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Background: Early loss of second primary molars may lead to different malocclusions, mainly caused by the mesial migration of the first permanent molar. To prevent space loss in the dental arch, different types of space maintainers (SM) are used., Objectives: The main objective of this systematic review is to examine the evidence in the literature regarding the effect of SM, including the clinical effect, risk of developing caries and periodontal disease, patient satisfaction, and cost-effectiveness after the premature loss of the second primary molar in children., Search Methods: The present systematic review was made according to PRISMA. The literature search was performed using four databases (last search 30/8/2022): PubMed, Cochrane Central Register of Controlled Trials (CENTRAL), Scopus, and Web of Science., Selection Criteria: The studies included were randomized controlled trials, economic evaluations, and non-randomized clinical studies with a defined control group., Data Collection and Analysis: Data collected by the two authors were in regard to reports, studies, participants, research designs, and interventions. The assessment of the risk of bias was made using the ROBINSON-I tool., Results: The search yielded 1058 articles after the removal of duplicates. Two studies were included in the final review with a moderate risk of bias, and measured space changes in the dental arch and the periodontal status of patients treated with SM. The main results indicate that treatment with SM can preserve arch length, but also cause an increase in plaque accumulation and other periodontal parameters. However, there is an overall lack of scientific evidence regarding the effect of the treatment., Limitations: No studies that fulfilled the eligibility criteria were found on cost-effectiveness, risk of caries development, and patient satisfaction., Conclusions: The scientific evidence is lacking regarding the clinical effect, cost effect, and side-effects such as caries and periodontal disease when using SM in children with a premature loss of the second primary molar., Registration: PROSPERO Registration (CRD 42021290130)., (© The Author(s) 2023. Published by Oxford University Press on behalf of the European Orthodontic Society.)

Natural killer (NK) cells are classically associated with immune surveillance and destruction of tumor cells. Inconsistent with this function, NK cells are found in advanced human tumors including renal cell carcinoma (RCC). NK cells with non-classical phenotypes (CD56 + CD16 dim/neg ; termed decidua NK (dNK) cells) accumulate at the maternal-fetal interface during embryo implantation. These dNK cells are poorly cytotoxic, proangiogenic, and facilitate placenta development. As similarities between embryo implantation and tumor growth exist, we tested the hypothesis that an analogous shift in NK cell phenotype and function occurs in RCC tumors. Our results show that peripheral NK (pNK) cells of RCC patients were uniformly CD56 + CD16 bright , but lacked full cytotoxic ability. By comparison, RCC tumor-infiltrated NK (TiNK) cells were significantly enriched for CD56 + CD16 dim-neg cells, a phenotype of dNK cells. Gene expression analysis revealed that angiogenic and inflammatory genes were significantly increased for RCC TiNK versus RCC pNK populations, with enrichment of genes in the hypoxia inducible factor (HIF) 1α pathway. Consistent with this finding, NK cells cultured under hypoxia demonstrated limited cytotoxicity capacity, but augmented production of vascular endothelial growth factor (VEGF). Finally, comparison of gene expression data for RCC TiNK and dNK cells revealed a shared transcriptional signature of genes with known roles in angiogenesis and immunosuppression. These studies confirm conversion of pNK cells to a dNK-like phenotype in RCC tumors. These characteristics are conceivably beneficial for placentation, but likely exploited to support early tumor growth and promote metastasis., Competing Interests: CONFLICTS OF INTEREST The authors declare no conflicts of interest.