No abstract

Dear Editor, Melanoma, squamous cell carcinoma (SCC), and basal cell carcinoma (BCC) are three major types of skin cancer. Among them, melanoma is the most severe form and accounts for~4% of all newly diagnosed cancers annually in the United States. It is estimated that approximately 9500 people are diagnosed with skin cancer every day, and more than 1 million Americans are living with melanoma. Melanoma treatment is still a major challenge in the clinic. Photodynamic therapy (PDT) is composed of targeted ablation and immune activation, is less invasive than other therapies and has been widely used in the treatment of various cancers. However, the limitation of light penetration is an issue in PDT for deep cancer treatment. 1 To overcome this limitation and enable PDT for deep cancer treatment, researchers have proposed X-ray-induced PDT 1 and nanoparticle self-lighting PDT, 2 and these techniques have become intensively studied topics. Recently, Chen et al. 3 invented a new sensitizer called copper-cysteamine (Cu-Cy) that can be activated by UV, 4 X-rays, 5 microwave, 6 and ultrasound 7 to generate reactive oxygen species (ROS) to destroy cancer cells as well as bacteria. 8 As ROS generation by Cu-Cy nanoparticles (NPs) is not solely activated by regular light, it is more appropriate to call it oxidative therapy (OT) rather than PDT. Cu-Cy NPs of an average size of 96 nm have been tested for skin cancer treatment. 9 It was found that these Cu-Cy NP-based X-PDT exhibited a strong antitumor effect towards SCC. However, B16F10 melanoma was resistant to these Cu-Cy NP-based X-PDT, both in vitro and in vivo. 9 Size is known to be a sensitive factor influencing nanomaterial properties and performance. To further evaluate the effect of Cu-Cy NP-based X-PDT on melanoma, we applied particles with an average size of~40 nm for the treatment of melanoma, as the 40 nm Cu-Cy NPs have a larger surface area than other NPs, thereby producing more ROS. 10 In addition, the cell uptake is higher for the 40 nm NPs. As expected, the 40 nm Cu-Cy NPs were very effective in inhibiting melanoma under X-ray stimulation. These observations confirmed that the combination of Cu-Cy and X-rays facilitated cell apoptosis and/or necrosis of B16 cells. More interestingly, this combination promoted the formation of the antitumor immune response. These results suggest that Cu-Cy NPs can simultaneously facilitate radiotherapy, oxidative therapy, and immunotherapy for melanoma treatment, as illustrated in Fig. 1a. The distribution of Cu-Cy was assessed by confocal fluorescence microscopy. As shown in Supplementary Fig. S1, the uptake of Cu-Cy NPs in the nucleus after 6 h was substantially increased compared to that after 2 and 4 h of incubation. Next, the cytotoxicity was measured to assess the efficacy of Cu-Cy on B16 cells by the CCK8 viability assay. After incubation with various amounts of Cu-Cy for 24 h, the cells were irradiated with X-rays at

Pancreatic cancer is an aggressive malignancy that is unresponsive to conventional radiation and chemotherapy. Therefore, development of novel immune therapeutic strategies is urgently needed. L-4F, an Apolipoprotein A-I (ApoA-I) mimetic peptide, is engineered to mimic the anti-inflammatory and anti-oxidative functionalities of ApoA-I. In this work, H7 cells were orthotopically implanted in C57BL/6 mice and treated with L-4F. Then, pancreatic cancer progression and the inflammatory microenvironment were investigated in vivo. The cytotoxicity of L-4F toward H7 cells was assessed in vitro. Furthermore, we investigated the effects of L-4F on macrophage polarization by analyzing the polarization and genes of mouse bone marrow-derived macrophages in vitro. The results show that L-4F substantially reduced the tumorigenicity of H7 cells. L-4F inhibited inflammation by reducing the accumulation of inflammatory cells, such as IL-17A-, IL-4-, GM-CSF-, IL-1β-, and IL-6-producing cells and Th1 and Th17. Notably, L-4F also decreased the percentage of macrophages in tumor tissues, especially M2 macrophages (CD11b+F4/80+CD206+), which was also confirmed in vitro. Additionally, the expression of the M2 marker genes Arg1, MRC1, and CCL22 and the inflammatory genes IL-6, iNOS, and IL-12 was decreased by L-4F, indicating that L-4F prevents M2 type macrophage polarization. However, L-4F could not directly attenuate H7 cell invasion or proliferation and did not induce apoptosis. In addition, L-4F potently down-regulated STAT3, JNK and ERK signaling pathways but not affects the phosphorylation of p38 in RAW 264.7 cells. These results suggest that L-4F exhibits an effective therapeutic effect on pancreatic cancer progression by inhibiting tumor-associated macrophages and inflammation.

Common fragile sites (CFSs) are specific breakage-prone genomic regions and are present frequently in cancer cells. The (E2-independent) E3 ubiquitin-conjugating enzyme FATS (fragile site-associated tumor suppressor) has antitumor activity in cancer cells, but the function of FATS in immune cells is unknown. Here, we report a function of FATS in tumor development via regulation of tumor immunity. Fats−/− mice show reduced subcutaneous B16 melanoma and H7 pancreatic tumor growth compared with WT controls. The reduced tumor growth in Fats−/− mice is macrophage dependent and is associated with a phenotypic shift of macrophages within the tumor from tumor-promoting M2-like to antitumor M1-like macrophages. In addition, FATS deficiency promotes M1 polarization by stimulating and prolonging NF-κB activation by disrupting NF-κB/IκBα negative feedback loops and indirectly enhances both CD4+ T helper type 1 (Th1) and cytotoxic T lymphocyte (CTL) adaptive immune responses to promote tumor regression. Notably, transfer of Fats−/− macrophages protects mice against B16 melanoma. Together, these data suggest that FATS functions as an immune regulator and is a potential target in cancer immunotherapy.

The Aral Sea Basin in Central Asia is an important geographical environment unit in the center of Eurasia. It is of great significance to the ecological protection and sustainable development of Central Asia to carry out dynamic monitoring and effective evaluation of the eco-environmental quality of the Aral Sea Basin. In this study, the arid remote sensing ecological index (ARSEI) for large-scale arid areas was developed, which coupled the information of the greenness index, the salinity index, the humidity index, the heat index, and the land degradation index of arid areas. The ARSEI was used to monitor and evaluate the eco-environmental quality of the Aral Sea Basin from 2000 to 2019. The results show that the greenness index, the humidity index and the land degradation index had a positive impact on the quality of the ecological environment in the Aral Sea Basin, while the salinity index and the heat index exerted a negative impact on the quality of the ecological environment. The eco-environmental quality of the Aral Sea Basin demonstrated a trend of initial improvement, followed by deterioration, and finally further improvement. The spatial variation of these changes was significant. From 2000 to 2019, grassland and wasteland (saline alkali land and sandy land) in the central and western parts of the basin had the worst ecological environment quality. The areas with poor ecological environment quality are mainly distributed in rivers, wetlands, and cultivated land around lakes. During the period from 2000 to 2019, except for the surrounding areas of the Aral Sea, the ecological environment quality in other areas of the Aral Sea Basin has been improved in general. The correlation coefficients between the change in the eco-environmental quality and the heat index and between the change in the eco-environmental quality and the humidity index were-0.593 and 0.524, respectively. Climate conditions and human activities have led to different combinations of heat and humidity changes in the eco-environmental quality of the Aral Sea Basin. However, human activities had a greater impact. The ARSEI can quantitatively and intuitively reflect the scale and causes of large-scale and long-time period changes of the eco-environmental quality in arid areas; it is very suitable for the study of the eco-environmental quality in arid areas.