Background: Evidence from observational studies and clinical trials suggests that the gut microbiota is associated with cancer. However, the causal association between gut microbiota and cancer remains to be determined. Methods: We first identified two sets of gut microbiota based on phylum, class, order, family, and genus level information, and cancer data were obtained from the IEU Open GWAS project. We then performed two-sample Mendelian randomisation (MR) to determine whether the gut microbiota is causally associated with eight cancer types. Furthermore, we performed a bi-directional MR analysis to examine the direction of the causal relations. Results: We identified 11 causal relationships between genetic liability in the gut microbiome and cancer, including those involving the genus Bifidobacterium. We found 17 strong associations between genetic liability in the gut microbiome and cancer. Moreover, we found 24 associations between genetic liability in the gut microbiome and cancer using multiple datasets. Conclusions: Our MR analysis revealed that the gut microbiota was causally associated with cancers and may be useful in providing new insights for further mechanistic and clinical studies of microbiota-mediated cancer.

Bronchoalveolar lavage (BAL) galactomannan (GM) assay has been used for diagnosing invasive aspergillosis (IA). We aimed to derive a definitive estimate of the overall accuracy of BAL-GM for diagnosing IA. We undertook a systematic review of thirty diagnostic studies that evaluated the BAL-GM assay for diagnosing IA. PubMed and CBM (China Biological Medicine Database) databasees were searched for relevant studies published in all languages up until Feb 2012. The pooled diagnostic odds ratio (DOR) and summary receiver operating characteristic (SROC) were constructed for each cutoff value. Additionally, pooled sensitivity (SEN), specificity (SPE), and positive and negative likelihood ratios (PLR and NLR, respectively) were calculated for summarizing overall test performance. Thirty studies were included in this meta-analysis. The summary estimates of pooled DOR, SEN, SPE, PLR, and NLR of the BAL-GM assay (cutoff value 0.5) for proven or probable IA were 52.7 (95% confidence interval (CI) 31.8–87.3), 0.87 (95% CI 0.79–0.92), 0.89 (95% CI 0.85–0.92), 8.0 (95% CI 5.7–11.1) and 0.15 (95% CI 0.10–0.23) respectively. The SROC was 0.94 (95% CI 0.92–0.96). Compared with cutoff value of 0.5, it has higher DOR, SPE and PLR, and similar SEN and NLR with cutoff value of 1.0, which indicated the optimal cutoff value might be 1.0. Compared with BAL-GM, serum GM has a lower SEN and higher SPE, while PCR displays a lower SEN and a similar SPE. With the optimal cutoff value of 1.0, the BAL-GM assay has higher SEN compared to PCR and serum GM test. It is a useful adjunct in the diagnosis of proven and probable IA.

Background: High-mobility group box 1 (HMGB1) is a late mediator of lethal systemic inflammation. Acute liver failure (ALF) has been shown to trigger systemic inflammation in clinical and animal studies. To evaluate the possibility of HMGB1 cytoplasmic translocation in ALF, we determined whether HMGB1 is released in hepatocytes and end organ in patients with liver failure/injury. Methods: HepG2 cell were stimulated with LPS or TNF-α, the increase of HMGB1 extracellularly in the culture medium and intracellularly in various cellular fractions were determined by western blot or immunocytochemistry. To observe sub-cellular location of HMGB1 in hepatocytes, liver specimens were obtained from 6 patients with ALF caused by HBV infection, 10 patients with chronic viral hepatitis B, 6 healthy controls, as well as animals model of ALF by intraperitoneal administration of D-GalN (600 mg/kg) and LPS (0.5 mg/kg). Results: In HepG2 cell culture, LPS or TNF actively induced HMGB1 cytoplasmic translocation and release in a time- and dose-dependent fashion. In animal model of ALF, cytoplasmic HMGB1 translocation was observed in hepatocyts as early as 3 hours post onset of ALF. In patients with ALF caused by HBV infection, cytoplasmic HMGB1 translocation was similarly observed in some hepatocytes of the liver specimen. Conclusions: Cytoplasmic HMGB1 translocation may occur during ALF, which may potentially contribute to the pathogenesis of liver inflammatory diseases.

In this study, we aimed to investigate the causal associations of brain structure with bone mineral density (BMD). Based on the genome-wide association study (GWAS) summary statistics of 1 325 brain imaging-derived phenotypes (BIDPs) of brain structure from the UK Biobank and GWAS summary datasets of 5 BMD locations, including the total body, femoral neck, lumbar spine, forearm, and heel from the GEFOS Consortium, linkage disequilibrium score regression (LDSC) was conducted to determine the genetic correlations, and Mendelian randomization (MR) was then performed to explore the causal relationship between the BIDPs and BMD. Several sensitivity analyses were performed to verify the strength and stability of the present MR outcomes. To increase confidence in our findings, we also performed confirmatory MR between BIDPs and osteoporosis. LDSC revealed that 1.93% of BIDPs, with a false discovery rate (FDR) < 0.01, were genetically correlated with BMD. Additionally, we observed that 1.31% of BIDPs exhibited a significant causal relationship with BMD (FDR < 0.01) through MR. Both the LDSC and MR results demonstrated that the BIDPs “Volume of normalized brain,” “Volume of gray matter in Left Inferior Frontal Gyrus, pars opercularis,” “Volume of Estimated Total Intra Cranial” and “Volume-ratio of brain segmentation/estimated total intracranial” had strong associations with BMD. Interestingly, our results showed that more left BIDPs were causally associated with BMD, especially within and around the left frontal region. In conclusion, a part of the brain structure causally influences BMD, which may provide important perspectives for the prevention of osteoporosis and offer valuable insights for further research on the brain-bone axis.

Purpose: It has been reported that bone is the primary organ for manganese (Mn) accumulation, but the association between manganese and bone loss remains debatable. Therefore, this study aimed to evaluate the relationship between blood manganese and bone mineral density/bone mineral content (BMD/BMC) by using a representative sample from the National Health and Nutrition Examination Survey (NHANES).Methods: A total of 9732 subjects over the age of 18 with available data were enrolled in this study. The relationship between blood manganese and BMD/BMC of the total body, spine and femoral regions was evaluated using multivariate linear regression models. Subgroup analyses were also performed.Results: We observed a negative association between blood manganese and BMD/BMC in the femoral neck and total body in the fully adjusted model, especially femoral neck BMD in women aged 50–70 years.Conclusion: In brief, people exposed to manganese should be aware of the increased risk of osteopenia or osteoporosis. Besides, due to the lack of available data, there are no definite values for the tolerable upper intake level (UL), average requirement (AR) and population reference intake (PRI) of manganese. The results of our study may provide some references for the establishment of AR, PRI and UL of Mn.