A new Suzuki synthesis of triphenylethylenes that inhibit aromatase and bind to estrogen receptors α and β

The design and synthesis of dual aromatase inhibitors/selective estrogen receptor modulators (AI/SERMs) is an attractive strategy for the discovery of new breast cancer therapeutic agents. Previous efforts led to the preparation of norendoxifen (4) derivatives with dual aromatase inhibitory activity and estrogen receptor binding activity. In the present study, some of the structural features of the potent AI letrozole were incorporated into the lead compound (norendoxifen) to afford a series of new dual AI/SERM agents based on a symmetrical diphenylmethylene substructure that eliminates the problem of E,Z isomerization encountered with norendoxifen-based AI/SERMs. Compound 12d had good aromatase inhibitory activity (IC50 = 62.2 nM) while also exhibiting good binding activity to both ER-α (EC50 = 72.1 nM) and ER-β (EC50 = 70.8 nM). In addition, a new synthesis was devised for the preparation of norendoxifen and its analogues through a bis-Suzuki coupling strategy.

Specific gene module pair-based target identification and drug discovery

Identification of the biological targets of a compound is of paramount importance for the exploration of the mechanism of action of drugs and for the development of novel drugs. A concept of the Connectivity Map (CMap) was previously proposed to connect genes, drugs, and disease states based on the common gene-expression signatures. For a new query compound, the CMap-based method can infer its potential targets by searching similar drugs with known targets (reference drugs) and measuring the similarities into their specific transcriptional responses between the query compound and those reference drugs. However, the available methods are often inefficient due to the requirement of the reference drugs as a medium to link the query agent and targets. Here, we developed a general procedure to extract target-induced consensus gene modules from the transcriptional profiles induced by the treatment of perturbagens of a target. A specific transcriptional gene module pair (GMP) was automatically identified for each target and could be used as a direct target signature. Based on the GMPs, we built the target network and identified some target gene clusters with similar biological mechanisms. Moreover, a gene module pair-based target identification (GMPTI) approach was proposed to predict novel compound–target interactions. Using this method, we have discovered novel inhibitors for three PI3K pathway proteins PI3Kα/β/δ, including PU-H71, alvespimycin, reversine, astemizole, raloxifene HCl, and tamoxifen

Photometric calibration of the Stellar Abundance and Galactic Evolution Survey (SAGES): Nanshan One-meter Wide-field Telescope g, r, and i band imaging data

In this paper, a total of approximately 2.6 million dwarfs were constructed as standard stars, with an accuracy of about 0.01-0.02 mag for each band, by combining spectroscopic data from the Large Sky Area Multi-Object Fiber Spectroscopic Telescope Data Release 7, photometric data from the corrected Gaia Early Data Release 3, and photometric metallicities. Using the spectroscopy based stellar color regression method (SCR method) and the photometric-based SCR method (SCR' method), we performed the relative calibration of the Nanshan One-meter Wide-field Telescope imaging data. Based on the corrected Pan-STARRS DR1 photometry, the absolute calibration was also performed. In the photometric calibration process, we analyzed the dependence of the calibration zero points on different images (observation time), different gates of the CCD detector, and different CCD positions. We found that the stellar flat and the relative gain between different gates depend on time. The amplitude of gain variation in three channels is approximately 0.5%-0.7% relative to the other channel, with a maximum value of 4%. In addition, significant spatial variations of the stellar flat fitting residual are found and corrected. Using repeated sources in the adjacent images, we checked and discovered internal consistency of about 1-2 mmag in all the filters. Using the PS1 magnitudes synthesized by Gaia DR3 BP/RP spectra by the synthetic photometry method, we found that the photometric calibration uniformity is about 1-2 mmag for all the bands, at a spatial resolution of 1.3 degree. A detailed comparison between the spectroscopy-based SCR and photometric-based SCR method magnitude offsets was performed, and we achieved an internal consistency precision of about 2 mmag or better with resolutions of 1.3 degree for all the filters. Which is mainly from the position-dependent errors of the E(B-V) used in SCR' method.Comment: 15 pages in Chinese language, 8 figures, Chinese Science Bulletin accepted and published online (https://www.sciengine.com/CSB/doi/10.1360/TB-2023-0052), see main results in Figures 6, 7 and

Fully-automated, CT-only GTV contouring for palliative head and neck radiotherapy.

Planning for palliative radiotherapy is performed without the advantage of MR or PET imaging in many clinics. Here, we investigated CT-only GTV delineation for palliative treatment of head and neck cancer. Two multi-institutional datasets of palliative-intent treatment plans were retrospectively acquired: a set of 102 non-contrast-enhanced CTs and a set of 96 contrast-enhanced CTs. The nnU-Net auto-segmentation network was chosen for its strength in medical image segmentation, and five approaches separately trained: (1) heuristic-cropped, non-contrast images with a single GTV channel, (2) cropping around a manually-placed point in the tumor center for non-contrast images with a single GTV channel, (3) contrast-enhanced images with a single GTV channel, (4) contrast-enhanced images with separate primary and nodal GTV channels, and (5) contrast-enhanced images along with synthetic MR images with separate primary and nodal GTV channels. Median Dice similarity coefficient ranged from 0.6 to 0.7, surface Dice from 0.30 to 0.56, and 95th Hausdorff distance from 14.7 to 19.7 mm across the five approaches. Only surface Dice exhibited statistically-significant difference across these five approaches using a two-tailed Wilcoxon Rank-Sum test (p ≤ 0.05). Our CT-only results met or exceeded published values for head and neck GTV autocontouring using multi-modality images. However, significant edits would be necessary before clinical use in palliative radiotherapy