Genetic prediction of causal association between serum bilirubin and hematologic malignancies: a two-sample Mendelian randomized and bioinformatics study.

Introduction: An increasing number of cohort studies have shown a correlation between serum bilirubin and tumors, but no definitive causal relationship has been established between serum bilirubin and hematological malignancies.Therefore, the aim of the present study was to assess the causal relationship of serum bilirubin, including total bilirubin (TBIL) and direct bilirubin (DBIL), with hematological malignancies, including leukemia, lymphoma, and myeloma. Methods: We used a genome-wide association study (GWAS) collection of TBIL, DBIL, and hematological malignancies data. Using two-sample Mendelian randomization(MR), we assessed the impact of TBIL and DBIL on hematological malignancies. For this study, the inverse variance weighting method (IVW) was the primary method of MR analysis. In the sensitivity analysis, the weighted median method, MR Egger regression, and MR-PRESSO test were used. To understand the mechanisms behind TBIL and DBIL, we used three different approaches based on screening single nucleotide polymorphisms (SNPs) and their associated genes, followed by bioinformatics analysis. Results: The IVW test results showed evidence of effects of TBIL (odds ratio [OR]: 4.47, 95% confidence interval [CI]: 1.58-12.62) and DBIL (OR: 3.31, 95% CI: 1.08-10.18) on the risk of acute myeloid leukemia (AML).The findings from bioinformatics indicated that TBIL could potentially undergo xenobiotic metabolism through cytochrome P450 and contribute to chemical carcinogenesis. Discussion: In this study, two-sample MR analysis revealed a causal relationship between TBIL, DBIL, and AML.

TcpC Inhibits M1 but Promotes M2 Macrophage Polarization via Regulation of the MAPK/NF-κB and Akt/STAT6 Pathways in Urinary Tract Infection.

TcpC is a multifunctional virulence factor of Uropathogenic Escherichia coli (UPEC). Macrophages can differentiate into two different subsets M1 and M2 that play distinct roles in anti-infection immunity. Here, we investigate the influence of TcpC on M1/M2 polarization and the potential mechanisms. Our data showed that M1 markers CD86 and iNOS were significantly inhibited, while the M2 markers CD163, CD206 and Arg-1 were enhanced in macrophages in kidneys from the TcpC-secreting wild-type CFT073 (CFT073wt)-infected pyelonephritis mouse model, compared with those in macrophages in kidneys from TcpC knockout CFT073 mutant (CFT073Δtcpc)-infected mice. CFT073wt or recombinant TcpC (rTcpC) treatment inhibits LPS + IFN-γ-induced CD80, CD86, TNF-α and iNOS expression, but promotes IL-4-induced CD163, CD206, Arg-1 and IL-10 expression in both human and mouse macrophage cell lines THP-1 and J774A.1. Moreover, rTcpC significantly attenuated LPS + IFN-γ-induced phosphorylation of p38, ERK, p50 and p65 but enhanced IL-4-induced phosphorylation of Akt and STAT6. These data suggest that TcpC inhibits M1 but promotes M2 macrophage polarization by down-regulation of p38, ERK/NF-κB and up-regulation of the Akt/STAT6 signaling pathway, respectively. Our findings not only illuminate the regulatory effects of TcpC on macrophage M1/M2 polarization and its related signaling pathways, but also provide a novel mechanism underlying TcpC-mediated immune evasion of macrophage-mediated innate immunity.

Dosimetric Comparison, Treatment Efficiency Estimation, and Biological Evaluation of Popular Stereotactic Radiosurgery Options in Treating Single Small Brain Metastasis.

OBJECTIVES: This study aimed to show the advantages of each stereotactic radiosurgery (SRS) treatment option for single small brain metastasis among Gamma Knife (GK), Cone-based VMAT (Cone-VMAT), and MLC-based CRT (MLC-CRT) plans. MATERIALS AND METHODS: GK, Cone-VMAT, and MLC-CRT SRS plans were retrospectively generated for 11 patients with single small brain metastasis whose volume of gross tumor volume (GTV) ranged from 0.18 to 0.76 cc (median volume 0.60 cc). Dosimetric parameters, treatment efficiency, and biological parameters of the three techniques were compared and evaluated. The metric variation with the planning target volume (PTV) was also studied. RESULTS: The conformity index (CI) was similar in GK and MLC-CRT plans, higher than Cone-VMAT. Cone-VMAT achieved comparable volume covered by 12 Gy (V12) and gradient index (GI) as GK, lower than MLC-CRT. The heterogeneity index (HI) of GK, Cone-VMAT, and MLC-CRT decreased sequentially. GK gave the lowest volume covered by 3 Gy (V3) and 6 Gy (V6), while MLC-CRT got the highest. The beam-on time and treatment time of GK, Cone-VMAT, and MLC-CRT decreased in turn. Tumor control probability (TCP) of all three SRS plans was greater than 98%, and normal tissue complication probability (NTCP) of all organs at risk (OARs) was below 0.01%. GK and Cone-VMAT resulted in superior TCP and NTCP of the normal brain tissue than MLC-CRT. The relative value of Cone-VMAT and GK for all metrics hardly changed with the target volume. Except for the unchanged HI and TCP, the other results of MLC-CRT with respect to GK improved as the target volume increased. MLC-CRT could produce higher CI than GK and Cone-VMAT when the target volume increased above 2 and 1.44 cc, respectively. CONCLUSION: For single small brain metastases, Cone-VMAT may be used as an alternative to GK-free centers. In addition to the advantage of short treatment time, MLC-CRT showed superiority in CI as the target volume increased. Treatment centers can choose appropriate SRS technique on a case-by-case basis according to institutional conditions and patients' individual needs.