Objectives
To develop and validate a radiomics predictive model based on pre-treatment multiparameter magnetic resonance imaging (MRI) features and clinical features to predict a pathological ...complete response (pCR) in patients with locally advanced rectal cancer (LARC) after receiving neoadjuvant chemoradiotherapy (CRT).
Methods
One hundred and eighty-six consecutive patients with LARC (training dataset,
n
= 131; validation dataset,
n
= 55) were enrolled in our retrospective study. A total of 1,188 imaging features were extracted from pre-CRT T2-weighted (T2-w), contrast-enhanced T1-weighted (cT1-w) and ADC images for each patient. Three steps including least absolute shrinkage and selection operator (LASSO) regression were performed to select key features and build a radiomics signature. Combining clinical risk factors, a radiomics nomogram was constructed. The predictive performance was evaluated by receiver operator characteristic (ROC) curve analysis, and then assessed with respect to its calibration, discrimination and clinical usefulness.
Results
Thirty-one of 186 patients (16.7%) achieved pCR. The radiomics signature derived from joint T2-w, ADC, and cT1-w images, comprising 12 selected features, was significantly associated with pCR status and showed better predictive performance than signatures derived from either of them alone in both datasets. The radiomics nomogram, incorporating the radiomics signature and MR-reported T-stages, also showed good discrimination, with areas under the ROC curves (AUCs) of 0.948 (95% CI, 0.907-0.989) and 0.966 (95% CI, 0.924-1.000), as well as good calibration in both datasets. Decision curve analysis confirmed its clinical usefulness.
Conclusions
This study demonstrated that the pre-treatment radiomics nomogram can predict pCR in patients with LARC and potentially guide treatments to select patients for a “wait-and-see” policy.
Key Points
• Radiomics analysis of pre-CRT multiparameter MR images could predict pCR in patients with LARC.
• Proposed radiomics signature from joint T2-w, ADC and cT1-w images showed better predictive performance than individual signatures.
• Most of the clinical characteristics were unable to predict pCR.
•Volatile-related gene expression in apple is differentially controlled by ethylene and 1-MCP.•Ethylene and 1-MCP on volatile-related gene expression reveal a complex nature of control in ...apples.•Volatile biosynthesis genes in apples regulated by ethylene are identified.
The effects of ethylene and 1-methylcyclopropene (1-MCP) on apple fruit volatile biosynthesis and gene expression were investigated. Statistical analysis identified 17 genes that changed significantly in response to ethylene and 1-MCP treatments. Genes encoding branched-chain amino acid aminotransferase (BCAT), aromatic amino acid aminotransferase (ArAT) and amino acid decarboxylases (AADC) were up-regulated during ripening and further enhanced by ethylene treatment. Genes related to fatty acid synthesis and metabolism, including acyl-carrier-proteins (ACPs), malonyl-CoA:ACP transacylase (MCAT), acyl-ACP-desaturase (ACPD), lipoxygenase (LOX), hydroperoxide lyase (HPL), alcohol dehydrogenase (ADH), pyruvate decarboxylase (PDC2), β-oxidation, acyl-CoA synthetase (ACS), enoyl-CoA hydratase (ECHD), acyl-CoA dehydrogenase (ACAD), and alcohol acyltransferases (AATs) also increased during ripening and in response to ethylene treatment. Allene oxide synthase (AOS), alcohol dehydrogenase 1 (ADH1), 3-ketoacyl-CoA thiolase and branched-chain amino acid aminotransferase 2 (BCAT2) decreased in ethylene-treated fruit. Treatment with 1-MCP and ethylene generally produced opposite effects on related genes, which provides evidence that regulation of these genes is ethylene dependent.
Bromodomain-Containing Protein 4 (BRD4) can play an important role in gene transcriptional regulation of tumor development and survival by participating in histone modification epigenetic mechanism. ...Although it has been reported that novel allosteric inhibitors such as ZL0590 have a high affinity with target protein BRD4 and good efficacy, their inhibitory mechanism has not been studied further. The aim of this study was to reveal the inhibition mechanism of allosteric inhibitor ZL0590 on Free-BRD4 and BRD4 binding MS436 (orthosteric inhibitor) by molecular dynamics simulation combined with a Markov model. Our results showed that BRD4-ZL0590 led to α-helices formation of 100-105 compared with Free-BRD4; the combination of MS436 caused residues 30-40 and 95-105 to form α-helices, while the combination of allosteric inhibitors untangled the α-helices formed by the MS436. The results of Markov flux analysis showed that the binding process of inhibitors mainly involved changes in the degree of α-helices at ZA loop. The binding of ZL0590 reduced the distance between ZA loop and BC loop, blocked the conformation at the active site, and inhibited the binding of MS436. After the allosteric inhibitor binding, the MS436 that could normally penetrate into the interior of the pocket was floating on the edge of the active pocket and did not continue to penetrate into the active pocket as expected. In summary, we provide a theoretical basis for the inhibition mechanism of ZL0590 against BRD4, which can be used as a reference for improving the development of drug targets for cancer therapy.
Fibroblast activation protein-α (FAP) is a type II integral serine protease that is specifically expressed by activated fibroblasts. Cancer-associated fibroblasts (CAFs) in the tumor stroma have an ...abundant and stable expression of FAP, which plays an important role in promoting tumor growth, invasion, metastasis, and immunosuppression. For example, in females with a high incidence of breast cancer, CAFs account for 50–70% of the cells in the tumor’s microenvironment. CAF overexpression of FAP promotes tumor development and metastasis by influencing extracellular matrix remodeling, intracellular signaling, angiogenesis, epithelial-to-mesenchymal transition, and immunosuppression. This review discusses the basic biological characteristics of FAP and its applications in the diagnosis and treatment of various cancers. We review the emerging basic and clinical research data regarding the use of nanomaterials that target FAP.
There are reports indicating that licochalcones can inhibit the proliferation, migration, and invasion of cancer cells by promoting the expression of autophagy-related proteins, inhibiting the ...expression of cell cycle proteins and angiogenic factors, and regulating autophagy and apoptosis. This study aims to reveal the potential mechanisms of licochalcone A (LCA), licochalcone B (LCB), licochalcone C (LCC), licochalcone D (LCD), licochalcone E (LCE), licochalcone F (LCF), and licochalcone G (LCG) inhibition in liver cancer through computer-aided screening strategies. By using machine learning clustering analysis to search for other structurally similar components in licorice, quantitative calculations were conducted to collect the structural commonalities of these components related to liver cancer and to identify key residues involved in the interactions between small molecules and key target proteins. Our research results show that the seven licochalcones molecules interfere with the cancer signaling pathway via the NF-κB signaling pathway, PDL1 expression and PD1 checkpoint pathway in cancer, and others. Glypallichalcone, Echinatin, and 3,4,3′,4′-Tetrahydroxy-2-methoxychalcone in licorice also have similar structures to the seven licochalcones, which may indicate their similar effects. We also identified the key residues (including ASN364, GLY365, TRP366, and TYR485) involved in the interactions between ten flavonoids and the key target protein (nitric oxide synthase 2). In summary, we provide valuable insights into the molecular mechanisms of the anticancer effects of licorice flavonoids, providing new ideas for the design of small molecules for liver cancer drugs.
► Expression of genes involved in ethylene biosynthesis and perception in apple fruit during ripening were investigated. ► Gene expression of ACS1 and ACO1 are ethylene dependent. ► Gene expression ...of ethylene perception related genes responded differently to ethylene and 1-MCP treatment. ► Ethylene and 1-MCP on ethylene biosynthesis and perception related gene expression reveal the dynamic and complex nature of the roles of ethylene.
Ethylene plays an important role in regulating fruit ripening and senescence and directly influences the development of the eating quality of fresh apples, including appearance, color, texture, and flavor. Apple fruit (Malus domestica Borkh.) is a well-known climacteric fruit and a good model system to study fruit ripening and senescence. To better understand fruit ripening and the role of ethylene perception and signal transduction, apples harvested at a pre-climacteric stage were allowed to naturally ripen, or ripening was either stimulated by treatment with 36μLL−1 ethylene for 24h or inhibited by 1-MCP treatment (1.0μLL−1 for 24h), respectively. Postharvest physiological indices including respiration and ethylene production were monitored for 22d for ethylene treatment and 47d for 1-MCP treatment. Based on an efficiency test, 20 genes in relation to ethylene biosynthesis and perception were investigated using real-time qPCR during the post-treatment period. The ETR2, ETR5, ERSs, EIL4, ERFs genes together with ACS1 and ACO1 genes were significantly up-regulated in fruit during ripening. Ethylene treatment further enhanced the expression of ACO2, ETR1, CTR1s and EIN2A genes, while the ACS3 and ACO3, and EIN2B genes were only slightly affected. 1-MCP treatment significantly inhibited expression of ACS1, ACO1 and ACO2 ethylene biosynthesis genes, which coincided with ethylene production. 1-MCP treatment also reduced expression of ETR1, ETR2, ETR5, ERSs, CTR1, EIN2A, EIL4 and ERFs genes, while having a limited effect on ACS3, ACO3, and EIN2B. This study demonstrated the complexity and dynamic changes of transcriptional profiles of ethylene perception and biosynthesis in response to fruit ripening, ethylene, and 1-MCP treatment. Understanding of the significant changes of these genes and their function may help to explore the mechanisms controlling apple fruit ripening and its response to exogenous ethylene stimuli and action inhibition at the receptor level during ripening and senescence.
Type 2 diabetes mellitus (T2DM) is marked by persistent hyperglycemia, insulin resistance, and pancreatic β-cell dysfunction, imposing substantial health burdens and elevating the risk of systemic ...complications and cardiovascular diseases. While the pathogenesis of diabetes remains elusive, a cyclical relationship between insulin resistance and inflammation is acknowledged, wherein inflammation exacerbates insulin resistance, perpetuating a deleterious cycle. Consequently, anti-inflammatory interventions offer a therapeutic avenue for T2DM management. In this study, a herb called Baikal skullcap, renowned for its repertoire of bioactive compounds with anti-inflammatory potential, is posited as a promising source for novel T2DM therapeutic strategies. Our study probed the anti-diabetic properties of compounds from Baikal skullcap via network pharmacology, molecular docking, and cellular assays, concentrating on their dual modulatory effects on diabetes through Protein Tyrosine Phosphatase 1B (PTP1B) enzyme inhibition and anti-inflammatory actions. We identified the major compounds in Baikal skullcap using liquid chromatography-mass spectrometry (LC-MS), highlighting six flavonoids, including the well-studied baicalein, as potent inhibitors of PTP1B. Furthermore, cellular experiments revealed that baicalin and baicalein exhibited enhanced anti-inflammatory responses compared to the active constituents of licorice, a known anti-inflammatory agent in TCM. Our findings confirmed that baicalin and baicalein mitigate diabetes via two distinct pathways: PTP1B inhibition and anti-inflammatory effects. Additionally, we have identified six flavonoid molecules with substantial potential for drug development, thereby augmenting the T2DM pharmacotherapeutic arsenal and promoting the integration of herb-derived treatments into modern pharmacology.
Background
Accurate pre-treatment prediction of neoadjuvant chemotherapy (NACT) resistance in patients with locally advanced gastric cancer (LAGC) is essential for timely surgeries and optimized ...treatments. We aim to evaluate the effectiveness of deep learning (DL) on computed tomography (CT) images in predicting NACT resistance in LAGC patients.
Methods
A total of 633 LAGC patients receiving NACT from three hospitals were included in this retrospective study. The training and internal validation cohorts were randomly selected from center 1, comprising 242 and 104 patients, respectively. The external validation cohort 1 comprised 128 patients from center 2, and the external validation cohort 2 comprised 159 patients from center 3. First, a DL model was developed using ResNet-50 to predict NACT resistance in LAGC patients, and the gradient-weighted class activation mapping (Grad-CAM) was assessed for visualization. Then, an integrated model was constructed by combing the DL signature and clinical characteristics. Finally, the performance was tested in internal and external validation cohorts using area under the receiver operating characteristic (ROC) curves (AUC).
Results
The DL model achieved AUCs of 0.808 (95% CI 0.724–0.893), 0.755 (95% CI 0.660–0.850), and 0.752 (95% CI 0.678–0.825) in validation cohorts, respectively, which were higher than those of the clinical model. Furthermore, the integrated model performed significantly better than the clinical model (
P
< 0.05).
Conclusions
A CT-based model using DL showed promising performance for predicting NACT resistance in LAGC patients, which could provide valuable information in terms of individualized treatment.
To explore the potential use of CDK inhibitors in pancreatic ductal adenocarcinoma (PDAC) therapy, a series of novel 2-((4-sulfamoylphenyl)amino)-pyrrolo2,3-dpyrimidine derivatives was designed, ...synthesised, and investigated for inhibition on both CDK kinase activity and cellular proliferation of pancreatic cancer. Most of new sulphonamide-containing derivatives demonstrated strong inhibitory activity on CDK9 and obvious anti-proliferative activity in cell culture. Moreover, two new compounds suppressed cell proliferation of multiple human pancreatic cancer cell lines. The most potent compound 2g inhibited cancer cell proliferation by blocking Rb phosphorylation and induced apoptosis via downregulation of CDK9 downstream proteins Mcl-1 and c-Myc in MIA PaCa-2 cells. CDK9 knockdown experiment suggests its anti-proliferative activity is mainly mediated by CDK9. Additionally, 2g displayed moderate tumour inhibition effect in AsPC-1 derived xenograft mice model. Altogether, this study provided a new start for further optimisation to develop potential CDK inhibitor candidates for PDAC treatment by alone or combination use.
In radiation therapy, cancerous region segmentation in magnetic resonance images (MRI) is a critical step. For rectal cancer, the automatic segmentation of rectal tumors from an MRI is a great ...challenge. There are two main shortcomings in existing deep learning-based methods that lead to incorrect segmentation: 1) there are many organs surrounding the rectum, and the shape of some organs is similar to that of rectal tumors; 2) high-level features extracted by conventional neural networks often do not contain enough high-resolution information. Therefore, an improved U-Net segmentation network based on attention mechanisms is proposed to replace the traditional U-Net network.
The overall framework of the proposed method is based on traditional U-Net. A ResNeSt module was added to extract the overall features, and a shape module was added after the encoder layer. We then combined the outputs of the shape module and the decoder to obtain the results. Moreover, the model used different types of attention mechanisms, so that the network learned information to improve segmentation accuracy.
We validated the effectiveness of the proposed method using 3773 2D MRI datasets from 304 patients. The results showed that the proposed method achieved 0.987, 0.946, 0.897, and 0.899 for Dice, MPA, MioU, and FWIoU, respectively; these values are significantly better than those of other existing methods.
Due to time savings, the proposed method can help radiologists segment rectal tumors effectively and enable them to focus on patients whose cancerous regions are difficult for the network to segment.
The proposed method can help doctors segment rectal tumors, thereby ensuring good diagnostic quality and accuracy.
PDF
