The E3 ubiquitin ligase FBXO38 maintains the antitumor function of natural killer cells by sustaining IL-15R signaling.

Natural killer (NK) cells are the main innate antitumor effector cells but their function is often constrained in the tumor microenvironment (TME). It has been reported that the E3 ligase FBXO38 accelerates PD-1 degradation in tumor-infiltrating T cells to unleash their cytotoxic function. In this study, we found that the transcriptional levels of FBXO38 in intratumoral NK cells of cancer patients and tumor-bearing mice were significantly lower than in peritumoral NK cells. Conditional knock-out (cKO) of FBXO38 in NK cells accelerated tumor growth and increased tumor metastasis. FBXO38 deficiency resulted in impaired proliferation and survival of tumor-infiltrating NK (TINK) cells. Mechanistically, FBXO38 deficiency enhanced TGF-ß signaling, including elevating expression of Smad2 and Smad3, which suppressed expression of the transcription factor Eomes and further reduced expression of surface IL-15Rß and IL-15Rγc on NK cells. Consequently, FBXO38 deficiency led to TINK cell hyporesponsiveness to IL-15. Consistent with these observations, FBXO38 mRNA expression was positively correlated with the proliferation of TINK cells in multiple human tumors. To study the therapeutic potential of FBXO38, mice bearing human tumors were treated with FBXO38 overexpressed human primary NK cells and showed a significant reduction in tumor size and prolonged survival. In conclusion, our results suggest that FBXO38 sustains NK-cell expansion and survival to promote antitumor immunity, and have potential therapeutic implications as they suggest FBXO38 could be harnessed to enhance NK cell-based cancer immunotherapy.

Changes in sleep quality of children with epilepsy and anxiety of their caregivers after COVID-19 infection: a case-series report.

Objective: To study the changes in epileptic seizures and sleep quality in children with epilepsy (CWE) and the changes in anxiety of their caregivers after infection with COVID-19. Methods: Outpatients and inpatients of CWEs were selected as subjects and a questionnaire survey was used to carry out this case-series study. The demographic information of the CWEs and their caregivers, information about epilepsy, and information about the vaccination, infection, and treatment of COVID-19 were collected. The changes in sleep quality of CWEs and the changes in anxiety of their caregivers were assessed by the Child Sleep Habits Questionnaire (CSHQ) and Caregiver Anxiety Scale (CAS). Risk factors affecting sleep habits in CWEs and caregiver anxiety were further analyzed by one-way analysis of variance. Results: A total of 312 children were included in the study. Among them, 134 patients (42.9%) were female. The average age of the children was 9.30 ± 3.88 years, and the duration of epilepsy was 4.59 ± 3.36 years. A total of 221 of the 312 children were infected with COVID-19, and all the infected children developed fever, which lasted for 1.71 ± 1.13 days. 10 children were satisfied with controlled seizures for more than 1 year and relapsed after COVID-19 infection (4.2%), 4 cases (3.6%) with increased seizures, and 8 children with reduced seizures (7.7%), 17 children (7.7%) had no change in seizures, and 182 children (82.3%) remained seizure-free after the COVID-19 infection. The average sleep time of the CWEs was 9.25 ± 1.04 h and the average total score of the CSHQ was 37.25 ± 5.19, among which 44 cases (14.1%) had more than 41 points. As the result of the CAS, 16 of them (5.13%) scored above 50 and the average total score was 31.49 ± 8.09. The control of seizures, age of onset, types of anti-seizure medicines (ASMs), and seizure duration were risk factors affecting sleep quality. Accordingly, the score of CAS was significantly lower when there was more than one caregiver who cared for the CWE. Conclusions: COVID-19 infection did not cause an increase in seizures in CWEs, nor did it worsen their sleep quality of them or aggravate the anxiety of their caregivers.

[Increment of chemokine CXCL9/Mig in plasma correlated with acute graft-versus-host disease after allogeneic hematopoietic stem cell transplantation].

To investigate the relationship between the plasma levels of chemokine CXCL9/Mig and acute graft-versus-host disease (aGVHD) after allogeneic hematopoietic stem cell transplantation (allo-HSCT). The plasma levels of CXCL9/Mig of 35 patients who received all-HSCT were detected by using ELISA assay, these patients included 13 patients with grade 0-I, 12 patients with grade II and 10 patients with grade III - IV aGVHD, respectively. The four different time points including prior to allo-HSCT, one week before aGVHD onset, the plateau of aGVHD and time after completely controlled, were studied. The results showed that the plasma levels of CXCL9/Mig in the patients with serious aGVHD (grade II - IV) were significantly increased during aGVHD than those in the patients without aGVHD or with slight aGVHD (P < 0.001). It was found that CXCL9/Mig levels were significantly correlated with the severity of grade aGVHD (P < 0.001). Another important finding was that CXCL9/Mig levels obviously increased at one week before aGVHD was diagnosed. CXCL9/Mig level was not obviously correlated with CMV infection or other infectious complication (P > 0.05). It is concluded that the plasma level of CXC19/Mig significantly correlated with the severity of aGVHD and plays a critical role in pathogenesis of aGVHD, the changes in plasma level of CXCL9/Mig after allo-HSCT may be used as a valuable indicator for early diagnosis of aGVHD, finally, provide a early therapeutic approach to reduce aGVHD severity and improve the outcome for patients after allo-HSCT.