Comprehensive Pan-cancer Analysis of CMPK2 as Biomarker and Prognostic Indicator for Immunotherapy.

INTRODUCTION: UMP-CMP kinase 2 (CMPK2) is involved in mitochondrial DNA synthesis which can be oxidized and released into the cytoplasm in innate immunity. It initiates the assembly of NLRP3 inflammasomes and mediates various pathological processes such as human immunodeficiency virus infection and systemic lupus erythematosus. However the role of CMPK2 in tumor progression and tumor immunity remains unclear. METHOD: In this study we conducted a systematical analysis of CMPK2 across 33 different cancers based on datasets such as Genotype Tissue-Expression (GTEx) The Cancer Genome Atlas (TCGA) the Cancer Cell Line Encyclopedia (CCLE) and Tumor Immune Syngeneic Mouse (TISMO). Our focus encompassed the characterization of CMPK2 expression patternsclinical significance potential regulatory mechanisms and its relationship with the tumor immune profile including responsiveness to immune checkpoint inhibitor treatment. CMPK2 expression was elevated in 23 cancers and decreased in two cancers. Receiver operating characteristic curve analysis indicated that CMPK2 expression had a high diagnostic value for 16 cancers. Kaplan-Meier survival analysis showed that high CMPK2 expression was associated with Lower Overall Survival (OS)Disease- Specific Survival (DSS) and Progression-Free Interval (PFI) in Kidney Cutaneous Chromophobe (KICH) Uterine Corpus Endometrial Carcinoma (UCEC) and Uveal Melanoma (UVM) and the opposite was true in Skin Cutaneous Melanoma (SKCM). Immune microenvironment-related analysis revealed strong associations between CMPK2 expression and immune cell infiltration as well as immune checkpoint expression across various tumors. RESULT: Notably in four mouse immunotherapy cohorts CMPK2 expression in treated mouse tumors was post-treatment. In five clinical immunotherapy cohorts patients with high CMPK2 expression show better responses to immunotherapy. Furthermore the methylation level of the CMPK2 gene was closely correlated to its expression and tumor prognosis. Among these cancers the clinical and immunological indications of SKCM are particularly closely related to CMPK2 expression. CONCLUSION: Our analysis preliminarily describes the complex function of CMPK2 in cancer progression and immune microenvironment highlighting its potential as a diagnostic and therapeutic target for immunotherapy.

Long-term effects of hematopoietic growth factors in aplastic anemia patients treated with immunosuppression: Meta-analysis of randomized controlled trials.

BACKGROUND AND PURPOSE: Immunosuppressive therapy is the frontline treatment for aplastic anemia patients ineligible for transplantation. The long-term effects of hematopoietic growth factors (HGF) added to standard immunosuppressive therapy are still unclear. We performed a systematic review and meta-analysis to clarify this issue. METHODS: A comprehensive search of databases was conducted including 5 international electronic databases (Cochrane, PubMed, Embase, Web of Science, and LILACS) and 4 Chinese electronic databases (Chinese Bio-medicine Database, Chinese National Knowledge Infrastructure, WanFang Data, and China Science and Technology Journal Database databases) from database inception until February, 2022. We included randomized controlled trials that assigned patients with acquired aplastic anemia treated with immunosuppressive therapy (IST), which compared between the addition of HGF and placebo or no treatment. The co-primary outcome were the overall survival (OS) and late clonal malignant evolution at the end of follow-up. RESULTS: Nine randomized controlled trials including 719 participants were identified. The addition of growth factors to immunosuppression yielded no difference in OS (relative risks [RR], 1.08, 95% confidence interval [CI] 0.99-1.18). HGF was not associated with higher occurrence of secondary myelodysplastic syndromes/acute myeloid leukemia (RR, 1.09, 95% CI 0.43-2.78) or paroxysmal nocturnal hemoglobulinemia (RR, 1.38, 95% CI 0.68-2.81) at the end of follow-up. No difference were found in overall response (RR, 1.16, 95% CI 0.98-1.37), infections occurrence (RR, 0.82; 95% CI, 0.51-1.31) or relapse (RR, 0.65; 95% CI, 0.37-1.13). CONCLUSIONS: HGF as an adjunct to IST has no impact on long-term OS, late clonal malignant evolution, response rate, relapse or infections occurrence. HGF could be added to standard IST for high-risk patients with delayed neutrophil recovery without concern for long-term consequences but could not be recommended as routine clinical practice. TRIAL REGISTRATION NUMBER: PROSPERO CRD42021275188.

Phenotypic and genotypic characterization of two factor VII deficiency patients from southeastern China.

The congenital factor VII deficiency (FVIID) is a rare autosomal recessive haemorrhagic disease caused by mutations in the F7 gene. The aim of this study was to identify the mutations causing FVII deficiency and explain the genotype-phenotype association in two unrelated Chinese patients. Mutation detection was conducted by sequencing the whole F7 gene coding exons, exon-intron boundaries and the untranslated regions of 3' and 5'. Then, the genetic information was analyzed to predict the structures of the mutated proteins. A total of four different mutations were detected, including three missense mutations (c.64G>A, c.286A>G, and c.722C>A, predicting p.Gly22Ser, p.Arg96Gly, p.Thr241Asn, respectively) and one insertion mutation (c.204_205insCGGC, predicting p. Leu68Argfs ∗ 37), among which two were reported for the first time (p.Arg96Gly, p.Leu68Argfs ∗ 37). Multiple sequence alignments of FVII protein revealed that the residues p.Arg96 and p.Thr241 were highly conserved. The novel missense mutation p.Arg96Gly was determined as damaging with online software Polyphen-2 and SIFT. We investigated two asymptomatic patients diagnosed with severe FVII deficiency and identified two novel mutations (the mutation p.Arg96Gly and p.Leu68Argfs ∗ 37). Identification of the F7 mutations was important for genetic counseling and accurate prediction of the inheritance pattern.