. We sought to investigate the robustness of the device and the reproducibility of the algorithm in a bench and in-silico study.

Predictive stability, novel HPLC-MS analysis and semi-automatic compounding process for the emergency implementation of a production line of pancuronium in injectable solution.

During the early months of the COVID-19 pandemic, the international medical product supply chain was tight, causing breaks in the availability of neuromuscular blocking agents essential for the treatment of patients in intensive care units. The present study describes the pharmaceutical development of an injectable 2 mg/mL solution of pancuronium bromide (PC) in a very short lapse of time. The sterile solution was compounded into a good manufacturing practice grade A clean room, filtered (0.

Analytical modeling and Monte Carlo simulations of multi-parallel slit and knife-edge slit prompt gamma cameras.

Present and validate an analytical model (AM) to calculate efficiency and spatial resolution of multi-parallel slit (MPS) and knife-edge slit (KES) cameras in the context of prompt gamma (PG) imaging in proton therapy, as well as perform a fair comparison between two prototypes of these cameras with their design specifications.Monte Carlo (MC) simulations with perfect (ideal) conditions were performed to validate the proposed AM, as well as simulations in realistic conditions for the comparison of both prototypes. The spatial resolution obtained from simulations was derived from reconstructed PG profiles.

Management of reirradiations: A clinical and technical overview based on a French survey.

Introduction: The reirradiation number increased due to systemic therapies and patient survival. Few guidelines regarding acceptable cumulative doses to organs at risk (OARs) and appropriate dose accumulation tools need, made reirradiation challenging. The survey objective was to present the French current technical and clinical practices in reirradiations.

Simulation of X-ray projections on GPU: Benchmarking gVirtualXray with clinically realistic phantoms.

Background And Objectives: This study provides a quantitative comparison of images created using gVirtualXray (gVXR) to both Monte Carlo (MC) and real images of clinically realistic phantoms. gVirtualXray is an open-source framework that relies on the Beer-Lambert law to simulate X-ray images in realtime on a graphics processor unit (GPU) using triangular meshes.

Methods: Images are generated with gVirtualXray and compared with a corresponding ground truth image of an anthropomorphic phantom: (i) an X-ray projection generated using a Monte Carlo simulation code, (ii) real digitally reconstructed radiographs (DRRs), (iii) computed tomography (CT) slices, and (iv) a real radiograph acquired with a clinical X-ray imaging system.