Single-cell transcriptomics reveals comprehensive microenvironment and highlights the dysfuntional state of NK cells in endometrioid carcinoma.

Endometrioid endometrial cancer (EEC) is one of the most common gynecologic malignancies. The interaction between cancer cells and the cells in the tumor microenvironment (TME) plays a crucial role in determining disease progression and response to treatment. To better understand the diversity in the TME of ECC, we conducted a comprehensive analysis using single-cell RNA sequencing across 21 samples, including 16 ECC and 5 adjacent normal tissues. We primarily focused on tumor-infiltrating natural killer (NK) cells and their cell-cell interactions with other immune cell types. We identified a CD56dim_DNAJB1 NK cells subset, which had low cytotoxic capability and high stress levels, suggesting a dysfunctional state. This subset showed strong interactions with tumor-associated macrophages through several ligand-receptor pairs. Additionally, we observed that tumor-infiltrating LAMP3+ dendritic cells may inhibit CD8+ T cells or attract regulatory T cells to the tumor area. These dendritic cells also had impaired activation effects on NK cells within the TME. Our study provides valuable insights into the role of NK cells in cancer immunity and highlights the potential of targeting specific NK cell subsets for therapeutic purposes.

DYNC1H1 variants associated with infant-onset epilepsy without neurodevelopmental disorders.

OBJECTIVES: The DYNC1H1 variants are associated with abnormal brain morphology and neuromuscular disorders that are accompanied by epilepsy. This study aimed to explore the relationship between DYNC1H1 variants and epilepsy. MATERIALS AND METHODS: Trios-based whole-exome sequencing was performed on patients with epilepsy. Previously reported epilepsy-related DYNC1H1 variants were systematically reviewed to analyse genotype-phenotype correlation. RESULTS: The DYNC1H1 variants were identified in four unrelated cases of infant-onset epilepsy, including two de novo and two biallelic variants. Two patients harbouring de novo missense variants located in the stem and stalk domains presented with refractory epilepsies, whereas two patients harbouring biallelic variants located in the regions between functional domains had mild epilepsy with infrequent focal seizures and favourable outcomes. One patient presented with pachygyria and neurodevelopmental abnormalities, and the other three patients presented with normal development. These variants have no or low frequencies in the Genome Aggregation Database. All the missense variants were predicted to be damaging using silico tools. Previously reported epilepsy-related variants were monoallelic variants, mainly de novo missense variants, and all the patients presented with severe epileptic phenotypes or developmental delay and malformations of cortical development. Epilepsy-related variants were clustered in the dimerization and stalk domains, and generalized epilepsy-associated variants were distributed in the stem domain. CONCLUSION: This study suggested that DYNC1H1 variants are potentially associated with infant-onset epilepsy without neurodevelopmental disorders, expanding the phenotypic spectrum of DYNC1H1. The genotype-phenotype correlation helps to understand the underlying mechanisms of phenotypic variation.

Cytokines and Exhaled Nitric Oxide Are Risk Factors in Preterm Infants for Bronchopulmonary Dysplasia.

Bronchopulmonary dysplasia (BPD) is the most common complication of extremely preterm birth. This study was aimed at detecting cytokine and fractional exhaled nitric oxide (FeNO) levels to evaluate their mechanisms and predicted significance for BPD. Preterm infants born at gestational age ≤ 32 weeks were recruited, and clinical data were collected. We detected ten cytokines, including IFN-γ, IL-10, IL-12p70, IL-13, IL-1ß, IL-2, IL-4, IL-6, IL-8, and TNF-α on Days 1-3, Days 7-14, and Days 21-28 after birth by using the Meso Scale Discovery (MSD) technology. The FeNO levels of infants were measured when they met the discharge criteria. A total of 46 preterm infants were enrolled, consisting of 14 infants in BPD group and 32 infants in the control group. The gestational age (27.5 ± 1.3 vs. 29.9 ± 1.3 weeks) and birth weight (1021 ± 261 g vs. 1489 ± 357 g) were lower in the BPD group. The following were high-risk factors for BPD, as determined by multivariate logistic regression analysis: gestational age < 30 weeks, birth weight < 1000 g, PDA, longer mechanical ventilation, and higher FeNO. The cytokines of IL-6 and IL-8 on Days 7-14 and IL-4, IL-6, IL-8, and TNF-α on Days 21-28 were also high-risk factors for BPD. IL-6 contributed to BPD disease severity. Conclusion. The preterm infants with PDA and prolonged mechanical ventilation tended to develop BPD. The IL-6 and IL-8 were significantly increased on Days 7-14 and were high-risk factors for BPD. Moreover, the IL-6 level was associated with BPD disease severity. We speculated that NO was related to BPD via Th2 cell-mediated inflammatory responses such as IL-4 and IL-6. Cytokines might predict the occurrence of BPD.