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Background: The potential of preoperative CT in the assessment of myeloid immune response and its application in predicting prognosis and immune-checkpoint therapy outcomes in hepatocellular carcinoma (HCC) has not been explored. Methods: A total of 165 patients with pathological slides and multi-phase CT images were included to develop a radiomics signature for predicting the imaging-based myeloid response score (iMRS). Overall survival (OS) and recurrence-free survival (RFS) were assessed according to the iMRS risk group and validated in a surgical resection cohort (n = 98). The complementary advantage of iMRS incorporating significant clinicopathologic factors was investigated by the Cox proportional hazards analysis. Additionally, the iMRS in inferring the benefits of immune checkpoint therapy was explored in an immunotherapy cohort (n = 36). Results: We showed that AUCs of the optimal radiomics signature for iMRS were 0.941 [95% confidence interval (CI), 0.909–0.973] and 0.833 (0.798–0.868) in the training and test cohorts, respectively. High iMRS was associated with poor RFS and OS. The prognostic performance of the Clinical-iMRS nomogram was better than that of a single parameter (p < 0.05), with a 1-, 3-, and 5-year C-index for RFS of 0.729, 0.709, and 0.713 in the training, test, and surgical resection cohorts, respectively. A high iMRS score predicted a higher proportion of objective response (vs. progressive disease or stable disease; odds ratio, 2.311; 95% CI, 1.144–4.672; p = 0.020; AUC, 0.718) in patients treated with anti-PD-1 and PD-L1. Conclusions: iMRS may provide a promising method for predicting local myeloid immune responses in HCC patients, inferring postsurgical prognosis, and evaluating benefits of immune checkpoint therapy. [ABSTRACT FROM AUTHOR]

Background: Sex hormones and their related receptors have been reported to impact the development and progression of tumors. However, their influence on the composition and function of the tumor microenvironment is not well understood. We aimed to investigate the influence of sex disparities on the proliferation and accumulation of macrophages, one of the major components of the tumor microenvironment, in hepatocellular carcinoma (HCC). Methods: Immunohistochemistry was applied to assess the density of immune cells in HCC tissues. The role of sex hormone related signaling in macrophage proliferation was determined by immunofluorescence and flow cytometry. The underlying regulatory mechanisms were examined with both in vitro experiments and murine HCC models. Results: We found higher levels of macrophage proliferation and density in tumor tissues from male patients compared to females. The expression of G protein–coupled estrogen receptor 1 (GPER1), a non-classical estrogen receptor, was significantly decreased in proliferating macrophages, and was inversely correlated with macrophage proliferation in HCC tumors. Activation of GPER1 signaling with a selective agonist G-1 suppressed macrophage proliferation by downregulating the MEK/ERK pathway. Additionally, G-1 treatment reduced PD-L1 expression on macrophages and delayed tumor growth in mice. Moreover, patients with a higher percentage of GPER1+ macrophages exhibited longer overall survival and recurrence-free survival compared to those with a lower level. Conclusions: These findings reveal a novel role of GPER1 signaling in regulating macrophage proliferation and function in HCC tumors and may offer a potential strategy for designing therapies based on understanding sex-related disparities of patients. [ABSTRACT FROM AUTHOR]

Many soils face dual challenges of cadmium (Cd) contamination and salinization. However, the response of crops, especially wheat, to combined Cd and salinity stress is not understood. Here, wheat was grown in a hydroponic model for 14 days under single and combined Cd and NaCl stresses. Growth parameters, tissue Cd2+ and Na+ contents, and leaf chlorophyll (Chl), O2•−, and MDA levels were determined. Comparative transcriptomic and metabolomic analyses of the leaves were performed. The results showed that combined stress had a greater inhibitory effect on Chl contents and generated more O2•− and MDA, resulting in more severe wheat growth retardation than those under Cd or NaCl stress. Stress-induced decrease in Chl levels may be attributed to the inhibition of Chl biosynthesis, activation of Chl degradation, or a decline in glutamate content. Cd addition weakened the promotional effect of NaCl on SOS1 gene expression, thereby increasing the Na+ content. Contrastingly, NaCl supplementation downregulated the Nramp and ZIP gene expressions related to Cd uptake and transport, thereby impeding Cd2+ accumulation. All stresses enhanced tryptophan content via promoting tryptophan biosynthesis. Meanwhile, Cd and NaCl stresses activated phenylpropanoid biosynthesis and purine metabolism, respectively, thereby increasing the levels of caffeic acid, fumaric acid, and uric acid. Activating the TCA cycle was important in the wheat's response to combined stress. Additionally, NaCl and combined stresses affected starch and sucrose metabolism, resulting in sucrose and trehalose accumulation. Our findings provide a comprehensive understanding of the response of wheat to the combined Cd and salinity stress. [ABSTRACT FROM AUTHOR]

Introduction Hepatocellular carcinoma (HCC) is one of the most prevalent malignancies worldwide, with an increasing incidence and a dismal prognosis (1-4). In contrast to most other malignancies, 90% of HCCs [...], BACKGROUND. Despite an increasing appreciation of the roles that myeloid cells play in tumor progression and therapy, challenges remain in interpreting the tumor-associated myeloid response balance and its translational value. We aimed to construct a simple and reliable myeloid signature for hepatocellular carcinoma (HCC). METHODS. Using in situ immunohistochemistry, we assessed the distribution of major myeloid subtypes in both peri- and intratumoral regions of HCC. A 2-feature-based, myeloid-specific prognostic signature, named the myeloid response score (MRS), was constructed using an L1-penalized Cox regression model based on data from a training subset (n = 244), a test subset (n = 244), and an independent internal (n = 341) and 2 external (n = 94; n = 254) cohorts. RESULTS. The MRS and the MRS-based nomograms displayed remarkable discriminatory power, accuracy, and clinical usefulness for predicting recurrence and patient survival, superior to current staging algorithms. Moreover, an increase in MRS was associated with a shift in the myeloid response balance from antitumor to protumor activities, accompanied by enhanced [CD8.sup.+] T cell exhaustion patterns. Additionally, we provide evidence that the MRS was associated with the efficacy of sorafenib treatment for recurrent HCC. CONCLUSION. We identified and validated a simple myeloid signature for HCC that showed remarkable prognostic potential and may serve as a basis for the stratification of HCC immune subtypes. FUNDING. This work was supported by the National Science and Technology Major Project of China, the National Natural Science Foundation of China, the Science and Information Technology of Guangzhou, the Fundamental Research Funds for the Central Universities, the Guangdong Basic and Applied Basic Research Foundation, and the China Postdoctoral Science Foundation.