Tumor-Type Agnostic, Targeted Therapies: BRAF Inhibitors Join the Group

In the present review, we briefly discuss the breakthrough advances in precision medicine using a tumor-agnostic approach and focus on BRAF treatment modalities, the mechanisms of resistance and the diagnostic approach in cancers with BRAF mutations. Tumor-type agnostic drug therapies work across cancer types and present a significant novel shift in precision cancer medicine. They are the consequence of carefully designed clinical trials that showed the value of tumor biomarkers, not just in diagnosis but in therapy guidance. Six tumor-agnostic drugs (with seven indications) have been approved through October 2022 by FDA. The first tumor-agnostic treatment modality was pembrolizumab for MSI-H/dMMR solid tumors, approved in 2017. This was followed by approvals of larotrectinib and entrectinib for cancers with NTRK fusions without a known acquired resistance mutation. In 2020, pembrolizumab was approved for all TMB-high solid cancers, while a PD-L1 inhibitor dostarlimab-gxly was approved for dMMR solid cancers in 2021. A combination of BRAF/MEK inhibitors (dabrafenib/trametinib) was approved as a tumor-agnostic therapy in June 2022 for all histologic types of solid metastatic cancers harboring BRAFV600E mutations. In September 2022, RET inhibitor selpercatinib was approved for solid cancers with RET gene fusions. CONCLUSION: Precision cancer medicine has substantially improved cancer diagnostics and treatment. Tissue type-agnostic drug therapies present a novel shift in precision cancer medicine. This approach rapidly expands to provide treatments for patients with different cancers harboring the same molecular alteration

Analytic pulse technique for computational electromagnetics

Numerical modeling of electromagnetic waves is an important tool for understanding the interaction of light and matter, and lies at the core of computational electromagnetics. Traditional approaches to injecting and evolving electromagnetic waves, however, can be prohibitively expensive and complex for emerging problems of interest and can restrict the comparisons that can be made between simulation and theory. As an alternative, we demonstrate that electromagnetic waves can be incorporated analytically by decomposing the physics equations into analytic and computational parts. In particle-in-cell simulation of laser--plasma interaction, for example, treating the laser pulse analytically enables direct examination of the validity of approximate solutions to Maxwell's equations including Laguerre--Gaussian beams, allows lower-dimensional simulations to capture 3-D--like focusing, and facilitates the modeling of novel space--time structured laser pulses such as the flying focus. The flexibility and new routes to computational savings introduced by this analytic pulse technique are expected to enable new simulation directions and significantly reduce computational cost in existing areas.Comment: 26 pages, 9 figure

Water-based and Biocompatible 2D Crystal Inks: from Ink Formulation to All- Inkjet Printed Heterostructures

Fully exploiting the properties of 2D crystals requires a mass production method able to produce heterostructures of arbitrary complexity on any substrate, including plastic. Solution processing of graphene allows simple and low-cost techniques such as inkjet printing to be used for device fabrication. However, available inkjet printable formulations are still far from ideal as they are either based on toxic solvents, have low concentration, or require time-consuming and expensive formulation processing. In addition, none of those formulations are suitable for thin-film heterostructure fabrication due to the re-mixing of different 2D crystals, giving rise to uncontrolled interfaces, which results in poor device performance and lack of reproducibility. In this work we show a general formulation engineering approach to achieve highly concentrated, and inkjet printable water-based 2D crystal formulations, which also provides optimal film formation for multi-stack fabrication. We show examples of all-inkjet printed heterostructures, such as large area arrays of photosensors on plastic and paper and programmable logic memory devices, fully exploiting the design flexibility of inkjet printing. Finally, dose-escalation cytotoxicity assays in vitro also confirm the inks biocompatible character, revealing the possibility of extending use of such 2D crystal formulations to drug delivery and biomedical applications

Exact solutions for the electromagnetic fields of a flying focus

The intensity peak of a "flying focus" travels at a programmable velocity over many Rayleigh ranges while maintaining a near-constant profile. Assessing the extent to which these features can enhance laser-based applications requires an accurate description of the electromagnetic fields. Here we present exact analytical solutions to Maxwell's equations for the electromagnetic fields of a constant-velocity flying focus, generalized for arbitrary polarization and orbital angular momentum. The approach combines the complex source-point method, which transforms multipole solutions into beam-like solutions, with the Lorentz invariance of Maxwell's equations. Propagating the fields backward in space reveals the space-time profile that an optical assembly must produce to realize these fields in the laboratory. Comparisons with simpler paraxial solutions provide conditions for their reliable use when modeling a flying focus

Pros and Cons of 19 Sport-Related Concussion Educational Resources in Canada: Avenues for Better Care and Prevention

Objective: The goal of this research was to assess the effectiveness of available concussion educational resources in Canada, the means used to disseminate this knowledge and the impact of these educational resources on players' concussion prevention knowledge.Methods: We assessed concussion knowledge before and after exposure to one or more of 19 resources introduced through a national program aimed to increase awareness and knowledge of concussion. The effectiveness of the mode of delivery was measured by changes in concussion knowledge scores (CKS) between pre and pro scores.Measures: Concussion knowledge scores (CKS) were calculated for pre- and post- exposure to concussion educational resources and used as a measure of both, the effectiveness of each resource as well as the effectiveness of the delivery method. The effectiveness of each educational resource was also measured by the respondents' rating of each concussion educational resource.Results: Respondents in post-survey had higher CKS than those in pre-survey. Two out of the 19 newly developed concussion educational resources were effective in improving the resource users' CKS. Linear regression showed that using more resources further increased CKS. Four out of six modes of delivery enhanced respondents' concussion knowledge.Conclusion: Our findings demonstrate that the newly developed Canadian concussion educational resources were effective at improving users' concussion knowledge. Our data demonstrates that using three or more resources further enhanced the users' concussion knowledge. Future research, however, is critical to assess whether concussion prevention knowledge is sufficient to reduce injuries and factors influencing it

System-size and centrality dependence of charged kaon and pion production in nucleus-nucleus collisions at 40A GeV and158A GeV beam energy

Measurements of charged pion and kaon production are presented in centrality selected Pb+Pb collisions at 40A GeV and 158A GeV beam energy as well as in semi-central C+C and Si+Si interactions at 40A GeV. Transverse mass spectra, rapidity spectra and total yields are determined as a function of centrality. The system-size and centrality dependence of relative strangeness production in nucleus-nucleus collisions at 40A GeV and 158A GeV beam energy are derived from the data presented here and published data for C+C and Si+Si collisions at 158A GeV beam energy. At both energies a steep increase with centrality is observed for small systems followed by a weak rise or even saturation for higher centralities. This behavior is compared to calculations using transport models (UrQMD and HSD), a percolation model and the core-corona approach.Comment: 32 pages, 14 figures, 4 tables, typo table II correcte

Charged Particle Production in Proton-, Deuteron-, Oxygen- and Sulphur-Nucleus Collisions at 200 GeV per Nucleon

The transverse momentum and rapidity distributions of net protons and negatively charged hadrons have been measured for minimum bias proton-nucleus and deuteron-gold interactions, as well as central oxygen-gold and sulphur-nucleus collisions at 200 GeV per nucleon. The rapidity density of net protons at midrapidity in central nucleus-nucleus collisions increases both with target mass for sulphur projectiles and with the projectile mass for a gold target. The shape of the rapidity distributions of net protons forward of midrapidity for d+Au and central S+Au collisions is similar. The average rapidity loss is larger than 2 units of rapidity for reactions with the gold target. The transverse momentum spectra of net protons for all reactions can be described by a thermal distribution with `temperatures' between 145 +- 11 MeV (p+S interactions) and 244 +- 43 MeV (central S+Au collisions). The multiplicity of negatively charged hadrons increases with the mass of the colliding system. The shape of the transverse momentum spectra of negatively charged hadrons changes from minimum bias p+p and p+S interactions to p+Au and central nucleus-nucleus collisions. The mean transverse momentum is almost constant in the vicinity of midrapidity and shows little variation with the target and projectile masses. The average number of produced negatively charged hadrons per participant baryon increases slightly from p+p, p+A to central S+S,Ag collisions.Comment: 47 pages, submitted to Z. Phys.

NA49 results on hadron production: indications of the onset of deconfinement ?

The NA49 experiment at the CERN SPS measured the energy and system size dependence of particle production in A+A collisions. A change of the energy dependence of several hadron production properties at low SPS energies is observed which suggests a scenario requiring the onset of deconfinement.Comment: XXXV International Symposium on Multiparticle Dynamics 200