Characterization of the distinct immune microenvironments between hepatocellular carcinoma and intrahepatic cholangiocarcinoma.

As two major types of primary liver cancers, the tumor immune microenvironment (TIME) of hepatocellular carcinoma (HCC) and intrahepatic cholangiocarcinoma (ICC) have been well studied separately. However, a systemic assessment of the similarities and differences between the TIME of HCC and ICC is still lacking. In this study, we pictured a landscape of combined TIME of HCC and ICC by sequencing and integrating 41 single-cell RNA-seq samples from four different tissue types of both malignancies. We found that T cells in HCC tumors generally exhibit higher levels of immunosuppression and exhaustion than those in ICC tumors. Myeloid cells in HCC and ICC tumors also exhibit distinct phenotypes and may serve as a key factor driving the differences between their TIMEs. Besides, we identified a cluster of EGR1+ macrophages specifically enriched in HCC tumors. Together, our study provides new insights into cellular composition, states and interactions in the TIMEs of HCC and ICC, which could pave the way for the development of future therapeutic targets for liver cancers.

Single-cell map of dynamic cellular microenvironment of radiation-induced intestinal injury.

Intestine is a highly radiation-sensitive organ that could be injured during the radiotherapy for pelvic, abdominal, and retroperitoneal tumors. However, the dynamic change of the intestinal microenvironment related to radiation-induced intestine injury (RIII) is still unclear. Using single-cell RNA sequencing, we pictured a dynamic landscape of the intestinal microenvironment during RIII and regeneration. We showed that the various cell types of intestine exhibited heterogeneous radiosensitivities. We revealed the distinct dynamic patterns of three subtypes of intestinal stem cells (ISCs), and the cellular trajectory analysis suggested a complex interconversion pattern among them. For the immune cells, we found that Ly6c+ monocytes can give rise to both pro-inflammatory macrophages and resident macrophages after RIII. Through cellular communication analysis, we identified a positive feedback loop between the macrophages and endothelial cells, which could amplify the inflammatory response induced by radiation. Besides, we identified different T cell subtypes and revealed their role in immunomodulation during the early stage of RIII through inflammation and defense response relevant signaling pathways. Overall, our study provides a valuable single-cell map of the multicellular dynamics during RIII and regeneration, which may facilitate the understanding of the mechanism of RIII.

RNA N6-methyladenosine modification-based biomarkers for absorbed ionizing radiation dose estimation.

Radiation triage and biological dosimetry are critical for the medical management of massive potentially exposed individuals following radiological accidents. Here, we performed a genome-wide screening of radiation-responding mRNAs, whose N6-methyladenosine (m6A) levels showed significant alteration after acute irradiation. The m6A levels of three genes, Ncoa4, Ate1 and Fgf22, in peripheral blood mononuclear cells (PBMCs) of mice showed excellent dose-response relationships and could serve as biomarkers of radiation exposure. Especially, the RNA m6A of Ncoa4 maintained a high level as long as 28 days after irradiation. We demonstrated its responsive specificity to radiation, conservation across the mice, monkeys and humans, and the dose-response relationship in PBMCs from cancer patients receiving radiation therapy. Finally, NOCA4 m6A-based biodosimetric models were constructed for estimating absorbed radiation doses in mice or humans. Collectively, this study demonstrated the potential feasibility of RNA m6A in radiation accidents management and clinical applications.

Electroacupuncture at Hua Tuo Jia Ji Acupoints Reduced Neuropathic Pain and Increased GABAA Receptors in Rat Spinal Cord.

Chronic constriction injury- (CCI-) induced neuropathic pain is the most similar model to hyperalgesia in clinical observation. Neuropathic pain is a neuronal dysfunction in the somatosensory system that may lead to spontaneous pain. In this study, electroacupuncture (EA) was applied at bilateral L4 and L6 of Hua Tuo Jia Ji points (EX-B2) for relieving neuropathic pain in rats. Eighteen Sprague-Dawley rats were randomly assigned to three groups: sham, 2-Hz EA, and 15-Hz EA groups. Following von Frey and cold plate tests, both the 2- and the 15-Hz EA groups had significantly lower mechanical and thermal hyperalgesia than the sham group. Western blot analysis results showed that γ-aminobutyric acid A (GABAA), adenosine A1 receptor (A1R), transient receptor potential cation channel subfamily V member 1 (TRPV1), TRPV4, and metabotropic glutamate receptor 3 (mGluR3) were similar in the dorsal root ganglion of all three groups. Furthermore, levels of GABAA receptors were higher in the spinal cord of rats in the 2- and 15-Hz EA groups compared with the sham control group. This was not observed for A1R, TRPV1, TRPV4, or mGluR3 receptors. In addition, all the aforementioned receptors were unchanged in the somatosensory cortex of the study rats, suggesting a central spinal effect. The study results provide evidence to support the clinical use of EA for specifically alleviating neuropathic pain.