Background Observational studies indicate that phospholipid fatty acids (FAs) have an impact on the etiology in cancers, but the results are conflicting. We aimed to investigate the causal association of phospholipid FAs with breast cancer and prostate cancer. Methods Fourteen single nucleotide polymorphisms (SNPs) were selected as instrumental variables to predict the level of 10 phospholipid FAs from Genome-wide association studies (GWAS). We obtained the summary statistics for the latest and largest GWAS datasets for breast cancer (113,789 controls and 133,384 cases) and prostate cancer (61,106 controls and 79,148 cases) from the Breast Cancer Association Consortium (BCAC) and Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium. Two-sample Mendelian randomization analysis was applied. Results The results demonstrate that the 10 individual plasma phospholipid FAs are not significantly associated with breast cancer risk and prostate cancer risk. Conclusion The evidence is insufficient to support the causal association of the 10 individual plasma phospholipid FAs with breast cancer and prostate cancer.
Background: Since the association of homocysteine and clinical results of observational studies are controversial on non-alcoholic fatty liver related disease, we compute the two-sample Mendelian Randomization (MR) study. Objective: To evaluate whether the plasma level of homocysteine has an effect on the risk of Non-alcoholic fatty liver disease (NAFLD), non-alcoholic steatohepatitis (NASH), and Cirrhosis after its progress, we investigated the causal relationships between plasma homocysteine and the three non-alcoholic fatty liver related diseases mentioned above. Design and methods: Summary estimates were elicited from the inverse-variance weighted (IVW) method through 12 single nucleotide polymorphisms (SNPs) which related to the plasma homocysteine, the SNPs were obtained from a large genome-wide association studies (GWAS) of 44,147 European participants. And the summary statistics for the latest and largest GWAS datasets for NAFLD (307576 in total and 1,578 cases), NASH (309055 in total and 99 cases) and Cirrhosis (306145 in total and 826 cases) were collected from Ristey FinnGen website where the association of genetic variations with blood metabolite levels was conducted using comprehensive metabolite profiling. The study was performed through two-sample MR method. Results: The result indicated that the plasma homocysteine is not significantly associated with NAFLD, and its progression, NASH and Cirrhosis. Conclusion: The evidence in this study is quite deficient to support the causal association of the individual plasma homocysteine with NAFLD, NASH and Cirrhosis, the putative of associations is not exist.
To investigate the distribution and projective feature of cat olivocochlear neurons.Eleven adult cats were divided into two groups randomly. The experimental group of eight cats was injected of 1% cholera toxin B (CTB) to the left cochlea, while injected of 5% fluoro gold (FG) to the right cochlea. The control group of three cats was injected of saline to bilateral cochlea. After a survival time of 7 days, serial frozen sections were cut in the cat brainstem. All the sections were processed by immunofluorescent procedure for CTB and FG, and the labeled olivocochlear neurons were observed by fluorescent microscope.In the experimental group, the mean total of olivocochlear neurons labeled by CTB and FG was 3210 +/- 168, including lateral olivocochlear neurons (LOC, 2298 +/- 120) and medial olivocochlear neurons (MOC, 913 +/- 64). The labeled neurons were divided into three different types according to their feature of projection: neurons which only projected to the ipsilateral cochlea, neurons which only projected to the contralateral cochlea, and double-labeled neurons which projected both to the ipsilateral and contralateral cochlea, but the double-labeled neurons comprised 3.9% and 15.1% in the LOC and MOC system respectively. No labeled neurons were found in the control group.There are three types of neurons in the cat olivocochlear system. The neurons which projected to the bilateral cochlea may distribute both in the LOC and MOC system.
Urea is largely derived from the urea cycle reactions through hepatic detoxification of free ammonia and cleared by urination, and the serum urea level is a crucial medical indicator for measuring the kidney function in patients with nephropathy; however, investigative revelations pointing to the serum urea level as a risk factor for cancer are very scarce, and relevant studies are restricted by potential biases. We aimed to explore the causal relationships of the serum urea level with cancer development by focusing on renal cell carcinoma (RCC) using the Mendelian randomization (MR) analyses. Summary estimates were collected from the inverse-variance weighted (IVW) method based on six single nucleotide polymorphisms (SNPs). The selected SNPs related to the serum urea were obtained from a large genome-wide association study (GWAS) of 13,312 European participants. The summary statistics of RCC were also available from public databases (IARC, n = 5219 cases, n = 8011 controls). Sensitivity analyses included the weighted median and MR-Egger methods. Serum urea was inversely associated with RCC in females (effect = 1.93; 95% CI: 1.24 to 3.01; p = 0.004) but exhibited null association with RCC in males, breast cancer (BRCA) in both genders and prostate cancer (PCa) in males. Similar conclusions were also drawn from the weighted median and MR-Egger. These findings reveal an intriguing link between serum urea and cancer risks for the very first time. Without ambiguity, the serum urea is causatively related to RCC specifically in females, although the mechanism(s) by which urea is involved in RCC development remains to be experimentally/clinically investigated. Our studies may well provide novel insights for RCC diagnosis, intervention and/or therapy.
Abstract Background Respectively, prostate cancer (PCa) and breast cancer (BC) are the second most and most commonly diagnosed cancer in men and women, and they account for a majority of cancer-related deaths world-wide. Cancer cells typically exhibit much-facilitated growth that necessitates upregulated glycolysis and augmented amino acid metabolism, that of glutamine and aspartate in particular, which is tightly coupled with an increased flux of the tricarboxylic acid (TCA) cycle. Epidemiological studies have exploited metabolomics to explore the etiology and found potentially effective biomarkers for early detection or progression of prostate and breast cancers. However, large randomized controlled trials (RCTs) to establish causal associations between amino acid metabolism and prostate and breast cancers have not been reported. Objective Utilizing two-sample Mendelian randomization (MR), we aimed to estimate how genetically predicted glutamate and aspartate levels could impact upon prostate and breast cancers development. Methods Single nucleotide polymorphisms (SNPs) as instrumental variables (IVs), associated with the serum levels of glutamate and aspartate were extracted from the publicly available genome-wide association studies (GWASs), which were conducted to associate genetic variations with blood metabolite levels using comprehensive metabolite profiling in 1,960 adults; and the glutamate and aspartate we have chosen were two of 644 metabolites. The summary statistics for the largest and latest GWAS datasets for prostate cancer (61,106 controls and 79,148 cases) were from the Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome (PRACTICAL) consortium, and datasets for breast cancer (113,789 controls and 133,384 cases) were from Breast Cancer Association Consortium (BCAC). The study was performed through two-sample MR method. Results Causal estimates were expressed as odds ratios (OR) and 95% confidence interval (CI) per standard deviation increment in serum level of aspartate or glutamate. Aspartate was positively associated with prostate cancer (Effect = 1.043; 95% confidence interval, 1.003 to 1.084; P = 0.034) and breast cancer (Effect = 1.033; 95% confidence interval, 1.004 to 1.063; P = 0.028); however, glutamate was neither associated with prostate cancer nor with breast cancer. The potential causal associations were robust to the sensitivity analysis. Conclusions Our study found that the level of serum aspartate could serve as a risk factor that contributed to the development of prostate and breast cancers. Efforts on a detailed description of the underlying biochemical mechanisms would be extremely valuable in early assessment and/or diagnosis, and strategizing clinical intervention, of both cancers.
Abstract Lactic acidosis is a feature of solid tumors and plays fundamental role(s) rendering cancer cells to adapt to diverse metabolic stresses, but the mechanism underlying its roles in redox homeostasis remains elusive. Here we show that G6PD is phosphorylated at tyrosine 249/322 by the SRC through the formation of a GSTP1-G6PD-SRC complex. Lactic acid attenuates this formation and the phosphorylation of G6PD by non-covalently binding with GSTP1. Furthermore, lactic acid increases the activity of G6PD and facilitates the PPP (NADPH production) through its sensor GSTP1, thereby exhibiting resistance to reactive oxygen species when glucose is scarce. Abrogating a GSTP1-mediated lactic acid signaling showed attenuated tumor growth and reduced resistance to ROS in breast cancer cells. Importantly, positive correlations between immuno-enriched SRC protein and G6PD Y249/322 phosphorylation specifically manifest in ER/PR positive or HER negative types of breast cancer. Taken together, these results suggest that GSTP1 plays a key role in tumor development by functioning as a novel lactate sensor.
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