Enhanced SLC35B2/SAV1 sulfation axis promotes tumor growth by inhibiting Hippo signaling in HCC.

BACKGROUND AND AIMS: Protein tyrosine sulfation (PTS) is a common posttranslational modification that regulates a variety of physiological and pathological processes. However, the role of PTS in cancer remains poorly understood. The goal of this study was to determine whether and how PTS plays a role in HCC progression. APPROACH AND RESULTS: By mass spectrometry and bioinformatics analysis, we identified SAV1 as a novel substrate of PTS in HCC. Oxidative stress upregulates the transcription of SLC35B2, a Golgi-resident transporter of sulfate donor 3'-phosphoadenosine 5'-phosphosulfate, leading to increased sulfation of SAV1. Sulfation of SAV1 disrupts the formation of the SAV1-MST1 complex, resulting in a decrease of MST1 phosphorylation and subsequent inactivation of Hippo signaling. These molecular events ultimately foster the growth of HCC cells both in vivo and in vitro. Moreover, SLC35B2 is a novel transcription target gene of the Hippo pathway, constituting a positive feedback loop that facilitates HCC progression under oxidative stress. CONCLUSIONS: Our findings reveal a regulatory mechanism of the SLC35B2/SAV1 sulfation axis in response to oxidative stress, highlighting its potential as a promising therapeutic target for HCC.

Oxidative Stress Promotes Liver Cancer Metastasis via RNF25-Mediated E-Cadherin Protein Degradation.

Loss of E-cadherin (ECAD) is required in tumor metastasis. Protein degradation of ECAD in response to oxidative stress is found in metastasis of hepatocellular carcinoma (HCC) and is independent of transcriptional repression as usually known. Mechanistically, protein kinase A (PKA) senses oxidative stress by redox modification in its ß catalytic subunit (PRKACB) at Cys200 and Cys344. The activation of PKA kinase activity subsequently induces RNF25 phosphorylation at Ser450 to initiate RNF25-catalyzed degradation of ECAD. Functionally, RNF25 repression induces ECAD protein expression and inhibits HCC metastasis in vitro and in vivo. Altogether, these results indicate that RNF25 is a critical regulator of ECAD protein turnover, and PKA is a necessary redox sensor to enable this process. This study provides some mechanistic insight into how oxidative stress-induced ECAD degradation promotes tumor metastasis of HCC.

HSPA8 Activates Wnt/ß-Catenin Signaling to Facilitate BRAF V600E Colorectal Cancer Progression by CMA-Mediated CAV1 Degradation.

BRAF V600E attracts wide attention in the treatment of colorectal cancer (CRC) as stratifying and predicting a refractory classification of CRC. Recent evidence indicates that Wnt/ß-catenin signaling is broadly activated and participates in the refractoriness of BRAF V600E CRC, but the underlying molecular mechanism needs to be elucidated. Here, heat shock 70 kDa protein 8 (HSPA8), an essential regulator in chaperone-mediated autophagy (CMA), is identified as a potential therapeutic target for advanced BRAF V600E CRC. These results show that HSPA8 is transcriptionally upregulated in BRAF V600E CRC, which promotes CMA-dependent degradation of caveolin-1 (CAV1) to release ß-catenin into the nucleus and thus activates the Wnt/ß-catenin pathway, contributing to metastasis and progression of BRAF V600E CRC. Of note, HSPA8 directly interacts with the KIFSN motif on CAV1, the interaction can be enhanced by p38 MAPK-mediated CAV1 S168 phosphorylation. Furthermore, pharmacological targeting HSPA8 by VER155008 exhibits synergistic effects with BRAF inhibitors on CRC mouse models. In summary, these findings discover the important role of the HSPA8/CAV1/ß-catenin axis in the development of refractory BRAF V600E CRC and highlight HSPA8 as a predictive biomarker and therapeutic target in clinical practice.

Redox signaling-mediated tumor extracellular matrix remodeling: pleiotropic regulatory mechanisms.

BACKGROUND: The extracellular matrix (ECM), a fundamental constituent of all tissues and organs, is crucial for shaping the tumor microenvironment. Dysregulation of ECM remodeling has been closely linked to tumor initiation and progression, where specific signaling pathways, including redox signaling, play essential roles. Reactive oxygen species (ROS) are risk factors for carcinogenesis whose excess can facilitate the oxidative damage of biomacromolecules, such as DNA and proteins. Emerging evidence suggests that redox effects can aid the modification, stimulation, and degradation of ECM, thus affecting ECM remodeling. These alterations in both the density and components of the ECM subsequently act as critical drivers for tumorigenesis. In this review, we provide an overview of the functions and primary traits of the ECM, and it delves into our current understanding of how redox reactions participate in ECM remodeling during cancer progression. We also discuss the opportunities and challenges presented by clinical strategies targeting redox-controlled ECM remodeling to overcome cancer. CONCLUSIONS: The redox-mediated ECM remodeling contributes importantly to tumor survival, progression, metastasis, and poor prognosis. A comprehensive investigation of the concrete mechanism of redox-mediated tumor ECM remodeling and the combination usage of redox-targeted drugs with existing treatment means may reveal new therapeutic strategy for future antitumor therapies.

MRI feature-based radiomics models to predict treatment outcome after stereotactic body radiotherapy for spinal metastases.

OBJECTIVE: This study aimed to extract radiomics features from MRI using machine learning (ML) algorithms and integrate them with clinical features to build response prediction models for patients with spinal metastases undergoing stereotactic body radiotherapy (SBRT). METHODS: Patients with spinal metastases who were treated using SBRT at our hospital between July 2018 and April 2023 were recruited. We assessed their response to treatment using the revised Response Evaluation Criteria in Solid Tumors (version 1.1). The lesions were categorized into progressive disease (PD) and non-PD groups. Radiomics features were extracted from T1-weighted image (T1WI), T2-weighted image (T2WI), and fat-suppression T2WI sequences. Feature selection involved intraclass correlation coefficients, minimal-redundancy-maximal-relevance, and least absolute shrinkage and selection operator methods. Thirteen ML algorithms were employed to construct the radiomics prediction models. Clinical, conventional imaging, and radiomics features were integrated to develop combined models. Model performance was evaluated using receiver operating characteristic (ROC) curve analysis, and the clinical value was assessed using decision curve analysis. RESULTS: We included 194 patients with 142 (73.2%) lesions in the non-PD group and 52 (26.8%) in the PD group. Each region of interest generated 2264 features. The clinical model exhibited a moderate predictive value (area under the ROC curve, AUC = 0.733), while the radiomics models demonstrated better performance (AUC = 0.745-0.825). The combined model achieved the best performance (AUC = 0.828). CONCLUSION: The MRI-based radiomics models exhibited valuable predictive capability for treatment outcomes in patients with spinal metastases undergoing SBRT. CRITICAL RELEVANCE STATEMENT: Radiomics prediction models have the potential to contribute to clinical decision-making and improve the prognosis of patients with spinal metastases undergoing SBRT. KEY POINTS: • Stereotactic body radiotherapy effectively delivers high doses of radiation to treat spinal metastases. • Accurate prediction of treatment outcomes has crucial clinical significance. • MRI-based radiomics models demonstrated good performance to predict treatment outcomes.

Oral squamous cell carcinomas: state of the field and emerging directions.

Oral squamous cell carcinoma (OSCC) develops on the mucosal epithelium of the oral cavity. It accounts for approximately 90% of oral malignancies and impairs appearance, pronunciation, swallowing, and flavor perception. In 2020, 377,713 OSCC cases were reported globally. According to the Global Cancer Observatory (GCO), the incidence of OSCC will rise by approximately 40% by 2040, accompanied by a growth in mortality. Persistent exposure to various risk factors, including tobacco, alcohol, betel quid (BQ), and human papillomavirus (HPV), will lead to the development of oral potentially malignant disorders (OPMDs), which are oral mucosal lesions with an increased risk of developing into OSCC. Complex and multifactorial, the oncogenesis process involves genetic alteration, epigenetic modification, and a dysregulated tumor microenvironment. Although various therapeutic interventions, such as chemotherapy, radiation, immunotherapy, and nanomedicine, have been proposed to prevent or treat OSCC and OPMDs, understanding the mechanism of malignancies will facilitate the identification of therapeutic and prognostic factors, thereby improving the efficacy of treatment for OSCC patients. This review summarizes the mechanisms involved in OSCC. Moreover, the current therapeutic interventions and prognostic methods for OSCC and OPMDs are discussed to facilitate comprehension and provide several prospective outlooks for the fields.

Assessment of Hidden Blood Loss in Spinal Metastasis Surgery: A Comprehensive Approach with MRI-Based Radiomics Models.

BACKGROUND: Patients undergoing surgery for spinal metastasis are predisposed to hidden blood loss (HBL), which is associated with poor surgical outcomes but unpredictable. PURPOSE: To evaluate the role of MRI-based radiomics models for assess the risk of HBL in patients undergoing spinal metastasis surgery. STUDY TYPE: Retrospective. SUBJECTS: 202 patients (42.6% female) operated on for spinal metastasis with a mean age of 58 ± 11 years were divided into a training (n = 162) and a validation cohort (n = 40). FIELD STRENGTH/SEQUENCE: 1.5T or 3.0T scanners. Sagittal T1-weighted and fat-suppressed T2-weighted imaging sequences. ASSESSMENT: HBL was calculated using the Gross formula. Patients were classified as low and high HBL group, with 1000 mL as the threshold. Radiomics models were constructed with radiomics features. The radiomics score (Radscore) was obtained from the optimal radiomics model. Clinical variables were accessed using univariate and multivariate logistic regression analyses. Independent risk variables were used to build a clinical model. Clinical variables combined with Radscore were used to establish a combined model. STATISTICAL TESTS: Predictive performance was evaluated using area under the curve (AUC), accuracy, sensitivity, specificity, and F1 score. Calibration curves and decision curves analyses were produced to evaluate the accuracy and clinical utility. RESULTS: Among the radiomics models, the fusion (T1WI + FS-T2WI) model demonstrated the highest predictive efficacy (AUC: 0.744, 95% confidence interval [CI]: 0.576-0.914). The Radscore model (AUC: 0.809, 95% CI: 0.664-0.954) performs slightly better than the clinical model (AUC: 0.721, 95% CI: 0.524-0.918; P = 0.418) and the combined model (AUC: 0.752, 95% CI: 0.593-0.911; P = 0.178). DATA CONCLUSION: A radiomics model may serve as a promising assessment tool for the risk of HBL in patients undergoing spinal metastasis surgery, and guide perioperative planning to improve surgical outcomes. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY: Stage 2.

Sertaconazole-repurposed nanoplatform enhances lung cancer therapy via CD44-targeted drug delivery.

BACKGROUND: Lung cancer is one of the most frequent causes of cancer-related deaths worldwide. Drug repurposing and nano-drug delivery systems are attracting considerable attention for improving anti-cancer therapy. Sertaconazole (STZ), an antifungal agent, has been reported to exhibit cytotoxicity against both normal and tumor cells, and its medical use is limited by its poor solubility. In order to overcome such shortcomings, we prepared a drug-repurposed nanoplatform to enhance the anti-tumor efficiency. METHODS: Nanoplatform was prepared by thin film dispersion. Drug release studies and uptake studies were measured in vitro. Subsequently, we verified the tumor inhibition mechanisms of HTS NPs through apoptosis assay, immunoblotting and reactive oxygen species (ROS) detection analyses. Antitumor activity was evaluated on an established xenograft lung cancer model in vivo. RESULTS: Our nanoplatform improved the solubility of sertaconazole and increased its accumulation in tumor cells. Mechanistically, HTS NPs was dependent on ROS-mediated apoptosis and pro-apoptotic autophagy to achieve their excellent anti-tumor effects. Furthermore, HTS NPs also showed strong inhibitory ability in nude mouse xenograft models without significant side effects. CONCLUSIONS: Our results suggest that sertaconazole-repurposed nanoplatform provides an effective strategy for lung cancer treatment.

Prediction of Primary Tumor Sites in Spinal Metastases Using a ResNet-50 Convolutional Neural Network Based on MRI.

We aim to investigate the feasibility and evaluate the performance of a ResNet-50 convolutional neural network (CNN) based on magnetic resonance imaging (MRI) in predicting primary tumor sites in spinal metastases. Conventional sequences (T1-weighted, T2-weighted, and fat-suppressed T2-weighted sequences) MRIs of spinal metastases patients confirmed by pathology from August 2006 to August 2019 were retrospectively analyzed. Patients were partitioned into non-overlapping sets of 90% for training and 10% for testing. A deep learning model using ResNet-50 CNN was trained to classify primary tumor sites. Top-1 accuracy, precision, sensitivity, area under the curve for the receiver-operating characteristic (AUC-ROC), and F1 score were considered as the evaluation metrics. A total of 295 spinal metastases patients (mean age ± standard deviation, 59.9 years ± 10.9; 154 men) were evaluated. Included metastases originated from lung cancer (n = 142), kidney cancer (n = 50), mammary cancer (n = 41), thyroid cancer (n = 34), and prostate cancer (n = 28). For 5-class classification, AUC-ROC and top-1 accuracy were 0.77 and 52.97%, respectively. Additionally, AUC-ROC for different sequence subsets ranged between 0.70 (for T2-weighted) and 0.74 (for fat-suppressed T2-weighted). Our developed ResNet-50 CNN model for predicting primary tumor sites in spinal metastases at MRI has the potential to help prioritize the examinations and treatments in case of unknown primary for radiologists and oncologists.

Radiomics from Mesorectal Blood Vessels and Lymph Nodes: A Novel Prognostic Predictor for Rectal Cancer with Neoadjuvant Therapy.

The objective of our study is to investigate the predictive value of various combinations of radiomic features from intratumoral and different peritumoral regions of interest (ROIs) for achieving a good pathological response (pGR) following neoadjuvant chemoradiotherapy (nCRT) in patients with locally advanced rectal cancer (LARC). This retrospective study was conducted using data from LARC patients who underwent nCRT between 2013 and 2021. Patients were divided into training and validation cohorts at a ratio of 4:1. Intratumoral ROIs (ROIITU) were segmented on T2-weighted imaging, while peritumoral ROIs were segmented using two methods: ROIPTU_2mm, ROIPTU_4mm, and ROIPTU_6mm, obtained by dilating the boundary of ROIITU by 2 mm, 4 mm, and 6 mm, respectively; and ROIMR_F and ROIMR_BVLN, obtained by separating the fat and blood vessels + lymph nodes in the mesorectum. After feature extraction and selection, 12 logistic regression models were established using radiomics features derived from different ROIs or ROI combinations, and five-fold cross-validation was performed. The average area under the receiver operating characteristic curve (AUC) was used to evaluate the performance of the models. The study included 209 patients, consisting of 118 pGR and 91 non-pGR patients. The model that integrated ROIITU and ROIMR_BVLN features demonstrated the highest predictive ability, with an AUC (95% confidence interval) of 0.936 (0.904-0.972) in the training cohort and 0.859 (0.745-0.974) in the validation cohort. This model outperformed models that utilized ROIITU alone (AUC = 0.779), ROIMR_BVLN alone (AUC = 0.758), and other models. The radscore derived from the optimal model can predict the treatment response and prognosis after nCRT. Our findings validated that the integration of intratumoral and peritumoral radiomic features, especially those associated with mesorectal blood vessels and lymph nodes, serves as a potent predictor of pGR to nCRT in patients with LARC. Pending further corroboration in future research, these insights could provide novel imaging markers for refining therapeutic strategies.

Nano-Econazole Enhanced PD-L1 Checkpoint Blockade for Synergistic Antitumor Immunotherapy against Pancreatic Ductal Adenocarcinoma.

Insufficienct T lymphocyte infiltration and unresponsiveness to immune checkpoint blockade therapy are still major difficulties for the clinical treatment of pancreatic ductal adenocarcinoma (PDAC). Although econazole has shown promise in inhibiting PDAC growth, its poor bioavailability and water solubility limit its potential as a clinical therapy for PDAC. Furthermore, the synergistic role of econazole and biliverdin in immune checkpoint blockade therapy in PDAC remains elusive and challenging. Herein, a chemo-phototherapy nanoplatform is designed by which econazole and biliverdin can be co-assembled (defined as FBE NPs), which significantly improve the poor water solubility of econazole and enhance the efficacy of PD-L1 checkpoint blockade therapy against PDAC. Mechanistically, econazole and biliverdin are directly released into the acidic cancer microenvironment, to activate immunogenic cell death via biliverdin-induced PTT/PDT and boost the immunotherapeutic response of PD-L1 blockade. In addition, econazole simultaneously enhances PD-L1 expression to sensitize anti-PD-L1 therapy, leading to suppression of distant tumors, long-term immune memory effects, improved dendritic cell maturation, and tumor infiltration of CD8+ T lymphocytes. The combined FBE NPs and α-PDL1 show synergistic antitumor efficacy. Collectively, FBE NPs show excellent biosafety and antitumor efficacy by combining chemo-phototherapy with PD-L1 blockade, which has promising potential in a precision medicine approach as a PDAC treatment strategy.

Predictive model based on DCE-MRI and clinical features for the evaluation of pain response after stereotactic body radiotherapy in patients with spinal metastases.

OBJECTIVE: To investigate the correlation of conventional MRI, DCE-MRI and clinical features with pain response after stereotactic body radiotherapy (SBRT) in patients with spinal metastases and establish a pain response prediction model. METHODS: Patients with spinal metastases who received SBRT in our hospital from July 2018 to April 2022 consecutively were enrolled. All patients underwent conventional MRI and DCE-MRI before treatment. Pain was assessed before treatment and in the third month after treatment, and the patients were divided into pain-response and no-pain-response groups. A multivariate logistic regression model was constructed to obtain the odds ratio and 95% confidence interval (CI) for each variable. C-index was used to evaluate the model's discrimination performance. RESULTS: Overall, 112 independent spinal lesions in 89 patients were included. There were 73 (65.2%) and 39 (34.8%) lesions in the pain-response and no-pain-response groups, respectively. Multivariate analysis showed that the number of treated lesions, pretreatment pain score, Karnofsky performance status score, Bilsky grade, and the DCE-MRI quantitative parameter Ktrans were independent predictors of post-SBRT pain response in patients with spinal metastases. The discrimination performance of the prediction model was good; the C index was 0.806 (95% CI: 0.721-0.891), and the corrected C-index was 0.754. CONCLUSION: Some imaging and clinical features correlated with post-SBRT pain response in patients with spinal metastases. The model based on these characteristics has a good predictive value and can provide valuable information for clinical decision-making. KEY POINTS: • SBRT can accurately irradiate spinal metastases with ablative doses. • Predicting the post-SBRT pain response has important clinical implications. • The prediction models established based on clinical and MRI features have good performance.

Discovery of canine drug toceranib phosphate as a repurposed agent against human hepatocellular carcinoma.

BACKGROUND AND AIMS: Human hepatocellular carcinoma (HCC) is an aggressive malignancy with poor clinical outcomes. There are limited therapeutic options for those diagnosed with terminal HCC and therefore incorporating novel agents into standard-of-care regimens is urgently needed. In contrast to de novo drug discovery, the strategy of repurposing compounds initially designed to treat animals might yield substantial advantages in terms of efficacy and safety. Given the evidence for the clinical efficacy of toceranib phosphate (TOC) against canine carcinomas, we aimed to investigate its therapeutic effect on human HCC. METHODS: The antitumor effects of TOC were evaluated using human HCC cell lines and cell-line-derived xenograft models. Changes in autophagic response upon TOC exposure were quantified through immunoblotting and immunofluorescence analysis. The role of TOC-triggered autophagy was addressed via pharmacological and genetic inhibition. RESULTS: We demonstrated TOC exhibited potent antitumor activity against human HCC cells by stimulating apoptosis in vitro and in vivo by a concomitant increase in autophagic flux. Blocking the TOC-triggered autophagy inhibited cellular proliferation and decreased tumour burden, indicating a protective role of autophagy against TOC-mediated HCC cell death. This role played by TOC-induced autophagy was further linked to the inactivation of the Akt/mTOR pathway that could be attributed to the upregulation of Cyr61. Moreover, treatment with sorafenib plus TOC resulted in pronounced synergistic effects on HCC cells. CONCLUSION: Our results elucidate a newly identified therapeutic potential of TOC in treating HCC, sparking a growing interest in repurposing such canine drugs for human use.

Targeting PSAT1 to mitigate metastasis in tumors with p53-72Pro variant.

The single-nucleotide polymorphism (SNP) of p53, in particular the codon 72 variants, has recently been implicated as a critical regulator in tumor progression. However, the underlying mechanism remains elusive. Here we found that cancer cells carrying codon 72-Pro variant of p53 showed impaired metastatic potential upon serine supplementation. Proteome-wide mapping of p53-interacting proteins uncovered a specific interaction of the codon 72 proline variant (but not p5372R) with phosphoserine aminotransferase 1 (PSAT1). Interestingly, p5372P-PSAT1 interaction resulted in dissociation of peroxisome proliferator-activated receptor-γ coactivator 1α (PGC-1α) that otherwise bound to p5372P, leading to subsequent nuclear translocation of PGC-1α and activation of oxidative phosphorylation (OXPHOS) and tricarboxylic acid (TCA) cycle. Depletion of PSAT1 restored p5372P-PGC-1α interaction and impeded the OXPHOS and TCA function, resulting in mitochondrial dysfunction and metastasis suppression. Notably, pharmacological targeting the PSAT1-p5372P interaction by aminooxyacetic acid (AOA) crippled the growth of liver cancer cells carrying the p5372P variant in both in vitro and patient-derived xenograft models. Moreover, AOA plus regorafenib, an FDA-proved drug for hepatocellular carcinoma and colorectal cancer, achieved a better anti-tumor effect on tumors carrying the p5372P variant. Therefore, our findings identified a gain of function of the p5372P variant on mitochondrial function and provided a promising precision strategy to treat tumors vulnerable to p5372P-PSAT1 perturbation.

Protein degradation: expanding the toolbox to restrain cancer drug resistance.

Despite significant progress in clinical management, drug resistance remains a major obstacle. Recent research based on protein degradation to restrain drug resistance has attracted wide attention, and several therapeutic strategies such as inhibition of proteasome with bortezomib and proteolysis-targeting chimeric have been developed. Compared with intervention at the transcriptional level, targeting the degradation process seems to be a more rapid and direct strategy. Proteasomal proteolysis and lysosomal proteolysis are the most critical quality control systems responsible for the degradation of proteins or organelles. Although proteasomal and lysosomal inhibitors (e.g., bortezomib and chloroquine) have achieved certain improvements in some clinical application scenarios, their routine application in practice is still a long way off, which is due to the lack of precise targeting capabilities and inevitable side effects. In-depth studies on the regulatory mechanism of critical protein degradation regulators, including E3 ubiquitin ligases, deubiquitylating enzymes (DUBs), and chaperones, are expected to provide precise clues for developing targeting strategies and reducing side effects. Here, we discuss the underlying mechanisms of protein degradation in regulating drug efflux, drug metabolism, DNA repair, drug target alteration, downstream bypass signaling, sustaining of stemness, and tumor microenvironment remodeling to delineate the functional roles of protein degradation in drug resistance. We also highlight specific E3 ligases, DUBs, and chaperones, discussing possible strategies modulating protein degradation to target cancer drug resistance. A systematic summary of the molecular basis by which protein degradation regulates tumor drug resistance will help facilitate the development of appropriate clinical strategies.

CCT251545 enhances drug delivery and potentiates chemotherapy in multidrug-resistant cancers by Rac1-mediated macropinocytosis.

It was well known that P-glycoprotein (P-gp/ABCB1) is a master regulator of multidrug resistance (MDR) in cancers. However, the clinical benefit from blocking this pathway remains inconclusive, which motivates a paradigm shift towards alternative strategies for enhancing drug influx. Using a patient-derived organoid (PDO)-based drug screening platform, we report that the combined use of chemotherapy and CCT251545 (CCT) displays robust synergistic effect against PDOs and reduces proliferation of MDR cancer cells in vitro, and results in regression of xenograft tumors, reductions in metastatic dissemination and recurrence rate in vivo. The synergistic activity mediated by CCT can be mainly attributed to the intense uptake of chemotherapeutic agents into the cells, accompanied by alterations in cell phenotypes defined as a mesenchymal epithelial transformation (MET). Mechanistically, analysis of the transcriptome coupled with validation in cellular and animal models demonstrate that the chemosensitizing effect of CCT is profoundly affected by Rac1-dependent macropinocytosis. Furthermore, CCT binds to NAMPT directly, resulting in elevated NAD levels within MDR cancer cells. This effect promotes the assembly of adherents junction (AJ) components with cytoskeleton, which is required for continuous induction of macropinocytosis and consequent drug internalization. Overall, our results illustrate the potential use of CCT as a combination partner for the commonly used chemotherapeutic drugs in the management of MDR cancers.

Hepatitis B Virus Reactivation in Cancer Patients Undergoing Immune Checkpoint Inhibitors Therapy: A Systematic Review.

Background: Immune checkpoint inhibitor (ICI) therapy is now administered to patients with advanced cancers. However, the safety and efficacy of ICIs in cancer patients with hepatitis B virus (HBV) infection is unknown. Therefore, we performed this systematic review to examine the safety and efficacy of ICIs in patients with HBV infection, with particular focus on HBV reactivation. Methods: Studies examining ICI treatment in patients with advanced cancer and HBV infection in PubMed from database inception to April 2022 were retrieved in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. In addition, reports of individuals diagnosed with HBV reactivation were supplemented through the Food and Drug Administration Adverse Event Reporting System. Results: We identified 20 articles (8 case reports, 10 retrospective case series, and 2 prospective clinical trials) and 2 meeting abstracts including 633 patients with advanced cancer and HBV infection treated with ICIs. The overall rate of HBV reactivation was 4.1% (26/633), and no HBV-related fatal events were reported. Among patients with HBV reactivation with known baseline data (20/26), HBV-DNA returned to undetectable status in 15 of 17 patients (88.2%) after a median 5.5 weeks (range, 1-14 weeks). Therapeutic responses to ICIs were observed in 14 of 88 patients (15.91%) with hepatocellular carcinoma, 6 of 45 patients (13.33%) with non-small cell lung cancer, and 3 of 13 patients (23.08%) with melanoma. Conclusion: ICIs may be safe and effective in patients with advanced cancer and HBV infection. However, there is still a need for clinical monitoring of liver enzymes and HBV-DNA during ICI therapy. Prospective trials are necessary to elucidate the appropriate antiviral therapy in these patients.

Disrupting metformin adaptation of liver cancer cells by targeting the TOMM34/ATP5B axis.

Metformin, a well-known antidiabetic drug, has been repurposed for cancer treatment; however, recently observed drug resistance and tumor metastasis have questioned its further application. Here, we found that long-term metformin exposure led to metabolic adaptation of hepatocellular carcinoma (HCC) cells, which was characterized by an obvious epithelial-mesenchymal transition (EMT) phenotype and compensatory elevation of oxidative phosphorylation (OXPHOS). TOMM34, a translocase of the outer mitochondrial membrane, was upregulated to promote tumor metastasis in response to metformin-induced metabolic stress. Mechanistically, TOMM34 interacted with ATP5B to preserve F1 FO -ATPase activity, which conferred mitochondrial OXPHOS and ATP production. This metabolic preference for OXPHOS suggested a large requirement of energy supply by cancer cells to survive and spread in response to therapeutic stress. Notably, disturbing the interaction between TOMM34 and ATP5B using Gboxin, a specific OXPHOS inhibitor, increased sensitivity to metformin and suppressed tumor progression both in vitro and in vivo. Overall, this study demonstrates a molecular link of the TOMM34/ATP5B-ATP synthesis axis during metformin adaptation and provides promising therapeutic targets for metformin sensitization in cancer treatment.

Differentiation of predominantly osteolytic from osteoblastic spinal metastases based on standard magnetic resonance imaging sequences: a comparison of radiomics model versus semantic features logistic regression model findings.

Background: The aim of this study was to compare the ability of a standard magnetic resonance imaging (MRI)-based radiomics model and a semantic features logistic regression model in differentiating between predominantly osteolytic and osteoblastic spinal metastases. Methods: We retrospectively analyzed standard MRIs and computed tomography (CT) images of 78 lesions of spinal metastases, of which 52 and 26 were predominantly osteolytic and osteoblastic, respectively. CT images were used as references for determining the sensitivity and specificity of standard MRI. Five standard MRI semantic features of each lesion were evaluated and used for constructing a logistic regression model to differentiate between predominantly osteolytic and osteoblastic metastases. For each lesion, 107 radiomics features were extracted. Six features were selected using a support vector machine (SVM) and were used for constructing classification models. Model performance was measured by means of the area under the curve (AUC) approach and compared using receiver operating characteristics (ROC) curve analysis. Results: The signal intensity on T1-weighted (T1W), T2-weighted (T2W), and fat-suppressed T2-weighted (FS-T2W) MRI sequences were significantly different between predominantly osteolytic and osteoblastic spinal metastases (P<0.001), as is the case with the existence of soft-tissue masses. The overall prediction accuracy of the models based on radiomics and semantic features was 78.2% and 75.6%, respectively, with corresponding AUCs of 0.82 and 0.79, respectively. Conclusions: The standard MRI-based radiomics model outperformed the semantic features logistic regression model with regard to differentiating predominantly osteolytic and osteoblastic spinal metastases.

Antiviral effect of lysosomotropic disaccharide trehalose on porcine hemagglutinating encephalomyelitis virus, a highly neurotropic betacoronavirus.

Many members of the genus Betacoronavirus are neurotropic viruses that frequently cause serious harm to humans or animals, including highly neurotropic porcine hemagglutinating encephalomyelitis virus (PHEV). Nevertheless, very few approved treatments exist to combat these viruses. Lysosomotropic trehalose, a widely used, nontoxic, natural disaccharide that can traverse the blood-brain barrier, has been proposed as a potential antiviral agent for use in prevention or treatment of betacoronavirus-associated infections. The purpose of this study was to determine if trehalose could inhibit PHEV infection of cells of a mouse central nervous system-derived neuroblastoma cell line in vitro or brain cells in vivo. Our results demonstrated that treatment of PHEV-infected mouse neuroblastoma cells and mice with trehalose reduced viral replication and that these trehalose antiviral effects were dependent on expression of lysosomal protein progranulin. Collectively, these results indicated that trehalose holds promise as a new antiviral agent for use in controlling neurotropic betacoronavirus infections.