Determination of inflection points of CyberKnife dose profiles within acceptability criteria of deviations in measurements

AimThe aim of this study was to determine the Inflection Points (IPs) of flattening filter free (FFF) CyberKnife dose profiles for cone-based streotactic radiotherapy. In addition, dosimetric field sizes were determined.BackgroundThe increased need for treatment in the early stages of cancer necessitated the treatment of smaller tumors. However, efforts in that direction required the modeling accuracy of the beam. Removal of the flattening filter (FF) from the path of x-ray beam has provided the solution to those efforts, but required a different normalization approach for the beam to ensure the delivery of the dose accurately. As a solution, researchers proposed a normalization factor based on IPs.Materials and methodsMeasurements using microDiamond (PTW 60019), Diode SRS (PTW 60018) and Monte Carlo (MC) calculations of dose profiles were completed at SAD 80 cm and 5 cm depth for 15–60 mm cones. Performance analysis of detectors with respect to MC calculation was carried out. Gamma evaluation method was used to determine achievable acceptability criteria for FFF CyberKnife beams.ResultsAcceptability within (3%–0.5 mm) was found to be anachievable criterion for all dose profile measurements of the cone beams used in this study. To determine the IP, the first and second derivatives of the dose profile were determined via the cubic spline interpolation technique.ConclusionDerivatives of the interpolated profiles showed that locations of IPs and 50% isodose points coincide.     

Targeting selective autophagy by AUTAC degraders

ABSTRACT

Targeted degradation is a promising new modality in drug discovery that makes it possible to reduce intracellular protein levels with small molecules. It is a complementary approach to the conventional protein knockdown typically used in laboratories and may offer a way to approach the currently undruggable human proteome. Recently, the first autophagy-mediated degraders, called AUTACs, were developed based on observations in a xenophagy study.     

Detailed evaluation of Mobius3D dose calculation accuracy for volumetric-modulated arc therapy

PurposeTo perform a detailed evaluation of dose calculation accuracy and clinical feasibility of Mobius3D. Of particular importance, multileaf collimator (MLC) modeling accuracy in the Mobius3D dose calculation algorithm was investigated.MethodsMobius3D was fully commissioned by following the vendor-suggested procedures, including dosimetric leaf gap (DLG) optimization. The DLG optimization determined an optimal DLG correction factor which minimized the average difference between calculated and measured doses for 13 patient volumetric-modulated arc therapy (VMAT) plans. Two sets of step-and-shoot plans were created to examine MLC and off-axis open fields modeling accuracy of the Mobius3D dose calculation algorithm: MLC test set and off-axis open field test set. The test plans were delivered to MapCHECK for the MLC tests and an ionization chamber for the off-axis open field test, and these measured doses were compared to Mobius3D-calculated doses.ResultsThe mean difference between the calculated and measured doses across the 13 VMAT plans was 0.6% with an optimal DLG correction factor of 1.0. The mean percentage of pixels passing gamma from a 3%/1 mm gamma analysis for the MLC test set was 43.5% across the MLC tests. For the off-axis open field tests, the Mobius3D-calculated dose for 1.5 cm square field was −4.6% lower than the chamber-measured dose.ConclusionsIt was demonstrated that Mobius3D has dose calculation uncertainties for small fields and MLC tongue-and-groove design is not adequately taken into consideration in Mobius3D. Careful consideration of DLG correction factor, which affects the resulting dose distributions, is required when commissioning Mobius3D for patient-specific QA.     

基于组合评价法的湖南省农业可持续发展区域分异

从农业资源与环境、农业生产与经济、农业人口与社会3个评价维度构建了区域农业可持续发展指标体系, 运用主成分分析法、熵值法、模糊Borda法、因子分析法及聚类分析法和GIS技术, 通过组合评价方法定量研究湖南省农业可持续发展区域分异现状。结果表明: 湖南省农业可持续发展在区域上总体呈现出不平衡的发展状态, 农业可持续发展综合水平以长株潭城市群为核心, 由东至西递减; 农业人口与社会可持续发展水平南北低中部高, 东部强西部弱; 农业生产与经济可持续发展水平围绕湘北洞庭湖农业区和湘南农业综合区向外围递减; 农业资源与环境可持续发展水平表现为一横两纵优势带和南北两个落后圈。     

Experimental models of maternal–fetal interface and their potential use for nanotechnology applications

During pregnancy, the placenta regulates the transfer of oxygen, nutrients, and residual products between the maternal and fetal bloodstreams and is a key determinant of fetal exposure to xenobiotics from the mother. To study the disposition of substances through the placenta, various experimental models are used, especially the perfused placenta, placental villi explants, and cell lineage models. In this context, nanotechnology, an area of study that is on the rise, enables the creation of particles on nanometric scales capable of releasing drugs aimed at specific tissues. An important reason for furthering the studies on transplacental transfer is to explore the potential of nanoparticles (NPs), in new delivery strategies for drugs that are specifically aimed at the mother, the placenta, or the fetus and that involve less toxicity. Due to the fact that the placental barrier is essential for the interaction between the maternal and fetal organisms as well as the possibility of NPs being used in the treatment of various pathologies, the aim of this review is to present the main experimental models used in studying the maternal–fetal interaction and the action of NPs in the placental environment.     

Knockdown of DNA‐binding protein A enhances the chemotherapy sensitivity of colorectal cancer via suppressing the Wnt/β‐catenin/Chk1 pathway

DNA‐binding protein A (dbpA) is reported to be upregulated in many cancers and associated with tumor progress. The present study aimed to investigate the role of dbpA in 5‐fluorouracil (5‐FU)‐resistant and oxaliplatin (L‐OHP)‐resistant colorectal cancer (CRC) cells. We found that 5‐FU and L‐OPH treatment promoted the expression of dbpA. Enhanced dbpA promoted the drug resistance of SW620 cells to 5‐FU and L‐OHP. DbpA knockdown inhibited cell proliferation, induced cell apoptosis, and cell cycle arrested in SW620/5‐FU and SW620/L‐OHP cells. Besides, dbpA short hairpin RNA (shRNA) enhanced the cytotoxicity of 5‐FU and L‐OHP to SW620/5‐FU and SW620/L‐OHP cells. Meanwhile, dbpA shRNA inhibited the activation of the Wnt/β‐catenin pathway that induced by 5‐FU stimulation in SW620/5‐FU cells. Activation of the Wnt/β‐catenin pathway or overexpression of checkpoint kinase 1 (Chk1) abrogated the promoting effect of dbpA downregulation on 5‐FU sensitivity of CRC cells. Importantly, downregulation of dbpA suppressed tumor growth and promoted CRC cells sensitivity to 5‐FU in vivo. Our study indicated that the knockdown of dbpA enhanced the sensitivity of CRC cells to 5‐FU via Wnt/β‐catenin/Chk1 pathway, and DbpA may be a potential therapeutic target to sensitize drug resistance CRC to 5‐FU and L‐OHP.     

Functional analysis of RPS27 mutations and expression in melanoma

Next‐generation sequencing has enabled genetic and genomic characterization of melanoma to an unprecedent depth. However, the high mutational background plus the limited depth of coverage of whole‐genome sequencing performed on cutaneous melanoma samples make the identification of novel driver mutations difficult. We sought to explore the somatic mutation portfolio in exonic and gene regulatory regions in human melanoma samples, for which we performed targeted sequencing of tumors and matched germline DNA samples from 89 melanoma patients, identifying known and novel recurrent mutations. Two recurrent mutations found in the RPS27 promoter associated with decreased RPS27 mRNA levels in vitro. Data mining and IHC analyses revealed a bimodal pattern of RPS27 expression in melanoma, with RPS27‐low patients displaying worse prognosis. In vitro characterization of RPS27‐high and RPS27‐low melanoma cell lines, as well as loss‐of‐function experiments, demonstrated that high RPS27 status provides increased proliferative and invasive capacities, while low RPS27 confers survival advantage in low attachment and resistance to therapy. Additionally, we demonstrate that 10 other cancer types harbor bimodal RPS27 expression, and in those, similarly to melanoma, RPS27‐low expression associates with worse clinical outcomes. RPS27 promoter mutation could thus represent a mechanism of gene expression modulation in melanoma patients, which may have prognostic and predictive implications.     

Advancing Aptamers as Molecular Probes for Cancer Theranostic Applications—The Role of Molecular Dynamics Simulation

Theranostics cover emerging technologies for cell biomarking for disease diagnosis and targeted introduction of drug ingredients to specific malignant sites. Theranostics development has become a significant biomedical research endeavor for effective diagnosis and treatment of diseases, especially cancer. An efficient biomarking and targeted delivery strategy for theranostic applications requires effective molecular coupling of binding ligands with high affinities to specific receptors on the cancer cell surface. Bioaffinity offers a unique mechanism to bind specific target and receptor molecules from a range of non‐targets. The binding efficacy depends on the specificity of the affinity ligand toward the target molecule even at low concentrations. Aptamers are fragments of genetic materials, peptides, or oligonucleotides which possess enhanced specificity in targeting desired cell surface receptor molecules. Aptamer–target binding results from several inter‐molecular interactions including hydrogen bond formation, aromatic stacking of flat moieties, hydrophobic interaction, electrostatic, and van der Waals interactions. Advancements in Systematic Evolution of Ligands by Exponential Enrichment (SELEX) assay has created the opportunity to artificially generate aptamers that specifically bind to desired cancer and tumor surface receptors with high affinities. This article discusses the potential application of molecular dynamics (MD) simulation to advance aptamer‐mediated receptor targeting in targeted cancer therapy. MD simulation offers real‐time analysis of the molecular drivers of the aptamer‐receptor binding and generate optimal receptor binding conditions for theranostic applications. The article also provides an overview of different cancer types with focus on receptor biomarking and targeted treatment approaches, conventional molecular probes, and aptamers that have been explored for cancer cells targeting.     

Discovery of a potent and selective adenylyl cyclase type 8 agonist by docking-based virtual screening

Adenylyl cyclases (ACs), which are responsible for catalyzing the conversion of adenosine triphosphate (ATP) into the second messenger cyclic adenosine monophosphate (cAMP), play a critical role in cell signal transduction. In this study, a combined approach involving docking-based virtual screening, with the combination of homology modeling followed by an in-vitro, and cell-based biological assay have been performed for discovering a class of novel potent and selective isoform adenylyl cyclase type 8 (AC8) agonist. The computer-aided virtual screening was used to identify fourteen virtual cluster compounds as potential hits which were further subjected to rigorous bioassays. A novel hit compound VHC-7 (ethyl 3-(2,4-dichlorobenzyl)-2-oxoindoline-3-carboxylate) was identified as a highly potent selective AC8 agonist with EC₅₀ value of 0.1052 ± 0.038 µM. Remarkably, the molecule herein reported can be explored further to discover greater number of hit compounds with better pharmacokinetic properties as well as to serve as a promising novel hit agonist of AC8 for the treatment of various central nervous system disorders and its associated diseases.     

RCSB Protein Data Bank: Enabling biomedical research and drug discovery

Analyses of publicly available structural data reveal interesting insights into the impact of the three‐dimensional (3D) structures of protein targets important for discovery of new drugs (e.g., G‐protein‐coupled receptors, voltage‐gated ion channels, ligand‐gated ion channels, transporters, and E3 ubiquitin ligases). The Protein Data Bank (PDB) archive currently holds > 155,000 atomic‐level 3D structures of biomolecules experimentally determined using crystallography, nuclear magnetic resonance spectroscopy, and electron microscopy. The PDB was established in 1971 as the first open‐access, digital‐data resource in biology, and is now managed by the Worldwide PDB partnership (wwPDB; wwPDB.org ). US PDB operations are the responsibility of the Research Collaboratory for Structural Bioinformatics PDB (RCSB PDB). The RCSB PDB serves millions of RCSB.org users worldwide by delivering PDB data integrated with ～40 external biodata resources, providing rich structural views of fundamental biology, biomedicine, and energy sciences. Recently published work showed that the PDB archival holdings facilitated discovery of ～90% of the 210 new drugs approved by the US Food and Drug Administration 2010–2016. We review user‐driven development of RCSB PDB services, examine growth of the PDB archive in terms of size and complexity, and present examples and opportunities for structure‐guided drug discovery for challenging targets (e.g., integral membrane proteins).