Using maximum plasma concentration (Cmax) to personalize taxane treatment and reduce toxicity.

Taxanes are a widely used class of anticancer agents that play a vital role in the treatment of a variety of cancers. However, toxicity remains a major concern of using taxane drugs as some toxicities are highly prevalent, they can not only adversely affect patient prognosis but also compromise the overall treatment plan. Among all kinds of factors that associated with taxane toxicity, taxane exposure has been extensively studied, with different pharmacokinetic (PK) parameters being used as toxicity predictors. Compared to other widely used predictors such as the area under the drug plasma concentration curve versus time (AUC) and time above threshold plasma drug concentration, maximum plasma concentration (Cmax) is easier to collect and shows promise for use in clinical practice. In this article, we review the previous research on using Cmax to predict taxane treatment outcomes. While Cmax and toxicity have been extensively studied, research on the relationship between Cmax and efficacy is lacking. Most of the articles find a positive relationship between Cmax and toxicity but several articles have contradictory findings. Future clinical trials are needed to validate the relationship between Cmax and treatment outcome and determine whether Cmax can serve as a useful surrogate endpoint of taxane treatment efficacy.

YANK2 activated by Fyn promotes glioma tumorigenesis via the mTOR-independent p70S6K activation pathway.

Glioma, particularly glioblastomas (GBM), is incurable brain tumor. The most targeted receptor tyrosine kinase (RTKs) drugs did not bring benefit to GBM patients. The mechanism of glioma growth continues to be explored to find more effective treatment. Here, we reported that Ser/Thr protein kinase YANK2 (yet another kinase 2) is upregulated in glioma tissues and promotes the growth and proliferation of glioma in vitro and in vivo. Further, we confirmed that oncogene Fyn directly activated YANK2 through phosphorylation its Y110, and Fyn-mediated YANK2 phosphorylation at Y110 site promotes glioma growth by increasing its stability. Finally, YANK2 was proved to be a novel upstream kinase of p70S6K and promotes glioma growth by directly phosphorylating p70S6K at T389. Taken together, we found a new mTOR-independent p70S6K activation pathway, Fyn-YANK2-p70S6K, which promotes glioma growth, and YANK2 is a potential oncogene and serves as a novel therapeutic target for glioma.

Co-transplantation of autologous treg cells: A groundbreaking cell therapy for brain diseases.

Cell therapy and regenerative medicine have made remarkable progress in treating neurodegenerative disorders. Induced pluripotent stem cells (iPSCs) offer a promising source for cell replacement therapies, but their practical application faces challenges due to poor survival and integration after transplantation. Park et al. propose a novel therapeutic strategy involving the co-transplantation of regulatory T cells (Tregs) and iPSC-derived dopamine neurons. This combined approach enhances the survival of transplanted cells and protects against neuroinflammation-induced damage. In PD animal models, the co-transplantation approach significantly suppressed the host immune response, resulting in improved behavioral recovery. Additionally, Tregs demonstrate acute neuroprotection and contribute to delayed neuro-restoration in ischemic stroke. This combined approach of cell therapy with immunomodulation offers a promising avenue for advancing our understanding of neurological diseases and promoting the development of novel treatments.

[Contralateral endoscopic approach for lumbar foraminal stenosis using unilateral biportal endoscopic surgery].

OBJECTIVE: To assess the feasibility and imaging outcomes of unilateral biportal endoscopic technique in the treatment of lumbar foraminal stenosis through contralateral approach. METHODS: The clinical data of 33 patients with lumbar foraminal stenosis treated with unilateral biportal endoscopic technique from January 2021 to July 2022 were retrospectively analyzed. There were 17 males and 16 females;age ranging from 34 to 72 years old with an average of (56.00±7.89) years old;operation time and perioperative complications were recorded;visual analogue scale (VAS) of pain was recorded, to evaluate the degree of low back pain and lower extremity pain, and Oswestry disability index (ODI) to evaluate the lumbar spine function. At the latest follow-up, the modified Macnab score was used to evaluate the clinical efficacy. RESULTS: All patients successfully completed the operation. The operation time ranged from 47 to 65 minutes, with an average of (56.10±5.19) minutes. The postoperative follow-up ranged from 12 to 18 months, with an average of (14.9±2.3) months. The VAS of low back and lower extermity pain before operation were (7.273±1.442) and (7.697±1.447) scores, ODI was (69.182±9.740)%. Postoperative lumbocrural pain VAS were (3.394±0.966) and (2.818±0.727) scores, ODI was (17.30±4.78) %. At the latest follow-up, VAS of back and lower extermity pain was (2.788±0.650) and (2.394±0.704) scores, ODI was (14.33±350)%. There were significant differences in VAS of low back and lower extremity pain and ODI before and after operation(P<0.05). At the latest follow-up, according to the modified Macnab criteria, 24 patients got excellent result, 5 as good, 2 as fair, and 2 as poor. CONCLUSION: Unilateral biportal endoscopic treatment of lumbar foraminal stenosis through the contralateral approach is a safe and efficient method, with few complications, quick postoperative recovery, and satisfactory clinical outcomes. During the follow-up period, no iatrogenic lumbar instability was observed.

Identification of hypoxic macrophages in glioblastoma with therapeutic potential for vasculature normalization.

Monocyte-derived tumor-associated macrophages (Mo-TAMs) intensively infiltrate diffuse gliomas with remarkable heterogeneity. Using single-cell transcriptomics, we chart a spatially resolved transcriptional landscape of Mo-TAMs across 51 patients with isocitrate dehydrogenase (IDH)-wild-type glioblastomas or IDH-mutant gliomas. We characterize a Mo-TAM subset that is localized to the peri-necrotic niche and skewed by hypoxic niche cues to acquire a hypoxia response signature. Hypoxia-TAM destabilizes endothelial adherens junctions by activating adrenomedullin paracrine signaling, thereby stimulating a hyperpermeable neovasculature that hampers drug delivery in glioblastoma xenografts. Accordingly, genetic ablation or pharmacological blockade of adrenomedullin produced by Hypoxia-TAM restores vascular integrity, improves intratumoral concentration of the anti-tumor agent dabrafenib, and achieves combinatorial therapeutic benefits. Increased proportion of Hypoxia-TAM or adrenomedullin expression is predictive of tumor vessel hyperpermeability and a worse prognosis of glioblastoma. Our findings highlight Mo-TAM diversity and spatial niche-steered Mo-TAM reprogramming in diffuse gliomas and indicate potential therapeutics targeting Hypoxia-TAM to normalize tumor vasculature.

Cross-talk between BCKDK-mediated phosphorylation and STUB1-dependent ubiquitination degradation of BCAT1 promotes GBM progression.

Branched-chain amino acid transferase 1 (BCAT1) is highly expressed in multiple cancers and is associated with poor prognosis, particularly in glioblastoma (GBM). However, the post-translational modification (PTM) mechanism of BCAT1 is unknown. Here, we investigated the cross-talk mechanisms between phosphorylation and ubiquitination modifications in regulating BCAT1 activity and stability. We found that BCAT1 is phosphorylated by branched chain ketoacid dehydrogenase kinase (BCKDK) at S5, S9, and T312, which increases its catalytic and antioxidant activity and stability. STUB1 (STIP1 homology U-box-containing protein 1), the first we found and reported E3 ubiquitin ligase of BCAT1, can also be phosphorylated by BCKDK at the S19 site, which disrupts the interaction with BCAT1 and inhibits its degradation. In addition, we demonstrate through in vivo and in vitro experiments that BCAT1 phosphorylation inhibiting its ubiquitination at multiple sites is associated with GBM proliferation and that inhibition of the BCKDK-BCAT1 axis enhances the sensitivity to temozolomide (TMZ). Overall, we identified novel mechanisms for the regulation of BCAT1 modification and elucidated the importance of the BCKDK-STUB1-BCAT1 axis in GBM progression.

Factors affecting the intraoperative calculi excretion during flexible ureteroscopy lithotripsy: an in vitro analysis.

OBJECTIVE: To explore the parameters influencing intraoperative calculi excretion (ICE) during flexible ureteroscopy lithotripsy (fURL) using in vitro simulation experiments. METHODS: 3D-printed human kidney models were used to simulate the elimination of gravel during fURL. The factors influencing the ICE during fURL were analyzed by comparing the effects of different degrees of hydronephrosis (mild, moderate, and severe), surgical positions (supine and lateral position), ratios of endoscope-sheath diameter (RESD) (0.625, 0.725, and 0.825), gravel sizes (0.50-1.00 mm, 0.25-0.50 mm, and 0.10-0.25 mm), and ureteral access sheaths (UASs) (traditional UAS and negative-pressure UAS) on ICE. RESULTS: The impacts of various UAS, RESD, degree of hydronephrosis, surgical positions, and gravel sizes on ICE were all significant (p < 0.05). We found no evidence of multicollinearity for all the independent variables, and the linear regression equation fitted as ICE ( g / min ) = 0.102 + 0.083 ∗ UAS grade - 0.050 ∗ RESD grade - 0.048 ∗ hydronephrosis grade + 0.065 ∗ position grade - 0.027 ∗ gravel size grade (R2 = 0.569). CONCLUSION: Employing negative-pressure UAS, smaller RESD, milder hydronephrosis, lateral position, and smaller gravel size contribute to improved ICE during fURL. Among them, the adoption of negative-pressure UAS had the most substantial effects.

The optimal ratio of endoscope-sheath diameter with negative-pressure ureteral access sheath: an in vitro research.

PURPOSE: To maintain safe intrarenal pelvic pressure (IPP), the combination of flexible ureteroscope (fURS) and traditional ureteral access sheath (T-UAS) should maintain a basic rule that is the ratio of endoscope-sheath diameter (RESD) ≤ 0.75. However, the negative-pressure ureteral access sheath (NP-UAS) may break the rule of negative pressure suction. This study aimed to examine the effect of NP-UAS on IPP and flow rate (FR) with varying RESD. METHODS: In a 3D-printed renal model, flexible ureteroscopy lithotripsy (fURL) was replicated. Six sizes of fURS paired with 12Fr T-UAS and NP-UAS resulted in six distinct RESDs of 0.63, 0.78, 0.87, 0.89, 0.90, and 0.91. While the irrigation pressure (IRP) was set between 100 and 800 cmH2O and the sucking pressure (SP) was set between 0 and 800 cmH2O, the IPP and FR were measured in each RESD. RESULTS: NP-UASs can reduce the IPP and increase the FR at the same RESD compared to T-UASs. The IPP decreased with increasing SP with NP-UAS. When RESD ≤ 0.78, T-UAS and NP-UAS can maintain IPP < 40 cmH2O in most circumstances. When RESD = 0.87, it is challenging for T-UAS to sustain IPP < 40 cmH2O; however, NP-UAS can do so. When RESD ≥ 0.89, it is difficult to maintain an IPP < 40 cmH2O even with NP-UAS. CONCLUSION: NP-UAS can decrease IPP and increase FR compared with T-UAS. To maintain a safe IPP, it is recommended that RESD < 0.85 when utilizing NP-UAS.

Lentinan inhibits cell invasion via M2 polarization of tumor-associated macrophages and Wnt/ß-catenin signaling in non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is an aggressive and devastating cancer due to its metastasis induced by increased invasion. Lentinan is a polysaccharide exerting antitumor roles in multiple cancers, including lung cancer. However, the influence of lentinan on cell invasion in NSCLC remains unclear. Cell invasion was detected by transwell analysis. Matrix metallopeptidase 9 (MMP9) levels were measured through immunofluorescence staining. The markers arginase-1 (Arg-1), CD206 and interleukin (IL)-10 (IL-10) of M2 macrophages, Wnt3a, and ß-catenin levels were measured by western blot or enzyme linked immunosorbent assay. Lentinan did not affect cell viability and proliferation in NSCLC cells. Lentinan suppressed cell invasion and reduced the expression and secretion of MMP9. Lentinan attenuated also M2 polarization of tumor-associated macrophages. Moreover, lentinan mitigated the M2 macrophage conditioned medium-mediated cell invasion and MMP9 alterations in NSCLC cells. Lentinan inhibited the activation of the Wnt/ß-catenin signaling in NSCLC cells. The activated Wnt/ß-catenin pathway reversed the suppressive effects of lentinan on cell invasion and MMP9 level in NSCLC cells. In conclusion, lentinan reduces cell invasion in NSCLC cells by inhibiting the M2 polarization of tumor-associated macrophages and the Wnt/ß-catenin signaling.

Optimizing the dewatering performance of zinc smelting iron Slag: Investigating the influence of ultrasonic Time, ultrasonic Power, and Liquid-Solid ratio using response surface methodology.

Iron slag, a byproduct of the wet zinc refining process, contains a substantial amount of valuable metals such as iron and zinc, making it highly valuable for comprehensive recovery and reuse. However, before recovery, the iron slag requires dehydration pretreatment. The water content in iron slag remains relatively high and difficult to remove even after pressure filtration, leading to extended drying times, reduced drying efficiency, and increased energy consumption. This study explores a novel ultrasonic pretreatment process for iron slag. Using the response surface methodology, we investigated the effects of ultrasonic power, ultrasonic time, liquid-to-solid ratio, and their interactions on the water content, capillary suction time (CST), and filtration resistance of the slag. Regression equations were established to predict the relationships between the water content, CST, filtration resistance, and the various factors. The optimal process parameters were determined as an ultrasonic power of 60 W, ultrasonic time of 22 s, and a liquid-to-solid ratio of 4:1. Under these conditions, the dehydration performance of the iron slag was optimal. The measured values closely matched the predicted values, demonstrating the reliability of the model and the feasibility of the optimized process. Our study of the mechanism of ultrasonic action on iron slag found that under the influence of ultrasonic waves, the particle size of the slag significantly decreased, and the particle morphology changed. Compared to conventional drying, the drying rate of the iron slag after ultrasonic pretreatment was accelerated, and the drying time was reduced.

Static magnetic field assisted thawing improves cryopreservation of mouse whole ovaries.

Ovarian tissue cryopreservation is considered to be the only means to preserve fertility for prepubertal girls and women whose cancer treatment cannot be postponed. However, ovarian tissues are inevitably damaged by oxidative stress during cryopreservation, which threatens follicle survival and development, and thus affects female fertility. Therefore, reducing tissue oxidative stress injury is one of the major challenges to achieving efficient cryopreservation of ovarian tissues, especially for whole ovaries. Here, we proposed a new method to improve the antioxidant capacity of whole ovaries during cryopreservation, static magnetic field assisted thawing. The results demonstrated that the antioxidant capacity of the ovarian tissue was significantly improved by static magnetic field treatment. In addition, ovarian tissue allograft transplantation was carried out, which successfully achieved vascular regeneration and maintained follicular development. The findings of this study not only provide a new reference for the preservation of female fertility, but also is a major step forward in the cryopreservation of tissues and organs. It will have good application prospects in the field of assisted reproduction and cryo-biomedicine.

Study on the Drying Kinetics of Zinc Smelting Iron Slag Assisted by Ultrasonic Waves.

This study investigates the impact of ultrasonic treatment on the drying kinetics of zinc smelting iron slag. Through the Arrhenius equation, it was found that the reaction order of zinc smelting iron slag remains constant at 1/2 before and after ultrasonic treatment, indicating a proportional relationship between the reaction rate and the square root of the reactant concentration. Despite the increased drying rate of the iron slag due to ultrasonic pretreatment, the reaction order remains at 1/2. Additionally, it was observed that the drying kinetics of untreated iron slag aligns with the Wang and Singh model, while the drying kinetics of ultrasonically pretreated iron slag fits the Page model. The Page model facilitates the prediction of drying rate and drying time for ultrasonically pretreated iron slag, enabling the optimization of the drying process, enhancing efficiency, and comparing drying performance under different conditions. Using ultrasonic pretreatment, the subsequent drying process of iron slag can significantly shorten the time and save energy. These findings provide essential theoretical foundations for optimizing the drying process of zinc smelting iron slag.

A new method for handling heterogeneous data in bioinformatics.

Heterogeneous data, especially a mixture of numerical and categorical data, widely exist in bioinformatics. Most of works focus on defining new distance metrics rather than learning discriminative metrics for mixed data. Here, we create a new support vector heterogeneous metric learning framework for mixed data. A heterogeneous sample pair kernel is defined for mixed data and metric learning is then converted to a sample pair classification problem. The suggested approach lends itself well to effective resolution through conventional support vector machine solvers. Empirical assessments conducted on mixed data benchmarks and cancer datasets affirm the exceptional efficacy demonstrated by the proposed modeling technique.

"Three-in-One" Nanozyme Composite for Augmented Cascade Catalytic Tumor Therapy.

Cascade catalytic reaction exhibits simple procedure and high efficiency, such as that from the orderly assembly of different enzymes in biological systems. Mimicking of the natural cascade procedure becomes critical, but the orderly assembly of different enzymes is still challenging. Herein, single Au-Pt nanozyme is reported with "three-in-one" functions to initiate cascade conversions for O2 supply as mimic catalase, H2 O2 production with its glucose oxidase-like property, and • OH generation as mimic peroxidase for chemodynamic therapy (CDT). Thus, the complex assembly and cross-talk among the different enzymes are avoided. To this end, metastable Cu2 O NPs, as scaffolds, are used to anchor ultrasmall Au-Pt nanozyme, while metal-organic framework (MOF) is used to encapsulate the nanozyme for tumor microenvironment response and shielding protein adsorption. Pluronic F127 is then modified on the surface to improve hydrophilicity and biocompatibility of the composite. The endogenous acidity and glutathione in tumor degrade MOF to expose nanozyme for cascade catalytic CDT. The high photothermal conversion ability also enhances the CDT, while Cu2+ ions consume GSH to further improve CDT efficiency as augmented cascade catalytic tumor therapy. Thus, a new paradigm is provided with drug-free single nanozyme for improving tumor therapeutic efficacy and minimizing side effects.

Predicting histopathological types and molecular subtype of breast tumors: A comparative study using amide proton transfer-weighted imaging, intravoxel incoherent motion and diffusion kurtosis imaging.

PURPOSE: To evaluate the predictive performance of multiparameter and histogram features derived from amide proton transfer-weighted imaging (APTWI), intravoxel incoherent motion (IVIM) and diffusion kurtosis imaging (DKI) for histopathological types of breast tumors. METHODS: Region of interest (ROI) was delineated by outlining the largest slice of the tumor on the false-color images of the DKI, IVIM and APTWI parameters, and extracted the histogram features. Receiver operating characteristic (ROC) curve was used to evaluate the performance of parameters in predicting benign and malignant breast lesions, molecular prognostic biomarkers, lymph node status, and subtypes of breast lesions. The Spearman correlation coefficient was used to determine the correlations between each parameter and clinical-pathological factors. RESULTS: All 52 breast lesions were enrolled in this prospective study, including 8 benign lesions and 44 breast cancers. To diagnose malignant and benign breast lesions, the value of APT (min) performed best, with the AUC reaching 0.983. According to the different imaging methods, the APTWI performed best. To predict the positive status of ER, PR, Ki67, the value of Dapp (uniformity), Dapp (uniformity), f (entropy) performed best, with the AUC values reaching 0.743, 0.770, 0.848, respectively. For the identification of Luminal B, HER2-enriched, and TNBC breast cancers, Kapp (max), f (kurtosis), and Dapp (uniformity) performed best, with AUC values reaching 0.679, 0.826, 0.771, respectively. CONCLUSION: This study found the APTWI, IVIM and DKI parameters could diagnose breast cancer. The histogram features of DKI and IVIM, based on tumor heterogeneity, may help to predict breast cancer subtypes.

Early Identification of Pathologic Complete Response to Neoadjuvant Chemotherapy Using Multiphase DCE-MRI by Siamese Network in Breast Cancer: A Longitudinal Multicenter Study.

BACKGROUND: Siamese network (SN) using longitudinal DCE-MRI for pathologic complete response (pCR) identification lack a unified approach to phases selection. PURPOSE: To identify pCR in early-stage NAC, using SN with longitudinal DCE-MRI and introducing IPS for phases selection. STUDY TYPE: Multicenter, longitudinal. POPULATION: Center A: 162 female patients (50.63 ± 8.41 years) divided 7:3 into training and internal validation cohorts. Center B: 61 female patients (50.08 ± 7.82 years) were used as an external validation cohort. FIELD STRENGTH/SEQUENCE: Center A: single vendor 3.0 T with a compressed-sensing volume interpolated breath-hold examination sequence. Center B: single vendor 1.5 T with volume interpolated breath-hold examination sequence. ASSESSMENT: Patients underwent DCE-MRI before and after two NAC cycles, with tumor regions of interest (ROI) manually delineated. Histopathology was the reference for pCR identification. Models developed included a clinical one, four SN models based on IPS-selected phases, and integrated models combining clinical and SN features. STATISTICAL TESTS: Model performance was evaluated using the area under the receiver operating characteristic curve (AUC). The DeLong test was used to compare AUCs. Net reclassification improvement and integrated discrimination improvement (IDI) tests were employed for performance comparison. P < 0.05 was considered significant. RESULTS: In internal and external validation cohorts, the clinical model showed AUCs of 0.760 and 0.718. SN and integrated models, with increasing phases via IPS, achieved AUCs ranging from 0.813 to 0.951 and 0.818 to 0.922. Notably, SN-3 and integrated-3 and integrated-4 outperformed the clinical model. However, input phases beyond 20% did not significantly enhance performance (IDI test: SN-4 vs. SN-3, P = 0.314 and 0.630; integrated-4 vs. integrated-3, P = 0.785 and 0.709). DATA CONCLUSION: The longitudinal multiphase DCE-MRI based on the SN demonstrates promise for identifying pCR in breast cancer. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 4.

STAM-binding Protein-like 1 Promotes Growth and Migration of Colorectal Cancer by NF-κB Pathway.

BACKGROUND: STAM-binding protein-like 1 (STAMBPL1) functions as a deubiquitinase to cleave Lys63 ubiquitin linkage, and is associated with cancer dissemination and progression. The role of STAMBPL1 in colorectal cancer (CRC) remains unclear. METHODS: STAMBPL1 expression was determined by western blot and qRT-PCR. Cell proliferation was detected by colony formation and MTT assays, and apoptosis was assessed by flow cytometry. The metastasis was evaluated by transwell and wound healing assays. An animal xenograft experiment was used to investigate the effect of STAMBPL1 on tumor growth. RESULTS: The expression of STAMBPL1 was elevated in CRC cells. Knockdown of STAMBPL1 reduced cell viability of CRC and suppressed the proliferation, invasion, and migration. Apoptosis of CRC was induced by silence of STAMBPL1. Tumor growth of CRC was also suppressed by the silence of STAMBPL1. Knockdown of STAMBPL1 increased IκB and decreased phosphorylation of IκB to reduce p65 phosphorylation. CONCLUSION: Knockdown of STAMBPL1 inhibited cell growth and metastasis of CRC through inactivation of the NF-κB pathway.

Nano Self-Assembly for Apoptosis Induction and Early Therapeutic Efficacy Monitoring.

Real-time monitoring of early antitumor efficacy is one of the key issues in realizing high-efficiency and more precise tumor treatment. As a highly specific event in the early stage of apoptosis, the release of cytochrome c may act as a key biomarker for monitoring cell apoptosis. However, achieving real-time monitoring of the cytochrome c release in vivo remains a challenge. Herein, we report a novel integrated nanosystem named DFeK nanoparticle (DFeK NP) to achieve a favorable collaboration of inducing tumor cell apoptosis and monitoring early therapeutic efficacy, which combined the cytochrome c-activated DNA nanoprobe cApt-App with pro-apoptotic peptide [KLAKLAK]2 and ferrous ions. [KLAKLAK]2 can target the mitochondria to disrupt the mitochondrial membrane together with reactive oxygen species produced by ferrous ions via the Fenton reaction to promote mitochondrial damage. Then, cytochrome c is released from damaged mitochondria to trigger apoptosis, further activating the cApt-App probe from the fluorescence "off" state to the "on" state. The cytochrome c-specific "off-to-on" transition was successfully applied in fluorescence imaging of cytochrome c in vivo and thus achieved real-time early therapeutic efficacy monitoring. Collectively, this work presents a valuable integrated tool for tumor inhibition and therapeutic efficacy evaluation to realize more precise and more effective tumor treatment.

Pancreatic ductal adenocarcinoma with synchronous and metachronous hepatic metastasis predicted by contrast-enhanced ultrasound.

Background: Contrast-enhanced ultrasound (CEUS) has proven valuable in diagnosing benign and malignant pancreatic diseases, but its value in evaluating hepatic metastasis remains to be further explored. This study investigated the relationship between CEUS features of pancreatic ductal adenocarcinoma (PDAC) and concomitant or recurrent liver metastases after treatment. Methods: This retrospective study included 133 participants with PDAC who were diagnosed with pancreatic lesions with CEUS at Peking Union Medical College Hospital from January 2017 to November 2020. According to the CEUS classification methods in our center, all the pancreatic lesions were classified as either with rich or poor blood supply. Additionally, quantitative ultrasonographic parameters were measured in the center and periphery of all pancreatic lesions. CEUS modes and parameters of the different hepatic metastasis groups were compared. The diagnostic performance of CEUS was calculated for diagnosing synchronous and metachronous hepatic metastasis. Results: The proportions of rich blood supply and poor blood supply were 46% (32/69) and 54% (37/69), respectively, in the no hepatic metastasis group; 42% (14/33) and 58% (19/33), respectively, in the metachronous hepatic metastasis (MHM) group; and 19% (6/31) and 81% (25/31), respectively, in the synchronous hepatic metastasis (SHM) group. The wash-in slope ratio (WIS ratio) between the center of the lesion and around the lesion and peak intensity ratio (PI ratio) between the center of the lesion and around the lesion had higher values in the negative hepatic metastasis group (P<0.05). In predicting synchronous and metachronous hepatic metastasis, the WIS ratio had the best diagnostic performance. The sensitivity (SEN), specificity (SPE), accuracy (ACC), positive predictive value (PPV), and negative predictive value (NPV) were 81.8%, 95.7%, 91.2%, 90.0%, and 91.7%, respectively, for MHM; and 87.1%, 95.7%, 93.0%, 90.0%, and 94.3%, respectively, for SHM. Conclusions: CEUS would be helpful in image surveillance for synchronous or metachronous hepatic metastasis of PDAC.

Osthole inhibits malignant phenotypes and induces ferroptosis in KRAS-mutant colorectal cancer cells via suppressing AMPK/Akt signaling.

PURPOSE: Ferroptosis is a form of cell death driven by iron-dependent lipid peroxidation. Intriguingly, KRAS-mutant cancers are particularly vulnerable to ferroptosis. Osthole is a natural coumarin extracted from Cnidium spp. and other Apiaceous plants. In the present study, we explored the antitumor potential of osthole in KRAS-mutant colorectal cancer (CRC) cells. METHODS: Cell viability assay, EdU incorporation assay, flow cytometry, tumor xenograft model, western blot, immunochemistry staining, immunofluorescence, transcriptome RNA sequencing and quantitative reverse transcription-PCR were performed to evaluate the influence of osthole treatment on KRAS-mutant CRC cells. RESULTS: We found that osthole treatment suppressed proliferation and tumor growth of KRAS-mutant CRC cell lines HCT116 and SW480. Moreover, osthole treatment increased ROS production and induced ferroptosis. Osthole treatment also promoted autophagy, but inhibition of autophagy by ATG7 knockdown or 3-MA showed no influence on osthole-induced ferroptosis. In comparison, osthole increased lysosomal activation, and co-treatment with lysosome inhibitor Baf-A1 attenuated osthole-induced ferroptosis. Besides, osthole treatment reduced the phosphorylation of AMPK, Akt and mTOR in HCT116 and SW480 cells, while restored AMPK signaling by AMPK agonist AICAR partially abrogated ferroptosis induced by osthole treatment. Finally, co-treatment with osthole increased the cytotoxicity of cetuximab in KRAS-mutant CRC cells in vitro and in vivo. CONCLUSION: Our results suggested that the natural product osthole exerted its anticancer effects in KRAS-mutant CRC cells via inducing ferroptosis, and this was partially through inhibiting AMPK/Akt/mTOR signaling. Our results may expand our current knowledge for the use of osthole as an anticancer agent.