Prediction of the solubility of organic compounds in high-temperature water using machine learning

The estimation of the solubility of organic compounds in high-temperature water is important for designing chemical processes. This study aimed at predicting the solubility of organic compounds in high-temperature water in the range of 100–250 °C using machine learning. The chemical structure of the organic compound was converted into 196 descriptors (parameters) using an open-source toolkit. The experimental solubility data were regressed using the descriptors, temperature, and water density. The regression methods of ordinary least squares, least absolute shrinkage and selection operator (Lasso), and support vector regression (SVR) were compared. A regression method combining the Lasso and SVR (Lasso + SVR) was developed. The model thus obtained this method was found to accurately predict the solubility of organic compounds in high-temperature water, with a root-mean-square error of 0.5. The findings in this study would be useful for predicting the solubility of any organic compound in high-temperature water.ArticleThe Journal of Supercritical Fluids.190:105733(2022)journal articl

Development of a fluorescent chemical probe for 3D and high-resolution imaging of tumor hypoxia

Rapid cellular proliferation and incomplete neovascularization in solid tumors leads to spatially heterogeneous regions with relatively low oxygen concentrations, called hypoxia. Hypoxia in tumors causes significant changes in various physiological processes such as DNA repair pathways, anaerobic respiration, metabolic reprograming, unregulated angiogenesis, and the spread of cancer stem cells [Chem. Soc. Rev. 2019, 48, 771–813]. Consequently, the plasticity of these processes results in the acquisition of the malignant phenotype in tumors. Therefore, effective imaging methods that allow for the detailed analysis of hypoxia are needed to elucidate tumor pathophysiology.To date, a variety of imaging techniques for tumor hypoxia have been developed. Magnetic resonance imaging (MRI)- and positron emission tomography (PET)-based methods permit real-time monitoring and give three-dimensional (3D) information about tumor hypoxia without the limitation of imaging depth in vivo [Mol. Imaging Biol. 2010, 13, 399–410]. However, these imaging methods have poor resolution, restricting the detailed visualization of hypoxia-related biological events in cells or tissues. The imaging methods for tumor hypoxia with cellular resolution rely on tissue sectioning [Nat. Nanotechnol. 2016, 11, 724–730]. Although the reconstruction of serial sections theoretically enables 3D imaging of tumor hypoxia, it is impractical for multiple samples and difficult to obtain accurate data with the original tissue morphology.Recently, optical tissue-clearing techniques have been developed for depth-independent visualization. These techniques enable 3D imaging with fluorescent probes including genetically encoded proteins and chemical dyes in entire tissues without the preparation of tissue sections [Cell 2014, 157, 726–739]. However, the application of these techniques with conventional hypoxia probes suffers from some challenges. For example, a well-known hypoxia probe (pimonidazole) and hypoxia makers (e.g. HIF1-) need specific antibodies to be visualized [Nat. Commun. 2012, 3, 710–783]. Due to the low tissue permeability of antibodies [Mol. Cancer Ther. 2019, 18, 213–226], the existence of these probes deep inside tumors cannot be detected. Additionally, hypoxia probes lacking the ability to covalently bind to cellular components can be washed from tumors during tissue-clearing treatments.To achieve 3D and high-resolution imaging of tumor hypoxia throughout an entire tissue, we developed a fluorescent molecular probe for tumor hypoxia which is compatible with tissue-clearing. The fluorescent probe has low cytotoxicity, high fluorescence intensity in tissue-clearing solution, high tissue permeability, and the ability to covalently bind to cellular proteins only under hypoxic conditions. The designed probe was applied for the 3D imaging of spatially heterogeneous tumor hypoxia in combination with tissue-clearing.PACIFICHEM202

Development of a Hyperpolarized Molecular Probe for in vivo Detection of Aminopeptidase N Activity

Aminopeptidase N (APN) is an enzyme which preferentially cleaves peptides with neutral residues at N-terminus. This peptidase has attracted many interests as an important biomarker of cancers because of its relationship with malignancy, metastasis and angiogenesis. However, APN-activity detection in deep areas has not been achieved although several kinds of fluorescent and luminescent probes have been developed to date1. Nuclear magnetic resonance (NMR) is a powerful technique to monitor molecules in a body because this technique has advantages in high tissue penetration and low invasiveness, allowing a molecular detection at deep area. However, the sensitivity of NMR is severely low for in vivo application. To overcome this problem, dynamic nuclear polarization (DNP) has emerged. NMR signals are dramatically enhanced by using this method.Previously, a DNP-NMR molecular probe for detection of APN-activity has been reported by our group2. This probe was designed in points of view of APN-selectivity and spin-lattice relaxation time (T1) related with hyperpolarized lifetime. By using this probe, APN-activity was successfully detected in experiments in vitro. However, this probe has not been applicable in vivo. In this study, we have developed a practical molecular probe for DNP-NMR to detect APN-activity in vivo through rational molecular design based on the previous probe. It is demonstrated that this probe has many advantages for in vivo application and enables detection of APN-activity in xenograft tumors bearing mice. 1) C. L. Schreiber, B. D. Smith, Contrast Media & Molecular Imaging 2018, 2018, 5315172. 2) R. Hata, H. Nonaka, Y. Takakusagi, K. Ichikawa, S. Sando, Angew. Chem., Int. Ed. 2016, 55, 1765.日本化学会第100 回春季年会 202

Development of Hyperpolarized Molecular Probes for in vivo Detection of Peptidase Activities

Detecting activities of peptidases in vivo is an attractive challenge in chemical biology because peptidase-activities are correlated strongly with various biological phenomena and diseases. Nuclear magnetic resonance (NMR) is a powerful technique for this purpose due to its advantages in high tissue penetration and low invasiveness, allowing a molecular detection at deep area. However, the sensitivity of NMR is severely low for in vivo application. To overcome this problem, dynamic nuclear polarization (DNP) has emerged. NMR signals are dramatically enhanced by using this method. However, there are few molecular probes to detect peptidase-activity by using DNP technique to date. Herein, we have developed a practical molecular probe for DNP-NMR to detect the activity of Aminopeptidase N (APN), which is a representative peptidase, in vivo through rational molecular design. It is demonstrated that this probe has many advantages for in vivo application and enables detection of APN-activity in xenograft tumors bearing mice. Starting with this success, we developed some DNP-NMR molecular probes for detecting peptidase-activities based on chemical design.PACIFICHEM202

Characterization of knowledge-based volumetric modulated arc therapy plans created by three different institutions’ models for prostate cancer

BackgroundThe aim of this study was to clarify factors predicting the performance of knowledge-based planning (KBP) models in volume modulated arc therapy for prostate cancer in terms of sparing the organ at risk (OAR).Materials and methodsIn three institutions, each KBP model was trained by more than 20 library plans (LP) per model. To validate the characterization of each KBP model, 45 validation plans (VP) were calculated by the KBP system. The ratios of overlap between the OAR volume and the planning target volume (PTV) to the whole organ volume (Voverlap/Vwhole) were analyzed for each LP and VP. Regression lines between dose–volume parameters (V90, V75, and V50) and Voverlap/Vwhole were evaluated. The mean OAR dose, V90, V75, and V50 of LP did not necessarily match those of VP.ResultsIn both the rectum and bladder, the dose–volume parameters for VP were strongly correlated with Voverlap/Vwhole at institutes A, B, and C (R > 0.74, 0.85, and 0.56, respectively). Except in the rectum at institute B, the slopes of the regression lines for LP corresponded to those for VP. For dose–volume parameters for the rectum, the ratios of slopes of the regression lines in VP to those in LP ranged 0.51–1.26. In the bladder, most ratios were less than 1.0 (mean: 0.77).ConclusionFor each OAR, each model made distinct dosimetric characterizations in terms of Voverlap/Vwhole. The relationship between dose–volume parameters and Voverlap/Vwhole of OARs in LP predicts the KBP models’ performance sparing OARs

Click3D: A whole-organ 3D imaging method utilizing tissue clearing-compatible click reaction

Click chemistry stands as an invaluable chemical technology, offering a multitude of applications through highly selective and efficient bioorthogonal reactions under biological environments. In the realm of bioimaging, pre-targeting strategies have often been employed, utilizing click reactions between molecular probes with a click handle and reporter molecules that make them observable. Recent efforts have integrated state-of-the-art tissue-clearing techniques with fluorescent labeling through click chemistry, allowing high-resolution 3D fluorescence imaging of the target molecules. Nevertheless, these techniques have faced a challenge in terms of limited staining depth, confining their use to imaging tissue sections or partial organs. In this study, we introduce Click3D, a method for thorough staining of whole tissues and whole organs using click chemistry. We identified click reaction conditions that improve staining depth with our custom-developed click staining depth assay. The Click3D protocol, optimized by incorporating these conditions, exhibits a substantially greater staining depth compared to conventional methods. Through the implementation of Click3D, we have successfully achieved whole-kidney imaging of nascent RNA and whole-tumor imaging of hypoxia. Remarkably, we have also accomplished whole-brain imaging of hypoxia by employing the clickable hypoxia probe, which has a small size and, therefore, has high permeability to cross the blood-brain barrier. The Click3D method, leveraging the versatility of click chemistry, is a foundational technology and is expected to have diverse applications employing various clickable probes

Mechanical performance of a commercial knowledge-based VMAT planning for prostate cancer

Abstract Background This study clarified the mechanical performance of volumetric modulated arc therapy (VMAT) plans for prostate cancer generated with a commercial knowledge-based treatment planning (KBP) and whether KBP system could be applied clinically without any major problems with mechanical performance. Methods Thirty consecutive prostate cancer patients who underwent VMAT using extant clinical plans were evaluated. The mechanical performance and dosimetric accuracy of the single optimized KBPs, which were trained with other 51 clinical plans, were compared with the clinical plans. The mechanical performance metrics were mean field area (MFA), mean asymmetry distance (MAD), cross-axis score (CAS), closed leaf score (CLS), small aperture score (SAS), leaf travel (LT), modulation complexity score (MCSv), and monitor unit (MU). The γ passing rates were evaluated with ArcCheck and EBT3 film. Results The mean mechanical performance metrics (clinical plan vs. KBP) were as follows: 18.28 cm2 vs. 17.25 cm2 (MFA), 21.08 mm vs. 20.47 mm (MAD), 0.54 vs. 0.55 (CAS), 0.040 vs. 0.051 (CLS), 0.20 vs. 0.23 (SAS5mm), 458.5 mm vs. 418.8 mm (LT), 0.27 vs. 0.27 (MCSv), and 618.2 vs. 622.1 (MU), respectively. Significant differences were observed for CLS and LT. The average γ passing rates (clinical plan vs. KBP) were as follows: 99.0% vs. 99.1% (3%/3 mm) and 92.4% vs. 92.5% (2%/2 mm) with ArcCHeck, and 99.5% vs. 99.4% (3%/3 mm) and 95.2% vs. 95.4% (2%/2 mm) with EBT3 film, respectively. Conclusions The KBP used lower multileaf collimator (MLC) travel and more closed or small MLC apertures than the clinical plan. The KBP system of VMAT for the prostate cancer was acceptable for clinical use without any major problems