Sorafenib plus memory like natural killer cell combination therapy in hepatocellular carcinoma.

Sorafenib, FDA-approved therapy for patients with advanced hepatocellular carcinoma (HCC), leads to limited improvement in overall survival. However, it may indirectly impact the expansion and activity of natural killer (NK) cells. While NK cell-based immunotherapies generally exhibit favorable safety profiles, their effectiveness in controlling solid tumor growth is constrained, primarily due to the absence of antigen specificity and suboptimal expansion and persistence within the tumor microenvironment. In this study, we postulated that enhancing NK cell functionality via cytokine activation could bolster their viability and cytotoxic capabilities, leading to an improved therapeutic response when combined with sorafenib. Memory-like (ML)-NK cells were generated through the supplementation of optimal concentrations of interleukin (IL)-12 and IL-18 cytokines. Following a single day of treatment, cytotoxicity against rat and human HCC cells was evaluated via flow cytometry analysis. A rat HCC model was developed in 30 animals via subcapsular implantation and assigned to control, NK, sorafenib, ML-NK, and combination groups. Sorafenib was administered orally, and NK cells were delivered via the intrahepatic artery. Tumor growth was measured one week after treatment evaluation. Therapeutic efficacy during in-vitro and in-vivo analysis was investigated through a one-way ANOVA test, followed by pairwise two-tailed Student t-tests, considering P < 0.05 statistically significant. The in-vitro experiment results demonstrated that sorafenib and conventional NK cell therapies induced more substantial cell death than the control group (P < 0.01). ML NK cells significantly improved cell death compared to conventional NK cell immunotherapy. Furthermore, sorafenib in combination with ML-NK cells significantly decreased the viability of HCC cells (P < 0.05) compared to sorafenib plus conventional NK cell combination therapy. In vivo experiments have shown that sorafenib and ML-NK cell immunotherapy reduced the growth rate of HCC tumors compared to conventional NK immunotherapy and control groups. Notably, a combination of sorafenib and ML-NK cell immunochemotherapy resulted in the most significant suppression of tumor growth when compared to other therapies. In conclusion, our experimental findings demonstrate that the concurrent administration of sorafenib and ML-NK immunotherapy enhances cytotoxicity against HCC by optimizing the therapeutic response through cytokine activation, resulting in a significant decrease in tumor growth.

Open pollution routing problem of logistics distribution in medical union based on differential search algorithm.

Medical care is a guarantee of people's daily life. Improving healthcare contributes to people's well-being. However, healthcare resources are characterized by uneven distribution. Financially well-off areas will have higher quality health care resources. Most of the medical resources are concentrated in public general hospitals, however, primary care institutions can hardly meet the growing needs of people. To solve this problem, Medical Union achieves efficient deployment of resources by integrating various medical institutions in the same area. In the process of logistics integration of the medical union, the scale of logistics distribution expands accordingly. Transportation vehicles have high operating costs and produce greenhouse gases in the process of distribution. The optimization of the driving path of logistics distribution vehicles can reduce the operating cost, fuel consumption and carbon emission. To solve this kind of decentralized and complex vehicle routing problem, this paper proposes a pollution routing problem model considering electrical vehicle usage, customer's soft time window expectation, open path and carbon cost. A modified Differential Search Algorithm with the comprehensive learning strategy and dynamic Cauchy variation strategy is advanced to solve the problem. Results show that the improved algorithm has good solving performance, and verifies the rationality of the proposed model, which will help to reduce carbon emissions and save the logistics and operating costs of medical devices.

Early assessment of irreversible electroporation ablation outcomes by analyzing MRI texture: preclinical study in an animal model of liver tumor.

OBJECTIVES: Accurate differentiation of temporary vs. permanent changes occurring following irreversible electroporation (IRE) holds immense importance for the early assessment of ablative treatment outcomes. Here, we investigated the benefits of advanced statistical learning models for an immediate evaluation of therapeutic outcomes by interpreting quantitative characteristics captured with conventional MRI. METHODS: The preclinical study integrated twenty-six rabbits with anatomical and perfusion MRI data acquired with a 3T clinical MRI scanner. T1w and T2w MRI data were quantitatively analyzed, and forty-six quantitative features were computed with four feature extraction methods. The candidate key features were determined by graph clustering following the filtering-based feature selection technique, RELIEFF algorithm. Kernel-based support vector machines (SVM) and random forest (RF) classifiers interpreting quantitative features of T1w, T2w, and combination (T1w+T2w) MRI were developed for replicating the underlying characteristics of the tissues to distinguish IRE ablation regions for immediate assessment of treatment response. Accuracy, sensitivity, specificity, and area under the receiver operating characteristics curve were used to evaluate classification performance. RESULTS: Following the analysis of quantitative variables, three features were integrated to develop a SVM classification model, while five features were utilized for generating RF classifiers. SVM classifiers demonstrated detection accuracy of 91.06%, 96.15%, and 98.04% for individual and combination MRI data, respectively. Besides, RF classifiers obtained slightly lower accuracy compared to SVM which were 95.06%, 89.40%, and 94.38% respectively. CONCLUSIONS: Quantitative models integrating structural characteristics of conventional T1w and T2w MRI data with statistical learning techniques identified IRE ablation regions allowing early assessment of treatment status.

Adverse events of sorafenib in hepatocellular carcinoma treatment.

Sorafenib is an oral multikinase inhibitor approved by the US Food and Drug Administration for treatment of the patients with surgically unresectable hepatocellular carcinoma (HCC). Sorafenib mitigates angiogenesis by targeting vascular endothelial growth factor receptors and platelet-derived growth factor receptors in endothelial cells and pericytes. Moreover, it suppresses cell proliferation via blockage of B-RAF and RAF1 of the mitogen-activated protein kinase pathway in tumor cells. Sorafenib has been the standard molecular targeted medication in the treatment of advanced-stage HCC patients ineligible for potentially curative interventional (radiofrequency or microwave ablation) or palliative trans-arterial chemoembolization (TACE) therapies for over a decade. However, it only increases overall survival by less than 3 months, and systemic exposure to sorafenib causes clinically significant toxicities (about 50% of patients). Given the high frequency and severity of these toxicities, sorafenib dose must be often reduced or discontinued altogether. In this review, we discussed the mechanism of sorafenib-associated adverse events and their management during HCC treatment.

Beneficial Effect of Antibiotics and Microbial Metabolites on Expanded Vδ2Vγ9 T Cells in Hepatocellular Carcinoma Immunotherapy.

Animal experiments and clinical trials have shown that the gut microbiota modulates host immunity and immune checkpoint-mediated responses to tumor cells. However, it remains unclear whether microbiota can also play a role in the tumor immune response of γδT cells, a kind of cell that targets cancer directly. Here, we report that microbiota dysbiosis induced by antibiotics enhanced γδT cell efficacy during tumor therapy in a mouse model. Further microbiota and metabolite analysis revealed that the alteration of γδT cell cytotoxicity might be closely associated with specific metabolites, which are produced by intestinal bacteria and stimulate γδT cells to release more cytotoxic cytokines, such as granzyme B and perforin. Among the metabolites that we analyzed, 3-indopropionic acid (IPA) showed the highest concentration in antibiotic-treated mice and can improve the cytotoxic ability of γδT cells both in vitro and in vivo. Our research determined how the gut microbiota can influence the antitumor ability of γδT cells and identified potential intermediate molecules that connect the gut microbiota and γδT cells.

Generation of human neutralizing monoclonal antibodies against the 2009 pandemic H1N1 virus from peripheral blood memory B lymphocytes.

The 2009 H1N1 influenza pandemic demonstrated the significance of a global health threat to human beings. Although pandemic H1N1 vaccines have been rapidly developed, passive serotherapy may offer superior immediate protection against infections in children, the elderly and immune-compromised patients during an influenza pandemic. Here, we applied a novel strategy based on Epstein-Barr virus (EBV)-immortalized peripheral blood memory B cells to screen high viral neutralizing monoclonal antibodies (MAbs) from individuals vaccinated with the 2009 pandemic H1N1 vaccine PANFLU.1. Through a massive screen of 13 090 immortalized memory B-cell clones from three selected vaccinees, seven MAbs were identified with both high viral neutralizing capacities and hemagglutination inhibition (HAI) activities against the 2009 pandemic H1N1 viruses. These MAbs may have important clinical implications for passive serotherapy treatments of infected patients with severe respiratory syndrome, especially children, the elderly and immunodeficient individuals. Our successful strategy for generating high-affinity MAbs from EBV-immortalized peripheral blood memory B cells may also be applicable to other infectious or autoimmune diseases.