A Selective FGFR1/2 PROTAC Degrader with Antitumor Activity.

The aberrant activation of FGFR acts as a potent driver of multiple types of human cancers. Despite the development of several conventional small-molecular FGFR inhibitors, their clinical efficacy is largely compromised because of low selectivity and side effects. In this study, we report the selective FGFR1/2-targeting proteolysis-targeting chimera BR-cpd7 that displays significant isoform specificity to FGFR1/2 with half maximal degradation concentration values around 10 nmol/L while sparing FGFR3. The following mechanistic investigation reveals the reduced FGFR signaling, through which BR-cpd7 induces cell-cycle arrest and consequently blocks the proliferation of multiple FGFR1/2-dependent tumor cells. Importantly, BR-cpd7 has almost no antiproliferative activity against cancer cells without FGFR aberrations, furtherly supporting its selectivity. In vivo, BR-cpd7 exhibits robust antitumor effects in FGFR1-dependent lung cancer at well-tolerated dose schedules, accompanied by complete FGFR1 depletion. Overall, we identify BR-cpd7 as a promising candidate for developing a selective FGFR1/2-targeted agent, thereby offering a new therapeutic strategy for human cancers in which FGFR1/2 plays a critical role.

Association between serum cotinine and hepatic steatosis and liver fibrosis in adolescent: a population-based study in the United States.

Tobacco exposure is known to be associated with a higher prevalence and incidence of liver diseases. Cotinine, a metabolite of nicotine, is a typical indicator of tobacco exposure. However, the relationship of serum cotinine levels with hepatic steatosis and liver fibrosis remains controversial and these relationships need more research to explored in American teenagers. Cross-sectional data included 1433 participants aged 12-19 from the National Health and Nutrition Examination Survey (NHANES) from 2017 to 2020 were thoroughly used for this study. The linear relationships between serum cotinine levels and the Liver Stiffness Measurement (LSM) and Controlled Attenuation Parameter (CAP) were examined using multiple linear regression models. Subgroup analysis, interaction tests, and nonlinear interactions were also carried out. Serum cotinine levels > 2.99 ng/ml [ß = 0.41 (0.07, 0.76), p = 0.018] and 0.05-2.99 ng/ml [ß = 0.24 (0.00, 0.49), p = 0.048] showed a significant positive connection with LSM in multivariate linear regression analysis when compared to serum cotinine levels ≤ 0.05 ng/ml (p for trend = 0.006). Moreover, we discovered an inverted U-shaped association of log2-transformed cotinine with LSM with an inflection point of 4.53 using a two-stage linear regression model. However, according to multiple regression analysis, serum cotinine and CAP did not significantly correlate (p = 0.512). In conclusion, this study demonstrated that smoking cessation and keep away from secondhand smoking may beneficial for liver health in American teenagers.

A selective Fibroblast Growth Factor Receptor 1/2 PROTAC degrader with antitumor activity.

The aberrant activation of fibroblast growth factor receptor (FGFR) acts as a potent driver of multiple types of human cancers. Despite the development of several conventional small-molecular FGFR inhibitors, their clinical efficacy is largely compromised due to low selectivity and side effects. Here, we report the selective FGFR1/2-targeting proteolysis targeting chimeric (PROTAC), BR-cpd7 that displays significant isoform specificity to FGFR1/2 with DC50 values around 10 nM, while sparing FGFR3. The following mechanistic investigation reveals the reduced FGFR signaling, through which BR-cpd7 induces cell cycle arrest and consequently blocks the proliferation of multiple FGFR1/2-dependent tumor cells. Importantly, BR-cpd7 has almost no anti-proliferative activity against cancer cells without FGFR aberrations, furtherly supporting its selectivity. In vivo, BR-cpd7 exhibits robust antitumor effects in FGFR1-dependent lung cancer at well-tolerated dose schedules, accompanied by complete FGFR1 depletion. Overall, we identify BR-cpd7 as a promising candidate for developing a selective FGFR1/2-targeted agent, thereby offering a new therapeutic strategy for human cancers in which FGFR1/2 plays a critical role.

Endoplasmic reticulum stress and therapeutic strategies in metabolic, neurodegenerative diseases and cancer.

The accumulation of unfolded or misfolded proteins within the endoplasmic reticulum (ER), due to genetic determinants and extrinsic environmental factors, leads to endoplasmic reticulum stress (ER stress). As ER stress ensues, the unfolded protein response (UPR), comprising three signaling pathways-inositol-requiring enzyme 1, protein kinase R-like endoplasmic reticulum kinase, and activating transcription factor 6 promptly activates to enhance the ER's protein-folding capacity and restore ER homeostasis. However, prolonged ER stress levels propels the UPR towards cellular demise and the subsequent inflammatory cascade, contributing to the development of human diseases, including cancer, neurodegenerative disorders, and diabetes. Notably, increased expression of all three UPR signaling pathways has been observed in these pathologies, and reduction in signaling molecule expression correlates with decreased proliferation of disease-associated target cells. Consequently, therapeutic strategies targeting ER stress-related interventions have attracted significant research interest. In this review, we elucidate the critical role of ER stress in cancer, metabolic, and neurodegenerative diseases, offering novel therapeutic approaches for these conditions.

A novel loss function to reproduce texture features for deep learning-based MRI-to-CT synthesis.

BACKGROUND: Studies on computed tomography (CT) synthesis based on magnetic resonance imaging (MRI) have mainly focused on pixel-wise consistency, but the texture features of regions of interest (ROIs) have not received appropriate attention. PURPOSE: This study aimed to propose a novel loss function to reproduce texture features of ROIs and pixel-wise consistency for deep learning-based MRI-to-CT synthesis. The method was expected to assist the multi-modality studies for radiomics. METHODS: The study retrospectively enrolled 127 patients with nasopharyngeal carcinoma. CT and MRI images were collected for each patient, and then rigidly registered as pre-procession. We proposed a gray-level co-occurrence matrix (GLCM)-based loss function to improve the reproducibility of texture features. This novel loss function could be embedded into the present deep learning-based framework for image synthesis. In this study, a typical image synthesis model was selected as the baseline, which contained a Unet trained mean square error (MSE) loss function. We embedded the proposed loss function and designed experiments to supervise different ROIs to prove its effectiveness. The concordance correlation coefficient (CCC) of the GLCM feature was employed to evaluate the reproducibility of GLCM features, which are typical texture features. Besides, we used a publicly available dataset of brain tumors to verify our loss function. RESULTS: Compared with the baseline, the proposed method improved the pixel-wise image quality metrics (MAE: 107.5 to 106.8 HU; SSIM: 0.9728 to 0.9730). CCC values of the GLCM features in GTVnx were significantly improved from 0.78 ± 0.12 to 0.82 ± 0.11 (p < 0.05 for paired t-test). Generally, > 90% (22/24) of the GLCM-based features were improved compared with the baseline, where the Informational Measure of Correlation feature was improved the most (CCC: 0.74 to 0.83). For the public dataset, the loss function also shows its effectiveness. With our proposed loss function added, the ability to reproduce texture features was improved in the ROIs. CONCLUSIONS: The proposed method reproduced texture features for MRI-to-CT synthesis, which would benefit radiomics studies based on image multi-modality synthesis.

Comprehensive evaluation of similarity between synthetic and real CT images for nasopharyngeal carcinoma.

BACKGROUND: Although magnetic resonance imaging (MRI)-to-computed tomography (CT) synthesis studies based on deep learning have significantly progressed, the similarity between synthetic CT (sCT) and real CT (rCT) has only been evaluated in image quality metrics (IQMs). To evaluate the similarity between synthetic CT (sCT) and real CT (rCT) comprehensively, we comprehensively evaluated IQMs and radiomic features for the first time. METHODS: This study enrolled 127 patients with nasopharyngeal carcinoma who underwent CT and MRI scans. Supervised-learning (Unet) and unsupervised-learning (CycleGAN) methods were applied to build MRI-to-CT synthesis models. The regions of interest (ROIs) included nasopharynx gross tumor volume (GTVnx), brainstem, parotid glands, and temporal lobes. The peak signal-to-noise ratio (PSNR), mean absolute error (MAE), root mean square error (RMSE), and structural similarity (SSIM) were used to evaluate image quality. Additionally, 837 radiomic features were extracted for each ROI, and the correlation was evaluated using the concordance correlation coefficient (CCC). RESULTS: The MAE, RMSE, SSIM, and PSNR of the body were 91.99, 187.12, 0.97, and 51.15 for Unet and 108.30, 211.63, 0.96, and 49.84 for CycleGAN. For the metrics, Unet was superior to CycleGAN (P < 0.05). For the radiomic features, the percentage of four levels (i.e., excellent, good, moderate, and poor, respectively) were as follows: GTVnx, 8.5%, 14.6%, 26.5%, and 50.4% for Unet and 12.3%, 25%, 38.4%, and 24.4% for CycleGAN; other ROIs, 5.44% ± 3.27%, 5.56% ± 2.92%, 21.38% ± 6.91%, and 67.58% ± 8.96% for Unet and 5.16% ± 1.69%, 3.5% ± 1.52%, 12.68% ± 7.51%, and 78.62% ± 8.57% for CycleGAN. CONCLUSIONS: Unet-sCT was superior to CycleGAN-sCT for the IQMs. However, neither exhibited absolute superiority in radiomic features, and both were far less similar to rCT. Therefore, further work is required to improve the radiomic similarity for MRI-to-CT synthesis. TRIAL REGISTRATION: This study was a retrospective study, so it was free from registration.

A more effective CT synthesizer using transformers for cone-beam CT-guided adaptive radiotherapy.

Purpose: The challenge of cone-beam computed tomography (CBCT) is its low image quality, which limits its application for adaptive radiotherapy (ART). Despite recent substantial improvement in CBCT imaging using the deep learning method, the image quality still needs to be improved for effective ART application. Spurred by the advantages of transformers, which employs multi-head attention mechanisms to capture long-range contextual relations between image pixels, we proposed a novel transformer-based network (called TransCBCT) to generate synthetic CT (sCT) from CBCT. This study aimed to further improve the accuracy and efficiency of ART. Materials and methods: In this study, 91 patients diagnosed with prostate cancer were enrolled. We constructed a transformer-based hierarchical encoder-decoder structure with skip connection, called TransCBCT. The network also employed several convolutional layers to capture local context. The proposed TransCBCT was trained and validated on 6,144 paired CBCT/deformed CT images from 76 patients and tested on 1,026 paired images from 15 patients. The performance of the proposed TransCBCT was compared with a widely recognized style transferring deep learning method, the cycle-consistent adversarial network (CycleGAN). We evaluated the image quality and clinical value (application in auto-segmentation and dose calculation) for ART need. Results: TransCBCT had superior performance in generating sCT from CBCT. The mean absolute error of TransCBCT was 28.8 ± 16.7 HU, compared to 66.5 ± 13.2 for raw CBCT, and 34.3 ± 17.3 for CycleGAN. It can preserve the structure of raw CBCT and reduce artifacts. When applied in auto-segmentation, the Dice similarity coefficients of bladder and rectum between auto-segmentation and oncologist manual contours were 0.92 and 0.84 for TransCBCT, respectively, compared to 0.90 and 0.83 for CycleGAN. When applied in dose calculation, the gamma passing rate (1%/1 mm criterion) was 97.5% ± 1.1% for TransCBCT, compared to 96.9% ± 1.8% for CycleGAN. Conclusions: The proposed TransCBCT can effectively generate sCT for CBCT. It has the potential to improve radiotherapy accuracy.

Porous Polymer Cubosomes with Ordered Single Primitive Bicontinuous Architecture and Their Sodium-Iodine Batteries.

Bicontinuous porous materials, which possess 3D interconnected pore channels facilitating a smooth mass transport, have attracted much interest in the fields of energy and catalysis. However, their synthesis remains very challenging. We report a general approach, using polymer cubosomes as the template, for the controllable synthesis of bicontinuous porous polymers with an ordered single primitive (SP) cubic structure, including polypyrrole (SP-PPy), poly-m-phenylenediamine (SP-PmPD), and polydopamine (SP-PDA). Specifically, the resultant SP-PPy had a unit cell parameter of 99 nm, pore diameter of 45 nm, and specific surface area of approximately 60 m2·g-1. As a proof of concept, the I2-adsorbed SP-PPy was employed as the cathode materials of newly emerged Na-I2 batteries, which delivered a record-high specific capacity (235 mA·h·g-1 at 0.5 C), excellent rate capability, and cycling stability (with a low capacity decay of 0.12% per cycle within 400 cycles at 1 C). The advantageous contributions of the bicontinuous structure and I3- adsorption mechanism of SP-PPy were revealed by a combination of ion diffusion experiments and theoretical calculations. This study opens a new avenue for the synthesis of porous polymers with new topologies, broadens the spectrum of bicontinuous-structured materials, and also develops a novel potential application for porous polymers.

Deep learning improves image quality and radiomics reproducibility for high-speed four-dimensional computed tomography reconstruction.

BACKGROUND AND PURPOSE: Hybrid iterative reconstruction (HIR) is the most commonly used algorithm for four-dimensional computed tomography (4DCT) reconstruction due to its high speed. However, the image quality is worse than that of model-based iterative reconstruction (MIR). Different reconstruction methods affect the stability of radiomics features. Herein, we developed a deep learning method to improve the quality and radiomics reproducibility of the high-speed reconstruction. MATERIALS AND METHODS: The 4DCT images of 70 patients were reconstructed using both the HIR and MIR algorithms. A cycle-consistent adversarial network was adopted to learn the mapping from HIR to MIR, and then generate synthetic MIR (sMIR) images from HIR. The performance was evaluated using the testing set (10 patients). RESULTS: The total reconstruction times for the HIR, MIR, and proposed sMIR images were approximately 2.5, 15, and 3.1 mins, respectively. The quality of sMIR images was close to that of MIR and was superior to that of HIR images, with noise reduced by 45-77% and contrast-to-noise ratio improved by 91-296%. The concordance correlation coefficients (CCC) of radiomic features improved from 0.89 ± 0.15 for HIR to 0.97 ± 0.07 for the proposed sMIR. The percentage of reproducible features (CCC ≥ 0.85) increased from 76.08% for HIR to 95.86% for sMIR, with an improvement of 19.78%. CONCLUSION: Compared to existing HIR algorithm, the proposed method improves the image quality and radiomics reproducibility of 4DCT images under high-speed reconstruction. It is computationally efficient and has potential to be integrated into any CT system.

Inhibitory Effect of Bovine Adipose-Derived Mesenchymal Stem Cells on Lipopolysaccharide Induced Inflammation of Endometrial Epithelial Cells in Dairy Cows.

Endometritis is a disease that affects reproductive health in dairy cows and causes serious economic damage to the dairy industry world-wide. Although in recent years, the application of mesenchymal stem cell (MSC) therapy for the treatment of inflammatory diseases has attracted much attention, there are few reports of the use of MSCs in dairy cows. In the present study, our objective was to explore the inhibitory effects of bovine adipose-derived mesenchymal stem cells (bAD-MSCs) on lipopolysaccharide (LPS) induced inflammation in bovine endometrial epithelial cells (bEECs) along with the potential underlying molecular mechanisms. We characterized isolated bAD-MSCs using cell surface marker staining and adipogenic/osteogenic differentiation, and analyzed them using immunofluorescence, flow cytometry (surface marker staining), and adipogenic and osteogenic differentiation. Furthermore, to understand the anti-inflammatory effects of bAD-MSCs on LPS induced bEEC inflammation, we used a bAD-MSC/bEEC co-culture system. The results showed that bAD-MSC treatments could significantly decrease LPS induced bEEC apoptosis and pro-inflammatory cytokine expression levels, such as interleukin-1ß (IL-1ß), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α). Furthermore, our results showed that bAD-MSC treatments could also significantly downregulate LPS induced p38, IkB-a, and JAK1 phosphorylation and Bax protein expression levels, which are closely related to inflammatory progress and cellular apoptosis in bEECs. Our findings demonstrate that bAD-MSCs play an inhibitory role in LPS induced bEEC inflammation and provide new insights for the clinical therapy of endometritis in dairy cows.

The glycolysis inhibitor 2-deoxyglucose ameliorates adjuvant-induced arthritis by regulating macrophage polarization in an AMPK-dependent manner.

Macrophages are highly plastic cells critical for the development of rheumatoid arthritis (RA). Macrophages exhibit a high degree of pro-inflammatory plasticity in RA, accompanied by a metabolic reprogramming from oxidative phosphorylation (OXPHOS) to glycolysis. 2-deoxyglucose (2-DG), a glycolysis inhibitor, has previously been shown to exhibit anti-inflammatory and anti-arthritic properties. However, the specific mechanisms of inflammatory modulation by 2-DG remain unclear. This study used 2-DG to treat rats with adjuvant arthritis (AA) and investigated its specific anti-arthritic mechanisms in the murine-derived macrophage cell line RAW264.7 in vitro. 2-DG reduced the arthritis index as well as alleviated cellular infiltration, synovial hyperplasia, and bone erosion in AA rats. Moreover, 2-DG treatment modulated peritoneal macrophage polarization, increasing levels of the arginase1 (Arg1) and decreasing expression of the inducible nitric oxide synthase (iNOS). 2-DG activated AMP-activated protein kinase (AMPK) via phosphorylation and reduced activation of the nuclear factor κB (NF-κB) in peritoneal macrophages of AA rats. In vitro, we verified that 2-DG promoted macrophage transition from M1 to M2-type by upregulating the expression of p-AMPKα and suppressing NF-κB activation in LPS-stimulated RAW264.7 cells. LPS-induced macrophages exhibited a metabolic shift from glycolysis to OXPHOS following 2-DG treatment, as observed by reduced extracellular acidification rate (ECAR), lactate export, glucose consumption, as well as an elevated oxygen consumption rate (OCR) and intracellular ATP concentration. Importantly, changes in polarization and metabolism in response to 2-DG were dampened after AMPKα knockdown. These findings indicate that the anti-arthritic 2-DG effect is mediated by a modulation of macrophage polarization in an AMPK-dependent manner.

Improved Cycling Performance of P2-Na0.67Ni0.33Mn0.67O2 Based on Sn Substitution Combined with Polypyrrole Coating.

P2-Na0.67Ni0.33Mn0.67O2 presents high working voltage with a theoretical capacity of 173 mAh g-1. However, the lattice oxygen on the particle surface participates in the redox reactions when the material is charged over 4.22 V. The resulting oxidized oxygen aggravates the electrolyte decomposition and transition metal dissolution, which cause severe capacity decay. The commonly reported cation substitution methods enhance the cycle stability by suppressing the high voltage plateau but lead to lower average working voltage and reduced capacity. Herein, we stabilized the lattice oxygen by a small amount of Sn substitution based on the strong Sn-O bond without sacrificing the high voltage performance and further protected the particle surface by polypyrrole (PPy) coating. The obtained Na0.67Ni0.33Mn0.63Sn0.04O2@PPy (3.3 wt %) composite showed excellent cycling stability with a reversible capacity of 137.6 (10) and 120.0 mAh g-1 (100 mA g-1) with a capacity retention of 95% (10 mA g-1, 50 cycles) and 82.5% (100 mA g-1, 100 cycles), respectively. The present work indicates that slight Sn substitution combined with PPy coating could be an effective approach to achieving superior cycling stability for high-voltage layered transition metal oxides.

Differential proteomics mass spectrometry of melanosis coli.

This study aims to reveal the biological relevancy between melanosis coli (MC) with colon cancer by analyzing the proteomics differences of tissues of melanosis coli, colon cancer, and normal ones to probe into the causes and development mechanisms of MC from the perspective of biomolecules. Fourteen differential protein spots were found in the study after using two-dimensional gel electrophoresis (2-DE) and bio-mass spectrometry (MALDI-TOF/TOF-MS). Specifically, six and eight differential protein spots in the melanosis coli tissues were detected, respectively, compared with the normal tissues and colon cancer tissues. Eight kinds of proteins, including keratin 8 (KRT8), keratin 18 (KRT18), fibrinogen beta chain isoform 2 preproprotein (FGB), catalase (CAT), 26s protease regulatory subunit 10b (PSMC6), isoform 1 of tropomyosin alpha-4 chain (TPM4), carbonic anhydrase 1 (CA1), isoform of prelammin-A/C (LMNA), were retrieved through the mass spectral database, which could be deemed as associated proteins of MC and colon cancer. The different expressions in the disease tissues indicate that these proteins may be connected with the carcinogenesis of MC as well as the malignant proliferation, development, differentiation, and diffusion of cancer cells.

[The clinical analysis of shallow anterior chamber after complex trabeculectomy surgery].

PURPOSE: To investigate the clinical cause, therapy and prognosis of shallow anterior chamber after complex trabeculectomy surgery of glaucoma. METHODS: A retrospective study of 267 patients (302 eyes) diagnosed with glaucoma at our hospital were reviewed. RESULTS: Forty-three among 302 eyes presented shallow anterior chamber（14.24%）.The main causes of shallow anterior chamber after surgery included excessive filtering function, conjunctival exudation, choroidal detachment and ciliary circle block. These patients recovered after receiving conservative or surgical treatment. CONCLUSION: The shallow anterior chamber is a complication frequently occurring following complex trabeculectomy surgery. The occurrence of this complication may be decreased by controlling filterableness and moderately applying mitomycin C intraoperatively; The prognosis may be significantly enhanced by detecting main measurements including anterior chamber, intraocular tension, filtration condition,and by interfering in shallow anterior chamber early after complex trabeculectomy surgery.

[Expression and clinical implication of Matrix Metalloproteinase-1 and Vascular Endothelial Growth Factor in retinoblastoma].

PURPOSE: To investigate the expression of matrix metalloproteinase-1 (MMP-1) and vascular endothelial growth factor(VEGF) in the retinoblastoma and to identify their relationships with clinicopathology characteristics in order to determine their effects on the angiogenesis. METHODS: Thirty-one patients with histologically proved retinoblastoma were enrolled to examine the expression of MMP-1and VEGF by Immunohistochemistry technique. The relationship between expression and the staging of tumor was analyzed. RESULTS: The MMP-1 and VEGF were highly expressed in retinoblastoma, and MMP-1, VEGF mainly expressed in tumor cells. MMP-1and VEGF was positively correlated with tumor stage(p<0.05). The expression MMP-1 was positively correlated with VEGF level (R=0.787, p<0.00). CONCLUSIONS: The MMP-1 and VEGF are highly expressed in retinoblastoma cells. The expression is related to clinical invasion and metastasis. MMP-1 expression is positively related to VEGF level.MMP-1and VEGF may play an important role in angiogenesis and tumor progression in retinoblastoma.