IL-22 signaling promotes sorafenib resistance in hepatocellular carcinoma via STAT3/CD155 signaling axis.

Introduction: Sorafenib is currently the first-line treatment for patients with advanced hepatocellular carcinoma (HCC). Nevertheless, sorafenib resistance remains a huge challenge in the clinic. Therefore, it is urgent to elucidate the mechanisms underlying sorafenib resistance for developing novel treatment strategies for advanced HCC. In this study, we aimed to investigate the role and mechanisms of interleukin-22 (IL-22) in sorafenib resistance in HCC. Methods: The in vitro experiments using HCC cell lines and in vivo studies with a nude mouse model were used. Calcium staining, chromatin immunoprecipitation, lactate dehydrogenase release and luciferase reporter assays were employed to explore the expression and roles of IL-22, STAT3 and CD155 in sorafenib resistance. Results: Our clinical results demonstrated a significant correlation between elevated IL-22 expression and poor prognosis in HCC. Analysis of transcriptomic data from the phase-3 STORM-trial (BIOSTORM) suggested that STAT3 signaling activation and natural killer (NK) cell infiltration may associate sorafenib responses. STAT3 signaling could be activated by IL-22 administration in HCC cells, and then enhanced sorafenib resistance in HCC cells by promoting cell proliferation and reducing apoptosis in vitro and in vivo. Further, we found IL-22/STAT3 axis can transcriptionally upregulate CD155 expression in HCC cells, which could significantly reduce NK cell-mediated HCC cell lysis in a co-culture system. Conclusions: Collectively, IL-22 could contribute to sorafenib resistance in HCC by activating STAT3/CD155 signaling axis to decrease the sensitivities of tumor cells to sorafenib-mediated direct cytotoxicity and NK cell-mediated lysis. These findings deepen the understanding of how sorafenib resistance develops in HCC in terms of IL-22/STAT3 signaling pathway, and provide potential targets to overcome sorafenib resistance in patients with advanced HCC.

Bone morphogenetic protein 10 and atrial fibrillation.

Background: The association between bone morphogenetic protein 10 (BMP10) and atrial fibrillation (AF) has been widely investigated by observational studies, but their causal relationships remain inconclusive. Here, we aimed to evaluate the causal effect of BMP10 on the risk of AF through single-nucleotide polymorphisms. Methods: A Mendelian randomization (MR) analytic framework was applied to data from two BMP10-specific genome-wide association studies comprising a total of 11,036,163 single-nucleotide polymorphisms of European ancestry. Instrument genetic variants associated with BMP10 were selected. A total of 12 AF-specific genome-wide association studies comprising a total of 5,095,117 European participants were included. Summary statistic-based methods of inverse variance weighted, MR Egger, weighted median, simple mode, and weighted mode methods were used. Pleiotropy and sensitivity were assessed. Results: Specific to AF-specific genome-wide association studies, we found that BMP10 was not associated with AF among different methods (all P > 0.05). We further identified no significant horizontal pleiotropy (all P > 0.05) and no fundamental impact among various data. Conclusions: This large-scale population study upon data from BMP10- and AF-specific genome-wide association studies and a longitudinal biobank cohort indicates plausible non-causal associations between BMP10 and AF in the European populations. Further studies regarding ancestral diversity are warranted to validate such causal associations.

Drug-Loaded Tumor-Derived Microparticles Elicit CD8+ T Cell-Mediated Anti-Tumor Response in Hepatocellular Carcinoma.

Background: Hepatocellular Carcinoma (HCC) poses significant challenges due to limited effective treatments and high recurrence rates. Immunotherapy, a promising approach, faces obstacles in HCC patients due to T-cell exhaustion and immunosuppression within the tumor microenvironment. Methods: Using doxorubicin-loaded tumor-derived microparticles (Dox-TMPs), the mice with H22 ascites model and subcutaneous tumors model were treated. Following the treatment, mice were re-challenged with H22 cells to compare the therapeutic effects and recurrence among different groups of mice, alongside examining the changes in the proportions of immune cells within the tumor microenvironment. Furthermore, Dox-TMPs were combined with anti-PD-1 to further validate their anti-tumor efficacy. In vitro studies using various liver cancer cell lines were conducted to verify the tumor-killing effects of Dox-TMPs. Additionally, CD8+ T cells from the abdominal cavity of tumor-free mice were co-cultured with H22 cells to confirm their specific tumor-killing abilities. Results: Dox-TMPs demonstrate effective anti-tumor effects both in vitro and in vivo. In vivo, their effectiveness primarily involves enhancing CD8+ T cell infiltration, alleviating T cell immunosuppression, and improving the immune microenvironment to combat tumors. When used in combination with anti-PD-1, their anti-tumor effects are further enhanced. Moreover, some mice treated with Dox-TMPs developed anti-tumor immunity, displaying a self-specific T-cell immune response upon re-challenged with tumor cells. This suggests that Dox-TMPs also have the potential to act as a long-term immune response against tumor recurrence, indicating their capability as a tumor vaccine. Conclusion: Dox-TMPs exhibit a dual role in liver cancer by regulating T cells within the tumor microenvironment, functioning both as an anti-tumor agent and a potential tumor vaccine.

Comparison of American and European guidelines for cardio-oncology of heart failure.

Heart failure is a complex clinical syndrome, whose signs and symptoms are caused by functional or structural impairment of ventricular filling or ejection of blood. Due to the interaction among anticancer treatment, patients' cardiovascular background, including coexisting cardiovascular diseases and risk factors, and cancer itself, cancer patients develop heart failure. Some drugs for cancer treatment may cause heart failure directly through cardiotoxicity or indirectly through other mechanisms. Heart failure in turn may make patients lose effective anticancer treatment, thus affecting the prognosis of cancer. Some epidemiological and experimental evidence shows that there is a further interaction between cancer and heart failure. Here, we compared the cardio-oncology recommendations among heart failure patients of the recent 2022 American guidelines, 2021 European guidelines, and 2022 European guidelines. Each guideline acknowledges the role of multidisciplinary (cardio-oncology) discussion before and during scheduled anticancer therapy.

Revelation of hidden 2D atmospheric turbulence strength fields from turbulence effects in infrared imaging.

Turbulence exists widely in the natural atmosphere and in industrial fluids. Strong randomness, anisotropy and mixing of multiple-scale eddies complicate the analysis and measurement of atmospheric turbulence. Although the spatially integrated strength of atmospheric turbulence can be roughly measured indirectly by Doppler radar or laser, direct measurement of two-dimensional (2D) strength fields of atmospheric turbulence is challenging. Here we attempt to solve this problem through infrared imaging. Specifically, we propose a physically boosted cooperative learning framework, termed the PBCL, to quantify 2D turbulence strength from infrared images. To demonstrate the capability of the PBCL, we constructed a dataset with 137,336 infrared images and corresponding 2D turbulence strength fields. The experimental results show that cooperative learning brings performance improvements, enabling the PBCL to simultaneously learn turbulence strength fields and inhibit adverse turbulence effects in images. Our work demonstrates the potential of imaging in measuring physical quantity fields.

A Lamin Family-Based Signature Predicts Prognosis and Immunotherapy Response in Hepatocellular Carcinoma.

Background: Lamin family members play crucial roles in promoting oncogenesis and cancer development. The values of lamin family in predicting prognosis and immunotherapy response remain largely unclarified. Our research is aimed at comprehensively estimating the clinical significance of lamin family in hepatocellular carcinoma and constructing a novel lamin family-based signature to predict prognosis and guide the precise immunotherapy. Methods: The expression features and prognostic value of LMNA, LMNB1, and LMNB2 were explored in the TCGA and GEO databases. The biological functions of LMNB1 and LMNB2 were validated by in vitro assays. A lamin family-based signature was built using the TCGA training set. The TCGA test set, entire TCGA set, and GSE14520 set were used to validate its predictive power. Univariate and multivariate analyses were performed to evaluate the independence of the lamin family-based signature from other clinicopathological characteristics. A nomogram was constructed using the lamin family-based signature and TNM stage. The associations of this signature with molecular pathways, clinical characteristics, immune cell infiltration, and immunotherapy response were analyzed. Results: Lamin family members were upregulated in HCC. Upregulation of LMNB1 and LMNB2 promoted HCC proliferation, migration, and invasion. The predictive signature was initially established based on LMNB1 and LMNB2 which could effectively identify differences in overall survival, immune cell infiltration, and clinicopathological characteristics of high- and low-risk patients. The nomogram showed high prognostic predictive accuracy. Importantly, the lamin family-based signature was correlated with immune suppression and expression of immune checkpoint molecules. Conclusions: The lamin family-based signature is a robust biomarker to predict overall survival and immunotherapy response in HCC. High-risk score patients have a poorer overall survival and might be more sensitive to immunotherapy. This signature may contribute to improving individualized prognosis prediction and precision immunotherapy for HCC patients.

Lamin B1 is a potential therapeutic target and prognostic biomarker for hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is an aggressive malignancy. Previous studies have found that lamin B1 (LMNB1) contributes to the development of human cancers. However, the biological functions and prognostic values of LMNB1 in HCC have not been adequately elucidated. In our present research, the expression pattern of LMNB1 was analyzed. The prognostic values of LMNB1 were evaluated by Kaplan-Meier survival analysis and Cox proportional hazards regression analysis. The effects of LMNB1 on HCC progression were assessed by Cell Counting Kit-8 (CCK-8), colony formation, wound healing, Transwell and in vivo xenograft assays. The mechanisms of LMNB1 in HCC progression were elucidated by gene set enrichment analysis (GSEA) and loss-of-function assays. Besides, a nomogram for predicting overall survival (OS) was constructed. The results demonstrated that LMNB1 was overexpressed in HCC and that increased LMNB1 expression predicted a dismal prognosis. Further experiments showed that LMNB1 facilitated cell proliferation and metastasis in HCC. Functional enrichment analysis revealed that LMNB1 modulated metastasis-associated biological functions such as focal adhesion, extracellular matrix, cell junctions and cell adhesion. Mechanistically, we revealed that LMNB1 promoted HCC progression by regulating the phosphatidylinositol 3-kinase (PI3K) and mitogen-activated protein kinase (MAPK) pathways. Moreover, incorporating LMNB1, Ki67 and Barcelona Clinic Liver Cancer (BCLC) stage into a nomogram showed better predictive accuracy than the Tumor-Node-Metastasis (TNM) stage and BCLC stage. In conclusion, LMNB1 may serve as an effective therapeutic target as well as a reliable prognostic biomarker for HCC.

Prognosis analysis of patients with pancreatic neuroendocrine tumors after surgical resection and the application of enucleation.

OBJECTIVE: To investigate the prognostic factors of patients with pancreatic neuroendocrine tumor (pNETs) after surgical resection, and to analyze the value of enucleation for pNETs without distant metastasis that are well-differentiated (G1) and have a diameter ≤ 4 cm. METHODS: Data from pNET patients undergoing surgical resection between 2004 and 2017 were collected from the Surveillance, Epidemiology, and End Results (SEER) database. Kaplan-Meier analysis and log-rank testing were used for the survival comparisons. Adjusted HRs with 95% CIs were calculated using univariate and multivariate Cox regression models to estimate the prognostic factors. P < 0.05 was regarded as statistically significant. RESULTS: This study found that female, cases diagnosed after 2010, and pancreatic body/tail tumors were protective factors for good survival, while histological grade G3, a larger tumor size, distant metastasis, AJCC 8th stage III-IV and age over 60 were independent prognostic factors for a worse OS/CSS. For the pNETs that were well-differentiated (G1) and had a tumor diameter ≤ 4 cm, the type of surgery was an independent factor for the long-term prognosis of this group. Compared with pancreaticoduodenectomy and total pancreatectomy, patients who were accepted enucleation had better OS/CSS. CONCLUSION: For pNETs patients undergoing surgical resection, sex, year of diagnosis, tumor location, pathological grade, tumor size, distant metastasis, race, and age were independent prognostic factors associated with the OS/CSS of patients. For pNETs patients with G1 and a tumor diameter less than 4 cm, if the tumor was located over 3 mm from the pancreatic duct, enucleation may be a wise choice.

Ultrasound assistant chemotherapy may be a novel modality for solid tumors.

Resistance to chemotherapy is the important reason for treatment failure in patients with cancer. Current methods which focus on the identification of more selective and potent drug resistance reversing agents are not satisfying. It is an urgent need for development of new approaches to overcoming drug resistance. The use of low power ultrasound in cancer therapy is a developing field. Recently, it was found that some anticancer drugs, upon ultrasonic irradiation, could create active oxygen species and effectively destruct cancer cells. This means that, in addition to cytotoxicity, these chemotherapeutic agents may be used as sonosensitizers and kill cancer cells by another mechanism. Moreover, local hyperthermia induced by ultrasound could enhance drug cytotoxicity. For the unique advantage of ultrasound, which are quite different from current therapy, we hypothesize that ultrasound assistant chemotherapy may be a new strategy to block drug resistance, which might enhance the efficacy of chemotherapeutic drugs, and reduce undesired side effects.

PDT combined with Intravesical BCG instillation would form an autovaccine for bladder cancer?

Bladder cancer is the second most common urologic malignancy after prostate cancer. Intravesical BCG as a treatment of superficial bladder cancer (SBC) has been used by urologists for over 30 years. Recently, photodynamic therapy (PDT), which uses a red laser and a photosensitive drug to destroy cancer cells, has been showed encouraging results in SBC treatment. However, BCG and PDT are applied to treatment of SBC alone. Currently, cancer vaccines are made in vitro. Several studies confirmed that tumour cells treated in vitro by PDT can be used for generating potent cancer vaccines, which were more effective than other modes of creating whole tumor vaccines, i.e., UV or ionizing irradiation [Gollnick SO, Vaughan L, Henderson BW. Generation of effective antitumor vaccines using photodynamic therapy. Cancer Res 2002;62:1604-8]. Moreover, BCG is a pleiotropic immune stimulator oriented to cellular immunity. We thought that: after PDT destroyed targeted tumor cells on a large scale, Intravesical BCG could elicit and amplify the immune responses, which would directly form an in situ autovaccine in vivo against the primary tumor and metastases at distant sites. In this paper, we propose that the combination of Intravesical BCG and PDT would be a promising new modality for bladder cancer.