Rational Design of Biomaterials to Potentiate Cancer Thermal Therapy.

Cancer thermal therapy, also known as hyperthermia therapy, has long been exploited to eradicate mass lesions that are now defined as cancer. With the development of corresponding technologies and equipment, local hyperthermia therapies such as radiofrequency ablation, microwave ablation, and high-intensity focused ultrasound, have has been validated to effectively ablate tumors in modern clinical practice. However, they still face many shortcomings, including nonspecific damages to adjacent normal tissues and incomplete ablation particularly for large tumors, restricting their wide clinical usage. Attributed to their versatile physiochemical properties, biomaterials have been specially designed to potentiate local hyperthermia treatments according to their unique working principles. Meanwhile, biomaterial-based delivery systems are able to bridge hyperthermia therapies with other types of treatment strategies such as chemotherapy, radiotherapy and immunotherapy. Therefore, in this review, we discuss recent progress in the development of functional biomaterials to reinforce local hyperthermia by functioning as thermal sensitizers to endow more efficient tumor-localized thermal ablation and/or as delivery vehicles to synergize with other therapeutic modalities for combined cancer treatments. Thereafter, we provide a critical perspective on the further development of biomaterial-assisted local hyperthermia toward clinical applications.

Tumor cell-intrinsic MELK enhanced CCL2-dependent immunosuppression to exacerbate hepatocarcinogenesis and confer resistance of HCC to radiotherapy.

BACKGROUND: The outcome of hepatocellular carcinoma (HCC) is limited by its complex molecular characteristics and changeable tumor microenvironment (TME). Here we focused on elucidating the functional consequences of Maternal embryonic leucine zipper kinase (MELK) in the tumorigenesis, progression and metastasis of HCC, and exploring the effect of MELK on immune cell regulation in the TME, meanwhile clarifying the corresponding signaling networks. METHODS: Bioinformatic analysis was used to validate the prognostic value of MELK for HCC. Murine xenograft assays and HCC lung metastasis mouse model confirmed the role of MELK in tumorigenesis and metastasis in HCC. Luciferase assays, RNA sequencing, immunopurification-mass spectrometry (IP-MS) and coimmunoprecipitation (CoIP) were applied to explore the upstream regulators, downstream essential molecules and corresponding mechanisms of MELK in HCC. RESULTS: We confirmed MELK to be a reliable prognostic factor of HCC and identified MELK as an effective candidate in facilitating the tumorigenesis, progression, and metastasis of HCC; the effects of MELK depended on the targeted regulation of the upstream factor miR-505-3p and interaction with STAT3, which induced STAT3 phosphorylation and increased the expression of its target gene CCL2 in HCC. In addition, we confirmed that tumor cell-intrinsic MELK inhibition is beneficial in stimulating M1 macrophage polarization, hindering M2 macrophage polarization and inducing CD8 + T-cell recruitment, which are dependent on the alteration of CCL2 expression. Importantly, MELK inhibition amplified RT-related immune effects, thereby synergizing with RT to exert substantial antitumor effects. OTS167, an inhibitor of MELK, was also proven to effectively impair the growth and progression of HCC and exert a superior antitumor effect in combination with radiotherapy (RT). CONCLUSIONS: Altogether, our findings highlight the functional role of MELK as a promising target in molecular therapy and in the combination of RT therapy to improve antitumor effect for HCC.

Prediction of the Ki-67 expression level in head and neck squamous cell carcinoma with machine learning-based multiparametric MRI radiomics: a multicenter study.

BACKGROUND: This study aimed to develop and validate a machine learning (ML)-based fusion model to preoperatively predict Ki-67 expression levels in patients with head and neck squamous cell carcinoma (HNSCC) using multiparametric magnetic resonance imaging (MRI). METHODS: A total of 351 patients with pathologically proven HNSCC from two medical centers were retrospectively enrolled in the study and divided into training (n = 196), internal validation (n = 84), and external validation (n = 71) cohorts. Radiomics features were extracted from T2-weighted images and contrast-enhanced T1-weighted images and screened. Seven ML classifiers, including k-nearest neighbors (KNN), support vector machine (SVM), logistic regression (LR), random forest (RF), linear discriminant analysis (LDA), naive Bayes (NB), and eXtreme Gradient Boosting (XGBoost) were trained. The best classifier was used to calculate radiomics (Rad)-scores and combine clinical factors to construct a fusion model. Performance was evaluated based on calibration, discrimination, reclassification, and clinical utility. RESULTS: Thirteen features combining multiparametric MRI were finally selected. The SVM classifier showed the best performance, with the highest average area under the curve (AUC) of 0.851 in the validation cohorts. The fusion model incorporating SVM-based Rad-scores with clinical T stage and MR-reported lymph node status achieved encouraging predictive performance in the training (AUC = 0.916), internal validation (AUC = 0.903), and external validation (AUC = 0.885) cohorts. Furthermore, the fusion model showed better clinical benefit and higher classification accuracy than the clinical model. CONCLUSIONS: The ML-based fusion model based on multiparametric MRI exhibited promise for predicting Ki-67 expression levels in HNSCC patients, which might be helpful for prognosis evaluation and clinical decision-making.

The role of metabolic reprogramming of oxygen-induced macrophages in the dynamic changes of atherosclerotic plaques.

Atherosclerosis (As) is a chronic vascular inflammatory disease. Macrophages are the most important immune cells in atherosclerotic plaques, and the phenotype of plaque macrophages shifts dynamically to adapt to changes in the plaque microenvironment. The aerobic microenvironment of early atherosclerotic plaques promotes the transformation of M2/alternatively activated macrophages mainly through oxidative phosphorylation; the anoxic microenvironment of advanced atherosclerotic plaques mainly promotes the formation of M1/classically activated macrophages through anaerobic glycolysis; and the adventitia angiogenesis of aged atherosclerotic plaques leads to an increase in the proportion of M2/M1 macrophages. Therefore, this review deeply elucidates the dynamic change mechanism of plaque macrophages and the regulation of plaque oxygen content and immune metabolism to find new targets for the treatment of As.

Dual-energy computed tomography for predicting histological grading and survival in patients with pancreatic ductal adenocarcinoma.

OBJECTIVES: We evaluated the value of dual-energy computed tomography (DECT) parameters derived from pancreatic ductal adenocarcinoma (PDAC) to discriminate between high- and low-grade tumors and predict overall survival (OS) in patients. METHODS: Data were retrospectively collected from 169 consecutive patients with pathologically confirmed PDAC who underwent third-generation dual-source DECT enhanced dual-phase scanning before surgery between January 2017 and March 2023. Patients with prior treatments, other malignancies, small tumors, or poor-quality scans were excluded. Two radiologists evaluated three clinical and seven radiological features and measured sixteen DECT-derived parameters. Univariate and multivariate analyses were applied to select independent predictors. A prediction model and a corresponding nomogram were developed, and the area under the curve (AUC), calibration, and clinical applicability were assessed. The correlations between factors and OS were evaluated using Kaplan-Meier survival and Cox regression analyses. RESULTS: One hundred sixty-nine patients were randomly divided into training (n = 118) and validation (n = 51) cohorts, among which 43 (36.4%) and 19 (37.3%) had high-grade PDAC confirmed by pathology, respectively. The vascular invasion, normalized iodine concentration in the venous phase, and effective atomic number in the venous phase were independent predictors for histological grading. A nomogram was constructed to predict the risk of high-grade tumors in PDAC, with AUCs of 0.887 and 0.844 in the training and validation cohorts, respectively. The nomogram exhibited good calibration and was more beneficial than a single parameter in both cohorts. Pathological- and nomoscore-predicted high-grade PDACs were associated with poor OS (all p < 0.05). CONCLUSIONS: The nomogram, which combines DECT parameters and radiological features, can predict the histological grade and OS in patients with PDAC before surgery. KEY POINTS: Question Preoperative determination of histological grade in PDAC is crucial for guiding treatment, yet current methods are invasive and limited. Findings A DECT-based nomogram combining vascular invasion, normalized iodine concentration, and effective atomic number accurately predicts histological grade and OS in PDAC patients. Clinical relevance The DECT-based nomogram is a reliable, non-invasive tool for predicting histological grade and OS in PDAC. It provides essential information to guide personalized treatment strategies, potentially improving patient management and outcomes.

Boosting the sonodynamic performance of CoBiMn-layered double hydroxide nanoparticles via tumor microenvironment regulation for ultrasound imaging-guided sonodynamic therapy.

Sonodynamic therapy (SDT), a promising strategy for cancer treatment with the ability for deep tissue penetration, has received widespread attention in recent years. Sonosensitizers with intrinsic characteristics for tumor-specific curative effects, tumor microenvironment (TME) regulation and tumor diagnosis are in high demand. Herein, amorphous CoBiMn-layered double hydroxide (a-CoBiMn-LDH) nanoparticles are presented as multifunctional sonosensitizers to trigger reactive oxygen species (ROS) generation for ultrasound (US) imaging-guided SDT. Hydrothermal-synthesized CoBiMn-LDH nanoparticles are etched via a simple acid treatment to obtain a-CoBiMn-LDH nanoparticles with abundant defects. The a-CoBiMn-LDH nanoparticles give greater ROS generation upon US irradiation, reaching levels ~ 3.3 times and ~ 8.2 times those of the crystalline CoBiMn-LDH nanoparticles and commercial TiO2 sonosensitizer, respectively. This excellent US-triggered ROS generation performance can be attributed to the defect-induced narrow band gap and promoted electrons and holes (e-/h+) separation. More importantly, the presence of Mn4+ enables the a-CoBiMn-LDH nanoparticles to regulate the TME by decomposing H2O2 into O2 for hypoxia relief and US imaging, and consuming glutathione (GSH) for protection against ROS clearance. Biological mechanism analysis shows that a-CoBiMn-LDH nanoparticles modified with polyethylene glycol can serve as a multifunctional sonosensitizer to effectively kill cancer cells in vitro and eliminate tumors in vivo under US irradiation by activating p53, apoptosis, and oxidative phosphorylation-related signaling pathways.

The biological applications of near-infrared optical nanomaterials in atherosclerosis.

PURPOSE OF REVIEW: Atherosclerosis, a highly pathogenic and lethal disease, is difficult to locate accurately via conventional imaging because of its scattered and deep lesions. However, second near-infrared (NIR-II) nanomaterials show great application potential in the tracing of atherosclerotic plaques due to their excellent penetration and angiographic capabilities. RECENT FINDINGS: With the development of nanotechnology, among many nanomaterials available for the visual diagnosis and treatment of cardiovascular diseases, optical nanomaterials provide strong support for various biomedical applications because of their advantages, such as noninvasive, nondestructive and molecular component imaging. Among optical nanomaterials of different wavelengths, NIR-II-range (900 ~ 1700 nm) nanomaterials have been gradually applied in the visual diagnosis and treatment of atherosclerosis and other vascular diseases because of their deep biological tissue penetration and limited background interference. This review explored in detail the prospects and challenges of the biological imaging and clinical application of NIR-II nanomaterials in treating atherosclerosis.

Glycerophospholipid-driven lipid metabolic reprogramming as a common key mechanism in the progression of human primary hepatocellular carcinoma and cholangiocarcinoma.

Metabolic reprogramming, a key mechanism regulating the growth and recurrence of hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), still lacks effective clinical strategies for its integration into the precise screening of primary liver cancer. This study utilized ultra-high-performance liquid chromatography with quadrupole time-of-flight mass spectrometry to conduct a comprehensive, non-targeted metabolomics analysis, revealing significant upregulation of lipid metabolites such as phosphatidylcholine and lysophosphatidylcholine in patients with HCC and CCA, particularly within the glycerophospholipid metabolic pathway. Hematoxylin and eosin and immunohistochemical staining demonstrated marked upregulation of phospholipase A2 in tumor tissues, further emphasizing the potential of lipid metabolism as a therapeutic target and its important part in the course of cancer. This work provides a new viewpoint for addressing the clinical challenges associated with HCC and CCA, laying the groundwork for the broad application of early diagnosis and personalized treatment strategies, and ultimately aiming to provide tailored and precise therapeutic options for patients.

Knockdown of PKMYT1 is associated with autophagy inhibition and apoptosis induction and suppresses tumor progression in hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is a cancerous tumor that ranks as the third leading cause of cancer death across the globe. Protein kinase membrane-associated tyrosine/threonine kinase 1 (PKMYT1) is overexpressed in many cancer types, including HCC, but the potential mechanism and biological function of PKMYT1 are not fully understood. MATERIALS AND METHODS: The expression level of PKMYT1 was detected in human HCC tissues and adjacent tissues. We then established HCC cell lines with PKMYT1 knockdown and observed proliferation, migration, autophagy, apoptosis in cell lines and tumor growth in a nude mouse model. To investigate the underlying mechanism by which PKMYT1 regulates autophagy and apoptosis, RNA sequencing was performed in HCC-LM3 cells with and without PKMYT1 knockdown. RESULTS: Here, we observed that human HCC tissues had higher expression of PKMYT1 than adjacent tissues. Overexpression of PKMYT1 was closely associated with poor prognosis in HCC patients. PKMYT1 knockdown inhibited the proliferative potential and migration of HCC cell lines. We also found that downregulation of PKMYT1 inhibited autophagy and induced apoptosis. RNA sequencing analysis showed that the MAPK and PI3K-AKT pathways, which have been reported to affect autophagy and apoptosis, may be regulated after PKMYT1 knockdown by KEGG pathway enrichment analysis. Furthermore, we identified that knockdown of PKMYT1 attenuated the phosphorylation levels of p38 MAPK, ERK and PI3K/Akt/mTOR, which might mediate autophagy inhibition and apoptosis induction via these signaling pathways to inhibit the development of HCC. CONCLUSION: Our study suggests that PKMYT1 functions as an oncogene and may be a new target for HCC treatment.

TACE responser NDRG1 acts as a guardian against ferroptosis to drive tumorgenesis and metastasis in HCC.

BACKGROUND: The treatment efficacy of transarterial chemoembolization (TACE) for hepatocellular carcinoma (HCC) varies widely between individuals. The aim of this study was to identify subtype landscapes and responser related to TACE, and further clarify the regulatory effect and corresponding mechanism of NDRG1 on HCC tumorgenesis and metastasis. METHODS: The principal component analysis (PCA) algorithm was used to construct a TACE response scoring (TRscore) system. The random forest algorithm was applied to identify the TACE response-related core gene NDRG1 of HCC, and its role in the prognosis of HCC was explored. The role of NDRG1 in the progression and metastasis of HCC and functional mechanism were confirmed using several experimental methods. RESULTS: Based on the GSE14520 and GSE104580 cohorts, we identified 2 TACE response-related molecular subtypes for HCC with significant differences in clinical features, and the TACE prognosis of Cluster A was significantly better than that of Cluster B (p < 0.0001). We then established the TRscore system and found that the low TRscore group showed a higher probability of survival and a lower rate of recurrence than the high TRscore group (p < 0.05) in both the HCC and TACE-treated HCC cohorts within the GSE14520 cohort. NDRG1 was determined to be the the hub gene associated with the TACE response of HCC and its high expression suggested a poor prognosis. Furthermore, The suppression of NDRG1 konckdown in tumorgenesis and metastasis of HCC was clarified in both vivo and vitro, which was importantly achieved through inducing ferroptosis in HCC cells, especially contributing to RLS3-induced ferroptosis. CONCLUSION: The constructed TACE response-related molecular subtypes and TRscores can specifically and accurately predict TACE prognosis for HCC. In addition, the TACE response-related hub gene NDRG1 may act as a guardian against ferroptosis to drive tumorgenesis and metastasis in HCC, which laid a new foundation for the development of new potential targeted therapy strategies to improve disease prognosis in HCC patients.

The Presence of Lung Cancer Affects SARS-CoV-2 Vaccine Uptake and Attitude in Chinese Patients: A Clinical Cross-Sectional Investigation.

With the SARS-CoV-2 mutations evolving and prompt of SARS-CoV-2 vaccines, no information is available on SARS-CoV-2 vaccination status in Chinese patients with lung cancer. An electronic questionnaire including sociodemographic characteristics, vaccine status, side effect post-vaccination, and attitude towards a fourth dose of vaccine was conducted within 1018 Chinese patients with lung cancer from October 18th, 2022, to November 25th, 2022. Among 1018 patients, a total of 75 (13.7%) patients reported acceptable systemic adverse events in those had received the SARS-CoV-2 vaccine (549, 54%), the most common of which was fever (39, 7%). Factors including females (OR, 1.512; 95% CI, 1.076-2.124), residents in the municipality (OR, 2.048; 95% CI, 1.238-3.389), undergoing therapy (OR, 2.897; 95% CI, 1.348-6.226), disagree to vaccines is safe for patients with lung cancer (OR, 3.816; 95% CI, 2.198-6.626) contributed to hesitancy. Among 373 patients had received three doses, half respondents (206, 55.2%) were hesitant to receive a fourth dose due to the safety concern and efficacy towards the variants. In conclusion, low vaccine uptake rates in patients with lung cancer could be improved by increasing confidence in vaccine safety, particularly for those with negative beliefs. Appropriate guidance and individualized vaccination plans that meet the healthcare needs of patients with lung cancer were needed during the constantly evolving pandemic.

Safety, efficacy and pharmacokinetics of BPI-9016M in c-MET overexpression or MET exon 14 skipping mutation patients with locally advanced or metastatic non-small-cell lung cancer: a phase Ib study.

BACKGROUND: As a potential target receptor tyrosine kinase, mesenchymal-epithelial transition factor (MET) exhibits high aberrant expression across various tumors. This study aimed to evaluated the safety, tolerability, efficacy and pharmacokinetics (PK) of BPI-9016M, a novel tyrosine kinase inhibitor (TKI) targeting c-MET, in c-MET overexpression or MET exon 14 skipping mutation patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC). METHODS/DESIGN: In this two-part multicenter phase Ib study, eligible patients with locally advanced or metastatic NSCLC harboring c-MET overexpression or MET exon 14 skipping mutation were enrolled into Part A (tested positive for c-MET overexpression [immunohistochemical staining score ≥ 2+]; 300 mg quaque die [QD], 450 mg QD and 600 mg QD cohorts) or Part B (tested positive for MET exon 14 skipping mutation; 400 mg bis in die [BID] cohort), respectively. The primary endpoints were safety, objective response rate (ORR) and disease control rate (DCR), the second endpoints were PK parameters, progression-free survival (PFS) and overall survival (OS). RESULTS: Between March 15, 2017 and September 18, 2021, 38 patients were enrolled (Part A, n = 34; Part B, n = 4). Of 38 patients, 32 (84.2%) patients completed the treatment protocol. As of the data cut-off date on January 27, 2022, all patients reported at least one treatment-emergent adverse event (TEAE). Ninety-two point one percent (35/38) of patients experienced treatment-related adverse events (TRAEs), and grade ≥ 3 TRAEs were observed in 11 (28.9%) patients. The most common TRAEs were elevated alanine aminotransferase (ALT, 14/38, 36.8%) and elevated aspartate aminotransferase (AST, 11/38, 28.9%). Only one (2.6%) patient had treatment-related serious adverse event (SAE) in 600 mg QD cohort due to thrombocytopenia. PK analysis showed BPI-9016M and its main metabolites (M1 and M2-2) reached steady state after seven days of continuous administration. At the dose of 300 mg QD and 450 mg QD, the exposure of BPI-9016M increased with increasing dose. Exposure of BPI-9016M was similar at 450 mg QD and 600 mg QD, which may exhibit a saturation trend. In all patients, ORR and DCR were 2.6% (1/38, 95% confidence interval [CI] 0.1-13.8%) and 42.1% (16/38, 95% CI 26.3-59.2%), respectively. Only one partial response (PR) patient was observed at a dose of 600 mg QD in Part A. In Part B, DCR was 75.0% (3/4, 95% CI 19.4-99.4%). The median PFS and OS in all 38 patients were 1.9 months (95% CI 1.9-3.7) and 10.3 months (95% CI 7.3-not evaluable [NE]), respectively. CONCLUSION: BPI-9016M showed manageable safety profile in c-MET overexpression or MET exon 14 skipping mutation patients with locally advanced or metastatic NSCLC, but showed limited efficacy. TRIAL REGISTRATION: Clinicaltrials.gov NCT02929290 (11/10/2016).

A pre-treatment CT-based weighted radiomic approach combined with clinical characteristics to predict durable clinical benefits of immunotherapy in advanced lung cancer.

OBJECTIVES: To develop a pre-treatment CT-based predictive model to anticipate inoperable lung cancer patients' progression-free survival (PFS) to immunotherapy. METHODS: This single-center retrospective study developed and cross-validated a radiomic model in 185 patients and tested it in 48 patients. The binary endpoint is the durable clinical benefit (DCB, PFS ≥ 6 months) and non-DCB (NDCB, PFS < 6 months). Radiomic features were extracted from multiple intrapulmonary lesions and weighted by an attention-based multiple-instance learning model. Aggregated features were then selected through L2-regularized ridge regression. Five machine-learning classifiers were conducted to build predictive models using radiomic and clinical features alone and then together. Lastly, the predictive value of the model with the best performance was validated by Kaplan-Meier survival analysis. RESULTS: The predictive models based on the weighted radiomic approach showed superior performance across all classifiers (AUCs: 0.75-0.82) compared with the largest lesion approach (AUCs: 0.70-0.78) and the average sum approach (AUCs: 0.64-0.80). Among them, the logistic regression model yielded the most balanced performance (AUC = 0.87 [95%CI 0.84-0.89], 0.75 [0.68-0.82], 0.80 [0.68-0.92] in the training, validation, and test cohort respectively). The addition of five clinical characteristics significantly enhanced the performance of radiomic-only model (train: AUC 0.91 [0.89-0.93], p = .042; validation: AUC 0.86 [0.80-0.91], p = .011; test: AUC 0.86 [0.76-0.96], p = .026). Kaplan-Meier analysis of the radiomic-based predictive models showed a clear stratification between classifier-predicted DCB versus NDCB for PFS (HR = 2.40-2.95, p < 0.05). CONCLUSIONS: The adoption of weighted radiomic features from multiple intrapulmonary lesions has the potential to predict long-term PFS benefits for patients who are candidates for PD-1/PD-L1 immunotherapies. KEY POINTS: • Weighted radiomic-based model derived from multiple intrapulmonary lesions on pre-treatment CT images has the potential to predict durable clinical benefits of immunotherapy in lung cancer. • Early line immunotherapy is associated with longer progression-free survival in advanced lung cancer.

SMYD3 associates with the NuRD (MTA1/2) complex to regulate transcription and promote proliferation and invasiveness in hepatocellular carcinoma cells.

BACKGROUND: SMYD3, a member of the SET and MYND domain-containing (SMYD) family, is a histone methyltransferase (HMT) and transcription factor that plays an important role in transcriptional regulation in human carcinogenesis. RESULTS: Using affinity purification and mass spectrometry assays to identify SMYD3-associated proteins in hepatocellular carcinoma (HCC) cells, we found several previously undiscovered SMYD3-interacting proteins, including the NuRD (MTA1/2) complex, the METTL family, and the CRL4B complex. Transcriptomic analysis of the consequences of knocking down SMYD3, MTA1, or MTA2 in HCC cells showed that SMYD3/NuRD complex targets a cohort of genes, some of which are critically involved in cell growth and migration. qChIP analyses showed that SMYD3 knockdown led to a significant reduction in the binding of MTA1 or MTA2 to the promoters of IGFBP4 and led to a significant decrease in H4K20me3 and a marked increase in H4Ac at the IGFBP4 promoter. In addition, we demonstrated that SMYD3 promotes cell proliferation, invasion, and tumorigenesis in vivo and in vitro and found that its expression is markedly upregulated in human liver cancer. Knockdown of MTA1 or MTA2 had the same effect as knockdown of SMYD3 on proliferation and invasion of hepatocellular carcinoma cells. Catalytic mutant SMYD3 could not rescue the phenotypic effects caused by knockdown of SMYD3. Inhibitors of SMYD3 effectively inhibited the proliferation and invasiveness of HCC cells. CONCLUSIONS: These findings revealed that SMYD3 could transcriptionally repress a cohort of target genes expression by associating with the NuRD (MTA1/2) complex, thereby promoting the proliferation and invasiveness of HCC cells. Our results support the case for pursuing SMYD3 as a practical prognostic marker or therapeutic target against HCC.

[CT-Based Weighted Radiomic Score Predicts Tumor Response to Immunotherapy in Non-Small Cell Lung Cancer].

Objective To develop a CT-based weighted radiomic model that predicts tumor response to programmed death-1(PD-1)/PD-ligand 1(PD-L1)immunotherapy in patients with non-small cell lung cancer.Methods The patients with non-small cell lung cancer treated by PD-1/PD-L1 immune checkpoint inhibitors in the Peking Union Medical College Hospital from June 2015 to February 2022 were retrospectively studied and classified as responders(partial or complete response)and non-responders(stable or progressive disease).Original radiomic features were extracted from multiple intrapulmonary lesions in the contrast-enhanced CT scans of the arterial phase,and then weighted and summed by an attention-based multiple instances learning algorithm.Logistic regression was employed to build a weighted radiomic scoring model and the radiomic score was then calculated.The area under the receiver operating characteristic curve(AUC)was used to compare the weighted radiomic scoring model,PD-L1 model,clinical model,weighted radiomic scoring + PD-L1 model,and comprehensive prediction model.Results A total of 237 patients were included in the study and randomized into a training set(n=165)and a test set(n=72),with the mean ages of(64±9)and(62±8)years,respectively.The AUC of the weighted radiomic scoring model reached 0.85 and 0.80 in the training set and test set,respectively,which was higher than that of the PD-L1-1 model(Z=37.30,P<0.001 and Z=5.69,P=0.017),PD-L1-50 model(Z=38.36,P<0.001 and Z=17.99,P<0.001),and clinical model(Z=11.40,P<0.001 and Z=5.76,P=0.016).The AUC of the weighted scoring model was not different from that of the weighted radiomic scoring + PD-L1 model and the comprehensive prediction model(both P>0.05).Conclusion The weighted radiomic scores based on pre-treatment enhanced CT images can predict tumor responses to immunotherapy in patients with non-small cell lung cancer.

Piperlongumine synergistically enhances the antitumour activity of sorafenib by mediating ROS-AMPK activation and targeting CPSF7 in liver cancer.

Sorafenib, a multikinase inhibitor, is the first-line agent for advanced liver cancer. Sorafenib strongly inhibits both cell proliferation and tumour angiogenesis. However, the development of drug resistance hampers its anticancer efficacy. To improve the antitumour activity of sorafenib, we demonstrate that piperlongumine (PL), an alkaloid isolated from the fruits and roots of Piper longum L., enhances the cytotoxicity of sorafenib in HCCLM3 and SMMC7721 cells using the cell counting kit-8 test. Flow cytometry analysis indicated that PL and sorafenib cotreatment induced robust reactive oxygen species (ROS) generation and mitochondrial dysfunction, thereby increasing the number of apoptotic cells and the ratio of G2/M phase cells in both HCCLM3 and SMMC7721 cells. Furthermore, AMP-protein kinase (AMPK) signalling was activated by excess ROS accumulation and mediated growth inhibition in response to PL and sorafenib cotreatment. RNA-sequencing analysis indicated that PL treatment disrupted RNA processing in HCCLM3 cells. In particular, PL treatment decreased the expression of cleavage and polyadenylation specificity factor 7 (CPSF7), a subunit of cleavage factor I, in a time- and concentration-dependent manner in HCCLM3 and SMMC7721 cells. CPSF7 knockdown using a gene interference strategy promoted growth inhibition of PL or sorafenib monotherapy, whereas CPSF7 overexpression alleviated the cytotoxicity of sorafenib in cultured liver cancer cells. Finally, PL and sorafenib coadministration significantly reduced the weight and volume of HCCLM3 cell xenografts in vivo. Taken together, our data indicate that PL displays potential synergistic antitumour activity in combination with sorafenib in liver cancer.

Homogenous multifunctional microspheres induce ferroptosis to promote the anti-hepatocarcinoma effect of chemoembolization.

Transcatheter arterial chemoembolization (TACE) is one of the main palliative therapies for advanced hepatocellular carcinoma (HCC), which is also regarded as a promising therapeutic strategy for cancer treatment. However, drug-loaded microspheres (DLMs), as commonly used clinical chemoembolization drugs, still have the problems of uneven particle size and unstable therapeutic efficacy. Herein, gelatin was used as the wall material of the microspheres, and homogenous gelatin microspheres co-loaded with adriamycin and Fe3O4 nanoparticles (ADM/Fe3O4-MS) were further prepared by a high-voltage electrospray technology. The introduction of Fe3O4 nanoparticles into DLMs not only provided excellent T2-weighted magnetic resonance imaging (MRI) properties, but also improved the anti-tumor effectiveness under microwave-induced hyperthermia. The results showed that ADM/Fe3O4-MS plus microwave irradiation had significantly better antitumor efficacy than the other types of microspheres at both cell and animal levels. Our study further confirmed that ferroptosis was involved in the anti-tumor process of ADM/Fe3O4-MS plus microwave irradiation, and ferroptosis marker GPX4 was significantly decreased and ACSL4 was significantly increased, and ferroptosis inhibitors could reverse the tumor cell killing effect caused by ADM/Fe3O4-MS to a certain extent. Our results confirmed that microwave mediated hyperthermia could amplify the antitumor efficacy of ADM/Fe3O4-MS by activating ferroptosis and the introduction of Fe3O4 nanoparticles can significantly improve TACE for HCC. This study confirmed that it was feasible to use uniform-sized gelatin microspheres co-loaded with Fe3O4 nanoparticles and adriamycin to enhance the efficacy of TACE for HCC.

Integrated analyses identify miR-34c-3p/MAGI3 axis for the Warburg metabolism in hepatocellular carcinoma.

Activated oncogenes and loss of tumor suppressors contribute to reprogrammed energy metabolism and induce aerobic glycolysis, also known as Warburg effect. MicroRNAs are profoundly implicated in human malignancies by inhibiting translation of multiple mRNA targets. Using hepatocellular carcinoma (HCC) molecular profiles from The Cancer Genome Atlas (TCGA), we identified a handful of dysregulated microRNA in HCC glycolysis, especially miR-34c-3p. Antagonization of miR-34c-3p inhibited the lactate production, glucose consumption, extracellular acidification rate (ECAR), and aggressive proliferation in HCC cells. Hijacking glycolysis by 2-deoxy-d-glucose or galactose largely abrogated the suppressive effects of miR-34c-3p inhibition in HCC. Membrane associated guanylate kinase, WW, and PDZ domain containing 3 (MAGI3) is then identified as a direct functional target of miR-34c-3p in regulating HCC glycolysis and oncogenic activities. Mechanistically, MAGI3 physically interacted with ß-catenin to regulate its transcriptional activity and c-Myc expression, which further facilitates the Warburg effect by increasing expression of glycolytic genes including HK2, PFKL, and LDHA. Moreover, overexpressed miR-34c-3p and reduced MAGI3 predicted poor clinical outcome and was closely associated with the maximum standard uptake value (SUVmax) in HCC patients who received preoperative 18 F-FDG PET/CT. Our findings elucidate critical several microRNAs implicated in HCC glycolysis and reveal a novel function of miR-34c-3p/MAGI3 axis in Warburg effect through regulating ß-catenin activity.

Prediction of tumor response via a pretreatment MRI radiomics-based nomogram in HCC treated with TACE.

OBJECTIVES: To develop and validate a pre-transcatheter arterial chemoembolization (TACE) MRI-based radiomics model for predicting tumor response in intermediate-advanced hepatocellular carcinoma (HCC) patients. MATERIALS: Ninety-nine intermediate-advanced HCC patients (69 for training, 30 for validation) treated with TACE were enrolled. MRI examinations were performed before TACE, and the efficacy was evaluated according to the mRECIST criterion 3 months after TACE. A total of 396 radiomics features were extracted from T2-weighted pre-TACE images, and least absolute shrinkage and selection operator (LASSO) regression was applied to feature selection and model construction. The performance of the model was evaluated by receiver operating characteristic (ROC) curves, calibration curves, and decision curves. RESULTS: The AFP value, Child-Pugh score, and BCLC stage showed a significant difference between the TACE response (TR) and non-TACE response (nTR) patients. Six radiomics features were selected by LASSO and the radiomics score (Rad-score) was calculated as the sum of each feature multiplied by the non-zero coefficient from LASSO. The AUCs of the ROC curve based on Rad-score were 0.812 and 0.866 in the training and validation cohorts, respectively. To improve the diagnostic efficiency, the Rad-score was further integrated with the above clinical indicators to form a novel predictive nomogram. Results suggested that the AUC increased to 0.861 and 0.884 in the training and validation cohorts, respectively. Decision curve analysis showed that the radiomics nomogram was clinically useful. CONCLUSION: The radiomics and clinical indicator-based predictive nomogram can well predict TR in intermediate-advanced HCC and can further be applied for auxiliary diagnosis of clinical prognosis. KEY POINTS: • The therapeutic outcome of TACE varies greatly even for patients with the same clinicopathologic features. • Radiomics showed excellent performance in predicting the TACE response. • Decision curves demonstrated that the novel predictive model based on the radiomics signature and clinical indicators has great clinical utility.

T-cell exhaustion interrelates with immune cytolytic activity to shape the inflamed tumor microenvironment.

Direct quantification of exhausted T cells in human cancer is lacking, and its predictive value for checkpoint-based treatment remains poorly investigated. We sought to systematically characterize the pan-cancer landscape and molecular hallmarks of T-cell dysfunction for the purpose of precision immunotherapy. Here, we defined a transcriptional signature for T-cell exhaustion through analyzing differential gene expression between PD-1-high and PD-1-negative CD8+ T lymphocytes from primary non-small cell lung cancer (NSCLC), followed by positive correlation tests with PDCD1 in TCGA lung carcinomas. A 78-gene signature for exhausted CD8+ T cells (GET) was identified and validated to reflect dysfunctional immune state spanning different species and disease models. We discovered that GET estimation significantly correlated with intratumoral immune cytolytic activity (CYT) and T-cell-inflamed gene expression profile (GEP) across 30 solid tumor types. Miscellaneous tumor-intrinsic and -extrinsic properties, in particular leukocyte proportions, genomic abnormalities, specific mutational signatures, and signaling pathways, were notably associated with GET levels. Furthermore, higher GET expression predicted an increased likelihood of clinical response to immune checkpoint inhibitors. These findings highlight the interrelation between T-cell exhaustion and immune cytolytic activity at the pan-cancer scale. The resulting inflamed tumor microenvironment may further crosstalk with other molecular and clinicopathological factors, which should be properly considered during immunotherapy biomarker development. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.